WO2025242585A1 - Crystalline forms of salts of elinzanetant and compositions containing salts of elinzanetant - Google Patents

Crystalline forms of salts of elinzanetant and compositions containing salts of elinzanetant

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Publication number
WO2025242585A1
WO2025242585A1 PCT/EP2025/063650 EP2025063650W WO2025242585A1 WO 2025242585 A1 WO2025242585 A1 WO 2025242585A1 EP 2025063650 W EP2025063650 W EP 2025063650W WO 2025242585 A1 WO2025242585 A1 WO 2025242585A1
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WIPO (PCT)
Prior art keywords
elinzanetant
hydrate
salt
pharmaceutical composition
pseudo
Prior art date
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PCT/EP2025/063650
Other languages
French (fr)
Inventor
Jorma Hassfeld
Michal SOWA
Krischan ZIEM
Dominique Anna BOCK
Varvara Igorivna NIKOLAYENKO
Adrian Dobrowolski
Maximilian Franz Ludwig KARL
Johanna Anlahr
Gabriele Winter
Corinna BODE
Marcus-Hillert SCHULTZE-MOSGAU
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Bayer Consumer Care AG
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Bayer Consumer Care AG
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Publication date
Application filed by Bayer Consumer Care AG filed Critical Bayer Consumer Care AG
Publication of WO2025242585A1 publication Critical patent/WO2025242585A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to crystalline forms of 2-[3,5-bis(trifluoromethyl)phenyl]- N- ⁇ 4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1 - c][1 ,4]oxazin-8(1 H)-yl]pyridin-3-yl ⁇ -N,2-dimethylpropanamide benzenesulfonate, such as to (pseudo)polymorphic hydrate forms, to the processes for their preparation.
  • the invention relates to pharmaceutical compositions comprising salts of elinzanetant, such as those comprising a non-ionic surfactant.
  • the invention relates to said crystalline forms and the pharmaceutical compositions for use in the treatment of diseases and disorders.
  • Elinzanetant or its salts were initially amorphous and hygroscopic, respectively, as described in WO 2007/028654 A1 and WO 2011/023733 A1 , not allowing for the provision of stable, solid pharmaceutical compositions.
  • the 4-methylbenzenesulfonate salt (tosylate) was initially developed (WO 2010/015626).
  • WO 2010/015626 4-methylbenzenesulfonate salt
  • elinzanetant offers a poor aqueous solubility and solid formulations comprising anhydrate Form 1 of elinzanetant free base showed within clinical studies an undesired PK profile e.g., high variability for tablets and hard gelatin capsules.
  • a liquid formulation in a soft gelatin capsule was provided (WO 2019/175253 A1 ). These soft gelatin capsules are used in clinical development and for the launch of the commercial drug product.
  • the disadvantage of the described capsules of prior art is the fact, that due to the limited drug load, the size of the capsules is large (Size-20) and for a desired daily dose of 120 mg, two soft gelatin capsules each containing 60 mg must be taken. As this is of low convenience to the patients who take the drug, a potential cause for the non-compliance of the patients to the treatment is created.
  • Solid pharmaceutical compositions such as tablets
  • a solid pharmaceutical composition such as a tablet, that allows the administration of the daily dose of e.g. 120 mg in a single dosage unit, e.g. a tablet.
  • the problem of providing such solid pharmaceutical composition having an acceptable bioavailability exists and is solved by the present invention.
  • the benzenesulfonate salt of elinzanetant in form of a hydrate provides crystalline forms that show high thermal stability and a dried state without amorphization and high stability under sorption and desorption of water. Further, it has been surprisingly found that crystalline hydrate forms of the benzenesulfonate salt of elinzanetant show an enhanced dissolution rate as compared to the free base in crystalline or amorphous form, the tosylate salt and even as compared to the amorphous form of the benzenesulfonate salt of elinzanetant.
  • the present invention is based on the unexpected discovery of the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant, which include (pseudo)polymorphic form Hydrate 1 , (pseudo)polymorphic form Hydrate 2 and (pseudo)polymorphic form Hydrate 3. Further, in a subsequent study, additional crystalline hydrate forms, namely Hydrates 6 and 7, have been identified also being crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the invention.
  • the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant surprisingly provide an enhanced dissolution behavior even over the known tosylate salt or amorphous forms of the free base or benzenesulfonate salt.
  • the present invention in one embodiment relates to crystalline hydrate forms of the benzenesulfonate salt of elinzanetant.
  • the invention relates to the (pseudo)polymorphic form Hydrate 2, the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant, the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant, or the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant.
  • the Hydrate 2 form of the benzenesulfonate salt of elinzanetant surprisingly showed the best combination of stability (e.g. with respect to maintaining the (pseudo)polymorphic form, even under differing ambient conditions) and dissolution behaviour.
  • the (pseudo)polymorphic form Hydrate 2 exhibited particularly surprising favourable properties, such as a favourable combination of thermal and moisture stability, and enhanced dissolution behaviour.
  • the invention relates to the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant.
  • polymorphic forms and polymorphs have the same meaning.
  • (Pseudo)polymorphic forms and (pseudo)polymorphs are likewise synonyms and relate to polymorphic forms that contain water molecules (hydrates) or solvents (solvates) within its crystalline structure. All together - the polymorphic forms, the (pseudo)polymorphic forms and the amorphous form - are different solid forms of the salts, in particular the benzenesulfonate salt, of the compound of formula (I).
  • the invention in one embodiment further relates to a method for preparing the crystalline hydrate according to the disclosure comprising: (i) providing the compound of formula (I), preferably in a solvent; (ii) adding benzenesulfonic acid; and (iii) isolating the crystalline form of the benzenesulfonate salt of elinzanetant.
  • a salt of elinzanetant with a non-ionic surfactant allows for the provision of solid pharmaceutical composition with a high drug load and sufficient dissolution profile and bioavailability to obtain a single dosage unit for the provision of a high daily dose, e.g. a dose of e.g. 120 mg.
  • the solid pharmaceutical compositions comprising elinzanetant and non-ionic surfactants according to the disclosure showed a surprisingly superior release profile as compared to the low and prolonged release profile observed with ionic surfactants such as sodium dodecyl sulphate (SDS).
  • SDS sodium dodecyl sulphate
  • the invention in one embodiment relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising a crystalline salt of elinzanetant and a non-ionic surfactant.
  • FIG. 1 A shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2 measured with XRPD method A.
  • FIG. 1 B shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured with XRPD method B.
  • FIG. 2 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2 with DSC method A.
  • FIG. 3 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate
  • FIG. 4 shows an Infrared Spectroscopy analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2 with IR method A.
  • FIG. 5A shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 2 prepared according to Example 2 with DVS method A.
  • FIG. 5B shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 3 prepared according to Example 4 with DVS method A.
  • FIG. 6 shows an X-Ray Powder Diffraction analysis of Pattern 4 corresponding to Example 5 measured with XRPD method A.
  • FIG . 7 shows a Differential Scanning Calorimetry analysis of Pattern 4 corresponding to Example 5 with DSC method A.
  • FIG. 8 shows a Thermogravimetric analysis of Pattern 4 corresponding to Example 5 with TGA method A.
  • FIG. 9 shows an Infrared Spectroscopy of Pattern 4 corresponding to Example 5 with IR method A.
  • FIG. 10 shows an X-Ray Powder Diffraction analysis of Pattern D corresponding to Example 5 measured with XRPD method B.
  • FIG. 11 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4 measured with XRPD method A.
  • FIG. 12 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4 with DSC method A.
  • FIG. 13 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate
  • FIG. 14 shows an Infrared Spectroscopy analysis of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4 with IR method A.
  • FIG. 15 shows an X-Ray Powder Diffraction analysis of Pattern G corresponding to Example 4 measured with XRPD method B.
  • FIG. 16 shows an X-Ray Powder Diffraction analysis of Pattern 5 corresponding to Example 6 measured with XRPD method A.
  • FIG. 17 shows a Differential Scanning Calorimetry analysis of Pattern 5 corresponding to Example 6 with DSC method A.
  • FIG. 18 shows a Thermogravimetric analysis of Pattern 5 corresponding to Example 6 with TGA method A.
  • FIG. 19 shows an Infrared Spectroscopy of Pattern 5 corresponding to Example 6 with IR method A.
  • FIG. 20 shows an X-Ray Powder Diffraction analysis of Pattern 6 corresponding to Example 7 measured with XRPD method A.
  • FIG. 21 shows a Differential Scanning Calorimetry analysis of Pattern 6 corresponding to Example 7 with DSC method A.
  • FIG. 22 shows a Thermogravimetric analysis of Pattern 6 corresponding to Example 8 with TGA method A.
  • FIG. 23 shows an X-Ray Powder Diffraction analysis of Pattern 8 corresponding to Example 8 measured with XRPD method A.
  • FIG. 24 shows a Differential Scanning Calorimetry analysis of Pattern 8 corresponding to Example 8 with DSC method A.
  • FIG. 25 shows a Thermogravimetric analysis of Pattern 8 corresponding to Example 8 with TGA method A.
  • FIG. 26 shows an X-Ray Powder Diffraction analysis of the amorphous form of the benzenesulfonate salt of elinzanetant corresponding to Example 9 measured with XRPD method A.
  • FIG. 27 shows a Differential Scanning Calorimetry analysis of the amorphous form corresponding to Example 9 with DSC method A
  • FIG. 28 shows a Thermogravimetric analysis of the amorphous form corresponding to Example 9 with TGA method A.
  • FIG. 29 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured at 20% relative humidity and 25 °C with XRPD method C.
  • FIG. 30 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured at 50% relative humidity and 25 °C with XRPD method C.
  • FIG. 31 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured at 80% relative humidity and 25 °C with XRPD method C.
  • FIG. 32 shows a 1 H-NMR-spectrum in d-DMSO of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2.
  • FIG. 33 shows a 1 H-NMR-spectrum in d-DMSO of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4.
  • FIG. 34 shows the comparison of XRPD measurements, from top to bottom: (pseudo)polymorphic form Hydrate 2 before micronization, (pseudo)polymorphic form Hydrate 2 after micronization, (pseudo)polymorphic form Hydrate 3 before micronization, (pseudo)polymorphic form Hydrate 3 after micronization with XRPD method B (note that one characteristic reflection for Hydrate 3 (2.7) is not represented, because measurement started at an angle of 3°).
  • FIG. 35 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form solvate form of the isopropanol solvate of the di-hydrochloride salt of elinzanetant measured with XRPD method B.
  • FIG. 36 shows the dissolution profile of elinzanetant salt and free base HPMC suspensions in 2 -stage biorelevant dissolution test with gastric condition of pH 2.4
  • FIG. 37A shows the release profile of direct compressed and wet granulated comparative elinzanetant benzenesulfonate salt tablets [Example numbers indicated in the FIG.] at 2 stage biorelevant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
  • FIG: 37B shows the release profile of elinzanetant benzenesulfonate salt tablets according to the present disclosure [Example numbers indicated in the FIG.] in comparison to suspension at 2 stage biorelevant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
  • FIG. 38A shows the release profile of direct compressed and wet granulated comparative elinzanetant di-HCI salt isopropanol solvate tablets [Example numbers indicated in the FIG.] at 2 stage biorelavant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
  • FIG. 38B shows the release profile of elinzanetant di-HCI salt isopropanol solvate tablets according to the present disclosure [Example numbers indicated in the FIG.] in comparison to suspension at 2 stage biorelevant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
  • FIG. 40 shows the dissolution profiling of different solid forms of Example 17.
  • FIG. 41 shows the dissolution profiling comparison the benzenesulfonate salt of elinzanetant in crystalline form (“Besylate”) and amorphous form (“Besylate, amorphous”).
  • FIG. 42 shows the IDR profile of Example 19 comparing Besylate in crystalline and amorphous form, the amorphous Free Base, and crystalline Tosylate.
  • FIG. 43 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 6 corresponding to Example 20 measured with XRPD method D.
  • FIG. 44 shows an Infrared Spectroscopy of the (pseudo)polymorphic form Hydrate 6 corresponding to Example 20 with IR method B.
  • FIG. 45 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate
  • FIG. 46 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 6 corresponding to Example 20 with DSC method B.
  • FIG. 47 shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 6 prepared according to Example 20 with DVS method B.
  • FIG. 48 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 measured with XRPD method B.
  • FIG. 49 shows an Infrared Spectroscopy of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 with IR method B.
  • FIG. 50 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 with TGA method B.
  • FIG. 51 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 with DSC method B.
  • FIG. 52 shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 7 prepared according to Example 21 with DVS method B.
  • FIG. 53 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Pattern 7 corresponding to Example 22 measured with XRPD method B.
  • FIG. 54 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Pattern 7 corresponding to Example 22 with TGA method B.
  • FIG. 55 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Pattern 7 corresponding to Example 22 with DSC method B.
  • “About” in a preferred embodiment refers to the quantities, percentages or proportions, and other numerical values ⁇ 5%.
  • the present disclosure relates to crystalline hydrate forms of the benzenesulfonate salt of elinzanetant.
  • the disclosure in an embodiment relates to crystalline hydrate forms of the benzenesulfonate salt of the compound of the formula (I).
  • benzenesulfonate salt of the compound of the formula (I) “2-[3,5-bis(trifluoromethyl)phenyl]-N- ⁇ 4-(4-fluoro-2-methylphenyl)-6- [(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-y l]pyridin-3-yl ⁇ - N,2-dimethylpropanamide benzenesulfonate”, “benzenesulfonate salt of 2-[3,5- bis(trifluoromethyl)phenyl]-N- ⁇ 4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-
  • the salt of formula (II) in some embodiments includes the salts of formulas (Ila), (lib), or (lie) or mixtures thereof:
  • the salt of formula (II) refers to the salt of formula (Ila).
  • Hydrate X When referring to a specific crystalline hydrate form of the benzenesulfonate salt of the compound of the formula (I), it is referred to herein interchangeably as “Hydrate X”, “Hydrate X form”, “(pseudo)polymorphic Hydrate X form”, or “(pseudo)polymorphic form Hydrate X”, wherein “X” denotes the identification number of the form.
  • variable occupancy hydrate forms are in one embodiment variable occupancy hydrate forms (also referred to as variable occupancy hydrates). That is, as will be readily understood by those skilled in the art, the amount of H2O molecules per elinzanetant and benzenesulfonic acid molecule in the crystalline structure of the hydrate form of the benzenesulfonate salt of elinzanetant may vary depending on the humidity of the environment, i.e. the relative humidity.
  • the hydrate forms of the benzenesulfonate of elinzanetant according to the disclosure are stable during repeated sorption and desorption while increasing and/or decreasing the amount of H2O molecules within the crystal structure, which is, as shown e.g. with XRPD, not associated with a significant change in the crystal lattice, except for possibly anisotropic expansion of the network to accommodate water (Doris E. Braun, et al., Navigating the Waters of Unconventional Crystalline Hydrates Molecular Pharmaceutics 2015 12 (8), 3069-3088 DOI: 10.1021 /acs.molpharmaceut.5b00357).
  • the crystal form is hence stable as long as water molecules are within the crystal.
  • n may have any value > 0 at a relative ambient humidity of over 0%.
  • n has a value between 0 and 2.5, more preferably 0.3 ⁇ n ⁇ 2.4.
  • n has a value of 0.3 to 2.4 at a relative environmental humidity between 10% and 98%; preferably at a temperature of about 20°C to 25°C.
  • the (pseudo)polymorphic form Hydrate 2 showed the best combination of thermal as well as sorption and mechanical stability and a dried state without amorphization and providing increased solubility and dissolution behavior.
  • the (pseudo)polymorphic form Hydrate 2 showed beneficial properties over the other solid forms of the benzenesulfonate salt of elinzanetant with regard to thermal stability as well as physical and crystalline stability during sorption and desorption of water. Furthermore, it has been surprisingly found, that the (pseudo)polymorphic form Hydrate 2 shows extraordinary stability under mechanical stress, e.g. applied by a pistil and mortar or during micronization, such as micronization using spiral jet mill technology, without changing its crystalline form or transition to the amorphous form. This unexpected property facilitates and allows the processing of elinzanetant to produce solid pharmaceutical compositions, such as tablets.
  • the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) (also referred to herein interchangeably as “Hydrate 2”, “Hydrate 2 form”, “(pseudo)polymorphic Hydrate 2 form”, or “(pseudo)polymorphic form Hydrate 2”).
  • Dynamic Vapour Sorption plot of the Hydrate 2 ( Figure 5a) was characteristic for a variable occupancy hydrate (also referred to as non-stoichiometric hydrate; cp.
  • the Hydrate 2 form in an embodiment of the present disclosure is a variable occupancy hydrate.
  • variable occupancy hydrate and “non-stochiometric hydrate” are used interchangeably herein. They refer to hydrates with different amounts of H2O molecules within their crystal structure depending on relative ambient humidity and/or temperature, while maintaining their crystal structure as measured by e.g. characteristic XRPD reflections; see also Jean-Rene Authelin, Thermodynamics of non-stoichiometric pharmaceutical hydrates, International 1-2 Journal of Pharmaceutics, Volume 303, Issues, 2005, Pages 37-53, https://doi.Org/10.1016/j.ijpharm.2005.07.007.
  • the (pseudo)polymorphic form Hydrate 2 preferably refers to the hydrate salt of formula (III) or (Illa), wherein n may have any value > 0.
  • n has a value between 0 and 2.1 , more preferably 0 ⁇ n ⁇ 2.0.
  • n has a value of between 0.3 to 2.0 at a relative environmental humidity between 10% and 98%; preferably at a temperature of about 20°C to 25°C.
  • n has a value of between 0.3 to 1.4 at a relative environmental humidity between 10% and 90%; preferably at a temperature of about 20°C to 25°C.
  • n has a value of between 0.2 to 0.4 at 10% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 0.3 at 10% relative humidity at a temperature of about 25°C.
  • n has a value of between 0.3 to 0.5 at 20% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 0.4 at 20% relative humidity at a temperature of about 25°C.
  • n has a value of between 0.5 to 0.7 at 50% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 0.6 at 50% relative humidity at a temperature of about 25°C.
  • n has a value of between 1.0 to 1.2 at 80% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 1 .1 at 80% relative humidity at a temperature of about 25°C.
  • n has a value of between 1.3 to 1.5 at 90% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 1 .4 at 90% relative humidity at a temperature of about 25°C.
  • n has a value of between 1.9 to 2.0 at 98% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 2.0 at 98% relative humidity at a temperature of about 25°C.
  • n-values given above might slightly vary, e.g., depending on the sorption/desorption cycle (cp. Example 11 , infra). Accordingly, these values are to be understood as “about” values.
  • (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) ensures that an undesired conversion into another form of the benzenesulfonate salt of the compound of the formula (I), even under continuous changes in humidity under ambient conditions, and an associated change in the properties as described above is prevented.
  • (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant is stable at relative humidity of between 10% and 75% at room temperature or increased temperatures of up to 40°C for up to 6 months or even longer. This increases the safety and quality of preparations and compositions comprising the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I).
  • the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphic form Hydrate 3 (also referred to herein as Hydrate 3).
  • the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphicform Hydrate 1 (also referred to herein as Hydrate 1 ).
  • the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphicform Hydrate 6 (also referred to herein as Hydrate 6).
  • the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphicform Hydrate 7 (also referred to herein as Hydrate 7). Also herein identified herein are the polymorphic forms showing Pattern D, Pattern G, Pattern 4, Pattern 5 (heterosolvate), Pattern 6, Pattern 7 and Pattern 8 of the benzenesulfonate salt of elinzanetant as shown in the Examples.
  • An embodiment of the present disclosure is substantially pure (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I).
  • purification shall encompass and refer to all types of purity like e.g. chemical purity, optical purity and purity with regard to the presence of other solid forms of the same compound.
  • impurity or “impurities” shall mean and refer to chemical purity i.e. is used with the meaning “other chemical compounds” present in isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I).
  • substantially pure (pseudo)polymorphic form Hydrate 2 shall mean that the sum of the mole or mass percent of impurities, optical isomers and other solid forms in the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) is less than about 5 mole or mass percent, preferably less than about 2 mole or mass percent, more preferably, less than about 1 mole or mass percent, most preferably, less than about 0.1 mole or mass percent.
  • the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 1 mass percent of impurities.
  • the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 1 mole or mass percent of optical isomers.
  • the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 2 mole or mass percent of other solid forms. In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0,1 mass percent of impurities.
  • the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0,1 mole or mass percent of optical isomers.
  • the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 1 mole or mass percent of other solid forms.
  • the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) is substantially free of other solid forms of the benzenesulfonate salt of the compound of the formula (I).
  • Another embodiment of the present disclosure is substantially pure (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I).
  • substantially pure (pseudo)polymorphic form Hydrate 3 shall mean that the sum of the mole or mass percent of impurities, optical isomers and other solid forms in the isolated (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I) is less than about 5 mole or mass percent, preferably less than about 2 mole or mass percent, more preferably, less than about 1 mole or mass percent, most preferably, less than about 0.1 mole or mass percent.
  • Another embodiment of the present disclosure is (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I) which is substantially free of other solid forms of the benzenesulfonate salt of the compound of the formula (I).
  • solid forms of the benzenesulfonate salt of elinzanetant or of elinzanetant identified herein are the amorphous forms, other polymorphic forms or (pseudo)polymorphic forms of the compound of formula (I), e.g. the anhydrate crystalline form as disclosed in WO 2011/023733 A1.
  • substantially free of other amorphous, polymorphic or (pseudo)polymorphic form(s) when used to describe (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant shall mean that the sum of mole or mass percent of other amorphous, polymorph or (pseudo)polymorphic forms of the isolated compound of the formula I and/or the benzenesulfonate salt of elinzanetant is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 5 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
  • the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 2 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
  • the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0.5 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
  • the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0.1 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
  • the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of elinzanetant is substantially free of amorphous, polymorphic or other (pseudo)polymorphic form(s).
  • substantially free of other amorphous, polymorphic or (pseudo)polymorphic form(s) when used to describe (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I) shall mean that the sum of mole or mass percent of other amorphous, polymorph or (pseudo)polymorphic forms of the isolated compound of the formula (I) and/or the benzenesulfonate salt of elinzanetant is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
  • the (pseudo)polymorphicform Hydrate 3 of the benzenesulfonate salt of elinzanetant is substantially free of amorphous, polymorphic or other (pseudo)polymorphic form(s).
  • (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant contains no impurities, optical isomers and other solid forms can be detected with the methods described.
  • Another embodiment of the present disclosure is (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant in which no impurities, optical isomers and other solid forms can be detected with the methods described.
  • XRPD X- ray powder diffraction
  • IR Infrared Spectroscopy
  • DSC Differential Scanning Calorimetry
  • DFS Dynamic Vapour Sorption
  • TGA Thermogravimetric Analysis
  • NMR Nuclear Magnetic Resonance
  • the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.8, 14.2, and 3.9, preferably at least the following reflections: 8.8, 14.2, 3.9, 11.5, and 15.6, in an embodiment at least the following reflections: 8.8, 14.2, 3.9, 11.5, 15.6, 16.2, and 17.3, in an embodiment at least the following reflections: 8.8, 14.2, 3.9, 11.5, 15.6, 16.2, 17.3, 22.7, 13.6 and 21.0, each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 2 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 1 a.
  • the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant is a variable occupancy hydrate, it exhibits the reflections as outlined above at different ambient humidities, with different H2O molecule occupancies (values for n in formula (III) or (Illa) as outlined herein above).
  • the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections:
  • the benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 3 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 11 .
  • the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections:
  • 16.5, 17.7, and 11.8, preferably at least the following reflections: 16.5, 17.7, 11.8, 20.2, and 15.8, in an embodiment at least the following reflections: : 16.5, 17.7, 11.8, 20.2,
  • the benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 6 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 43.
  • the (pseudo)polymorphic Hydrate 6 form of the benzenesulfonate salt of elinzanetant is a variable occupancy hydrate, it exhibits the reflections as outlined above at different ambient humidities, with different H2O molecule occupancies (values for n in formula (III) or (Illa) as outlined herein above).
  • the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections:
  • 14.2, 17.1 , and 16.1 preferably at least the following reflections: 14.2, 17.1 , 16.1 , 3.0, and 19.9, in an embodiment at least the following reflections: 14.2, 17.1 , 16.1 , 3.0, 19.9, 5.8, and 8.6, in an embodiment at least the following reflections: 14.2, 17.1 , 16.1 , 3.0, 19.9, 5.8, 8.6, 20.4, 21.8, and 23.6, each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 7 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 48.
  • the (pseudo)polymorphic Hydrate 7 form of the benzenesulfonate salt of elinzanetant is a variable occupancy hydrate, it exhibits the reflections as outlined above at different ambient humidities, with different H2O molecule occupancies (values for n in formula (III) or (Illa) as outlined herein above).
  • the polymorphic form Pattern G of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 16.0, 8.0, and 13.3, such as at least the following reflections: 16.0, 8.0, 13.3, 26.8, and 10.7, such as at least the following reflections: 16.0, 8.0, 13.3, 26.8, 10.7, 21.4, and 6.0, such as at least the following reflections: 16.0, 8.0, 13.3, 26.8, 10.7, 21 .4, 6.0, 18.7, 24.1 and 43.5 each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the polymorphic form Pattern G can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 15.
  • the polymorphic form Pattern D of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 19.8, 7.6, and 22.0, such as at least the following reflections: 19.8, 7.6, 22.0, 16.3, and 20.2, such as at least the following reflections: 19.8, 7.6, 22.0, 16.3, 20.2, 18.9, and 14.1 , such as at least the following reflections: 19.8, 7.6, 22.0, 16.3, 20.2, 18.9, 14.1 , 13.3, 24.7 and 11.4, each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the polymorphic form Pattern D can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 10.
  • the polymorphic form Pattern 4 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 13.3, 12.0, and 8.2, such as at least the following reflections: 13.3, 12.0, 8.2, 4.9, and 18.8, such as at least the following reflections: 13.3, 12.0, 8.2, 4.9, 18.8, 21.9, and 19.8, such as at least the following reflections: 13.3, 12.0, 8.2, 4.9, 18.8, 21.9, 19.8, 15.0, 16.2 and 19.6, each quoted as 20 value ⁇ 0.2°.
  • a X-Ray powder diffractogram at 25°C and with Cu- K alpha 1 as radiation source
  • the benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 4 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 6.
  • the polymorphic form Pattern 5 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 14.0, 8.7, and 19.5, such as at least the following reflections: 14.0, 8.7, 19.5, 16.3, and 19.8, such as at least the following reflections: 14.0, 8.7, 19.5, 16.3, 19.8, 15.8, and 11.3, such as at least the following reflections: 14.0, 8.7, 19.5, 16.3, 19.8, 15.8, 11.3, 17.0, 3.7 and 21 .4 each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 5 can also be characterized unambiguously by the X- Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 16.
  • the polymorphic form Pattern 6 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 13.1 , 16.4, 22.4, such as at least the following reflections: 13.1 , 16.4, 22.4, 18.9, 13.5, such as at least the following reflections: 13.1 , 16.4, 22.4, 18.9, 13.5, 15.7, 17.5, such as at least the following reflections: 13.1 , 16.4, 22.4, 18.9, 13.5, 15.7, 17.5, 14.8, 10.5 and 14.1 , each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 6 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 20.
  • the polymorphic form Pattern 8 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 14.2, 19.9, 21.2, such as at least the following reflections: 14.2, 19.9, 21.2, 8.7, 19.4, such as at least the following reflections: 14.2, 19.9, 21.2, 8.7, 19.4, 22.2, 16.1 , such as at least the following reflections: 14.2, 19.9, 21.2, 8.7, 19.4, 22.2, 16.1 , 21.4, 11.3 and 24.6, each quoted as 20 value ⁇ 0.2°.
  • the benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 8 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 23.
  • the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm’ 1 ): 1121 , 1185, 1282, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1121 , 1185, 1282, 1174, 683, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1121 , 1185, 1282, 1174, 683, 1105, 609, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1121 , 1185, 1282, 1174, 683, 1105, 609, 1017, 1084 and 1035.
  • the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant can also be
  • the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm’ 1 ): 1122, 683, 1278, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1122, 683, 1278, 1176, 1102, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1122, 683, 1278, 1176, 1102, 1082, 1016, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1122, 683, 1278, 1176, 1102, 1082, 1016, 1034, 611 and 691.
  • the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as
  • the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm’ 1 ): 1120, 1276, 609, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1120, 1276, 609, 681 , 896, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1120, 1276, 609, 681 , 896, 1374, 1486, in an embodiment at least the following values of the band maxima (cm’ 1 ): 1120, 1276, 609, 681 , 896, 1374, 1486, 1650, 1228 and 691.
  • the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 44.
  • the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm -1 ): 1122, 1274, 896, in an embodiment at least the following values of the band maxima (cm -1 ): 1122, 1274, 896, 681 , 611 , in an embodiment at least the following values of the band maxima (cm -1 ): 1122, 1274, 896,
  • the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 49.
  • the polymorphic form Pattern 4 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm -1 ): 1131 , 1117, 1104, such as at least the following values of the band maxima (cm -1 ): 1131 , 1117, 1104, 1012, 1279, such as at least the following values of the band maxima (cm -1 ): 1131 , 1117, 1104, 1012, 1279, 682, 612, such as at least the following values of the band maxima (cm -1 ) 1131 , 1117, 1104, 1012, 1279,
  • the polymorphic form Pattern 4 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 9.
  • the polymorphic form Pattern 5 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm -1 ): 1121 , 1281 , 1175, such as at least the following values of the band maxima (cm -1 ): 1121 , 1281 , 1175, 1035, 1017, such as at least the following values of the band maxima (cm -1 ): 1121 , 1281 , 1175, 1035, 1017, 682, 610, such as at least the following values of the band maxima (cm -1 ): 1121 , 1281 , 1175, 1035, 1017, 682, 610, 1106, 726 and 1226.
  • the polymorphic form Pattern 5 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 19.
  • Another object of the present disclosure is a method for preparing crystalline forms of the benzenesulfonate salt of elinzanetant.
  • Some embodiments of the present disclosure relate to a method for preparing crystalline forms of the benzenesulfonate salt of elinzanetant comprising the steps of providing the compound of formula (I) in a solvent; adding and optionally mixing with benzenesulfonic acid; and isolating the crystalline form of the benzenesulfonate salt of elinzanetant.
  • the term “providing” is to be understood - unless indicated otherwise - as the provision of a compound, irrespective of its form. It will be understood by those of ordinary skills in the art that a compound can be provided as solid or dissolved in an appropriate solvent. Accordingly, “providing” in context of the present disclosure includes provision as a solid, e.g.
  • the compound can be adopted in accordance with the needs, e.g. process optimization.
  • the compound can be provided in a solvent as obtained in previous steps like synthesis of the compound itself, or in a solvent after dissolving a solid form of the compound in a solvent prior to providing it.
  • the disclosure relates to a method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, the method comprising the steps of
  • the solvent is selected from the group of polar and/or aprotic solvents, for example, ethyl acetate, isopropyl acetate, toluene, DMSO, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), dimethylformamide (DMF), 1 ,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran (THF), acetonitrile, acetone, 1 ,4-dioxane, 2-methyl-THF, and n-butyl acetate, preferably selected from the group of toluene, ethyl acetate, isopropyl acetate, and n-butyl acetate, preferably selected from the group of toluene, ethyl acetate, isopropyl acetate, and n-butyl acetate,
  • the solvent is selected from the group consisting of toluene, ethyl acetate, and n-butyl acetate.
  • the solvent is toluene.
  • the solvent is ethyl acetate.
  • the solvent is n-butyl acetate.
  • Benzenesulfonic acid can be conducted using benzenesulfonic acid as a solid or in a solvent.
  • benzenesulfonic acid is added in solid form or in a solvent.
  • the benzenesulfonic acid is added as an aqueous solution.
  • the benzenesulfonic acid is present in the aqueous solution a concentration of 40% w/w to 48% w/w, preferably about 46% w/w.
  • the compound of formula (I) is provided in ethyl acetate as a solvent and added to a mixture of water and n-heptane.
  • the method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant comprises the steps of providing the compound of formula (I) in a mixture comprising ethyl acetate, water and n-heptane, adding and optionally mixing with benzenesulfonic acid; and isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant.
  • the method comprises the steps of:
  • the mixture is heated in step (iii) to a temperature of 45°C to 60°C, more preferably to a temperature of 50°C to 55°C.
  • the mixture obtained in step (iv) is filtered before cooling in step (v).
  • This optional step may be e.g. preformed to remove foreign solid particles, such as metal debris, fibres, as required by good manufacturing practice and regulatory provisions or rules.
  • a suspension is obtained in in step (v).
  • step (v) comprises cooling the mixture as obtained in step (iv) and then isothermally mixing for 6 hours to 48 hours until a suspension is obtained, in an embodiment for 10 hours to 24 hours, such as 12 hours to 16 hours.
  • step (v) particle size and/or processability can be optimized by seeding the mixture in step (v) with crystals of (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, preferably the mixture is seeded with said crystals at the end of step (v), i.e. after the target temperature has been reached.
  • the seeds are not critical for the solid-state but are preferably used optionally for particle size and processability reasons.
  • the seeding further has the advantage that isothermal mixing to obtain a suspension is drastically reduced. Accordingly, the time of isothermal mixing to obtain a suspension can be drastically reduced to 1 to 6 hours.
  • step (v) comprises the addition of crystals of (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, preferably at the end of step (v).
  • isothermally mixing after addition of the crystals is done for 1 h to 6 hours, preferably 1 to 3 hours, more preferably about 2 hours.
  • the cooling in step (v) refers to cooling to a temperature of 40°C to 50°C, more preferably to a temperature of about 45°C.
  • suspension is to be understood as a mixture of at least two phases, wherein at least one phase is solid and at least one is liquid.
  • the suspension in the method according to the disclosure is formed through crystallization of the benzeneulfonate salt of elinzanetant, wherein the crystals are suspended within the solvent(s) or solvent mixture. The formation of a suspension can be seen by increasing turbidity of the mixture.
  • the suspension is cooled to a temperature between 0°C and 35°C and isothermally mixed before isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, in an embodiment the suspension is cooled to a temperature of about 20°C to 25°C and isothermally mixed for a time between 0 min and 72 hours, in an embodiment about 0.5 hours to 1 hour.
  • Isolation in step (vi) may be conducted by methods for isolating solids from a suspension known by those skilled in the art. In an embodiment, isolation is conducted by filtration to obtain a filter cake, preferably using a filter.
  • the filter cake is in an embodiment washed and dried. Washing can be conducted with one or more appropriate solvents, preferably with a mixture of ethyl acetate and n-heptane, such as a mixture of 2:1 (v/v) of ethyl acetate and n-heptane.
  • the method comprises the steps of:
  • step (iii) heating the mixture obtained in step (ii) to a temperature of 50°C to 55°C;
  • step (v) cooling the mixture as obtained in step (iv) to a temperature of about 45°C and seeding the solution with crystals of (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant to obtain a suspension; cooling the suspension to a temperature of 20°C to 25°C and optionally isothermally mixing the suspension for about 1 hour;
  • the method comprises the steps of:
  • step (v) cooling the mixture of step (iv) to a temperature of about 45°C and seeding the solution with (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant to obtain a suspension;
  • the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the present disclosure can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, optic route or as an implant or stent.
  • hydrate crystalline form of the benzenesulfonate salt of elinzanetant for oral administration, it is possible to formulate the hydrate crystalline form of the benzenesulfonate salt of elinzanetant according to the present disclosure, to dosage forms known in the art that deliver the compounds of the disclosure rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with functional or non-functional coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with functional or non-functional coatings that dissolve with a delay or are insoluble
  • orally-disintegrating tablets for example, films/wafers, films/lyophylisates
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • crystalline forms of the benzenesulfonate salt of elinzanetant can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include, inter alia,
  • fillers and binders for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),
  • buffers for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)
  • mould release agents for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),
  • capsule materials for example gelatin, hydroxypropylmethylcellulose
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • antioxidants for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide, rice starch, calcium sulfate, calcium carbonate
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present disclosure furthermore relates to a pharmaceutical composition which comprise at least one crystalline hydrate form of the benzenesulfonate salt of elinzanetant according to the present disclosure, preferably the Hydrate 2 form, conventionally together with one or more pharmaceutically acceptable excipient(s), and to their use according to the present disclosure.
  • excipients are surfactants, fillers, binders, lubricants, disintegrant, sweeteners, flavoring agents, and colorants. It may come to happen that a person skilled in the art assigns similar or even identical substances to be member of more than one of the above-mentioned groups of substances. Within the context of the present disclosure, the functional descriptions of the substances are however intentionally filled with specific substances to clarify their respective property assigned to them.
  • compositions within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • surfactants or ‘surface active agents’ are organic compounds containing a hydrophilic "water-seeking” group, and a hydrophobic "water-avoiding” group.
  • salts of elinzanetant can be formulated in a solid pharmaceutical composition, such as a tablet, with the desired properties, if they are formulated together with a non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • non-ionic surfactants provide for a surprisingly and drastically increased dissolution behavior as compared to ionic surfactants, as well as a sufficient bioavailability.
  • the present disclosure also relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising a salt of elinzanetant and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the solid pharmaceutical composition is selected from the group consisting of granules, solid mixture, pellets, tablets, dragees, sachets, pills, and melts.
  • the solid pharmaceutical composition is a tablet.
  • the solid pharmaceutical composition is an immediate release solid pharmaceutical composition, including an immediate release tablet, immediate release granules, immediate release pellets, immediate release solid mixture immediate release dragees, immediate release sachets, immediate release pills, and immediate release melts.
  • the solid pharmaceutical composition is an immediate release tablet.
  • “Immediate” release in one embodiment relates to a rapid dissolution of elinzanetant from the composition occurring in vitro.
  • Rapid dissolution is defined as the in vitro dissolution of more than 50% of the comprised elinzanetant over about 30 minutes, in particular at least 55% over about 30 minutes, even more particular at least 60% over about 30 minutes of elinzanetant (which was present in the solid pharmaceutical composition, such as the tablet, as the salt of elinzanetant) from the solid pharmaceutical composition, preferably the tablet, containing a salt of elinzanetant using an USP-2 paddle apparatus in Fasted State Simulated Gastric Fluid (FaSSGF) at pH 2.4 with 500 mL vessels at 37°C ⁇ 0.5°C and a rotation speed of the paddles of approx. 75 rpm.
  • FaSSGF Fasted State Simulated Gastric Fluid
  • the solid pharmaceutical composition When administered, the solid pharmaceutical composition first enters the acidic environment of the stomach before entering the more neutral environment of the duodenum. Accordingly, it may be desirable for the solid pharmaceutical composition, such as a tablet, to allow dissolution of elinzanetant in vitro within a certain time after adding it to a solution of acidic conditions for a certain time and rebuffering from that acidic to a more neutral condition.
  • “rapid dissolution” is defined as the in vitro dissolution of at least 60% of the comprised elinzanetant within 35 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate for 30 min, and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • At least 80% of the comprised elinzanetant is dissolved in vitro within 210 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate for 30 min, and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37°C ⁇ 0.5°C and 75 rpm as stirring rate.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • the dissolution rates above refer to the dissolution from the tablet core, i.e. the tablet without coating. Depending on the type of coating the dissolution rate may be slightly decreased.
  • Bioavailability in one embodiment is defined as the fraction (percentage) of an administered dose or the concentration (pg drug per mL blood) of elinzanetant that reaches the blood stream (systemic circulation) within a time period after administration of the pharmaceutical composition, e.g. the solid pharmaceutical composition according to the present disclosure, tmax is the time where the highest concentration of elinzanetant is found in the bloodstream after administration, whereas Cmax is the maximum concentration of elinzanetant found in the bloodstream after administration.
  • the area under the curve represents the total amount of elinzanetant which was in the bloodstream over the period studied, or extrapolated to infinity to obtain the total AUC.
  • the present disclosure relates to pharmaceutical composition, such as a solid pharmaceutical composition, comprising elinzanetant or a pharmaceutical acceptable salt thereof, wherein the pharmaceutical composition exhibits a bioavailability essentially, such as Cmax and/or total AUC as a solid pharmaceutical composition according to the present disclosure, such as tablets having the composition of Example 14.2.3 of the present disclosure.
  • Essentially in context with the present disclosure refers to values that are within a range of ⁇ 30% from the respective value, such as within a range of ⁇ 25% from the respective value.
  • “essentially” refers to bioequivalence, such as the bioequivalence according to the US Food and Drug Administration FDA, e.g. a range between -20% and +25% from the respective value, in other words between 80% and 125% of the respective value.
  • Bioavailability is in one embodiment evaluated by determining Cmax and/or AUC after administration of the pharmaceutical formulation to a subject, such as a human subject.
  • the administration may be performed with the desired dose.
  • Cmax and/or AUC are determined after administration of a single dose of 120 mg elinzanetant to a subject.
  • administration for determining is performed in the morning, during the day or in the evening. In one embodiment administration for determining is performed under fasted conditions, such as in the morning before food uptake.
  • the solid pharmaceutical composition of the present disclosure when administered at a single dose of 120 mg under fasted conditions, exhibits a Cmax of between 700 pg/L and 1500 pg/L, such as between 700 pg/L and 1400pg/L. In one embodiment the Cmax is 1063 pg/L ⁇ 25%, such as between 80% and 125% of 1063 pg/L.
  • the pharmaceutical composition of the present disclosure when administered at a single dose of 120 mg, exhibits a total AUC of between 4500 pg*h/L and 7500 pg*h/L, such as between 5000 pg*h/L and 7100 pg*h/L. In one embodiment the total AUC is 7248 pg*h/L ⁇ 25%, such as between 80% and 125% of 7248 pg*h/L.
  • the values herein for Cmax and total AUC refer to the geometric mean.
  • non-ionic surfactant refers to surfactants not comprising an ionic moiety (such as sulphate, sulphonate, ether sulphate, ether phosphate, ether carboxylate or carboxylate) and include derivatives of ethylene oxide, such as polyoxyethylene, and/or propylene oxide with an alcohol containing an active hydrogen atom.
  • fatty acids esters of polyoxyethylene are macrogololeate, macrogolstearate, macrogol-15-hydroxystearate (e.g. Kolliphor® HS 15), macrogol- 30-dipolyhydroxystarate, polyoxyethylene(8)-stearate (e.g. Myrj® S8), polyoxyethylene(20)-stearate (e.g. Myrj® S20), polyoxyethylene(40)-stearate (e.g.
  • Myrj® S40 polyoxyethylene(50)-stearate (e.g. Myrj® S50), polyoxyethylene(100)- stearate (e.g. Myrj® S100), and polyoxyethylene(9)-stearate (e.g. Cremophor® S9).
  • fatty alcohol ethers of polyoxyethylene are macrogolcetylstearyl ether, macrogollauryl ether, lauronacrogol 400, macrogololeyl ether, macrogolstearyl ether, polyoxyethylene laurylether/macrogol laurylether (e.g. Brij® L4, Brij® 23), polyoxyethylene cetylether/macrogol cetylether (e.g.
  • Brij® C2 Brij® C10, Brij® C20
  • polyoxyethylene stearylether/macrogol stearyl ether e.g. Brij® S10, Brij® S20, Cremophor® A6, or Cremophor® A25
  • polyoxyethylene oleylether/macrogol oleylether e.g. Brij® 010, Brij® 020
  • partial fatty acid esters of sorbitan are sorbitan monolaurate (e.g. Span® 20), sorbitan monopalmitate (e.g. Span® 40), sorbitan monostearate (e.g. Span® 60), sorbitan tristearate (e.g.
  • Span® 65 sorbitan monooleate
  • Span® 80 sorbitan sesquioleate
  • Span® 83 sorbitan sesquioleate
  • sorbitan trioleate e.g. Span® 85
  • partial fatty acid esters of polyoxyethylene sorbitan/polysorbates are polyoxyethylene(20)-sorbitan monolaurate (e.g. Tween® 20), polyoxyethylene(4)-sorbitan monolaurate (e.g. Tween® 21 ), polyoxyethylene(20)-sorbitan monopalmitate (e.g. Tween® 40), polyoxyethylene(20)- sorbitan monostearate (e.g.
  • Tween® 60 polyoxyethylene(4)-sorbitan monostearate (e.g. Tween® 61 ), polyoxyethylene(20)-sorbitan tristearate (e.g. Tween® 65), polyoxyethylene(20)-sorbitan monooleate (e.g. Tween® 80), polyoxyethylene(5)- sorbitan monooleate (e.g. Tween® 81 ), and polyoxyethylene(20)-sorbitan trioleate (e.g. Tween® 85).
  • An example for fatty acid esters of polyoxyethylene sorbitol is macrogol-40-sorbitolheptaoleat.
  • fatty acid esters of polyoxyethylene and glycerol are macrogol-6-glycerolcaprylocaprate (e.g. Softigen® 767), macrogolglycerolcaprylocaprate, macrogolglycerollaurate, macrogolglycerolcocoate, macrogol-20-glycerolmonostearate, macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g. Kolliphor® RH 40, Cremophor® RH 40), macrogolglycerololeate, macrogolglycerolricinoleate (e.g.
  • macrogol-6-glycerolcaprylocaprate e.g. Softigen® 767
  • macrogolglycerolcaprylocaprate e.g. Softigen® 767
  • macrogolglycerolcaprylocaprate e.g. Softigen® 767
  • macrogolglycerolcaprylocaprate e.g. Softigen® 767
  • Kolliphor® EL Kolliphor® ELP, or Cremophor® EL
  • macrogolglycerollinoleate macrogol-20- glycerolmonolaurate
  • macrogol-20-glycerolmonooleate examples include polyoxyethylene - polyoxypropylene - block copolymers/poloxamers.
  • polyoxyethylene - polyoxypropylene - block copolymers/poloxamers are poly- (ethylenglykol)-block-poly-(propylenglykol)-block-poly-(ethylenglykol) (e.g.
  • poloxamer 338 e.g. Synperonic® PE/F108
  • poloxamer 184 e.g. Synperonic® L 64
  • poloxamer 407 e.g. Pluronic® F- 127
  • poloxamer 188 e.g. Pluronic® F-68
  • fatty acid esters of saccharose are saccharose distearate, saccharose dioleate, saccharose dipalmitate, saccharose monostearate, saccharose monopalmitate, saccharose monooleate, saccharose monomyristate, and saccharose monolaurate.
  • Examples for partial fatty acids of polyhydric alcohols are ethylenglycolmonostearate, glycerolmonostearate, glycerolmonooleate, pentaerythrimonostearate, glyceroldibehenate, glyceroldistearate, glycerolmonocaprylate, glycerolmonocarprylocaprate, glycerolmonolinoleate, glycerolmonooleate, glycerolmonostearate 40-55, ethylenglycolmonoplamitostearate, diethylenglycolpalmitostearate, propylenglycoldicaprylocaprate, propylenglycoldilaurate, propylenglycolmonolaurate, and propylenglycolmonopalmitostearate.
  • fatty acid esters of polyglycerol are polyglycerololeate, polyglycerolpoly(12-hydroxystearate) and triglyceroldiisostearate.
  • fatty acid esters of glycol is propylene glycol monostearate (PGMS, e.g. Lexemul® P MB).
  • non-ionc surfactants are D-a-tocopheryl-1000-succinate/vitamin E TPGS, fatty alcohols such as cetylalcohol, cetylstearylalcohol, stearylalcohol, oleylalcohol, emulsifying cetylstearylalcohol and non-ionic emulsifying alcohols such as mixtures of cetylstearylalcohol, macrogol-80-cetylstearyl ether and glycerlomonostearate (e.g. Rofetan® NS), lanolin alcohols, and sterines such as cholesterol.
  • fatty alcohols such as cetylalcohol, cetylstearylalcohol, stearylalcohol, oleylalcohol, emulsifying cetylstearylalcohol and non-ionic emulsifying alcohols such as mixtures of cetylstearylalcohol, macrogol-80-cetylstearyl
  • the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20, polysorbate 40, polysorbate 80, and macrogol-15-hydroxystearate; or mixtures thereof.
  • non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, polysorbate 20, and macrogol-15-hydroxystearate; or mixtures thereof.
  • the salt of elinzanetant in the solid pharmaceutical composition is selected from benzenesulfonate, preferably according to the embodiments as disclosed herein, 4-methylbenzenesulfonate, and di-hydrochloride salt, and mixtures thereof, or a hydrate or solvate thereof.
  • the solid pharmaceutical composition according to the disclosure comprises the crystalline 4-methylbenzenesulfonate salt of elinzanetant and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the 4-methylbenzenesulfonate is in anhydrous crystalline form 1 as disclosed in WO 2010/015626 A1 , which is incorporated herein by reference.
  • the 4- methylbenzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.0, 10.3, 14.5, 15.0, and 17.7; preferably at least the following reflections: 3.2, 6.2, 8.0, 10.3, 12.4, 14.5, 15.0,16.2, 17.2, 17.7, 18.6, 20.0, and 22.9; each quoted as 20 value ⁇ 0.2°.
  • a X-Ray powder diffractogram at 25°C and with Cu-K alpha 1 as radiation source
  • the solid pharmaceutical composition according to the disclosure comprises crystalline di-hydrochloride salt of elinzanetant, or a solvate thereof, and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the di-hydrochloride salt of elinzanetant is present as an isopropanol solvate.
  • the di-hydrochloride salt isopropanol solvate can be produced as disclosed in Example 7 of WO 2021/094247 A1 , which is incorporated herein by reference.
  • the polymorphic form di-hydrochloride isopropanol solvate of the compound of formula (I) can be preferably characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 13.7, 17.5, 20.4, preferably at least the following reflections: 13.7, 17.5, 20.2, 20.4, 20.8, more preferably at least the following reflections: 10.1 , 13.0, 13.7, 17.5, 20.2, 20.4, 20.8, most preferably at least the following reflections: 7.9, 8.8, 10.1 , 13.0, 13.4, 13.7, 17.5, 20.2, 20.4 and 20.8, each quoted as 20 value ⁇ 0.2°.
  • the polymorphic form di-hydrochloride isopropanol solvate of the compound of formula (I) can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 35.
  • the solid pharmaceutical composition according to the disclosure comprises crystalline benzenesulfonate salt of elinzanetant or a solvate or hydrate thereof and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the solid pharmaceutical composition according to the disclosure comprises a crystalline hydrate form of the benzenesulfonate salt of elinzanetant according to the embodiments as disclosed herein and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the solid pharmaceutical composition according to the disclosure comprises the crystalline Hydrate 3 form of the benzenesulfonate salt of elinzanetant according to the disclosure and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the solid pharmaceutical composition according to the disclosure comprises the crystalline Hydrate 2 form of the benzenesulfonate salt of elinzanetant including all embodiments as disclosed herein and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
  • the crystalline Hydrate 2 form of the benzenesulfonate salt of elinzanetant in the composition has the preferred embodiments as disclosed herein.
  • the concentration of the salt of elinzanetant in the solid pharmaceutical composition may be adapted according to the needs. It may for example be adapted to the total amount of elinzanetant necessary per dosage form, e.g., to provide for a pharmaceutically effective amount of elinzanetant.
  • the concentration of the salt of elinzanetant or a hydrate or solvate thereof ranges from 5% w/w to 50% w/w, such as from 10% w/w to 40% w/w; and in one embodiment the concentration of the salt of elinzanetant or a hydrate or solvate thereof is from 20% w/w to 35% w/w.
  • the concentration of the non-ionic surfactant ranges from about 0.5% w/w to about 50% w/w, from about 0.5% w/w to about 25% w /w, from about 0.5% w/w to about 10.0% w/w, from about 0.5% w/w to about 7.0% w/w.
  • the solid pharmaceutical composition may optionally contain one or more further pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are selected from the group consisting of fillers, binders, lubricants, disintegrants, sweeteners, flavouring agents, and colorants; or mixtures thereof.
  • an excipient may serve, e.g. as a binder or a filler or may serve to provider for both.
  • Filler and/or binder in the solid pharmaceutical composition according to the present disclosure are selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof.
  • the filler according to the present disclosure in one embodiment are selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium
  • an excipient may serve, e.g., as a disintegrant.
  • disintegrants expand and dissolve when wet and thereby facilitate disintegration of a solid pharmaceutical composition, such as a tablet, releasing the active ingredients.
  • Disintegrants in one embodiment of the present disclosure are those selected from the group consisting of alginic acid, cross-linked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium); or a mixture thereof.
  • the disintegrant of the present disclosure is croscarmellose sodium or cross-linked polyvinylpyrrolidone; or a mixture thereof.
  • the disintegrant is croscarmellose sodium.
  • an excipient may serve, e.g. as lubricant.
  • Lubricants prevent ingredients from sticking, e.g., to production equipment.
  • the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof.
  • lubricants according to the present disclosure are selected from the group consisting of magnesium stearate, stearic acid and talcum, or mixtures thereof.
  • the pharmaceutical composition may contain agents that provide for a certain taste, such as sweeteners or flavoring agents.
  • Sweeteners suitable in the context of the present disclosure are those selected from the group consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol.
  • sweeteners are added in amounts to achieve the desired grade of sweetness and may be adapted by those skilled in the art.
  • Flavoring agents in the context of the present disclosure are natural flavoring substances obtained from plant or animal raw materials, nature-identical flavoring substances obtained by synthesis or isolated through chemical processes, which are chemically and organoleptically identical to flavoring substances naturally present in products intended for human consumption and artificial flavoring substances.
  • the flavoring agent is selected from the group consisting of synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart.
  • synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural
  • the solid pharmaceutical composition may optionally contain colorants.
  • Colorants are commonly used to color an uncolored pharmaceutical composition or to enhance its color, to minimize batch-to-batch variations or to replace a color already present to complement its effect and also to provide for a desirable appearance.
  • Colorants in context with the present disclosure may be selected from the group consisting of dyes or pigment such as indigo carmine, riboflavin, titanium dioxide, rice starch, calcium sulfate and calcium carbonate. In the context of the present disclosure colorants may be added in amounts to achieve the desired color and/or grade of color.
  • the solid pharmaceutical composition comprises one or more disintegrant selected from those disclosed herein above.
  • the one or more disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof.
  • the solid pharmaceutical composition comprises croscarmellose sodium.
  • the concentration of the disintegrant ranges from about 0.1 % w/w to about 20% w/w, from about 1 % w/w to about 10% w /w, from about 2% w/w to about 6% w/w.
  • the solid pharmaceutical composition comprises one or more one or more binder selected from those disclosed herein above.
  • the binder is selected from the group consisting of microcrystalline cellulose or silicified microcrystalline cellulose; or a mixture thereof.
  • the solid pharmaceutical composition comprises microcrystalline cellulose.
  • the concentration of the binder ranges from about 10% w/w to about 90% w/w, from about 30% w/w to about 80% w /w, from about 50% w/w to about 70% w/w.
  • the solid pharmaceutical composition comprises a lubricant.
  • the lubricant of the present disclosure is magnesium stearate.
  • the concentration of the lubricant ranges from about 0.1 % w/w to about 5% w/w, from about 0.1 % w/w to about 2% w /w, from about 0.5% w/w to about 1 .5% w/w.
  • the one or more further pharmaceutically acceptable excipient comprises a flow regulator, such as silicon dioxide.
  • the concentration of the flow regulator ranges from about 0.1 % w/w to about 5% w/w, from about 0.1 % w/w to about 1 % w /w, from about 0.1 % w/w to about 0.6% w/w.
  • the disclosure relates to a solid pharmaceutical composition, preferably a tablet, comprising a salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, a lubricant and optionally one or more further pharmaceutically acceptable excipients.
  • a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a nonionic surfactant, a binder, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • the binder is microcrystalline cellulose. Accordingly, in one embodiment, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • the binder is silicified microcrystalline cellulose.
  • the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, silicified microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, silicified microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, silicified microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
  • a particular preferred lubricant is magnesium stearate.
  • the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disintegrant is croscarmellose sodium.
  • the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, a binder, croscarmellose sodium, a lubricant, and one or more further pharmaceutically acceptable excipients. Further, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • a particular preferred non-ionic surfactant is macrogolglycerolricinoleate.
  • the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, macrogolglycerolricinoleate, a binder, a disintegrant, a lubricant, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, macrogolglycerolricinoleate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, macrogolglycerolricinoleate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, macrogolglycerolricinoleate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
  • solid dosage form preferably the tablet, may be coated by pharmaceutically acceptable excipients.
  • the optional coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxy-propylcellulose, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polyvinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl aery late-m ethyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g.
  • polyethylene glycol 3350 polyethylene glycol 3350
  • glycerol triacetate or triethyl citrate and/or colorants/pigments such as, for example, titanium dioxide, rice starch, calcium sulfate, calcium carbonate, iron oxide (e.g. red iron oxide, yellow iron oxide, black iron oxide), indigotin or suitable color lakes, and/or anti-tacking agents such as talc, and/or opacifiers such as titanium dioxide, rice starch, calcium sulfate, calcium carbonate.
  • An optional coating may comprise HPMC and polyethylene glycol, and iron oxide, such as iron oxide red and/or iron oxide yellow.
  • the coating may comprise an opacifier, such titanium dioxide, rice starch, calcium sulfate.
  • a mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available coatings.
  • the coating is about 0.5% to 10% by weight of the coated tablet, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet.
  • the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow and titanium dioxide.
  • the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow, and one or more opacifier selected from the group consisting of rice starch, calcium sulfate, and calcium carbonate.
  • non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20, polysorbate 40, polysorbate 80, and macrogol-15-hydroxystearate; or mixtures thereof;
  • a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof;
  • the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol,
  • a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
  • a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof, and
  • (f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w.
  • non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20, polysorbate 40, polysorbate 80, and macrogol-15-hydroxystearate;
  • a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof;
  • the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol,
  • a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
  • a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof, and
  • (f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w.
  • the di-hydrochloride salt of elinzanetant is present as a solvate, such as the isopropanol solvate.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w;
  • magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
  • (f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 55.79% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 61 .00% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w;
  • magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
  • (f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 55.79% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 58.92% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,
  • magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
  • (f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 55.79% w/w;
  • a non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, preferably between 2% w/w and 5% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 80 (Tween 80), and macrogol-15-hydroxystearate; or mixtures thereof;
  • a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g.
  • a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
  • a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof; and
  • (f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,
  • magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
  • (f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 57.02% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,
  • magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w
  • croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w
  • (f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 57.02% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 60.15% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 62.23% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,
  • magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w
  • croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w
  • (f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 57.02% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 60.15% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 61 .19% w/w;
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 62.23% w/w;
  • croscarmellose sodium at a concentration of about 5.21 % w/w.
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of about 60.74% w/w;
  • the disclosure relates to a tablet comprising:
  • the disclosure relates to a tablet comprising:
  • microcrystalline cellulose at a concentration of 64.85% w/w;
  • the disclosure relates to a tablet comprising:
  • croscarmellose sodium at a concentration of about 2.91 % w/w
  • silicon dioxide at a concentration of about 0.58% w/w
  • the concentrations as listed refer to the solid pharmaceutical composition in the core of a solid oral dosage form, such as a tablet core.
  • the core may be, e.g., being coated with coatings to achieve further desired properties.
  • the invention relates to a method for preparing the solid pharmaceutical composition according to the present disclosure comprising the steps of:
  • the method comprises the step of dry granulation. Dry granulation may be performed after step (ii). In case the optional step (ii) is not performed, dry granulation may be performed after step (i).
  • step (ii) subsequently adding and blending one or more further excipients to the blend obtained in step (i);
  • step (iii) subjecting the blend obtained after step (ii) to dry granulation.
  • the method comprises the steps of (i) blending the crystalline salt of elinzanetant or a hydrate or solvate thereof, and the at least one non-ionic surfactant, and one or more excipient to obtain a blend;
  • step (ii) subsequently adding and blending one or more further excipients to the blend obtained in step (i);
  • step (iii) subjecting the blend obtained after step (ii) to dry granulation.
  • step (ii) subjecting the blend obtained after step (i) to dry granulation.
  • one or more further excipients may be added and mixed with the granules, e.g. before compression.
  • the salt of elinzanetant or a hydrate or solvate thereof is selected from the group consisting of benzenesulfonate salt of elinzanetant, 4-methyl- benzenesulfonate salt of elinzanetant, and di-hydrochloride salt of elinzanetant.
  • the salt of elinzanetant is the benzenesulfonate salt of elinzanetant, in particular a hydrate form of the benzenesulfonate salt of elinzanetant according to the present disclosure, more particular the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the present disclosure.
  • Blending of non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof, and optionally one or more excipient in step (i) can be performed by suitable measures, such as rubbing, e.g. by a mortar or pistil, mixing, such as high shear mixing, fluid bed blending or extrusion, e.g. by twin screw extrusion. In one embodiment blending is performed dry.
  • One or more excipients can be blended with the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i). In one embodiment, all excipients of the solid pharmaceutical composition are blended with the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i). In another embodiment, one or more excipients are blended with the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i), and one or more further excipients are added in step (ii).
  • step (i) only the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i) are blended in step (i), and one or more excipients are added in step (ii). That is, after blending the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i) one or more further excipients according to the present disclosure may be optionally added to the blend.
  • Adding and blending in step (ii) may comprise mixing the one or more further pharmaceutically acceptable excipient with the blend of the non-ionic surfactant and the crystalline salt of elinzanetant obtained in step (i).
  • the one or more further pharmaceutically acceptable excipient may be added and blended in step (ii) by methods known in the art, e.g. by a mortar or pistil, mixing, such as free-fall blending, high shear mixing, fluid bed blending or extrusion, e.g. by twin screw extrusion.
  • the solid pharmaceutical composition may be provided as obtained.
  • the obtained composition may be further processed to prepare the desired form and/or to add one or more further excipients as needed.
  • the solid pharmaceutical composition is subjected to direct compression or compression after dry granulation, e.g. to obtain a tablet.
  • the direct compression is subjected to the obtained solid pharmaceutical composition.
  • the blend is subjected to dry granulation, thereafter optionally blended with one or more further excipients, and subjected to compression.
  • the present disclosure also relates to a solid pharmaceutical composition according to the present disclosure obtainable by a method for preparing the solid pharmaceutical composition according to the present disclosure.
  • the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant have useful pharmacological properties and may be employed for the prevention and treatment of diseases and disorders.
  • the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure may open up a further treatment alternative and may therefore be an enrichment of pharmacy.
  • the solid pharmaceutical compositions as disclosed herein have useful pharmacological properties and may be employed for the prevention and treatment of diseases and disorders.
  • the salts and pharmaceutical compositions according to the present disclosure may open up a further treatment alternative and may therefore be an enrichment of pharmacy.
  • the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure as well as the solid pharmaceutical compositions according to the present disclosure can be used to treat, prevent or ameliorate different diseases or disorders.
  • Elinzanetant and its pharmaceutically acceptable salts are suited for the treatment of diseases and disorders, such as psychotic disorders (WO 2007/028654 A1 ), and sex hormone-dependent diseases and disorders (WO 2016/184829 A1 ). Sex hormone-dependent diseases and disorders have been proven to be ameliorated by administration of elinzanetant in various clinical studies.
  • disease or disorder is a sex hormone-dependent disease or disorder.
  • the sex hormone-dependent disease or disorder is selected form the group consisting of vasomotor symptoms, pathological gain of excess body fat and/or excess body weight, insomnia, sleep disturbances, night-time awakenings, anxiety, depression, urinary symptoms of urgency, dysuria.
  • sex hormone-dependent disease or disorder means a disease or disorder which is exacerbated by, or caused by, excessive, inappropriate, or unregulated sex hormone production. Sex hormone-dependent diseases or disorders may occur in both sexes/genders, men and women. Accordingly, in one embodiment of the present disclosure, the disease or disorder is a sex hormone- dependent disease or disorder in males. In a further embodiment of the present disclosure the disease or disorder is a sex hormone-dependent disease or disorder in females.
  • BPH benign prostatic hyperplasia
  • metastatic prostatic carcinoma testicular cancer
  • breast cancer breast cancer
  • androgen dependent acne seborrhea
  • hypertrichosis male pattern baldness
  • vasomotor symptoms in adolescents’ precocious puberty.
  • diseases or disorders in women include but are not limited to endometriosis, adenomyosis, abnormal puberty, uterine fibroids, heavy menstrual bleeding, hormone-dependent cancers (ovarian cancer, breast cancer), hyperandrogenism, hirsutism, hypertrichosis, female androgenetic alopecia, androgen dependent acne, seborrhea, virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans ), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized the ca cells in ovarian stroma), other manifestations of high intra ovarian androgen concentrations (e.g.
  • follicular maturation arrest atresia, an ovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen producing tumor (virilizing ovarian or adrenal tumor), pathological gain of excess body fat and/or excess body weight, pre-eclampsia, diabetes, fatigue, irritability, cognitive decline, hair-loss, dry skin, insomnia, sleep disturbances, nighttime awakenings, anxiety and depression, decreases in sexual desire, vaginal dryness and pain, connective tissue loss and muscle bulk reduction, urinary symptoms of urgency, hidradenitis suppurativa, dysuria, osteoporosis.
  • Sex hormone-dependent diseases or disorders may be caused and/or associated with different conditions, which can have natural (such as menopause or adrenopause), surgical (such as bilateral oophorectomy in women, or orchiectomy or prostatectomy in men), radiological (i.e. radiation therapy) or chemical causes (e.g. adjuvant endocrine therapy).
  • natural such as menopause or adrenopause
  • surgical such as bilateral oophorectomy in women, or orchiectomy or prostatectomy in men
  • radiological i.e. radiation therapy
  • chemical causes e.g. adjuvant endocrine therapy
  • Vasomotor symptoms or sleep disturbances or night-time awakenings can for example be caused by different conditions.
  • the condition may be menopause- associated conditions, such as peri-menopause, the menopause, or the postmenopause.
  • menopause-associated conditions such as peri-menopause, the menopause, or the postmenopause.
  • association with menopause in one embodiment it is meant to include peri-menopause, menopause and post-menopause, more preferably peri-menopause and menopause.
  • sex hormone-dependent diseases or disorders may be associated with adrenopause.
  • the disease or disorder is a disease or disorder that is associated with menopause or adrenopause.
  • sex hormone-dependent diseases or disorders e.g., vasomotor symptoms
  • hormone signalling and/or regulation such as adjuvant endocrine therapy, e.g., using aromatase inhibitors such as anastrozole, exemestane, letrozole and testolactone; gonadotropinreleasing hormone receptor agonists such as such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin; gonadotropin-releasing hormone receptor antagonists such as ASP1701 , elagolix, relugolix and linzagolix (OBE2109); selective estrogen receptor modulators (SERMs) such as chili
  • the disease or disorder is a sex hormone-dependent disease or disorder selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances, and night-time awakenings. Yet a further embodiment refers to the disease or disorder being vasomotor symptoms.
  • these sex hormone-dependent diseases or disorders are associated with menopause or caused by adjuvant endocrine therapy.
  • the disease or disorder being selected from the group consisting of vasomotor symptoms associated with menopause, insomnia associated with menopause, sleep disturbances associated with menopause, and night-time awakenings associated with menopause.
  • the disease or disorder is vasomotor symptoms associated with menopause.
  • the disease or disorder being selected from the group consisting of vasomotor symptoms associated or caused by adjuvant endocrine therapy, insomnia or caused by adjuvant endocrine therapy, sleep disturbances or caused by adjuvant endocrine therapy, and night-time awakenings or caused by adjuvant endocrine therapy.
  • the disease or disorder is vasomotor symptoms or caused by adjuvant endocrine therapy.
  • the present disclosure further relates to a method for the treatment and/or prophylaxis of diseases and disorders, including the aforementioned diseases and disorders, using an effective amount of at least one of the hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure, including the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the disclosure.
  • the present disclosure further relates to a method for the treatment and/or prophylaxis of sex hormone dependent disease or disorder comprising administrating to a subject in need thereof an effective amount of at least one of the hydrate forms of the compound of formula (I) according to the disclosure, preferably the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the disclosure.
  • the present disclosure further relates to a method for the treatment and/or prophylaxis of sex hormone dependent disease or disorder comprising administrating to a subject in need thereof a solid pharmaceutical composition according to the present disclosure.
  • the solid pharmaceutical composition according to the present disclosure comprises an effective amount of elinzanetant.
  • the sex hormone-dependent disease or disorder is elected from the group consisting of vasomotor symptoms, insomnia and sleep disturbances comprising administrating to a subject in need thereof an effective amount of at least one of the hydrate forms of the compound of formula (I) according to the disclosure, preferably the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the disclosure.
  • the salts of elinzanetant and the hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure can be administered alone or in combination with other active substances if necessary.
  • the present disclosure further relates to medicinal products containing at least salt of elinzanetant, such as one of the hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure and one or more further active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases.
  • An embodiment of the present disclosure is a pharmaceutical composition according to the present disclosure comprising substantially pure (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, and more preferred (pseudo)polymorphic Hydrate 2 form which is substantially free of other solid forms of the elinzanetant and other solid forms of the benzenesulfonate salt of elinzanetant.
  • the pharmaceutical composition comprises the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of the compound of the formula (I) in accordance with the present disclosure.
  • the effective dosage of the compound of this disclosure can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the daily dose in an embodiment rages from about 40 mg to 300 mg elinzanetant and can be administered one or more times per day.
  • the daily dose rages from 80 mg to 160 mg, more preferably from 100 mg to 160 mg, more preferably from 120 mg to 160 mg.
  • the daily dose is 120 mg.
  • the daily dose in an embodiment refers to the amount of elinzanetant to be administered with one day. The skilled person will recognize that these amounts relate to the active pharmaceutical ingredient. Hence, the amounts reflect the amounts of elinzanetant per se without considering the counter ion of the respective salt.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present disclosure or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume.
  • XRPD X-Ray Powder Diffraction
  • Data were collected in a two-theta range of 1 .5° to 50°.
  • the tube voltage and current were 40 kV and 40 mA, respectively.
  • XRPD X-Ray Powder Diffraction
  • the sample was placed onto a special zerobackground silicon wafer, after careful grinding.
  • Data were collected in a two-theta range of either 4° to 50° or 3° to 40°.
  • the tube voltage and current were set to 30 kV and 10 mA, respectively.
  • XRPD X-Ray Powder Diffraction
  • the sample was placed onto a Powder bed in sample holder for temperature/humidity chamber.
  • Data were collected in a two-theta range of 3.5° to 40°.
  • the tube voltage and current were set to 40 kV and 40 mA, respectively.
  • XRPD X-Ray Powder Diffraction
  • DSC data were obtained on Netzsch Phoenix DSC 204 F1. Approximately 5-15 mg of each sample was placed into an aluminium DSC crucible and the weight was accurately recorded. The hermetically sealed crucibles with one pinhole were used for analysis. The samples were heated under a nitrogen atmosphere (20 mL/min) at a rate of 10 °C/min.
  • DSC data were obtained on Mettler-Toledo DSC3+. Approximately 4-10 mg of each sample was placed into an aluminium DSC crucible and the weight was accurately recorded. The hermetically sealed crucibles with one pinhole were used for analysis. The samples were heated under a nitrogen atmosphere (20 mL/min) at a rate of 20 K/min.
  • TGA analyses were performed on a Perkin Elmer Thermogravimetric Analyzer Pyris 6 TGA. Approximately 10-15 mg of sample was placed in a fared crucible and weighted accurately in the TG furnace. The samples were heated in nitrogen at a rate of 10°C/min.
  • TGA analyses were performed on a Mettler-Toledo TGA/DSC3+. Approximately 4-10 mg of sample was placed in a fared crucible and weighted accurately in the TG furnace. The samples were heated in nitrogen at a rate of 20K/min.
  • IR spectra were acquired on a IR Spectrometer Broker Alpha ii in ATR-geometry. Each spectrum represents 34 co-added scans with a resolution of 2 cm -1 in the following measuring range: 4000 - 600 cm -1 .
  • NMR 1 H NMR spectra were acquired on a Bruker Advance DRX 400 spectrometer (at 400 MHz) at room temperature in deuterated solvent (d6-DMSO). Information about the chemical shift 5 is given in ppm, relative to the irradiation frequency. The signal of the deuterated solvent is used as internal standard.
  • the (pseudo)polymorph of the second measurement was stable and identified as(pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant.
  • Thermogravimetric analysis shows a mass loss characteristic for solvated/hydrated forms (FIG. 13), and Nuclear Magnetic Resonance (NMR) spectroscopy which has shown no presence of organic solvents in the sample (FIG. 33), hence confirming that the mass loss seen in TGA belongs to water and the pseudo(polymorphic) form is a hydrate.
  • the solid was prepared in a 4 mL PTFE vial.
  • Example 2 ((pseudo)polymorphic form Hydrate 2) was analyzed with XRPD Method A.
  • the reflection peak maxima (2 Theta) are given in the Table below and the pattern is also shown in Table 1 and Figure 1 (a).
  • the product of Example 3 ((pseudo)polymorphic form Hydrate 2) was analyzed with XRPD Method B and showed a similar reflection pattern as shown in Figure 1 (b).
  • Table 1 Reflections of XRPD of the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant isolation.
  • the Pattern is shown in Table 2 and Figure 15 was named Pattern G.
  • Another XRPD analysis was performed using Method A.
  • the pattern of the peak maxima changed as seen in Table 2 below and Figure 11 , and turned out to be (pseudo)polymorphic form Hydrate 3. It turned out that the Hydrate 3 is stable at ambient conditions.
  • Table 2 Reflections of XRPD of the crystalline form Pattern G and of the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant
  • Example 5 The product of Example 5 was first analyzed using XRPD method B directly after isolation. The Pattern is shown in Table 3 below and Figure 10 and was named Pattern D. After storage at room temperature another XRPD analysis was performed using Method A. The pattern of the peak maxima changed as seen in Table 3 and Figure 6 and was named Pattern 4.
  • Example 6 The products of Example 6 (Pattern 5), Example 7 (Pattern 6) and Example 8 (Pattern 8) were analyzed after isolation using XRPD Method A. The results are shown in the Table below and Figure 16 (Pattern 5), Figure 20 (Pattern 6) and Figure 23 (Pattern 8).
  • Table 4 Reflections of XRPD of crystalline forms of Pattern 5, Pattern 6 and Pattern 8 of the benzenesulfonate salt of elinzanetant
  • Thermogravimetric Analyses were conducted for the isolated polymorphs and/or (pseudo)polymorphs to identify mass loss phenomena that would indicate formation of a hydrate or a solvate. The results are shown in Figure 3 (Hydrate 2), Figure 8 (Pattern 4), Figure 13 (Hydrate 3), Figure 18 (Pattern 5), Figure 22 (Pattern 6), Figure 25 (Pattern 8), Figure 45 (Hydrate 6), Figure 50 (Hydrate 7), Figure 54 (Pattern 7).
  • TGA Thermogravimetric Analyses
  • X-Ray Powder Diffraction (XRPD) analysis was conducted for Hydrate 2 form at different relative humidity conditions, to further confirm the non-stoichiometric hydrate assignment.
  • XRPD X-Ray Powder Diffraction
  • the Hydrate 2 form of the benzenesulfonate salt of elinzanetant was produced by dissolving 10 g of elinzanetant in 75 mL of ethyl acetate. The solution was heated to 70 °C within 30 minutes and a solution of 2.6 g of benzenesulfonic acid in 13.8 mL of water was added to that solution during 20 minutes. The resulting mixture was cooled down to 5 °C and the resulting suspension was stirred at 5 °C overnight.
  • the crystallized solid was isolated by filtration, washed with 20 mL ethyl acetate, and dried in vacuum at 45 °C to yield 10.5 g (84.91 %) of solid of the Hydrate 2 form of the benzenesulfonate salt of elinzanetant.
  • the Hydrate 3 form of the benzenesulfonate salt of elinzanetant was produced by dissolving 10 g of elinzanetant in 100 mL of MtBE. The solution was heated to 50 °C within 30 minutes and a solution of 2.6 g of benzenesulfonic acid in 13.8 mL of water was added to that solution during 15 minutes. The resulting mixture was stirred at 50 °C for 60 minutes and subsequently cooled down to 5 °C within 300 minutes.
  • the Hydrate 2 form shows advantageous crystallinity and mechanical stability over the Hydrate 3 form. This can be seen in the Figure 34, where the Hydrate 2 form shows more intensive and sharp reflections compared to Hydrate 3 form. Moreover, after micronizing the Hydrate 2 form and the Hydrate 3 form using a spiral jet-mill, it can be seen that the diffraction pattern of micron ized Hydrate 2 form shows conserved crystallinity (intensity of reflections is the same as before micronization), whereas the diffraction pattern of micronized Hydrate 3 shows a significant reduction of crystallinity (amorphization), typically leading to issues with physical properties, water content, wettability, reproducibility and physical stability (e.g. through slow re-crystallization). Those issues are present for the more stable Hydrate 2 form.
  • Tablets with a dose of 120 mg elinzanetant related to the free base were investigated. Tablets were produced by compressing the respective composition below using either a compression simulator ((StylOne Evolution, Medelpharm) or a conventional rotary die press (Fette 102i, Fette compacting). Oval tablets with a length of 16 mm and a width of 7 mm were produced targeting a resistance to crushing of 150 N.
  • Example 13 Comparative Examples
  • compositions were manufactured as comparative examples.
  • Example 13.1.1 Elinzanetant di-HCI salt sodium dodecyl sulfate composition
  • the blend was wet granulated by adding the elinzanetant di-HCI salt suspension dropwise in the mortar and blending it manually. Wet granules were afterwards dried within an oven for 2 h and the dried granules manually crushed with the pistil. The granules were blended with 0.043 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
  • Example 13.1.2 Elinzanetant benzenesulfonate salt sodium dodecyl sulfate composition
  • the blend was wet granulated by adding the elinzanetant benzenesulfonate suspension dropwise in the mortar and blending it. Wet granules were afterwards dried within an oven for 2 h and the dried granules crushed with the pistil. The granules were blended with 0.043 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
  • Example 13.1.3 Elinzanetant di-HCI salt sodium dodecyl sulfate composition
  • the granules were post-blended with 0.26 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer.
  • the final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
  • the granules were post-blended with 0.26 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer.
  • the final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
  • Example 13.1.5 Elinzanetant benzenesulfonate salt composition without surfactant
  • Example 14 Compositions in accordance with the present disclosure
  • 156.14 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 10.42 g macrogolglycerolricinoleate were blended with a mortar and pestle.
  • 304.94 g microcrystalline cellulose (MCC) and 26.05 g croscarmellose sodium were blended in a free fall mixer for 10 min.
  • Microcrystalline cellulose-croscarmellose sodium blend was split and the first part was mixed for 10 min on a free fall blender with the elinzanetant benzenesulfonate salt/surfactant blend. This pre-blend was manually sieved through an 800 pm sieve and blended again for 10 min.
  • the second part of the microcrystalline cellulose-croscarmellose sodium blend was added and the mixture blended again for 10 min.
  • the blend was manually sieved trough an 800 pm sieve and blended again for further 10 min.
  • One half of the resulting blend was mixed with 2.59 g of sieved magnesium stearate for 5 min in a free fall blender.
  • one half of the blend was mixed with 1.98 g silicon dioxide for 5 min within a turbula mixer and sieved manually through an 800 pm mesh.
  • the sieved material was blended again for 5 min.
  • 0.71 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 2 min within a turbula mixer.
  • the final blend was tableted on a compression simulator (StylOne Evolution, Medelpharm) using 16x7 mm oval punches with a weight of 483.5 mg.
  • elinzanetant benzenesulfonate salt prepared according to Example 3 and 10.48 g macrogolglycerolricinoleate were blended with a mortar and pestle.
  • 306.7 g microcrystalline cellulose and 26.2 g croscarmellose sodium were blended in a free fall mixer for 10 min.
  • Microcrystalline cellulose-croscarmellose blend was split in two parts and one part was mixed for 10 min on a free fall blender with the elinzanetant benzenesulfonate salt/macrogolglycerolricinoleate blend. This pre-blend was manually sieved through an 800 pm sieve and blended again for 10 min.
  • microcrystalline cellulose-croscarmellose sodium blend was added and the mixture blended again for 10 min.
  • the blend was manually sieved trough an 800 pm sieve and blended again for further 10 min.
  • This blend was roller compacted and dry granulated. 0.59 g silicon dioxide and 5.85 g microcrystalline cellulose were mixed for 5 min within a turbula mixer.
  • This blend and 93.12 g of the dry granules were mixed for 5 min on a turbula mixer and sieved manually through a 1 mm sieve.
  • the sieved material was blended again for 5 min.
  • 0.49 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 2 min within a turbula mixer.
  • the final blend was tableted on a compression simulator (StylOne Evolution, Medelpharm) using 16x7 mm oval punches with a weight of 513 mg.
  • the blend was manually sieved trough an 800 pm sieve and blended again for further 10 min. This blend was roller compacted and dry granulated. 5.94 g silicon dioxide and 59.42 g microcrystalline cellulose were mixed for 5 min within a freefall blender and sieved manually through a 1 mm sieve. The sieved blend and the dry granules were mixed for 10 min. 7.62 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 5 min.
  • the ready-to-press blend was tableted on a rotary die press (Fette 102i, Fette Compacting) using 16x7 mm oval punches with a weight of 514 mg. Tablets were coated within a drum coater with a yellow HPMC-based lacquer.
  • the blend was manually sieved trough an 800 pm sieve and blended again for further 10 min.
  • This blend was roller compacted and dry granulated.
  • 13.78 g silicon dioxide and 137.78 g microcrystalline cellulose were mixed for 5 min within a freefall blender and sieved manually through a 1 mm sieve.
  • the sieved blend and 2.19 kg of the dry granules were mixed for 10 min.
  • 23.65 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 5 min.
  • the ready-to-press blend was tableted on a rotary die press (Fette 102i, Fette Compacting) using 16x7 mm oval punches with a weight of 515 mg.
  • a 0.5% hydroxypropylmethylcellulose 15 Centipoise (HPMC 15 cp) aqueous solution was prepared.
  • HPMC 15 cp hydroxypropylmethylcellulose 15 Centipoise
  • elinzanetant salts a suspension with a content based on elinzanetant free base of 12.5 mg/ml were used as well, which resulted in a concentration of a suspension with 15.84 mg/mL for elinzanetant 4- methylbenzenesulfonate (tosylate) salt, 14.99 mg/ml for elinzanetant di-HCI salt isopropanol solvate and 15.72 for elinzanetant benzenesulfonate salt.
  • soft gelatin capsules When referring to soft gelatin capsules herein, the soft gelatin capsules having a gelatin shell and the following composition as a filling are meant.
  • Soft gelatin capsules formulation (fill mass) was as follows: elinzanetant 5.00% w/w; Glycerol Monocaprylocaprate (Capmul MCM) 37.05% w/w; Caprylocaproyl polyoxyl-8 glycerides (Labrasol ALF) 9.50% w/w; Polysorbate 80 (Tween 80) 9.50% w/w; Glyceryl Monooleate (Peceol) 38.00% w/w; and DL-Alpha tocopherol (Vitamin E) 0.95% w/w; with a total amount of 60 mg elinzanetant per capsule.
  • the soft gelatin capsules and manufacture of the same are disclosed in WO 2019/175253 A1 in particular as Example 1 a.
  • WO 2019/175253 A1
  • Fasted State Simulated Intestinal Fluid Double concentrated FaSSIF; herein referred to as FaSSIF
  • Fasted State Simulated Gastric Fluid herein referred to as FaSSGF
  • Dissolution was tested using USP XXIII Paddle Method II in 500 mL vessels at 37 ⁇ 0.5°C. Rotation speed of the paddles was 75 rpm for tablets and suspension, in case of soft gelatin capsules 100 rpm was used to enable a homogenous distribution of the fill mass.
  • FaSSGF Fasted State Simulated Gastric Fluid
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • Example 13.2.1 .1 A simple direct compression composition (Example 13.2.1 .1 , Examplel 3.2.1 .2) for the elinzanetant di-hydrochloride salt as well as for the elinzanetant benzenesulfonate salt showed a disintegration of below 15 min (Table 13 and 14), but the dissolution was slowed down with an incomplete release as compared to the suspension. Micron ization of the salts showed no improvement on the profile and API release was comparable for micro and macro quality of the salts (Data not shown).
  • Table 13 Disintegration and dissolution characteristics of tablets containing the benzenesulfonate salt of elinzanetant
  • Table 14 Disintegration and dissolution characteristics of tablets containing the dihydrochloride salt of elinzanetant
  • Embedment of the salts in hydrophilic carriers e.g. polyethylene glycol, lactose
  • hydrophilic carriers e.g. polyethylene glycol, lactose
  • change of disintegrant Example 13.2.1.3, Example 13.2.1.4 did as well not change the observed release of less than 50% after 210 minutes (FIG. 37A, and 38A or Table13, 14).
  • non-ionic surfactants e.g. macrogol-15-hydroxystearate, polysorbate 20, macrogolglycerolricinoleate
  • examples 14.1.1.1 to Example 14.2.3 resulted in an enhancement of the tablet release profile and led to similar, desirable results as for the suspension ( Figure 38B and Figure 37B).
  • ionic surfactants such as sodium dodecyl sulphate (SDS) (Example 13.2.3.1 , Example 13.2.3.2), showed a drastically lowered and prolonged release profile.
  • SDS sodium dodecyl sulphate
  • a combined single- and multiple-dose, open-label, fixed sequence, crossover study was conducted in healthy female and male participants to investigate the relative bioavailability of elinzanetant using soft gelatin capsules as disclosed herein above and used in phase iii clinical studies with a composition according to the present disclosure.
  • EXAMPLE 17 Dissolution of crystalline hydrate of the benzenesulfonate salt of elinzanetant compared to 4-methyl benzenesulfonate salt of elinzanetant and free base of elinzanetant
  • the crystalline elinzanetant free base was prepared in its anhydrate form in analogy to Example 8 disclosed in WO 2021/094247 A1 with heptane instead of iso-octane as anti-solvent:
  • the dihydrochloride salt mono-isopropanol solvate (WO 2021/094247 A1 ; Example 7) was free based in methyl-terf-butylether (MTBE) using aqueous sodium hydroxide and the layers were separated. The organic layer is washed with aqueous sodium N-acetylcysteine solution, then aqueous sodium bicarbonate solution and then water.
  • MTBE was removed by distillation, n-heptane was added, and part of the solvent was removed by distillation. Isopropanol was added, the solution was heated and the solution then filtered to remove any particulates.
  • the product was crystallized by addition of n- heptane, isolated, washed and dried to give elinzanetant free base. It was either micronized using jet milling (“free base, micronized”) under nitrogen or used as the crystalline free base without micronization (“free base, macro”). The amorphous form of elinzanetant (“free base, amorphous”) was produced by quench-cooling.
  • the quench-cooling was performed by heating the powdered sample of crystalline elinzanetant in an aluminum pan 5°C above its melting point, following an isothermal period of 5 minutes to ensure full liquefication. Afterwards the aluminum pan was transferred on top of an ice block to cool the melt forming a stable glass. Amorphous solid state was confirmed via XRPD Method C.
  • the amorphous form of 4-methylbenzenesulfonate salt of elinzanetant (“Tosylate”) was produced by suspending 200mg of crystalline elinzanetant free base in 2m L water and adding 658 pL of a 1 mol/L p-toluenesulfonic acid solution. The suspension was inoculated with Tosylate (see WO 2010/015626 A1 ) and stirred for 10 days at room temperature. Afterwards it was vacuumed off and washed three times with 0.5mL water each and air dried at room temperature for three days. The resulting batch was characterized via XRPD Method C as amorphous with crystalline amounts.
  • the crystalline form of 4-methylbenzenesulfonate salt of elinzanetant (“Tosylate, crystalline”) was produced by suspending 16.0 g of the anhydrate Form 1 compound of formula (I) (elinzanetant) (see WO 2011/023733 A1 ) in 72 g butyl-acetate, 28 g heptane, 4.62 g p-toluenesulfonic acid, and 16 g H2O at room temperature. The resulting biphasic system was heated up to 70°C. The solution was cooled down to room temperature. The crystals were isolated by filtration. The wet filter cake was dried in vacuum at 60 °C to yield 19.0 g of dry Tosylate, crystalline (94.4% yield).
  • the crystalline hydrate of the benzenesulfonate salt of elinzanetant (“Besylate”) was produced by suspending 280mg of crystalline elinzanetant free base in 2.8mL water and adding 921 pL of a 1 mol/L benzenesulfonic acid solution. The suspension was inoculated with Hydrate 3 and stirred for 5 days at room temperature. Afterwards it was vacuumed off and washed three times with 0.5mL water each and air dried at room temperature for three days. The resulting batch was characterized via XRPD Method C as crystalline (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant.
  • Fasted State Simulated Intestinal Fluid was set at 1 .5 mg in 6 mL FaSSIF respectively.
  • FaSSIF was prepared by weighing 0.42 g NaOH, 4.47 g NaH2PO4* 2 H2O and 6.186 g NaCI in 0.9 L water. The pH was adjusted to 6.50 ⁇ 0.05 with 1 N sodium hydroxide or 1 N hydrochloric acid.
  • the flask was filled up to 1 L with water and 2.24 g SIF powder (Biorelevant Ltd) was added. The dissolution was recorded as the amount dissolved per volume (pg/mL) during a time interval of 0 min to 350 min. During the duration a crossbar stirrer at 100 rpm was used.
  • the comparison in Figure 40 shows a slow dissolution rate for the crystalline free base, which is slightly improved by particle size reduction (micronization) and by use of the tosylate salt, whereby the provision of the crystalline form of the tosylate salt further improves the dissolution.
  • the amorphous free base shows improved dissolution profile as compared to the crystalline free base, but a slower dissolution as compared to crystalline tosylate.
  • the crystalline hydrate of the benzenesulfonate salt of elinzanetant shows a massive improvement with a very fast dissolution rate, clearly outperforming all other forms.
  • EXAMPLE 18 Dissolution of crystalline hydrate of the benzenesulfonate salt of elinzanetant compared to the amorphous form of the benzenesulfonate salt of elinzanetant
  • the crystalline benzenesulfonate salt of elinzanetant was prepared as in Example 17, and was hence the (pseudo)polymorphic form Hydrate 3 (“crystalline”).
  • amorphous Besylate The amorphous benzenesulfonate salt of elinzanetant (“amorphous Besylate”) was produced by suspending 200mg of crystalline elinzanetant free base in 2mL water and adding 658 pL of a 1 mol/L benzenesulfonic acid solution. The suspension was inoculated with a hydrate form of the benzenesulfonate salt of elinzanetant and stirred for one week at room temperature. Afterwards it was vacuumed off and washed three times with 0.5mL water each and air dried at room temperature for two days. The resulting batch was characterized via XRPD Method C as amorphous.
  • High-resolution small-scale powder dissolution profiling was performed with the PION pDiss ProfilerTM as described in Example 17.
  • the dissolution was measured as the amount dissolved per volume (pg/mL) during a time interval of 0 min to 90 min.
  • EXAMPLE 19 Intrinsic dissolution rate (IDR) comparison of crystalline and amorphous benzenesulfonate salt of elinzanetant and amorphous elinzanetant
  • Crystalline hydrate of the benzenesulfonate salt of elinzanetant (“besylate crystalline”) was prepared as disclosed in Example 3 using butyl acetate instead of ethyl acetate.
  • XRPD confirmed crystalline (pseudo)polymorphic form Hydrate 2.
  • the amorphous form of the free base (“free base amorphous”) was prepared by rotary evaporation ( 50°C, ⁇ 20mbar) of a solution of 5g of crystalline free base in 30g acetone. XRPD confirmed the amorphous solid state.
  • Besylate amorphous The amorphous form of the benzenesulfonate salt of elinzanetant (“besylate amorphous”) was prepared by rotary evaporation ( 50°C, ⁇ 20mbar) of a solution of 5g of crystalline Besylate hydrate 2 in 50g acetone. XRPD confirmed the amorphous solid state.
  • Crystalline tosylate of elinzanetant (“Tosylate, crystalline”) was prepared as disclosed in Example 17.
  • the IDR profiling was performed with the PION pDiss ProfilerTM, equipped with the intrinsic dissolution rate kit from the same manufacturer.
  • the kit uses hollow metal cylinders and a manual tablet press to produce tablets with a surface of 0.0707cm 2 .
  • the tablets were manufactured with 5mg of crystalline or amorphous benzenesulfonate salt of elinzanetant, or amorphous elinzanetant free base pressed under 100psi.
  • the intrinsic dissolution rate levels off the factor of particle size and allows a comparison based on the intrinsic properties of the samples.
  • the results further confirm the surprising results obtained from Example 17 and 18 and show the greatly enhanced dissolution rate as an intrinsic feature of the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant as compared to the free base and the crystalline tosylate salt of elinzanetant.
  • the dissolution is surprisingly further enhanced in the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant as compared to the amorphous form of the salt.
  • Example 20 Preparation of (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant
  • Table 18 Infrared Spectra Bands of crystalline (pseudo)polymorphic form Hydrate 6 Thermogravimetric analysis is shown in Figure 45 and the Differential Scanning Calorimetry analysis in Figure 46. They showed: 2.4% mass loss, 1.2% residual moisture and 1.2% loss during melting (onset 142°C and peak at 158°C).
  • Hydrate 6 of the benzenesulfonate salt of elinzanetant exhibits good stability after sorption and desorption. Solubility in water was tested to compare Hydrate 2 form, Hydrate 3 form, and Hydrate 6 form. Solubilities were recorded by suspending 25 mg of the respective drug substance in 2 ml water in glass vials with magnetic stirrer bars. The suspensions were stirred at 25 °C ⁇ 2 °C for 24 h ⁇ 4 h prior to filtration and analysis via HPLC-UV.
  • Example 21 Preparation of (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant A further crystalline (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant was obtained as follows.
  • Table 20 Reflections of XRPD of crystalline form of the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant
  • Table 21 Infrared Spectra Bands of crystalline (pseudo)polymorphic form Hydrate 7
  • Thermogravimetric analysis is shown in Figure 50 showing a 2.5% mass loss and the Differential Scanning Calorimetry analysis is seen in Figure 51 . Furthermore, a DVS test was conducted with the (pseudo)polymorphic form Hydrate 6 in accordance with Example 11 . The results are shown in Table 22 and Figure 52.
  • %RH re ative ambient humidity
  • % d.b. dry base
  • Thermogravimetric analysis is shown in Figure 54 showing a mass loss of 2.4% and the Differential Scanning Calorimetry analysis in Figure 55.
  • the present disclosure relates to the following items.
  • a crystalline hydrate of the benzenesulfonate salt of elinzanetant preferably a variable occupancy hydrate.
  • a Method for preparing the crystalline hydrate according to any one of item 1 to 6 comprising: i) providing elinzanetant, preferably in a solvent; ii) adding benzenesulfonic acid; and iii) isolating the crystalline form of the benzenesulfonate salt of elinzanetant.
  • a pharmaceutical composition comprising a crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of items 1 to 6 and optionally one or more further pharmaceutically acceptable excipients.
  • a solid pharmaceutical composition comprising a crystalline salt of elinzanetant and a non-ionic surfactant.
  • nonionic surfactant is selected from the group consisting of macrogolglycerolricinoleate (Kolliphor EL), Tween 20, macrogol-15- hydroxystearate (Kolliphor HS 15), Polyoxyethylensorbitan-fatty acid esters (e.g. Polyoxyethylen (20) sorbitanmonolaurate, Polyoxyethylen (4) sorbitanmonolaurate, Polyoxyethylen(20)sorbitanmonostearate,
  • nonionic surfactant is selected from the group consisting of macrogolglycerolricinoleate (Kolliphor EL), Tween 20, macrogol-15- hydroxystearate (Kolliphor HS 15), Polyoxyethylensorbitan-fatty acid esters (e.g. Polyoxyethylen (20) sorbitanmonolaurate, Polyoxyethylen (4) sorbitanmonolaurate, Polyoxyethylen(20)sorbit
  • Polyoxyethylen(20)sorbitanmonooleate glycol fatty acid esters, fatty alcohols (Cetyl-alcohol, stearyl alcohol), polyoxyethylen fatty acid esters (e.g. polyoxyethylenstearate, polyoxyethylen-400-monostearate,
  • Polyoxyethylenrizinoleat polyoxythelen fatty alcohol ethers (e.g. Polyoxyethylnelaurylether, and Polyocyethylensteralether), saccharose fatty acid esters (e.g. saccharosedistearate, saccharosemonopalmitate).
  • polyoxythelen fatty alcohol ethers e.g. Polyoxyethylnelaurylether, and Polyocyethylensteralether
  • saccharose fatty acid esters e.g. saccharosedistearate, saccharosemonopalmitate.
  • FaSSGF Fasted State Simulated Gastric Fluid
  • the solid pharmaceutical composition according to any one of items 12 to 15, wherein the in vitro dissolution of elinzanetant is that at least 60% is dissolved within 35 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37° and 75 rpm as stirring rate for 30 min and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37° and 75 rpm as stirring rate.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • the solid pharmaceutical composition according to any one of items 12 to 17 obtainable by blending the salt of elinzanetant or a hydrate or solvate thereof with a non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients to obtain a blend.
  • 5% w/w to 50% w/w of the crystalline salt of elinzanetant such as from 10% w/w to 40% w/w; or from 20 % w/w to 35% w/w;
  • non-ionic surfactant 0.5% w/w to 10% w/w of the non-ionic surfactant, preferably about 1 % w/w to 7% w/w.
  • solid pharmaceutical composition according to any one of items 12 to 22, wherein the solid pharmaceutical composition further comprises one or more pharmaceutical acceptable binder.
  • the one or more pharmaceutical acceptable binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol,
  • the solid pharmaceutical composition according to item 26 wherein the one or more disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof.
  • the solid pharmaceutical composition according to any one of items 12 to 31 and 22 to 31 , wherein the solid pharmaceutical composition form comprises:
  • a non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogol- glycerolhydroxystearate, polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 80 (Tween 80), and macrogol-15- hydroxystearate; or mixtures thereof;
  • a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone, hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof;
  • a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
  • a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof; and
  • a method of treating or preventing of a sex hormone-dependent disease comprising administering to a subject in need thereof a therapeutically effective amount of crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of items 1 to 6, or a pharmaceutical composition of item 11 , or a sold pharmaceutical composition according to any one of items 12 to 32.
  • a method for preparing the solid pharmaceutical composition according to any one of items 12 to 33 comprising the steps of:
  • step (ii) optionally subsequently adding and blending one or more further excipients to the blend.
  • the method according to item 37 wherein after step (ii) the blend is subjected to dry granulation.
  • the method according to item 38 wherein the pharmaceutical composition is subjected to compression after granulation.
  • the method according to item 37 wherein after step (ii) the blend is subjected to direct compression.
  • the method according to item 37 wherein all excipients of the pharmaceutical composition are blended with the crystalline salt of elinzanetant or hydrate or solvate thereof and the at least one non-ionic surfactant in step (i).
  • the method according to item 41 wherein the blend is subjected to dry granulation.

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Abstract

The present disclosure relates to crystalline forms of 2-[3,5- bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7- (hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]pyridin-3-yl}-N,2- dimethylpropanamide benzenesulfonate, such as to (pseudo)polymorphic hydrate forms, to the processes for their preparation. Further, the disclosure relates to pharmaceutical compositions comprising salts of elinzanetant, such as those comprising a non-ionic surfactant. Moreover, the disclosure relates to said crystalline forms and the pharmaceutical compositions for use in the treatment of diseases and disorders.

Description

Crystalline Forms of Salts of Elinzanetant and Compositions containing Salts of Elinzanetant
The present invention relates to crystalline forms of 2-[3,5-bis(trifluoromethyl)phenyl]- N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1 - c][1 ,4]oxazin-8(1 H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide benzenesulfonate, such as to (pseudo)polymorphic hydrate forms, to the processes for their preparation. Further, the invention relates to pharmaceutical compositions comprising salts of elinzanetant, such as those comprising a non-ionic surfactant. Moreover, the invention relates to said crystalline forms and the pharmaceutical compositions for use in the treatment of diseases and disorders.
Background of the Invention
The compound 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6- [(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2, 1 -c][ 1 ,4]oxazin-8(1 H)-yl]pyrid in-3-y I}- N,2-dimethylpropanamide (herein also referred to by its INN: elinzanetant) is being developed for treatment of different diseases and conditions (WO 2007/028654 A1 ), including sex-hormone dependent diseases and disorders (WO 2016/184829 A1 ).
Different approaches have been carried out in order to obtain forms and compositions suitable for administration of elinzanetant in the desired dosage.
Elinzanetant or its salts were initially amorphous and hygroscopic, respectively, as described in WO 2007/028654 A1 and WO 2011/023733 A1 , not allowing for the provision of stable, solid pharmaceutical compositions. To obtain a crystalline form of elinzanetant, the 4-methylbenzenesulfonate salt (tosylate) was initially developed (WO 2010/015626). During early clinical studies the elinzanetant tosylate salt of elinzanetant was used, but only offering an acceptable PK profile when administered as a suspension.
Further, the crystalline anhydrate Form 1 of elinzanetant free base was developed (WO 2011/023733 A1 ; herein also referred to as Modification 1 or Mod. 1 ). However, elinzanetant offers a poor aqueous solubility and solid formulations comprising anhydrate Form 1 of elinzanetant free base showed within clinical studies an undesired PK profile e.g., high variability for tablets and hard gelatin capsules. To mitigate its slow dissolution and the high variability of the PK profile, a liquid formulation in a soft gelatin capsule was provided (WO 2019/175253 A1 ). These soft gelatin capsules are used in clinical development and for the launch of the commercial drug product. The disadvantage of the described capsules of prior art is the fact, that due to the limited drug load, the size of the capsules is large (Size-20) and for a desired daily dose of 120 mg, two soft gelatin capsules each containing 60 mg must be taken. As this is of low convenience to the patients who take the drug, a potential cause for the non-compliance of the patients to the treatment is created.
Hence, there is a need for providing a form of elinzanetant in a stable crystalline form that provides superior dissolution characteristics and allows for provision of dosage forms with higher drug load, such as solid pharmaceutical compositions, e.g. tablets. Further, there is a need for the provision of solid pharmaceutical compositions comprising elinzanetant having the desired stability, dissolution and PK behavior.
Solid pharmaceutical compositions, such as tablets, are preferred because tablets are more stable and usually have a longer shelf life than capsules. Unlike capsules, tablets can be cut in two for a smaller dose if required. Tablets are also cheaper compared to capsules. Hence, it was a further objective of the present invention to provide for a solid pharmaceutical composition, such as a tablet, that allows the administration of the daily dose of e.g. 120 mg in a single dosage unit, e.g. a tablet. Furthermore, the problem of providing such solid pharmaceutical composition having an acceptable bioavailability exists and is solved by the present invention.
Brief Description of the Invention
The inventors now have surprisingly found that the benzenesulfonate salt of elinzanetant in form of a hydrate provides crystalline forms that show high thermal stability and a dried state without amorphization and high stability under sorption and desorption of water. Further, it has been surprisingly found that crystalline hydrate forms of the benzenesulfonate salt of elinzanetant show an enhanced dissolution rate as compared to the free base in crystalline or amorphous form, the tosylate salt and even as compared to the amorphous form of the benzenesulfonate salt of elinzanetant.
The present invention is based on the unexpected discovery of the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant, which include (pseudo)polymorphic form Hydrate 1 , (pseudo)polymorphic form Hydrate 2 and (pseudo)polymorphic form Hydrate 3. Further, in a subsequent study, additional crystalline hydrate forms, namely Hydrates 6 and 7, have been identified also being crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the invention.
The crystalline hydrate forms of the benzenesulfonate salt of elinzanetant surprisingly provide an enhanced dissolution behavior even over the known tosylate salt or amorphous forms of the free base or benzenesulfonate salt. Hence, the present invention in one embodiment relates to crystalline hydrate forms of the benzenesulfonate salt of elinzanetant. In one embodiment, the invention relates to the (pseudo)polymorphic form Hydrate 2, the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant, the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant, or the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant.
It further turned out that the Hydrate 2 form of the benzenesulfonate salt of elinzanetant surprisingly showed the best combination of stability (e.g. with respect to maintaining the (pseudo)polymorphic form, even under differing ambient conditions) and dissolution behaviour. The (pseudo)polymorphic form Hydrate 2 exhibited particularly surprising favourable properties, such as a favourable combination of thermal and moisture stability, and enhanced dissolution behaviour. Hence, in an embodiment the invention relates to the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant.
Further, the polymorphic forms/(pseudo)polymorphic forms showing Pattern G, Pattern D, Pattern 4, Pattern 5, Pattern 6, Pattern 7 and Pattern 8 as shown in the examples have been identified. In addition, the amorphous form exists.
In this context with the present invention crystalline modifications, polymorphic forms and polymorphs have the same meaning. (Pseudo)polymorphic forms and (pseudo)polymorphs are likewise synonyms and relate to polymorphic forms that contain water molecules (hydrates) or solvents (solvates) within its crystalline structure. All together - the polymorphic forms, the (pseudo)polymorphic forms and the amorphous form - are different solid forms of the salts, in particular the benzenesulfonate salt, of the compound of formula (I). The invention in one embodiment further relates to a method for preparing the crystalline hydrate according to the disclosure comprising: (i) providing the compound of formula (I), preferably in a solvent; (ii) adding benzenesulfonic acid; and (iii) isolating the crystalline form of the benzenesulfonate salt of elinzanetant.
Furthermore, the inventors have surprisingly found that formulating a salt of elinzanetant with a non-ionic surfactant allows for the provision of solid pharmaceutical composition with a high drug load and sufficient dissolution profile and bioavailability to obtain a single dosage unit for the provision of a high daily dose, e.g. a dose of e.g. 120 mg. The solid pharmaceutical compositions comprising elinzanetant and non-ionic surfactants according to the disclosure showed a surprisingly superior release profile as compared to the low and prolonged release profile observed with ionic surfactants such as sodium dodecyl sulphate (SDS).
Hence, the invention in one embodiment relates to a solid pharmaceutical composition comprising a crystalline salt of elinzanetant and a non-ionic surfactant.
Further details and embodiments of the invention are defined by the disclosure herein. When referring to “disclosure” the definition of further aspects and embodiments of the invention is meant.
Figure Legend:
The skilled artisan will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings or claims in any way.
FIG. 1 A shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2 measured with XRPD method A.
FIG. 1 B shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured with XRPD method B.
FIG. 2 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2 with DSC method A. FIG. 3 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate
2 corresponding to Example 2 with TGA method A.
FIG. 4 shows an Infrared Spectroscopy analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2 with IR method A.
FIG. 5A shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 2 prepared according to Example 2 with DVS method A.
FIG. 5B shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 3 prepared according to Example 4 with DVS method A.
FIG. 6 shows an X-Ray Powder Diffraction analysis of Pattern 4 corresponding to Example 5 measured with XRPD method A.
FIG . 7 shows a Differential Scanning Calorimetry analysis of Pattern 4 corresponding to Example 5 with DSC method A.
FIG. 8 shows a Thermogravimetric analysis of Pattern 4 corresponding to Example 5 with TGA method A.
FIG. 9 shows an Infrared Spectroscopy of Pattern 4 corresponding to Example 5 with IR method A.
FIG. 10 shows an X-Ray Powder Diffraction analysis of Pattern D corresponding to Example 5 measured with XRPD method B.
FIG. 11 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4 measured with XRPD method A.
FIG. 12 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4 with DSC method A.
FIG. 13 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate
3 corresponding to Example 4 with TGA method A.
FIG. 14 shows an Infrared Spectroscopy analysis of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4 with IR method A. FIG. 15 shows an X-Ray Powder Diffraction analysis of Pattern G corresponding to Example 4 measured with XRPD method B.
FIG. 16 shows an X-Ray Powder Diffraction analysis of Pattern 5 corresponding to Example 6 measured with XRPD method A.
FIG. 17 shows a Differential Scanning Calorimetry analysis of Pattern 5 corresponding to Example 6 with DSC method A.
FIG. 18 shows a Thermogravimetric analysis of Pattern 5 corresponding to Example 6 with TGA method A.
FIG. 19 shows an Infrared Spectroscopy of Pattern 5 corresponding to Example 6 with IR method A.
FIG. 20 shows an X-Ray Powder Diffraction analysis of Pattern 6 corresponding to Example 7 measured with XRPD method A.
FIG. 21 shows a Differential Scanning Calorimetry analysis of Pattern 6 corresponding to Example 7 with DSC method A.
FIG. 22 shows a Thermogravimetric analysis of Pattern 6 corresponding to Example 8 with TGA method A.
FIG. 23 shows an X-Ray Powder Diffraction analysis of Pattern 8 corresponding to Example 8 measured with XRPD method A.
FIG. 24 shows a Differential Scanning Calorimetry analysis of Pattern 8 corresponding to Example 8 with DSC method A.
FIG. 25 shows a Thermogravimetric analysis of Pattern 8 corresponding to Example 8 with TGA method A.
FIG. 26 shows an X-Ray Powder Diffraction analysis of the amorphous form of the benzenesulfonate salt of elinzanetant corresponding to Example 9 measured with XRPD method A.
FIG. 27 shows a Differential Scanning Calorimetry analysis of the amorphous form corresponding to Example 9 with DSC method A FIG. 28 shows a Thermogravimetric analysis of the amorphous form corresponding to Example 9 with TGA method A.
FIG. 29 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured at 20% relative humidity and 25 °C with XRPD method C.
FIG. 30 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured at 50% relative humidity and 25 °C with XRPD method C.
FIG. 31 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 3 measured at 80% relative humidity and 25 °C with XRPD method C.
FIG. 32 shows a 1H-NMR-spectrum in d-DMSO of the (pseudo)polymorphic form Hydrate 2 corresponding to Example 2.
FIG. 33 shows a 1H-NMR-spectrum in d-DMSO of the (pseudo)polymorphic form Hydrate 3 corresponding to Example 4.
FIG. 34 shows the comparison of XRPD measurements, from top to bottom: (pseudo)polymorphic form Hydrate 2 before micronization, (pseudo)polymorphic form Hydrate 2 after micronization, (pseudo)polymorphic form Hydrate 3 before micronization, (pseudo)polymorphic form Hydrate 3 after micronization with XRPD method B (note that one characteristic reflection for Hydrate 3 (2.7) is not represented, because measurement started at an angle of 3°).
FIG. 35 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form solvate form of the isopropanol solvate of the di-hydrochloride salt of elinzanetant measured with XRPD method B.
FIG. 36 shows the dissolution profile of elinzanetant salt and free base HPMC suspensions in 2 -stage biorelevant dissolution test with gastric condition of pH 2.4
FIG. 37A shows the release profile of direct compressed and wet granulated comparative elinzanetant benzenesulfonate salt tablets [Example numbers indicated in the FIG.] at 2 stage biorelevant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
FIG: 37B shows the release profile of elinzanetant benzenesulfonate salt tablets according to the present disclosure [Example numbers indicated in the FIG.] in comparison to suspension at 2 stage biorelevant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
FIG. 38A shows the release profile of direct compressed and wet granulated comparative elinzanetant di-HCI salt isopropanol solvate tablets [Example numbers indicated in the FIG.] at 2 stage biorelavant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
FIG. 38B shows the release profile of elinzanetant di-HCI salt isopropanol solvate tablets according to the present disclosure [Example numbers indicated in the FIG.] in comparison to suspension at 2 stage biorelevant dissolution test with gastric condition of pH 2.4, (vertical dotted line: timepoint of re-buffering).
FIG. 39 shows the geometric mean and standard deviation (SD) concentration-time profiles of elinzanetant for Reference (circles) and Tablets (triangles) (N=24).
FIG. 40 shows the dissolution profiling of different solid forms of Example 17.
FIG. 41 shows the dissolution profiling comparison the benzenesulfonate salt of elinzanetant in crystalline form (“Besylate”) and amorphous form (“Besylate, amorphous”).
FIG. 42 shows the IDR profile of Example 19 comparing Besylate in crystalline and amorphous form, the amorphous Free Base, and crystalline Tosylate.
FIG. 43 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 6 corresponding to Example 20 measured with XRPD method D.
FIG. 44 shows an Infrared Spectroscopy of the (pseudo)polymorphic form Hydrate 6 corresponding to Example 20 with IR method B.
FIG. 45 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate
6 corresponding to Example 20 with TGA method B FIG. 46 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 6 corresponding to Example 20 with DSC method B.
FIG. 47 shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 6 prepared according to Example 20 with DVS method B.
FIG. 48 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 measured with XRPD method B.
FIG. 49 shows an Infrared Spectroscopy of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 with IR method B.
FIG. 50 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 with TGA method B.
FIG. 51 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Hydrate 7 corresponding to Example 21 with DSC method B.
FIG. 52 shows a Dynamic Vapour Sorption analysis of the (pseudo)polymorphic form Hydrate 7 prepared according to Example 21 with DVS method B.
FIG. 53 shows an X-Ray Powder Diffraction analysis of the (pseudo)polymorphic form Pattern 7 corresponding to Example 22 measured with XRPD method B.
FIG. 54 shows a Thermogravimetric analysis of the (pseudo)polymorphic form Pattern 7 corresponding to Example 22 with TGA method B.
FIG. 55 shows a Differential Scanning Calorimetry analysis of the (pseudo)polymorphic form Pattern 7 corresponding to Example 22 with DSC method B.
Detailed Description of the Invention
All numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about."
“About” in a preferred embodiment refers to the quantities, percentages or proportions, and other numerical values ±5%. The present disclosure relates to crystalline hydrate forms of the benzenesulfonate salt of elinzanetant.
The term “elinzanetant” is the INN of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2- methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2, 1 -c][ 1 ,4]oxazin-
8(1 H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide and in an embodiment refers to the same. In one embodiment “elinzanetant” refers to the compound of formula (I):
The terms “2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)- 7-(hydroxymethyl)hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-y l]pyridin-3-y l}-N , 2- dimethylpropanamide”, or “elinzanetant” are used interchangeably herein. In an embodiment these terms refer to the compound of formula (I).
The disclosure in an embodiment relates to crystalline hydrate forms of the benzenesulfonate salt of the compound of the formula (I).
In context with the present disclosure the terms “benzenesulfonate salt of the compound of the formula (I)”, “2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6- [(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-y l]pyridin-3-yl}- N,2-dimethylpropanamide benzenesulfonate”, “benzenesulfonate salt of 2-[3,5- bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-
(hydroxymethyl)hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-y l]pyridin-3-yl}-N ,2- dimethylpropanamide”, “benzenesulfonate salt of elinzanetant”, “benzenesulfonate of elinzanetant”, “elinzanetant benzenesulfonate salt”, “besylate of elinzanetant”, “besylate salt of elinzanetant”, “elinzanetant besylate”, and “elinzanetant besylate salt” are used synonymously and interchangeable. Preferably, these terms refer to a salt of formula (II):
The salt of formula (II) in some embodiments includes the salts of formulas (Ila), (lib), or (lie) or mixtures thereof:
In an embodiment, the salt of formula (II) refers to the salt of formula (Ila).
The terms “hydrate form of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2- methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2, 1 -c][1 ,4]oxazin-
8(1 H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide benzenesulfonate”, or “hydrate form of 2- [3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7- (hydroxymethyl)hexahydropyrazino[2, 1 -c][1 ,4]oxazin-8(1 H)-y l]pyridin-3-yl}-N ,2- dimethylpropanamide benzenesulfonate salt”, or “hydrate form of the benzenesulfonate of the compound of formula (I)”, or “hydrate form of the benzenesulfonate salt of the compound of formula (I)” or “hydrate form of the benzenesulfonate salt of elinzanetant”, “hydrate form of elinzanetant benzenesulfonate salt”, or “hydrate form of the benzenesulfonate of elinzanetant” are synonyms and interchangeably used herein. In an embodiment, the terms refer to a salt hydrate of formula (III):
(III). More preferably, these terms refer to a salt hydrate of formula (Illa):
When referring to a specific crystalline hydrate form of the benzenesulfonate salt of the compound of the formula (I), it is referred to herein interchangeably as “Hydrate X”, “Hydrate X form”, “(pseudo)polymorphic Hydrate X form”, or “(pseudo)polymorphic form Hydrate X”, wherein “X” denotes the identification number of the form.
The hydrate forms of the benzenesulfonate salt of elinzanetant are in one embodiment variable occupancy hydrate forms (also referred to as variable occupancy hydrates). That is, as will be readily understood by those skilled in the art, the amount of H2O molecules per elinzanetant and benzenesulfonic acid molecule in the crystalline structure of the hydrate form of the benzenesulfonate salt of elinzanetant may vary depending on the humidity of the environment, i.e. the relative humidity. It has surprisingly been shown in the examples that the hydrate forms of the benzenesulfonate of elinzanetant according to the disclosure are stable during repeated sorption and desorption while increasing and/or decreasing the amount of H2O molecules within the crystal structure, which is, as shown e.g. with XRPD, not associated with a significant change in the crystal lattice, except for possibly anisotropic expansion of the network to accommodate water (Doris E. Braun, et al., Navigating the Waters of Unconventional Crystalline Hydrates Molecular Pharmaceutics 2015 12 (8), 3069-3088 DOI: 10.1021 /acs.molpharmaceut.5b00357). The crystal form is hence stable as long as water molecules are within the crystal.
Accordingly, n may have any value > 0 at a relative ambient humidity of over 0%. Preferably, n has a value between 0 and 2.5, more preferably 0.3 < n < 2.4. Preferably, n has a value of 0.3 to 2.4 at a relative environmental humidity between 10% and 98%; preferably at a temperature of about 20°C to 25°C. Of all identified crystalline forms, the (pseudo)polymorphic form Hydrate 2 showed the best combination of thermal as well as sorption and mechanical stability and a dried state without amorphization and providing increased solubility and dissolution behavior. Surprisingly, the (pseudo)polymorphic form Hydrate 2 showed beneficial properties over the other solid forms of the benzenesulfonate salt of elinzanetant with regard to thermal stability as well as physical and crystalline stability during sorption and desorption of water. Furthermore, it has been surprisingly found, that the (pseudo)polymorphic form Hydrate 2 shows extraordinary stability under mechanical stress, e.g. applied by a pistil and mortar or during micronization, such as micronization using spiral jet mill technology, without changing its crystalline form or transition to the amorphous form. This unexpected property facilitates and allows the processing of elinzanetant to produce solid pharmaceutical compositions, such as tablets.
Accordingly, in an embodiment of the present disclosure the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) (also referred to herein interchangeably as “Hydrate 2”, “Hydrate 2 form”, “(pseudo)polymorphic Hydrate 2 form”, or “(pseudo)polymorphic form Hydrate 2”). Dynamic Vapour Sorption plot of the Hydrate 2 (Figure 5a) was characteristic for a variable occupancy hydrate (also referred to as non-stoichiometric hydrate; cp. Jean-Rene Authelin, Thermodynamics of non-stoichiometric pharmaceutical hydrates, International 1-2 Journal of Pharmaceutics, Volume 303, Issues, 2005, Pages 37-53, https://doi.Org/10.1016/j.ijpharm.2005.07.007). The nature of this pseudo(polymorphic) form was additionally verified using a thermogravimetric analysis (TGA), which shows a mass loss characteristic for solvated/hydrated forms, and Nuclear Magnetic Resonance (NMR) spectroscopy which has shown no presence of organic solvents in the sample, hence confirming that the mass loss seen in TGA belongs to water and the pseudo(polymorphic) form is a hydrate. Accordingly, the Hydrate 2 form in an embodiment of the present disclosure is a variable occupancy hydrate.
The terms “variable occupancy hydrate” and “non-stochiometric hydrate” are used interchangeably herein. They refer to hydrates with different amounts of H2O molecules within their crystal structure depending on relative ambient humidity and/or temperature, while maintaining their crystal structure as measured by e.g. characteristic XRPD reflections; see also Jean-Rene Authelin, Thermodynamics of non-stoichiometric pharmaceutical hydrates, International 1-2 Journal of Pharmaceutics, Volume 303, Issues, 2005, Pages 37-53, https://doi.Org/10.1016/j.ijpharm.2005.07.007.
Accordingly, the (pseudo)polymorphic form Hydrate 2 preferably refers to the hydrate salt of formula (III) or (Illa), wherein n may have any value > 0. In an embodiment, n has a value between 0 and 2.1 , more preferably 0 < n < 2.0. In an embodiment, n has a value of between 0.3 to 2.0 at a relative environmental humidity between 10% and 98%; preferably at a temperature of about 20°C to 25°C. In an embodiment, n has a value of between 0.3 to 1.4 at a relative environmental humidity between 10% and 90%; preferably at a temperature of about 20°C to 25°C.
In an embodiment, for the Hydrate 2 form according to the disclosure n has a value of between 0.2 to 0.4 at 10% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 0.3 at 10% relative humidity at a temperature of about 25°C.
In an embodiment, for the Hydrate 2 form according to the disclosure n has a value of between 0.3 to 0.5 at 20% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 0.4 at 20% relative humidity at a temperature of about 25°C.
In an embodiment, for the Hydrate 2 form according to the disclosure n has a value of between 0.5 to 0.7 at 50% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 0.6 at 50% relative humidity at a temperature of about 25°C.
In an embodiment, for the Hydrate 2 form according to the disclosure n has a value of between 1.0 to 1.2 at 80% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 1 .1 at 80% relative humidity at a temperature of about 25°C.
In an embodiment, for the Hydrate 2 form according to the disclosure n has a value of between 1.3 to 1.5 at 90% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 1 .4 at 90% relative humidity at a temperature of about 25°C.
In an embodiment, for the Hydrate 2 form according to the disclosure n has a value of between 1.9 to 2.0 at 98% relative humidity at a temperature of about 20°C to 25°C, more preferably n is 2.0 at 98% relative humidity at a temperature of about 25°C. As will be readily understood by the skilled person, the n-values given above might slightly vary, e.g., depending on the sorption/desorption cycle (cp. Example 11 , infra). Accordingly, these values are to be understood as “about” values.
(Pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) is therefore suitable and in an embodiment preferred over the other solid forms of the benzenesulfonate salt of the compound of the formula (I) for use in the pharmaceutical field, in particular suitable for pharmaceutical compositions, such as the solid pharmaceutical compositions according to the disclosure.
In particular, (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) ensures that an undesired conversion into another form of the benzenesulfonate salt of the compound of the formula (I), even under continuous changes in humidity under ambient conditions, and an associated change in the properties as described above is prevented. In particular it has been observed that (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant is stable at relative humidity of between 10% and 75% at room temperature or increased temperatures of up to 40°C for up to 6 months or even longer. This increases the safety and quality of preparations and compositions comprising the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I).
According to a further embodiment of the present disclosure the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphic form Hydrate 3 (also referred to herein as Hydrate 3).
According to a further embodiment of the present disclosure the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphicform Hydrate 1 (also referred to herein as Hydrate 1 ).
According to a further embodiment of the present disclosure the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphicform Hydrate 6 (also referred to herein as Hydrate 6).
According to a further embodiment of the present disclosure the crystalline form of the benzenesulfonate salt of the compound of the formula (I) is the (pseudo)polymorphicform Hydrate 7 (also referred to herein as Hydrate 7). Also herein identified herein are the polymorphic forms showing Pattern D, Pattern G, Pattern 4, Pattern 5 (heterosolvate), Pattern 6, Pattern 7 and Pattern 8 of the benzenesulfonate salt of elinzanetant as shown in the Examples.
Also identified is the amorphous form of the benzenesulfonate salt of elinzanetant.
An embodiment of the present disclosure is substantially pure (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I).
The terms “pure” or “purity” shall encompass and refer to all types of purity like e.g. chemical purity, optical purity and purity with regard to the presence of other solid forms of the same compound.
The term “impurity” or “impurities” shall mean and refer to chemical purity i.e. is used with the meaning “other chemical compounds” present in isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I).
The term “substantially pure (pseudo)polymorphic form Hydrate 2” shall mean that the sum of the mole or mass percent of impurities, optical isomers and other solid forms in the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) is less than about 5 mole or mass percent, preferably less than about 2 mole or mass percent, more preferably, less than about 1 mole or mass percent, most preferably, less than about 0.1 mole or mass percent.
In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 1 mass percent of impurities.
In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 1 mole or mass percent of optical isomers.
In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 2 mole or mass percent of other solid forms. In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0,1 mass percent of impurities.
In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0,1 mole or mass percent of optical isomers.
In an embodiment, the isolated (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 1 mole or mass percent of other solid forms.
In an embodiment of the present disclosure, the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) is substantially free of other solid forms of the benzenesulfonate salt of the compound of the formula (I).
Another embodiment of the present disclosure is substantially pure (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I).
The term “substantially pure (pseudo)polymorphic form Hydrate 3” shall mean that the sum of the mole or mass percent of impurities, optical isomers and other solid forms in the isolated (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I) is less than about 5 mole or mass percent, preferably less than about 2 mole or mass percent, more preferably, less than about 1 mole or mass percent, most preferably, less than about 0.1 mole or mass percent.
Another embodiment of the present disclosure is (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I) which is substantially free of other solid forms of the benzenesulfonate salt of the compound of the formula (I).
Other solid forms of the benzenesulfonate salt of elinzanetant or of elinzanetant identified herein are the amorphous forms, other polymorphic forms or (pseudo)polymorphic forms of the compound of formula (I), e.g. the anhydrate crystalline form as disclosed in WO 2011/023733 A1. The term “substantially free of other amorphous, polymorphic or (pseudo)polymorphic form(s)” when used to describe (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant shall mean that the sum of mole or mass percent of other amorphous, polymorph or (pseudo)polymorphic forms of the isolated compound of the formula I and/or the benzenesulfonate salt of elinzanetant is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent.
In an embodiment, the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 5 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
In an embodiment, the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 2 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
In an embodiment, the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0.5 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
In an embodiment, the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of the compound of the formula (I) contains less than 0.1 mole percent of other amorphous, polymorphic or (pseudo)polymorphic form(s).
In an embodiment, the (pseudo)polymorphicform Hydrate 2 of the benzenesulfonate salt of elinzanetant is substantially free of amorphous, polymorphic or other (pseudo)polymorphic form(s).
The term “substantially free of other amorphous, polymorphic or (pseudo)polymorphic form(s)” when used to describe (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of the compound of the formula (I) shall mean that the sum of mole or mass percent of other amorphous, polymorph or (pseudo)polymorphic forms of the isolated compound of the formula (I) and/or the benzenesulfonate salt of elinzanetant is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment, the (pseudo)polymorphicform Hydrate 3 of the benzenesulfonate salt of elinzanetant is substantially free of amorphous, polymorphic or other (pseudo)polymorphic form(s).
In an embodiment of the present disclosure, (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant contains no impurities, optical isomers and other solid forms can be detected with the methods described.
Another embodiment of the present disclosure is (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant in which no impurities, optical isomers and other solid forms can be detected with the methods described.
The limits of the contents of impurities, optical isomers and other solid forms need to be construed in view of the usual standard deviations at least of the method disclosed in the present application and used in the experimental section for determination in that concentration range. If no specific method is disclosed and used in the present application, the limits of the contents of impurities, optical isomers and other solid forms need to be construed in view of the expected variation of the results obtained by different methods known in the literature.
The different forms of the benzenesulfonate salt of elinzanetant were distinguished by X- ray powder diffraction (XRPD), Infrared Spectroscopy (IR), Differential Scanning Calorimetry (DSC), Dynamic Vapour Sorption (DVS), Thermogravimetric Analysis (TGA) and Nuclear Magnetic Resonance (NMR) spectroscopy.
The (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.8, 14.2, and 3.9, preferably at least the following reflections: 8.8, 14.2, 3.9, 11.5, and 15.6, in an embodiment at least the following reflections: 8.8, 14.2, 3.9, 11.5, 15.6, 16.2, and 17.3, in an embodiment at least the following reflections: 8.8, 14.2, 3.9, 11.5, 15.6, 16.2, 17.3, 22.7, 13.6 and 21.0, each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 2 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 1 a. In an embodiment, as the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant is a variable occupancy hydrate, it exhibits the reflections as outlined above at different ambient humidities, with different H2O molecule occupancies (values for n in formula (III) or (Illa) as outlined herein above).
The (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections:
2.7, 18.5, and 12.2, in an embodiment at least the following reflections: 2.7, 18.5, 12.2,
17.7, and 20.7, in an embodiment at least the following reflections: 2.7, 18.5, 12.2, 17.7,
20.7, 19.1 , and 17.5, in an embodiment at least the following reflections: 2.7, 18.5, 12.2,
17.7, 20.7, 19.1 , 17.5, 13.4, 10.6 and 16.0 each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 3 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 11 .
The (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections:
16.5, 17.7, and 11.8, preferably at least the following reflections: 16.5, 17.7, 11.8, 20.2, and 15.8, in an embodiment at least the following reflections: : 16.5, 17.7, 11.8, 20.2,
15.8. 15.5, and 13.0, in an embodiment at least the following reflections: 16.5, 17.7, 11.8,
20.2, 15.8, 15.5, 13.0, 19.3, 21.1 and 2.9, each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 6 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 43. In an embodiment, as the (pseudo)polymorphic Hydrate 6 form of the benzenesulfonate salt of elinzanetant is a variable occupancy hydrate, it exhibits the reflections as outlined above at different ambient humidities, with different H2O molecule occupancies (values for n in formula (III) or (Illa) as outlined herein above).
The (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections:
14.2, 17.1 , and 16.1 , preferably at least the following reflections: 14.2, 17.1 , 16.1 , 3.0, and 19.9, in an embodiment at least the following reflections: 14.2, 17.1 , 16.1 , 3.0, 19.9, 5.8, and 8.6, in an embodiment at least the following reflections: 14.2, 17.1 , 16.1 , 3.0, 19.9, 5.8, 8.6, 20.4, 21.8, and 23.6, each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the (pseudo)polymorphic form Hydrate 7 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 48. In an embodiment, as the (pseudo)polymorphic Hydrate 7 form of the benzenesulfonate salt of elinzanetant is a variable occupancy hydrate, it exhibits the reflections as outlined above at different ambient humidities, with different H2O molecule occupancies (values for n in formula (III) or (Illa) as outlined herein above).
The polymorphic form Pattern G of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 16.0, 8.0, and 13.3, such as at least the following reflections: 16.0, 8.0, 13.3, 26.8, and 10.7, such as at least the following reflections: 16.0, 8.0, 13.3, 26.8, 10.7, 21.4, and 6.0, such as at least the following reflections: 16.0, 8.0, 13.3, 26.8, 10.7, 21 .4, 6.0, 18.7, 24.1 and 43.5 each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the polymorphic form Pattern G can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 15.
The polymorphic form Pattern D of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 19.8, 7.6, and 22.0, such as at least the following reflections: 19.8, 7.6, 22.0, 16.3, and 20.2, such as at least the following reflections: 19.8, 7.6, 22.0, 16.3, 20.2, 18.9, and 14.1 , such as at least the following reflections: 19.8, 7.6, 22.0, 16.3, 20.2, 18.9, 14.1 , 13.3, 24.7 and 11.4, each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the polymorphic form Pattern D can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 10.
The polymorphic form Pattern 4 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 13.3, 12.0, and 8.2, such as at least the following reflections: 13.3, 12.0, 8.2, 4.9, and 18.8, such as at least the following reflections: 13.3, 12.0, 8.2, 4.9, 18.8, 21.9, and 19.8, such as at least the following reflections: 13.3, 12.0, 8.2, 4.9, 18.8, 21.9, 19.8, 15.0, 16.2 and 19.6, each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 4 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 6.
The polymorphic form Pattern 5 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 14.0, 8.7, and 19.5, such as at least the following reflections: 14.0, 8.7, 19.5, 16.3, and 19.8, such as at least the following reflections: 14.0, 8.7, 19.5, 16.3, 19.8, 15.8, and 11.3, such as at least the following reflections: 14.0, 8.7, 19.5, 16.3, 19.8, 15.8, 11.3, 17.0, 3.7 and 21 .4 each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 5 can also be characterized unambiguously by the X- Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 16.
The polymorphic form Pattern 6 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 13.1 , 16.4, 22.4, such as at least the following reflections: 13.1 , 16.4, 22.4, 18.9, 13.5, such as at least the following reflections: 13.1 , 16.4, 22.4, 18.9, 13.5, 15.7, 17.5, such as at least the following reflections: 13.1 , 16.4, 22.4, 18.9, 13.5, 15.7, 17.5, 14.8, 10.5 and 14.1 , each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 6 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 20.
The polymorphic form Pattern 8 of the benzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu- K alpha 1 as radiation source) which displays at least the following reflections: 14.2, 19.9, 21.2, such as at least the following reflections: 14.2, 19.9, 21.2, 8.7, 19.4, such as at least the following reflections: 14.2, 19.9, 21.2, 8.7, 19.4, 22.2, 16.1 , such as at least the following reflections: 14.2, 19.9, 21.2, 8.7, 19.4, 22.2, 16.1 , 21.4, 11.3 and 24.6, each quoted as 20 value ± 0.2°. The benzenesulfonate salt of elinzanetant in the polymorphic form Pattern 8 can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 23.
The (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm’1): 1121 , 1185, 1282, in an embodiment at least the following values of the band maxima (cm’1): 1121 , 1185, 1282, 1174, 683, in an embodiment at least the following values of the band maxima (cm’1 ): 1121 , 1185, 1282, 1174, 683, 1105, 609, in an embodiment at least the following values of the band maxima (cm’1): 1121 , 1185, 1282, 1174, 683, 1105, 609, 1017, 1084 and 1035. The (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 4.
The (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm’1): 1122, 683, 1278, in an embodiment at least the following values of the band maxima (cm’1): 1122, 683, 1278, 1176, 1102, in an embodiment at least the following values of the band maxima (cm’1): 1122, 683, 1278, 1176, 1102, 1082, 1016, in an embodiment at least the following values of the band maxima (cm’1): 1122, 683, 1278, 1176, 1102, 1082, 1016, 1034, 611 and 691. The (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 14.
The (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm’1): 1120, 1276, 609, in an embodiment at least the following values of the band maxima (cm’1): 1120, 1276, 609, 681 , 896, in an embodiment at least the following values of the band maxima (cm’1): 1120, 1276, 609, 681 , 896, 1374, 1486, in an embodiment at least the following values of the band maxima (cm’1): 1120, 1276, 609, 681 , 896, 1374, 1486, 1650, 1228 and 691. The (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 44. The (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm-1): 1122, 1274, 896, in an embodiment at least the following values of the band maxima (cm-1): 1122, 1274, 896, 681 , 611 , in an embodiment at least the following values of the band maxima (cm-1): 1122, 1274, 896,
681 , 611 , 1374, 1486, in an embodiment at least the following values of the band maxima (cm’1): 1122, 1274, 896, 681 , 611 , 1374, 1486, 1650, 1600 and 1017. The (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 49.
The polymorphic form Pattern 4 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm-1 ): 1131 , 1117, 1104, such as at least the following values of the band maxima (cm-1): 1131 , 1117, 1104, 1012, 1279, such as at least the following values of the band maxima (cm-1 ): 1131 , 1117, 1104, 1012, 1279, 682, 612, such as at least the following values of the band maxima (cm-1 ) 1131 , 1117, 1104, 1012, 1279,
682, 612, 1186, 1082 and 995. The polymorphic form Pattern 4 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 9.
The polymorphic form Pattern 5 of the benzenesulfonate salt of elinzanetant can be characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm-1): 1121 , 1281 , 1175, such as at least the following values of the band maxima (cm-1): 1121 , 1281 , 1175, 1035, 1017, such as at least the following values of the band maxima (cm-1): 1121 , 1281 , 1175, 1035, 1017, 682, 610, such as at least the following values of the band maxima (cm-1): 1121 , 1281 , 1175, 1035, 1017, 682, 610, 1106, 726 and 1226. The polymorphic form Pattern 5 of the benzenesulfonate salt of elinzanetant can also be characterized by IR spectrum as shown in Figure 19.
Process for preparing hydrate forms of the benzenesulfonate salt of elinzanetant
Another object of the present disclosure is a method for preparing crystalline forms of the benzenesulfonate salt of elinzanetant.
Some embodiments of the present disclosure relate to a method for preparing crystalline forms of the benzenesulfonate salt of elinzanetant comprising the steps of providing the compound of formula (I) in a solvent; adding and optionally mixing with benzenesulfonic acid; and isolating the crystalline form of the benzenesulfonate salt of elinzanetant. The term “providing” is to be understood - unless indicated otherwise - as the provision of a compound, irrespective of its form. It will be understood by those of ordinary skills in the art that a compound can be provided as solid or dissolved in an appropriate solvent. Accordingly, “providing” in context of the present disclosure includes provision as a solid, e.g. in crystalline or amorphous form, or dissolved in a solvent. The provision of compound can be adopted in accordance with the needs, e.g. process optimization. For example, the compound can be provided in a solvent as obtained in previous steps like synthesis of the compound itself, or in a solvent after dissolving a solid form of the compound in a solvent prior to providing it.
In an embodiment, the disclosure relates to a method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, the method comprising the steps of
- providing elinzanetant, preferably in a solvent;
- adding and optionally mixing with benzenesulfonic acid; and
- isolating the crystalline form of the benzenesulfonate salt of elinzanetant.
In an embodiment of the method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant the solvent is selected from the group of polar and/or aprotic solvents, for example, ethyl acetate, isopropyl acetate, toluene, DMSO, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), dimethylformamide (DMF), 1 ,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran (THF), acetonitrile, acetone, 1 ,4-dioxane, 2-methyl-THF, and n-butyl acetate, preferably selected from the group of toluene, ethyl acetate, isopropyl acetate, and n-butyl acetate. Most preferably the solvent is selected from the group consisting of toluene, ethyl acetate, and n-butyl acetate. In an embodiment, the solvent is toluene. In an embodiment the solvent is ethyl acetate.
In an embodiment the solvent is n-butyl acetate.
Adding and optionally mixing benzenesulfonic acid can be conducted using benzenesulfonic acid as a solid or in a solvent. Hence, in an embodiment benzenesulfonic acid is added in solid form or in a solvent. In an embodiment the benzenesulfonic acid is added as an aqueous solution. In an embodiment, the benzenesulfonic acid is present in the aqueous solution a concentration of 40% w/w to 48% w/w, preferably about 46% w/w.
In an embodiment, the compound of formula (I) is provided in ethyl acetate as a solvent and added to a mixture of water and n-heptane.
In an embodiment, the method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant comprises the steps of providing the compound of formula (I) in a mixture comprising ethyl acetate, water and n-heptane, adding and optionally mixing with benzenesulfonic acid; and isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant.
In a particular embodiment of the method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, the method comprises the steps of:
(i) providing a solution of the compound of formula (I) in a solvent, preferably the solvent is ethyl acetate or n-butyl acetate;
(ii) adding water and n-heptane to the solution of the compound of formula
(I) to obtain a mixture;
(iii) heating the mixture;
(iv) adding and optionally mixing benzenesulfonic acid to the heated mixture;
(v) cooling the mixture obtained in step (iv);
(vi) isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant.
In an embodiment, the mixture is heated in step (iii) to a temperature of 45°C to 60°C, more preferably to a temperature of 50°C to 55°C.
In an embodiment, the mixture obtained in step (iv) is filtered before cooling in step (v). This optional step may be e.g. preformed to remove foreign solid particles, such as metal debris, fibres, as required by good manufacturing practice and regulatory provisions or rules.
In an embodiment, a suspension is obtained in in step (v).
It has been found that the benzenesulfonate salt of elinzanetant crystallises spontaneously in its (pseudo)polymorphic Hydrate 2 form in steps (v) resulting in a suspension. This may be dependent on the time the mixture is kept and mixed at the temperature cooled to. Hence, in an embodiment, step (v) comprises cooling the mixture as obtained in step (iv) and then isothermally mixing for 6 hours to 48 hours until a suspension is obtained, in an embodiment for 10 hours to 24 hours, such as 12 hours to 16 hours.
It has also been surprisingly found that particle size and/or processability can be optimized by seeding the mixture in step (v) with crystals of (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, preferably the mixture is seeded with said crystals at the end of step (v), i.e. after the target temperature has been reached. The seeds are not critical for the solid-state but are preferably used optionally for particle size and processability reasons. The seeding further has the advantage that isothermal mixing to obtain a suspension is drastically reduced. Accordingly, the time of isothermal mixing to obtain a suspension can be drastically reduced to 1 to 6 hours. Hence, in one preferred embodiment of the method, step (v) comprises the addition of crystals of (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, preferably at the end of step (v). Optionally, isothermally mixing after addition of the crystals is done for 1 h to 6 hours, preferably 1 to 3 hours, more preferably about 2 hours.
In a preferred embodiment, the cooling in step (v) refers to cooling to a temperature of 40°C to 50°C, more preferably to a temperature of about 45°C.
The term “suspension” is to be understood as a mixture of at least two phases, wherein at least one phase is solid and at least one is liquid. Without being bound by hypothesis, the suspension in the method according to the disclosure is formed through crystallization of the benzeneulfonate salt of elinzanetant, wherein the crystals are suspended within the solvent(s) or solvent mixture. The formation of a suspension can be seen by increasing turbidity of the mixture.
In a preferred embodiment, after obtaining the suspension of step (v), the suspension is cooled to a temperature between 0°C and 35°C and isothermally mixed before isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, in an embodiment the suspension is cooled to a temperature of about 20°C to 25°C and isothermally mixed for a time between 0 min and 72 hours, in an embodiment about 0.5 hours to 1 hour. Isolation in step (vi) may be conducted by methods for isolating solids from a suspension known by those skilled in the art. In an embodiment, isolation is conducted by filtration to obtain a filter cake, preferably using a filter. The filter cake is in an embodiment washed and dried. Washing can be conducted with one or more appropriate solvents, preferably with a mixture of ethyl acetate and n-heptane, such as a mixture of 2:1 (v/v) of ethyl acetate and n-heptane.
In a particular embodiment of the method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, the method comprises the steps of:
(i) providing the compound of formula (I) in a solvent, wherein the solvent is ethyl acetate or n-butyl acetate;
(ii) adding water and n-heptane to the solution of the compound of formula (I) to obtain a mixture;
(iii) heating the mixture obtained in step (ii) to a temperature of 50°C to 55°C;
(iv) adding and mixing benzenesulfonic acid to the heated mixture;
(v) cooling the mixture as obtained in step (iv) to a temperature of about 45°C and seeding the solution with crystals of (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant to obtain a suspension; cooling the suspension to a temperature of 20°C to 25°C and optionally isothermally mixing the suspension for about 1 hour;
(vi) isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant by filtration; washing the filter cake with a mixture of 2:1 (v/v) of ethyl acetate and n-heptane and drying the filter cake.
In another embodiment of the method for preparing the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, the method comprises the steps of:
(i) providing the compound of formula (I) in a solvent, wherein the solvent is ethyl acetate;
(ii) adding water and n-heptane to the solution of the compound of formula (I) to obtain a mixture;
(iii) heating the mixture to a temperature of 50°C to 55°C; (iv) adding and mixing benzenesulfonic acid to the heated mixture and filtering the obtained mixture;
(v) cooling the mixture of step (iv) to a temperature of about 45°C and seeding the solution with (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant to obtain a suspension;
Cooling the suspension to about 20°C to 25°C and isothermally mixing the suspension for about 1 hour;
(vi) isolating the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant by; and
(vii) washing the filter cake with a mixture of 2:1 (v/v) of ethyl acetate and n- heptane and drying the filter cake.
Pharmaceutical compositions
It is possible for the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the present disclosure to have systemic and/or local activity. For this purpose, it can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, optic route or as an implant or stent.
For these administration routes, it is possible for the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the present disclosure, to be administered in suitable administration forms.
For oral administration, it is possible to formulate the hydrate crystalline form of the benzenesulfonate salt of elinzanetant according to the present disclosure, to dosage forms known in the art that deliver the compounds of the disclosure rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with functional or non-functional coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compound according to the disclosure in crystalline and/or amorphous and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The crystalline forms of the benzenesulfonate salt of elinzanetant can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, inter alia,
• fillers and binders (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),
• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),
• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetting agents (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),
• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),
• isotonicity agents (for example glucose, sodium chloride),
• adsorbents (for example highly-disperse silicas),
• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)),
• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),
• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),
• capsule materials (for example gelatin, hydroxypropylmethylcellulose),
• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
• penetration enhancers,
• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),
• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),
• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide, rice starch, calcium sulfate, calcium carbonate),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present disclosure furthermore relates to a pharmaceutical composition which comprise at least one crystalline hydrate form of the benzenesulfonate salt of elinzanetant according to the present disclosure, preferably the Hydrate 2 form, conventionally together with one or more pharmaceutically acceptable excipient(s), and to their use according to the present disclosure.
In the context of the present disclosure, “excipients” are surfactants, fillers, binders, lubricants, disintegrant, sweeteners, flavoring agents, and colorants. It may come to happen that a person skilled in the art assigns similar or even identical substances to be member of more than one of the above-mentioned groups of substances. Within the context of the present disclosure, the functional descriptions of the substances are however intentionally filled with specific substances to clarify their respective property assigned to them.
The expression ‘pharmaceutically acceptable’ refers to those excipients, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio. Surfactants (or ‘surface active agents’) are organic compounds containing a hydrophilic "water-seeking" group, and a hydrophobic "water-avoiding" group.
Solid pharmaceutical compositions with salts of elinzanetant
As disclosed herein above, the inventors have found that salts of elinzanetant can be formulated in a solid pharmaceutical composition, such as a tablet, with the desired properties, if they are formulated together with a non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
In particular, it has been found that non-ionic surfactants provide for a surprisingly and drastically increased dissolution behavior as compared to ionic surfactants, as well as a sufficient bioavailability.
Accordingly, the present disclosure also relates to a solid pharmaceutical composition comprising a salt of elinzanetant and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
In an embodiment the solid pharmaceutical composition is selected from the group consisting of granules, solid mixture, pellets, tablets, dragees, sachets, pills, and melts.
In an embodiment the solid pharmaceutical composition is a tablet.
In an embodiment the solid pharmaceutical composition, is an immediate release solid pharmaceutical composition, including an immediate release tablet, immediate release granules, immediate release pellets, immediate release solid mixture immediate release dragees, immediate release sachets, immediate release pills, and immediate release melts.
In an embodiment the solid pharmaceutical composition is an immediate release tablet.
“Immediate” release in one embodiment relates to a rapid dissolution of elinzanetant from the composition occurring in vitro. "Rapid dissolution" is defined as the in vitro dissolution of more than 50% of the comprised elinzanetant over about 30 minutes, in particular at least 55% over about 30 minutes, even more particular at least 60% over about 30 minutes of elinzanetant (which was present in the solid pharmaceutical composition, such as the tablet, as the salt of elinzanetant) from the solid pharmaceutical composition, preferably the tablet, containing a salt of elinzanetant using an USP-2 paddle apparatus in Fasted State Simulated Gastric Fluid (FaSSGF) at pH 2.4 with 500 mL vessels at 37°C±0.5°C and a rotation speed of the paddles of approx. 75 rpm.
When administered, the solid pharmaceutical composition first enters the acidic environment of the stomach before entering the more neutral environment of the duodenum. Accordingly, it may be desirable for the solid pharmaceutical composition, such as a tablet, to allow dissolution of elinzanetant in vitro within a certain time after adding it to a solution of acidic conditions for a certain time and rebuffering from that acidic to a more neutral condition. Accordingly, in one embodiment “rapid dissolution” is defined as the in vitro dissolution of at least 60% of the comprised elinzanetant within 35 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37°C±0.5°C and 75 rpm as stirring rate for 30 min, and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37°C±0.5°C and 75 rpm as stirring rate. In a further embodiment of the solid pharmaceutical composition at least 80% of the comprised elinzanetant is dissolved in vitro within 210 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37°C±0.5°C and 75 rpm as stirring rate for 30 min, and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37°C±0.5°C and 75 rpm as stirring rate.
In one embodiment the dissolution rates above refer to the dissolution from the tablet core, i.e. the tablet without coating. Depending on the type of coating the dissolution rate may be slightly decreased.
An object of the present invention is the provision of a pharmaceutical formulation having the desired bioavailability. Bioavailability in one embodiment is defined as the fraction (percentage) of an administered dose or the concentration (pg drug per mL blood) of elinzanetant that reaches the blood stream (systemic circulation) within a time period after administration of the pharmaceutical composition, e.g. the solid pharmaceutical composition according to the present disclosure, tmax is the time where the highest concentration of elinzanetant is found in the bloodstream after administration, whereas Cmax is the maximum concentration of elinzanetant found in the bloodstream after administration. The area under the curve (AUC(O-tiast)) represents the total amount of elinzanetant which was in the bloodstream over the period studied, or extrapolated to infinity to obtain the total AUC. In an embodiment, the present disclosure relates to pharmaceutical composition, such as a solid pharmaceutical composition, comprising elinzanetant or a pharmaceutical acceptable salt thereof, wherein the pharmaceutical composition exhibits a bioavailability essentially, such as Cmax and/or total AUC as a solid pharmaceutical composition according to the present disclosure, such as tablets having the composition of Example 14.2.3 of the present disclosure.
“Essentially” in context with the present disclosure refers to values that are within a range of ±30% from the respective value, such as within a range of ±25% from the respective value. In one embodiment “essentially” refers to bioequivalence, such as the bioequivalence according to the US Food and Drug Administration FDA, e.g. a range between -20% and +25% from the respective value, in other words between 80% and 125% of the respective value.
Bioavailability is in one embodiment evaluated by determining Cmax and/or AUC after administration of the pharmaceutical formulation to a subject, such as a human subject.
The administration may be performed with the desired dose. In one embodiment, Cmax and/or AUC are determined after administration of a single dose of 120 mg elinzanetant to a subject. In one embodiment administration for determining is performed in the morning, during the day or in the evening. In one embodiment administration for determining is performed under fasted conditions, such as in the morning before food uptake.
In one embodiment of the present disclosure, the solid pharmaceutical composition of the present disclosure, when administered at a single dose of 120 mg under fasted conditions, exhibits a Cmax of between 700 pg/L and 1500 pg/L, such as between 700 pg/L and 1400pg/L. In one embodiment the Cmax is 1063 pg/L ±25%, such as between 80% and 125% of 1063 pg/L.
In one embodiment of the present disclosure, the pharmaceutical composition of the present disclosure, the solid pharmaceutical composition of the present disclosure, when administered at a single dose of 120 mg, exhibits a total AUC of between 4500 pg*h/L and 7500 pg*h/L, such as between 5000 pg*h/L and 7100 pg*h/L. In one embodiment the total AUC is 7248 pg*h/L ±25%, such as between 80% and 125% of 7248 pg*h/L.
In one embodiment the values herein for Cmax and total AUC refer to the geometric mean.
Depending on the ionic type of the hydrophilic group surfactants are classified as anionic, cationic, amphoteric, and non-ionic surfactants. The term “non-ionic surfactant” of the present disclosures refers to surfactants not comprising an ionic moiety (such as sulphate, sulphonate, ether sulphate, ether phosphate, ether carboxylate or carboxylate) and include derivatives of ethylene oxide, such as polyoxyethylene, and/or propylene oxide with an alcohol containing an active hydrogen atom. However, other types such as alkyl phenols, sugar esters, alkanolamides, amine oxides, fatty acids, fatty amines and polyols or other surface-active substances, and mixtures of the forementioned comprising non-ionic moieties are included according to this disclosure. Examples for fatty acids esters of polyoxyethylene are macrogololeate, macrogolstearate, macrogol-15-hydroxystearate (e.g. Kolliphor® HS 15), macrogol- 30-dipolyhydroxystarate, polyoxyethylene(8)-stearate (e.g. Myrj® S8), polyoxyethylene(20)-stearate (e.g. Myrj® S20), polyoxyethylene(40)-stearate (e.g. Myrj® S40), polyoxyethylene(50)-stearate (e.g. Myrj® S50), polyoxyethylene(100)- stearate (e.g. Myrj® S100), and polyoxyethylene(9)-stearate (e.g. Cremophor® S9). Examples for fatty alcohol ethers of polyoxyethylene are macrogolcetylstearyl ether, macrogollauryl ether, lauronacrogol 400, macrogololeyl ether, macrogolstearyl ether, polyoxyethylene laurylether/macrogol laurylether (e.g. Brij® L4, Brij® 23), polyoxyethylene cetylether/macrogol cetylether (e.g. Brij® C2, Brij® C10, Brij® C20), polyoxyethylene stearylether/macrogol stearyl ether (e.g. Brij® S10, Brij® S20, Cremophor® A6, or Cremophor® A25), and polyoxyethylene oleylether/macrogol oleylether (e.g. Brij® 010, Brij® 020). Examples for partial fatty acid esters of sorbitan are sorbitan monolaurate (e.g. Span® 20), sorbitan monopalmitate (e.g. Span® 40), sorbitan monostearate (e.g. Span® 60), sorbitan tristearate (e.g. Span® 65), sorbitan monooleate (e.g. Span® 80), sorbitan sesquioleate (e.g. Span® 83, Arlacel® C), and sorbitan trioleate (e.g. Span® 85). Examples for partial fatty acid esters of polyoxyethylene sorbitan/polysorbates are polyoxyethylene(20)-sorbitan monolaurate (e.g. Tween® 20), polyoxyethylene(4)-sorbitan monolaurate (e.g. Tween® 21 ), polyoxyethylene(20)-sorbitan monopalmitate (e.g. Tween® 40), polyoxyethylene(20)- sorbitan monostearate (e.g. Tween® 60), polyoxyethylene(4)-sorbitan monostearate (e.g. Tween® 61 ), polyoxyethylene(20)-sorbitan tristearate (e.g. Tween® 65), polyoxyethylene(20)-sorbitan monooleate (e.g. Tween® 80), polyoxyethylene(5)- sorbitan monooleate (e.g. Tween® 81 ), and polyoxyethylene(20)-sorbitan trioleate (e.g. Tween® 85). An example for fatty acid esters of polyoxyethylene sorbitol is macrogol-40-sorbitolheptaoleat. Examples for fatty acid esters of polyoxyethylene and glycerol are macrogol-6-glycerolcaprylocaprate (e.g. Softigen® 767), macrogolglycerolcaprylocaprate, macrogolglycerollaurate, macrogolglycerolcocoate, macrogol-20-glycerolmonostearate, macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g. Kolliphor® RH 40, Cremophor® RH 40), macrogolglycerololeate, macrogolglycerolricinoleate (e.g. Kolliphor® EL, Kolliphor® ELP, or Cremophor® EL), macrogolglycerollinoleate, macrogol-20- glycerolmonolaurate, and macrogol-20-glycerolmonooleate. Examples for polyoxyethylene - polyoxypropylene - block copolymers/poloxamers are poly- (ethylenglykol)-block-poly-(propylenglykol)-block-poly-(ethylenglykol) (e.g.
Synperonic® F 68, Synperonic® F 108, Synperonic® PE/P84, Lutrol® F-68, Kolliphor® P 188, Pluronic® L 121 , or Synperonic® L 31 ), poloxamer 338 (e.g. Synperonic® PE/F108), poloxamer 184 (e.g. Synperonic® L 64), poloxamer 407 (e.g. Pluronic® F- 127), and poloxamer 188 (e.g. Pluronic® F-68 ). Examples for fatty acid esters of saccharose are saccharose distearate, saccharose dioleate, saccharose dipalmitate, saccharose monostearate, saccharose monopalmitate, saccharose monooleate, saccharose monomyristate, and saccharose monolaurate. Examples for partial fatty acids of polyhydric alcohols are ethylenglycolmonostearate, glycerolmonostearate, glycerolmonooleate, pentaerythrimonostearate, glyceroldibehenate, glyceroldistearate, glycerolmonocaprylate, glycerolmonocarprylocaprate, glycerolmonolinoleate, glycerolmonooleate, glycerolmonostearate 40-55, ethylenglycolmonoplamitostearate, diethylenglycolpalmitostearate, propylenglycoldicaprylocaprate, propylenglycoldilaurate, propylenglycolmonolaurate, and propylenglycolmonopalmitostearate. Examples for fatty acid esters of polyglycerol are polyglycerololeate, polyglycerolpoly(12-hydroxystearate) and triglyceroldiisostearate. Example for fatty acid esters of glycol is propylene glycol monostearate (PGMS, e.g. Lexemul® P MB). Further examples for non-ionc surfactants are D-a-tocopheryl-1000-succinate/vitamin E TPGS, fatty alcohols such as cetylalcohol, cetylstearylalcohol, stearylalcohol, oleylalcohol, emulsifying cetylstearylalcohol and non-ionic emulsifying alcohols such as mixtures of cetylstearylalcohol, macrogol-80-cetylstearyl ether and glycerlomonostearate (e.g. Rofetan® NS), lanolin alcohols, and sterines such as cholesterol.
In one embodiment of the present disclosure the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20, polysorbate 40, polysorbate 80, and macrogol-15-hydroxystearate; or mixtures thereof.
In a further embodiment of the present disclosure the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, polysorbate 20, and macrogol-15-hydroxystearate; or mixtures thereof.
In one embodiment the salt of elinzanetant in the solid pharmaceutical composition is selected from benzenesulfonate, preferably according to the embodiments as disclosed herein, 4-methylbenzenesulfonate, and di-hydrochloride salt, and mixtures thereof, or a hydrate or solvate thereof.
In one embodiment, the solid pharmaceutical composition according to the disclosure comprises the crystalline 4-methylbenzenesulfonate salt of elinzanetant and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients. Preferably, the 4-methylbenzenesulfonate is in anhydrous crystalline form 1 as disclosed in WO 2010/015626 A1 , which is incorporated herein by reference. Preferably 4-methylbenzenesulfonate salt of elinzanetant in anhydrous crystalline Form 1 characterized by substantially the same X-ray powder diffraction (XRPD) pattern as in Figure 1 of WO 2010/015626 A1. Preferably the 4- methylbenzenesulfonate salt of elinzanetant can be characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 8.0, 10.3, 14.5, 15.0, and 17.7; preferably at least the following reflections: 3.2, 6.2, 8.0, 10.3, 12.4, 14.5, 15.0,16.2, 17.2, 17.7, 18.6, 20.0, and 22.9; each quoted as 20 value ± 0.2°.
In one embodiment, the solid pharmaceutical composition according to the disclosure comprises crystalline di-hydrochloride salt of elinzanetant, or a solvate thereof, and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients. Preferably the di-hydrochloride salt of elinzanetant is present as an isopropanol solvate. The di-hydrochloride salt isopropanol solvate can be produced as disclosed in Example 7 of WO 2021/094247 A1 , which is incorporated herein by reference. The polymorphic form di-hydrochloride isopropanol solvate of the compound of formula (I) can be preferably characterized unambiguously by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 13.7, 17.5, 20.4, preferably at least the following reflections: 13.7, 17.5, 20.2, 20.4, 20.8, more preferably at least the following reflections: 10.1 , 13.0, 13.7, 17.5, 20.2, 20.4, 20.8, most preferably at least the following reflections: 7.9, 8.8, 10.1 , 13.0, 13.4, 13.7, 17.5, 20.2, 20.4 and 20.8, each quoted as 20 value ± 0.2°. The polymorphic form di-hydrochloride isopropanol solvate of the compound of formula (I) can also be characterized unambiguously by the X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) as shown in Figure 35.
In an embodiment, the solid pharmaceutical composition according to the disclosure comprises crystalline benzenesulfonate salt of elinzanetant or a solvate or hydrate thereof and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients. In an embodiment, the solid pharmaceutical composition according to the disclosure comprises a crystalline hydrate form of the benzenesulfonate salt of elinzanetant according to the embodiments as disclosed herein and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients. In one embodiment, the solid pharmaceutical composition according to the disclosure comprises the crystalline Hydrate 3 form of the benzenesulfonate salt of elinzanetant according to the disclosure and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients.
In an embodiment, the solid pharmaceutical composition according to the disclosure comprises the crystalline Hydrate 2 form of the benzenesulfonate salt of elinzanetant including all embodiments as disclosed herein and at least one non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients. The crystalline Hydrate 2 form of the benzenesulfonate salt of elinzanetant in the composition has the preferred embodiments as disclosed herein. The concentration of the salt of elinzanetant in the solid pharmaceutical composition may be adapted according to the needs. It may for example be adapted to the total amount of elinzanetant necessary per dosage form, e.g., to provide for a pharmaceutically effective amount of elinzanetant.
In some embodiments, the concentration of the salt of elinzanetant or a hydrate or solvate thereof ranges from 5% w/w to 50% w/w, such as from 10% w/w to 40% w/w; and in one embodiment the concentration of the salt of elinzanetant or a hydrate or solvate thereof is from 20% w/w to 35% w/w.
In some embodiments, the concentration of the non-ionic surfactant ranges from about 0.5% w/w to about 50% w/w, from about 0.5% w/w to about 25% w /w, from about 0.5% w/w to about 10.0% w/w, from about 0.5% w/w to about 7.0% w/w.
Further excipients
The solid pharmaceutical composition may optionally contain one or more further pharmaceutically acceptable excipients. In one embodiment pharmaceutically acceptable excipients are selected from the group consisting of fillers, binders, lubricants, disintegrants, sweeteners, flavouring agents, and colorants; or mixtures thereof.
It will be understood by those of ordinary skill in the art that excipients may be added to provide for different properties. Depending on the context, an excipient may serve, e.g. as a binder or a filler or may serve to provider for both. Filler and/or binder in the solid pharmaceutical composition according to the present disclosure in one embodiment are selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof. In a particular embodiment the filler according to the present disclosure is microcrystalline cellulose or silicified microcrystalline cellulose; or a mixture thereof.
Depending on the context, an excipient may serve, e.g., as a disintegrant. Without being bound by hypothesis, disintegrants expand and dissolve when wet and thereby facilitate disintegration of a solid pharmaceutical composition, such as a tablet, releasing the active ingredients. Disintegrants in one embodiment of the present disclosure are those selected from the group consisting of alginic acid, cross-linked polyvinylpyrrolidone, maize starch, modified starch, and starch derivatives such as sodium carboxymethyl starch, cellulose derivatives such as carmellose calcium (carboxymethylcellulose calcium) and croscarmellose sodium (cross-linked polymer of carboxymethylcellulose sodium); or a mixture thereof. In a particular embodiment the disintegrant of the present disclosure is croscarmellose sodium or cross-linked polyvinylpyrrolidone; or a mixture thereof. In a further embodiment of the present disclosure the disintegrant is croscarmellose sodium.
Depending on the context, an excipient may serve, e.g. as lubricant. Lubricants prevent ingredients from sticking, e.g., to production equipment. In an embodiment of the present disclosure the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof. In one embodiment of the present disclosure lubricants according to the present disclosure are selected from the group consisting of magnesium stearate, stearic acid and talcum, or mixtures thereof.
To provide for a pharmaceutical composition with desirable taste or to cover undesired taste, the pharmaceutical composition may contain agents that provide for a certain taste, such as sweeteners or flavoring agents. Sweeteners suitable in the context of the present disclosure are those selected from the group consisting of sucralose, saccharin, sodium-, potassium- or calcium saccharin, potassium acesulfame, neotame, alitame, glycyrrhizin or thaumatin, or sugars such as glucose, mannitol, fructose, saccharose, maltose, maltitol, galactose, sorbitol or xylitol. In the context of the present disclosure sweeteners are added in amounts to achieve the desired grade of sweetness and may be adapted by those skilled in the art. Flavoring agents in the context of the present disclosure are natural flavoring substances obtained from plant or animal raw materials, nature-identical flavoring substances obtained by synthesis or isolated through chemical processes, which are chemically and organoleptically identical to flavoring substances naturally present in products intended for human consumption and artificial flavoring substances. In a particular embodiment the flavoring agent is selected from the group consisting of synthetic/artificial flavoring agents such as amyl acetate (banana flavoring), benzaldehyde (cherry or almond flavor), ethyl butyrate (pineapple), methyl anthranilate (grape), natural flavoring agents such as essential oils and oleoresins, herbs and spices, and natural-identical flavoring agents which are flavoring substances that are obtained by synthesis or are isolated through chemical processes and whose chemical make-up is identical to their natural counterpart. In the context of the present disclosure flavoring agents may be added in amounts to achieve the desired taste and grade of taste.
The solid pharmaceutical composition may optionally contain colorants. Colorants are commonly used to color an uncolored pharmaceutical composition or to enhance its color, to minimize batch-to-batch variations or to replace a color already present to complement its effect and also to provide for a desirable appearance. Colorants in context with the present disclosure may be selected from the group consisting of dyes or pigment such as indigo carmine, riboflavin, titanium dioxide, rice starch, calcium sulfate and calcium carbonate. In the context of the present disclosure colorants may be added in amounts to achieve the desired color and/or grade of color.
In one embodiment the solid pharmaceutical composition comprises one or more disintegrant selected from those disclosed herein above. In a further embodiment the one or more disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof. In a yet further embodiment the solid pharmaceutical composition comprises croscarmellose sodium.
In some embodiments, the concentration of the disintegrant ranges from about 0.1 % w/w to about 20% w/w, from about 1 % w/w to about 10% w /w, from about 2% w/w to about 6% w/w.
In one embodiment the solid pharmaceutical composition comprises one or more one or more binder selected from those disclosed herein above. In a further embodiment the binder is selected from the group consisting of microcrystalline cellulose or silicified microcrystalline cellulose; or a mixture thereof. In a yet further embodiment, the solid pharmaceutical composition comprises microcrystalline cellulose.
In some embodiments, the concentration of the binder ranges from about 10% w/w to about 90% w/w, from about 30% w/w to about 80% w /w, from about 50% w/w to about 70% w/w. In one embodiment of the present disclosure the solid pharmaceutical composition comprises a lubricant. In one embodiment the lubricant of the present disclosure is magnesium stearate.
In some embodiments, the concentration of the lubricant ranges from about 0.1 % w/w to about 5% w/w, from about 0.1 % w/w to about 2% w /w, from about 0.5% w/w to about 1 .5% w/w.
In one embodiment the one or more further pharmaceutically acceptable excipient comprises a flow regulator, such as silicon dioxide.
In some embodiments, the concentration of the flow regulator ranges from about 0.1 % w/w to about 5% w/w, from about 0.1 % w/w to about 1 % w /w, from about 0.1 % w/w to about 0.6% w/w.
In one embodiment, the disclosure relates to a solid pharmaceutical composition, preferably a tablet, comprising a salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, a lubricant and optionally one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a nonionic surfactant, a binder, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
In an embodiment, the binder is microcrystalline cellulose. Accordingly, in one embodiment, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients. In one particular embodiment, the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
In an embodiment the binder is silicified microcrystalline cellulose. Accordingly, in one embodiment, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, silicified microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients. In one embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, silicified microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients. In an embodiment, the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, silicified microcrystalline cellulose, a disintegrant, a lubricant and one or more further pharmaceutically acceptable excipients.
A particular preferred lubricant is magnesium stearate. Accordingly, in one embodiment, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, magnesium stearate, and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, magnesium stearate, and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, a binder, a disintegrant, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
In an embodiment the disintegrant is croscarmellose sodium. Accordingly, in an embodiment, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, a binder, croscarmellose sodium, a lubricant, and one or more further pharmaceutically acceptable excipients. Further, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients. In one particularly preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, a non-ionic surfactant, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
A particular preferred non-ionic surfactant is macrogolglycerolricinoleate. Accordingly, in one embodiment, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, macrogolglycerolricinoleate, a binder, a disintegrant, a lubricant, and one or more further pharmaceutically acceptable excipients. Further, the disclosure relates to a solid pharmaceutical composition comprising a salt of elinzanetant, macrogolglycerolricinoleate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients. In one preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising benzenesulfonate salt of elinzanetant, macrogolglycerolricinoleate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients. In one particularly preferred embodiment, the disclosure relates to a solid pharmaceutical composition comprising the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, macrogolglycerolricinoleate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and one or more further pharmaceutically acceptable excipients.
Further the solid dosage form, preferably the tablet, may be coated by pharmaceutically acceptable excipients.
In the context of the present invention the optional coating is carried out with addition of customary coating and film-forming agents familiar to the person skilled in the art, such as hydroxy-propylcellulose, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polyvinyl-pyrrolidone, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon® VA64, BASF), shellac, acrylic and/or methacrylic acid ester copolymers with trimethylammonium methylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, ethyl aery late-m ethyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol (e.g. polyethylene glycol 3350), glycerol triacetate or triethyl citrate, and/or colorants/pigments such as, for example, titanium dioxide, rice starch, calcium sulfate, calcium carbonate, iron oxide (e.g. red iron oxide, yellow iron oxide, black iron oxide), indigotin or suitable color lakes, and/or anti-tacking agents such as talc, and/or opacifiers such as titanium dioxide, rice starch, calcium sulfate, calcium carbonate. An optional coating may comprise HPMC and polyethylene glycol, and iron oxide, such as iron oxide red and/or iron oxide yellow. Optionally the coating may comprise an opacifier, such titanium dioxide, rice starch, calcium sulfate. A mixture of the coating substances mentioned herein may also be used as a ready-to-use coating system such as commercially available coatings.
In one embodiment, the coating is about 0.5% to 10% by weight of the coated tablet, preferably 0.5% to 4.5% by weight of the coated tablet formulation, more preferably about 1.5% to 4.5% by weight of the coated tablet. In an embodiment the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow and titanium dioxide. In an embodiment the solid pharmaceutical composition is coated with a lacquer containing HPMC and polyethylene glycol, and iron oxide, such as iron oxide red, iron oxide yellow, and one or more opacifier selected from the group consisting of rice starch, calcium sulfate, and calcium carbonate.
In one embodiment the solid pharmaceutical composition comprises
(a) a crystalline salt of elinzanetant at a concentration of between 20% w/w and 40% w/w, wherein the salt is selected from the group consisting of benzenesulfonate salt, 4-methylbenzenesulfonate salt, and di-hydrochloride salt, or a hydrate or solvate thereof;
(b) a non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20, polysorbate 40, polysorbate 80, and macrogol-15-hydroxystearate; or mixtures thereof;
(c) a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof;
(d) a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
(e) a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof, and
(f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w.
In one embodiment the solid pharmaceutical composition comprises
(a) a crystalline di-hydrochloride salt of elinzanetant, or a solvate thereof, at a concentration of between 20% w/w and 40% w/w;
(b) a non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20, polysorbate 40, polysorbate 80, and macrogol-15-hydroxystearate;
(c) a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof;
(d) a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
(e) a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof, and
(f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w.
In an embodiment the di-hydrochloride salt of elinzanetant is present as a solvate, such as the isopropanol solvate.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of between 27% w/w and 35% w/w;
(b) polysorbate 20 at a concentration of between 0.5% w/w and 7% w/w;
(c) microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w;
(d) magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
(e) croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w; and
(f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of about 32.23% w/w;
(b) polysorbate 20 at a concentration of about 6.25% w/w;
(c) microcrystalline cellulose at a concentration of about 55.79% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of about 32.23% w/w; (b) polysorbate 20 at a concentration of about 1 .04% w/w;
(c) microcrystalline cellulose at a concentration of about 61 .00% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of between 27% w/w and 35% w/w;
(b) macrogol-15-hydroxystearate at a concentration of between 0.5% w/w and 7% w/w;
(c) microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w;
(d) magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
(e) croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w; and
(f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of about 32.23% w/w;
(b) macrogol-15-hydroxystearate at a concentration of about 6.25% w/w;
(c) microcrystalline cellulose at a concentration of about 55.79% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of about 32.23% w/w;
(b) macrogol-15-hydroxystearate at a concentration of about 3.13% w/w;
(c) microcrystalline cellulose at a concentration of about 58.92% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant at a concentration of between 27% w/w and 35% w/w; (b) macrogolglycerolricinoleate at a concentration of between 0.5% w/w and 7% w/w;
(c) microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,;
(d) magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
(e) croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w; and
(f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) crystalline isopropanol solvate of di-hydrochloride salt of elinzanetant, or a solvate thereof, at a concentration of about 32.23% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 6.25% w/w;
(c) microcrystalline cellulose at a concentration of about 55.79% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment the solid pharmaceutical composition comprises
(a) a crystalline hydrate form of the benzenesulfonate salt of elinzanetant, preferably the (pseudo)polymorphic Hydrate 2 form, at a concentration of between 20% w/w and 40% w/w;
(b) a non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, preferably between 2% w/w and 5% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerolhydroxystearate, polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 80 (Tween 80), and macrogol-15-hydroxystearate; or mixtures thereof;
(c) a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof; (d) a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
(e) a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof; and
(f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of between 27% w/w and 35% w/w;
(b) polysorbate 20 at a concentration of between 0.5% w/w and 7% w/w;
(c) microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,;
(d) magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w;
(e) croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w; and
(f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00 % w/w;
(b) polysorbate 20 (Tween 20) at a concentration of about 6.25% w/w;
(c) microcrystalline cellulose at a concentration of about 57.02% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of between 27% w/w and 35% w/w;
(b) macrogol-15-hydroxystearate at a concentration of between 0.5% w/w and 7% w/w;
(c) microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,;
(d) magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w; (e) croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w; and
(f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00% w/w;
(b) macrogol-15-hydroxystearate at a concentration of about 6.25% w/w;
(c) microcrystalline cellulose at a concentration of about 57.02% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00% w/w;
(b) macrogol-15-hydroxystearate at a concentration of about 3.13% w/w;
(c) microcrystalline cellulose at a concentration of about 60.15% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .85% w/w;
(b) macrogol-15-hydroxystearate at a concentration of about 1 .04% w/w;
(c) microcrystalline cellulose at a concentration of about 62.23% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of between 27% w/w and 35% w/w;
(b) macrogolglycerolricinoleate at a concentration of between 0.5% w/w and 7% w/w;
(c) microcrystalline cellulose at a concentration of between 50% w/w and 70% w/w,;
(d) magnesium stearate at a concentration of between 0.7% w/w and 1 .5% w/w; (e) croscarmellose sodium at a concentration of between 1.5% w/w and 6% w/w; and
(f) optionally silicon dioxide at a concentration of between 0.4% w/w and 0.7% w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 6.25% w/w;
(c) microcrystalline cellulose at a concentration of about 57.02% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 3.13% w/w;
(c) microcrystalline cellulose at a concentration of about 60.15% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 2.08% w/w;
(c) microcrystalline cellulose at a concentration of about 61 .19% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w.
In one embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 31 .00% w/w;
(b) Macrogolglycerolricinoleate (Kolliphor EL) at a concentration of about 1.04% w/w;
(c) microcrystalline cellulose at a concentration of about 62.23% w/w;
(d) magnesium stearate at a concentration of about 0.52% w/w; and
(e) croscarmellose sodium at a concentration of about 5.21 % w/w. In one particular embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 30.78% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 2.07% w/w;
(c) microcrystalline cellulose at a concentration of about 60.74% w/w;
(d) magnesium stearate at a concentration of about 0.72% w/w;
(e) croscarmellose sodium at a concentration of about 5.17% w/w; and
(f) silicon dioxide at a concentration of about 0.52% w/w.
In one particular embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 29.01 % w/w;
(b) macrogolglycerolricinoleate at a concentration of about 1 .95% w/w;
(c) microcrystalline cellulose at a concentration of 63.1 % w/w;
(d) magnesium stearate at a concentration of about 0.49% w/w;
(e) croscarmellose sodium at a concentration of about 4.87% w/w; and
(f) silicon dioxide at a concentration of about 0.58% w/w.
In one particular embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 28.95% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 1 .95% w/w;
(c) microcrystalline cellulose at a concentration of 64.85% w/w;
(d) magnesium stearate at a concentration of about 0.75% w/w;
(e) croscarmellose sodium at a concentration of about 2.92% w/w; and
(f) silicon dioxide at a concentration of about 0.58% w/w.
In one particular preferred embodiment, the disclosure relates to a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 28.89% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 1 .94% w/w;
(c) microcrystalline cellulose at a concentration of 64.67% w/w;
(d) magnesium stearate at a concentration of about 1 .00% w/w;
(e) croscarmellose sodium at a concentration of about 2.91 % w/w; and (f) silicon dioxide at a concentration of about 0.58% w/w.
As will be readily understood by the skilled person, the concentrations as listed, in an embodiment, refer to the solid pharmaceutical composition in the core of a solid oral dosage form, such as a tablet core. The core may be, e.g., being coated with coatings to achieve further desired properties.
Process for Preparing the Solid Pharmaceutical Composition:
The challenges to formulate a tablet with sufficient drug load have been unexpectedly overcome, when combining salts of elinzanetant according to the present disclosure with non-ionic surfactants.
Accordingly, in one embodiment the invention relates to a method for preparing the solid pharmaceutical composition according to the present disclosure comprising the steps of:
(i) blending the crystalline salt of elinzanetant or a hydrate or solvate thereof, and the at least one non-ionic surfactant, and optionally one or more excipient to obtain a blend; and
(ii) optionally subsequently adding one or more further excipients to the blend.
In one embodiment, the method comprises the step of dry granulation. Dry granulation may be performed after step (ii). In case the optional step (ii) is not performed, dry granulation may be performed after step (i).
In one embodiment the method comprises the steps of
(i) blending the crystalline salt of elinzanetant or a hydrate or solvate thereof, and the at least one non-ionic surfactant; and
(ii) subsequently adding and blending one or more further excipients to the blend obtained in step (i); and
(iii) subjecting the blend obtained after step (ii) to dry granulation.
In one embodiment the method comprises the steps of (i) blending the crystalline salt of elinzanetant or a hydrate or solvate thereof, and the at least one non-ionic surfactant, and one or more excipient to obtain a blend;
(ii) subsequently adding and blending one or more further excipients to the blend obtained in step (i); and
(iii) subjecting the blend obtained after step (ii) to dry granulation.
In one embodiment the method comprises the steps of
(i) blending the crystalline salt of elinzanetant or a hydrate or solvate thereof, and the at least one non-ionic surfactant, and one or more excipient to obtain a blend;
(ii) subjecting the blend obtained after step (i) to dry granulation.
After dry granulation one or more further excipients may be added and mixed with the granules, e.g. before compression.
In one embodiment the salt of elinzanetant or a hydrate or solvate thereof is selected from the group consisting of benzenesulfonate salt of elinzanetant, 4-methyl- benzenesulfonate salt of elinzanetant, and di-hydrochloride salt of elinzanetant. In one embodiment the salt of elinzanetant is the benzenesulfonate salt of elinzanetant, in particular a hydrate form of the benzenesulfonate salt of elinzanetant according to the present disclosure, more particular the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the present disclosure.
Blending of non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof, and optionally one or more excipient in step (i) can be performed by suitable measures, such as rubbing, e.g. by a mortar or pistil, mixing, such as high shear mixing, fluid bed blending or extrusion, e.g. by twin screw extrusion. In one embodiment blending is performed dry.
One or more excipients can be blended with the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i). In one embodiment, all excipients of the solid pharmaceutical composition are blended with the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i). In another embodiment, one or more excipients are blended with the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i), and one or more further excipients are added in step (ii). In yet another embodiment, only the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i) are blended in step (i), and one or more excipients are added in step (ii). That is, after blending the non-ionic surfactant and the crystalline salt of elinzanetant or hydrate or solvate thereof in step (i) one or more further excipients according to the present disclosure may be optionally added to the blend.
Adding and blending in step (ii) may comprise mixing the one or more further pharmaceutically acceptable excipient with the blend of the non-ionic surfactant and the crystalline salt of elinzanetant obtained in step (i). The one or more further pharmaceutically acceptable excipient may be added and blended in step (ii) by methods known in the art, e.g. by a mortar or pistil, mixing, such as free-fall blending, high shear mixing, fluid bed blending or extrusion, e.g. by twin screw extrusion.
After blending in step (i) or - if performed - after adding and blending in step (ii) , the solid pharmaceutical composition may be provided as obtained. In one embodiment the obtained composition may be further processed to prepare the desired form and/or to add one or more further excipients as needed. In one embodiment the solid pharmaceutical composition is subjected to direct compression or compression after dry granulation, e.g. to obtain a tablet. In one embodiment the direct compression is subjected to the obtained solid pharmaceutical composition. In one embodiment the blend is subjected to dry granulation, thereafter optionally blended with one or more further excipients, and subjected to compression.
The present disclosure also relates to a solid pharmaceutical composition according to the present disclosure obtainable by a method for preparing the solid pharmaceutical composition according to the present disclosure.
Method for treatment:
The crystalline hydrate forms of the benzenesulfonate salt of elinzanetant, particularly the (pseudo)polymorphic form Hydrate 2 according to the disclosure, have useful pharmacological properties and may be employed for the prevention and treatment of diseases and disorders. The crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure may open up a further treatment alternative and may therefore be an enrichment of pharmacy. Likewise, the solid pharmaceutical compositions as disclosed herein have useful pharmacological properties and may be employed for the prevention and treatment of diseases and disorders. The salts and pharmaceutical compositions according to the present disclosure may open up a further treatment alternative and may therefore be an enrichment of pharmacy.
The crystalline hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure as well as the solid pharmaceutical compositions according to the present disclosure can be used to treat, prevent or ameliorate different diseases or disorders. Elinzanetant and its pharmaceutically acceptable salts are suited for the treatment of diseases and disorders, such as psychotic disorders (WO 2007/028654 A1 ), and sex hormone-dependent diseases and disorders (WO 2016/184829 A1 ). Sex hormone-dependent diseases and disorders have been proven to be ameliorated by administration of elinzanetant in various clinical studies.
Accordingly, in an embodiment of the present disclosure disease or disorder is a sex hormone-dependent disease or disorder. In a particular preferred embodiment, the sex hormone-dependent disease or disorder is selected form the group consisting of vasomotor symptoms, pathological gain of excess body fat and/or excess body weight, insomnia, sleep disturbances, night-time awakenings, anxiety, depression, urinary symptoms of urgency, dysuria.
The term "sex hormone-dependent disease or disorder" as used herein means a disease or disorder which is exacerbated by, or caused by, excessive, inappropriate, or unregulated sex hormone production. Sex hormone-dependent diseases or disorders may occur in both sexes/genders, men and women. Accordingly, in one embodiment of the present disclosure, the disease or disorder is a sex hormone- dependent disease or disorder in males. In a further embodiment of the present disclosure the disease or disorder is a sex hormone-dependent disease or disorder in females.
Examples of such diseases or disorders in men include but are not limited to benign prostatic hyperplasia (BPH), metastatic prostatic carcinoma, testicular cancer, breast cancer, androgen dependent acne, seborrhea, hypertrichosis, male pattern baldness, vasomotor symptoms and in adolescents’ precocious puberty. Examples of such diseases or disorders in women include but are not limited to endometriosis, adenomyosis, abnormal puberty, uterine fibroids, heavy menstrual bleeding, hormone-dependent cancers (ovarian cancer, breast cancer), hyperandrogenism, hirsutism, hypertrichosis, female androgenetic alopecia, androgen dependent acne, seborrhea, virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans ), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized the ca cells in ovarian stroma), other manifestations of high intra ovarian androgen concentrations ( e.g. follicular maturation arrest, atresia, an ovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen producing tumor (virilizing ovarian or adrenal tumor), pathological gain of excess body fat and/or excess body weight, pre-eclampsia, diabetes, fatigue, irritability, cognitive decline, hair-loss, dry skin, insomnia, sleep disturbances, nighttime awakenings, anxiety and depression, decreases in sexual desire, vaginal dryness and pain, connective tissue loss and muscle bulk reduction, urinary symptoms of urgency, hidradenitis suppurativa, dysuria, osteoporosis.
Sex hormone-dependent diseases or disorders may be caused and/or associated with different conditions, which can have natural (such as menopause or adrenopause), surgical (such as bilateral oophorectomy in women, or orchiectomy or prostatectomy in men), radiological (i.e. radiation therapy) or chemical causes (e.g. adjuvant endocrine therapy).
Vasomotor symptoms or sleep disturbances or night-time awakenings can for example be caused by different conditions. In women the condition may be menopause- associated conditions, such as peri-menopause, the menopause, or the postmenopause. When referring to association with menopause herein, in one embodiment it is meant to include peri-menopause, menopause and post-menopause, more preferably peri-menopause and menopause.
In men, sex hormone-dependent diseases or disorders may be associated with adrenopause.
Accordingly, in one embodiment of the present disclosure, the disease or disorder, preferably the sex hormone-dependent disease or disorder, is a disease or disorder that is associated with menopause or adrenopause. Further, sex hormone-dependent diseases or disorders, e.g., vasomotor symptoms, may be caused in men and women by certain types of therapy interfering with hormone signalling and/or regulation, such as adjuvant endocrine therapy, e.g., using aromatase inhibitors such as anastrozole, exemestane, letrozole and testolactone; gonadotropinreleasing hormone receptor agonists such as such as leuprolide, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin; gonadotropin-releasing hormone receptor antagonists such as ASP1701 , elagolix, relugolix and linzagolix (OBE2109); selective estrogen receptor modulators (SERMs) such as bazedoxifene, clomifene, cyclofenil, tamoxifen, ormeloxifene, toremifene, raloxifene, lasofoxifene and ospemifene; selective estrogen receptor degraders (SERDs) such as fulvestrant, brilanestrant and elacestrant; CYP17 Al inhibitors such as abiraterone, ketoconazole and seviteronel; and combined androgen receptor blockers and CYP17 Al inhibitors such as galeterone.
In one embodiment of the disclosure, the disease or disorder is a sex hormone- dependent disease or disorder selected from the group consisting of vasomotor symptoms, insomnia, sleep disturbances, and night-time awakenings. Yet a further embodiment refers to the disease or disorder being vasomotor symptoms.
In one embodiment these sex hormone-dependent diseases or disorders are associated with menopause or caused by adjuvant endocrine therapy. Accordingly, an embodiment of the disclosure is the disease or disorder being selected from the group consisting of vasomotor symptoms associated with menopause, insomnia associated with menopause, sleep disturbances associated with menopause, and night-time awakenings associated with menopause. In an embodiment the disease or disorder is vasomotor symptoms associated with menopause. In a further embodiment of the disclosure is the disease or disorder being selected from the group consisting of vasomotor symptoms associated or caused by adjuvant endocrine therapy, insomnia or caused by adjuvant endocrine therapy, sleep disturbances or caused by adjuvant endocrine therapy, and night-time awakenings or caused by adjuvant endocrine therapy. In an embodiment the disease or disorder is vasomotor symptoms or caused by adjuvant endocrine therapy.
In some embodiments, the present disclosure further relates to a method for the treatment and/or prophylaxis of diseases and disorders, including the aforementioned diseases and disorders, using an effective amount of at least one of the hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure, including the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the disclosure.
In some embodiments, the present disclosure further relates to a method for the treatment and/or prophylaxis of sex hormone dependent disease or disorder comprising administrating to a subject in need thereof an effective amount of at least one of the hydrate forms of the compound of formula (I) according to the disclosure, preferably the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the disclosure. In some embodiments, the present disclosure further relates to a method for the treatment and/or prophylaxis of sex hormone dependent disease or disorder comprising administrating to a subject in need thereof a solid pharmaceutical composition according to the present disclosure. In one embodiment the solid pharmaceutical composition according to the present disclosure comprises an effective amount of elinzanetant.
In one embodiment the present disclosure the sex hormone-dependent disease or disorder is elected from the group consisting of vasomotor symptoms, insomnia and sleep disturbances comprising administrating to a subject in need thereof an effective amount of at least one of the hydrate forms of the compound of formula (I) according to the disclosure, preferably the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant according to the disclosure.
The salts of elinzanetant and the hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure can be administered alone or in combination with other active substances if necessary. The present disclosure further relates to medicinal products containing at least salt of elinzanetant, such as one of the hydrate forms of the benzenesulfonate salt of elinzanetant according to the disclosure and one or more further active substances, in particular for the treatment and/or prophylaxis of the aforementioned diseases.
An embodiment of the present disclosure is a pharmaceutical composition according to the present disclosure comprising substantially pure (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant, and more preferred (pseudo)polymorphic Hydrate 2 form which is substantially free of other solid forms of the elinzanetant and other solid forms of the benzenesulfonate salt of elinzanetant. In particular the pharmaceutical composition comprises the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of the compound of the formula (I) in accordance with the present disclosure.
Dosage of the pharmaceutical compositions of the present disclosure:
Based upon laboratory techniques known to evaluate compounds useful for the treatment of disorders, by pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compound of this disclosure can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The daily dose in an embodiment rages from about 40 mg to 300 mg elinzanetant and can be administered one or more times per day. Preferably the daily dose rages from 80 mg to 160 mg, more preferably from 100 mg to 160 mg, more preferably from 120 mg to 160 mg. In one embodiment, the daily dose is 120 mg. The daily dose in an embodiment refers to the amount of elinzanetant to be administered with one day. The skilled person will recognize that these amounts relate to the active pharmaceutical ingredient. Hence, the amounts reflect the amounts of elinzanetant per se without considering the counter ion of the respective salt.
Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present disclosure or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. The weight data in the tests and examples which follow are, unless stated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based on each case on the volume.
EXAMPLES
Crystalline forms of the benzenesulfonate salt of elinzanetant
Methods
X-Ray Powder Diffraction (XRPD)
XRPD Method A - Broker D8
For X-Ray Powder Diffraction (XRPD) the samples were placed into standard glass capillaries (0 = 0.7 mm or 1.0 mm). The measurements were performed at room temperature with a D8 Broker Advance Diffractometer (Cu-Ka1 = 1 .54059 A, Johansson primary beam monochromator, position sensitive detector) in transmission mode with the rotation of the sample. Data were collected in a two-theta range of 1 .5° to 50°. The tube voltage and current were 40 kV and 40 mA, respectively.
XRPD Method B - Broker D2
For X-Ray Powder Diffraction (XRPD) the sample was placed onto a special zerobackground silicon wafer, after careful grinding. The measurements were performed at room temperature with a Broker D2 Phaser Diffractometer (Cu-Ka1/2 = 1.5418 A, position sensitive detector) in reflection mode (Bragg-Brentano) with axial rotation of the sample. Data were collected in a two-theta range of either 4° to 50° or 3° to 40°. The tube voltage and current were set to 30 kV and 10 mA, respectively.
XRPD Method C - PANalytical EMPYREAN
For X-Ray Powder Diffraction (XRPD) the sample was placed onto a Powder bed in sample holder for temperature/humidity chamber. The measurements were performed at room temperature with a PANalytical EMPYREAN Diffractometer (Cu-Ka1/2 = 1 .5406 A) in Bragg-Brentano (Reflection) mode. Data were collected in a two-theta range of 3.5° to 40°. The tube voltage and current were set to 40 kV and 40 mA, respectively.
XRPD Method D - Stadi P (STOE)
For X-Ray Powder Diffraction (XRPD) the sample was prepared as a thin layer between two foils, after careful grinding. The measurements were performed at room temperature with a STOE Stadi P Diffractometer (Cu-Ka1/2 = 1.5418 A, Mythen position sensitive detector) in transmission mode. Data were collected in a two-theta range of either 2° to 30° or 2° to 40°. The tube voltage and current were set to 40 kV and 40 mA, respectively.
Differential Scanning Calorimetry (DSC)
Method A - Netzsch Phoenix DSC 204 F1
DSC data were obtained on Netzsch Phoenix DSC 204 F1. Approximately 5-15 mg of each sample was placed into an aluminium DSC crucible and the weight was accurately recorded. The hermetically sealed crucibles with one pinhole were used for analysis. The samples were heated under a nitrogen atmosphere (20 mL/min) at a rate of 10 °C/min.
Method B - Mettler-Toledo DSC3+
DSC data were obtained on Mettler-Toledo DSC3+. Approximately 4-10 mg of each sample was placed into an aluminium DSC crucible and the weight was accurately recorded. The hermetically sealed crucibles with one pinhole were used for analysis. The samples were heated under a nitrogen atmosphere (20 mL/min) at a rate of 20 K/min.
Thermogravimetric analysis (TGA)
Method A - Perkin Elmer Thermogravimetric Analyzer Pyris 6
TGA analyses were performed on a Perkin Elmer Thermogravimetric Analyzer Pyris 6 TGA. Approximately 10-15 mg of sample was placed in a fared crucible and weighted accurately in the TG furnace. The samples were heated in nitrogen at a rate of 10°C/min.
Method B - Mettler-Toledo TGA/DSC3+
TGA analyses were performed on a Mettler-Toledo TGA/DSC3+. Approximately 4-10 mg of sample was placed in a fared crucible and weighted accurately in the TG furnace. The samples were heated in nitrogen at a rate of 20K/min.
Infrared spectroscopy (IR)
Method A - Thermo Scientific Nicolet
IR spectra were acquired on a Thermo Scientific Nicolet iS10 in ATR-geometry. Each spectrum represents 64 co-added scans with a resolution of 4 cm’1 in the following measuring range: 4000 - 600 cm’1. Method B - Broker Alpha ii
IR spectra were acquired on a IR Spectrometer Broker Alpha ii in ATR-geometry. Each spectrum represents 34 co-added scans with a resolution of 2 cm-1 in the following measuring range: 4000 - 600 cm-1.
Dynamic vapour sorption (DVS)
Method A - DVS Resolution gravimetric sorption analyer
Water sorption was determined at 25°C using a DVS Resolution gravimetric sorption analyser (London, UK). The sample was dried for 1000 minutes at 0% relative humidity, after which the dry weight was recorded. The humidity was increased in steps of 10% to 90% RH and then decreased again to 0% RH. The equilibrium criterion was set to a relative mass change of dm / dt = 0.002% / minute.
Method B -IGAsorp Hidden Isochema
Water sorption was determined at 25°C using a IGAsorp Hidden Isochema analyzer. The sample was dried for 24 hours at 0% relative humidity, after which the dry weight was recorded. The humidity was increased in steps of 10% to 95% RH and then decreased again to 0% RH. The equilibrium criterion was set to a relative mass change of dm / dt = 0.001 % / minute.
Nuclear Magnetic Resonance (NMR)1H NMR spectra were acquired on a Bruker Advance DRX 400 spectrometer (at 400 MHz) at room temperature in deuterated solvent (d6-DMSO). Information about the chemical shift 5 is given in ppm, relative to the irradiation frequency. The signal of the deuterated solvent is used as internal standard.
Manufacture of different forms of benzenesulfonate salt of elinzanetant
Example 1
Preparation of the (pseudo)polvmorphic form Hydrate 1 of the benzenesulfonate salt of elinzanetant
10 g of the anhydrate Form 1 of compound of formula (I) (elinzanetant) (see WO 2011/023733 A1 ) was dissolved in 100 mL of toluene and the solution was heated up to 40 °C. A solution of 2.6 g of benzenesulfonic acid in 13.8 mL of water was dosed to the toluene solution during 60 minutes, while maintaining 40 °C temperature. The resulting suspension was stirred at 40 °C overnight. Afterwards the suspension was heated to 80 °C and tempered, forming a slightly turbid solution. The system was cooled down to 20 °C constantly over 60 minutes and stirred at that temperature over the weekend. The resulting suspension was filtered (pore size of between 10pm and 40pm), washed with 20 mL of toluene and dried at 45 °C in vacuum and N2 purge yielding 11.2 g of dry, partially crystalline benzenesulfonate salt of the compound of the formula (I) (90.7% yield).
Example 2
Preparation of (pseudo)polvmorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant
40 mg of the benzenesulfonate salt of the compound of the formula (I), prepared as described in Example 1 , were weighed into a 4 mL vial. 100 pL chloroform was added, the vessel was tightly closed and stirred for ten minutes on a magnetic stir plate at 25 °C. The solution is quickly drawn up completely with a syringe and filtered through the 0.2 pm ReZist® filter into a new 4 mL vial and placed in the fume cupboard at 25 °C for the evaporation experiment. After the end of the evaporation experiment, the sample is sealed and analyzed. Thermogravimetric analysis (TGA) shows a mass loss characteristic for solvated/hydrated forms (FIG. 3), and Nuclear Magnetic Resonance (NMR) spectroscopy which has shown no presence of organic solvents in the sample (FIG. 32), hence confirming that the mass loss seen in TGA belongs to water and the pseudo(polymorphic) form is a hydrate.
Example 3
Optimized process for preparation of (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant
15.0 g of the anhydrate Form 1 compound of formula (I) (elinzanetant) (see WO 2011/023733 A1 ) was dissolved in 75 mL of ethyl acetate, at room temperature. To the resulting solution, 5.0 g water and 37.5 mL of n-heptane were added and the biphasic system was heated up to 50°C to 55 °C. 3.60 g of benzenesulfonic acid (1.0 eq.) was added and mixed and the system becomes monophasic, i.e. a suspension. The solution was cooled down to 45 °C and seeded with 0.15 g of (pseudo)polymorphic form Hydrate 2 benzenesulfonate salt of the compound of the formula (I). After 1 hour of isothermal ageing the suspension was cooled down to room temperature in 1 hour, stirred for 4 hours and isolated by filtration (pore size of between 10pm and 40pm). The wet filter cake was washed with 45 mL of 2:1 (v:v) mixture of ethyl acetate and n- heptane and dried in vacuum at 60 °C to yield 18.2 g of dry (pseudo)polymorphic form Hydrate 2 (98% yield).
Example 4
Preparation of (pseudo)polvmorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant
40 mg of the benzenesulfonate salt of the compound of the formula (I) prepared as described in Example 1 above were placed into a 4 mL vial. 1000 pL water were added acquiring a suspension, which was optionally stirred. The vial was sealed properly with a screw cap and additional application of Parafilm®. The vial was then placed on a magnetic stirrer (stirring speed: 1000 rpm, temperature: fume hood environment: 25 °C, stirring time: seven days). The suspension was checked daily in order to verify a homogeneous suspension. After seven days the slurry was filtered over a 13 mm Hirsch-funnel equipped with a Whatman® paper filter No 540. The solid residues were dried in the air (approx, one hour) and then placed in a new, clean 4 mL vial with a PTFE seal. The sample was analyzed. Annotation: Due to instability reasons of the sample two measurements were performed. First measurement of sample using XRPD method B, showed a diffraction pattern (FIG. 15). This pattern was named Pattern G. After an exposure to ambient conditions for 5 days XRPD measurement was repeated using Method A. The diffraction pattern was different to the first measurement and is shown in Figure 11 . Accordingly, the polymorph/(pseudo)polymorph with Pattern G is metastable. The (pseudo)polymorph of the second measurement was stable and identified as(pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant. Thermogravimetric analysis (TGA) shows a mass loss characteristic for solvated/hydrated forms (FIG. 13), and Nuclear Magnetic Resonance (NMR) spectroscopy which has shown no presence of organic solvents in the sample (FIG. 33), hence confirming that the mass loss seen in TGA belongs to water and the pseudo(polymorphic) form is a hydrate.
Example 5
Preparation of (pseudo)polymorphic form of the benzenesulfonate salt of elinzanetant showing XRPD Pattern 4
40 mg of the benzenesulfonate salt of the compound of the formula (I) prepared as described in Example 1 above were weighed into a 4 mL vial. 50 pL 1 -propanol was added, the vessel was tightly closed and stirred for ten minutes on a magnetic stir plate at 25 °C. During stirring a solid was obtained spontaneously, which was handed over for analysis. Annotation: Due to instability reasons of the sample two measurements of example 5 were performed. First XRPD measurement of the sample using XRPD method B, named Pattern D, showed a different diffraction pattern (FIG. 10) in contrast to the second XRPD measurement using Method A subsequently named Pattern 4 (FIG. 6).
Example 6
Preparation of (pseudo)polvmorphic form of the benzenesulfonate salt of elinzanetant showing XRPD Pattern 5
40 mg of the benzenesulfonate salt of the compound of the formula (I) prepared as described in Example 1 above were weighed into a 4 mL vial. 100 pL anisole was added, the vessel was tightly closed and stirred for ten minutes on a magnetic stir plate at 25 °C. During stirring a solid was obtained spontaneously and analyzed.
Example 7
Preparation of (pseudo)polymorphic form of the benzenesulfonate salt of elinzanetant showing XRPD Pattern 6
40 mg of the benzenesulfonate salt of the compound of the formula (I) prepared as described in Example 1 above were weighed into a 4 mL vial. 100 pL tetramethylurea was added, the vessel was tightly closed and stirred for ten minutes on a magnetic stir plate at 25 °C. The solution is quickly drawn up completely with a syringe and filtered through the 0.2 pm ReZist® filter into a new 4 mL vial and placed in the fume cupboard at 25 °C for the evaporation experiment. After the end of the evaporation experiment, the sample was analyzed.
Example 8
Preparation of (pseudo)polymorphic form of the benzenesulfonate salt of elinzanetant showing XRPD Pattern 8
1000 mg of the benzenesulfonate salt of the compound of the formula (I) prepared as described in Example 1 above were weighed into a 4 mL vial. 500 pL 1 -propanol was added, the vessel was tightly closed and stirred for ten minutes on a magnetic stir plate at 25 °C. During stirring a solid was obtained spontaneously and analyzed. Example 9
Preparation of the benzenesulfonate salt of elinzanetant in an amorphous form 50 mg of the compound of formula (I) (elinzanetant) prepared as described in Example 1 above were weighed into a grinding jar. The vessel was tightly closed with a sealing ring and a lid. The grinding jar was clamped into the Fritsch Pulverisette® 23 and the sample was grinded for ten minutes. The following conditions were selected for grinding:
• one grinding ball 10 mm
• 50 Hz
• Temperature: room temperature
• Grinding time: 60 minutes
The solid was prepared in a 4 mL PTFE vial.
Example 10
Physical characterization of polymorphic forms of the benzenesulfonate salt of elinzanetant
X-Ray Powder Diffraction (XRPD)
Polymorphic forms of the benzenesulfonate salt of elinzanetant were manufactured as described above.
The product of Example 2 ((pseudo)polymorphic form Hydrate 2) was analyzed with XRPD Method A. The reflection peak maxima (2 Theta) are given in the Table below and the pattern is also shown in Table 1 and Figure 1 (a). The product of Example 3 ((pseudo)polymorphic form Hydrate 2) was analyzed with XRPD Method B and showed a similar reflection pattern as shown in Figure 1 (b).
Table 1: Reflections of XRPD of the (pseudo)polymorphic form Hydrate 2 of the benzenesulfonate salt of elinzanetant isolation. The Pattern is shown in Table 2 and Figure 15 was named Pattern G. After 5 days of storage at room temperature another XRPD analysis was performed using Method A. The pattern of the peak maxima changed as seen in Table 2 below and Figure 11 , and turned out to be (pseudo)polymorphic form Hydrate 3. It turned out that the Hydrate 3 is stable at ambient conditions. Table 2: Reflections of XRPD of the crystalline form Pattern G and of the (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant
The product of Example 5 was first analyzed using XRPD method B directly after isolation. The Pattern is shown in Table 3 below and Figure 10 and was named Pattern D. After storage at room temperature another XRPD analysis was performed using Method A. The pattern of the peak maxima changed as seen in Table 3 and Figure 6 and was named Pattern 4.
Table 3: Reflections of XRPD of crystalline forms of Pattern D and Pattern 4 of the benzenesulfonate salt of elinzanetant
The products of Example 6 (Pattern 5), Example 7 (Pattern 6) and Example 8 (Pattern 8) were analyzed after isolation using XRPD Method A. The results are shown in the Table below and Figure 16 (Pattern 5), Figure 20 (Pattern 6) and Figure 23 (Pattern 8). Table 4: Reflections of XRPD of crystalline forms of Pattern 5, Pattern 6 and Pattern 8 of the benzenesulfonate salt of elinzanetant
Infrared spectroscopy
(Pseudo)polymorphic forms of the benzenesulfonate salt of elinzanetant as disclosed in above’s examples as well as of Examples 20 and 21 were manufactured as described and analyzed by Infrared spectroscopy. The results are shown in Table 5, and Figure 4 ((pseudo)polymorphic form Hydrate 2), Figure 14 ((pseudo)polymorphic form Hydrate 3), Figure 9 (Pattern 4) and Figure 19 (Pattern 5). Table 5: Infrared Spectra Bands of crystalline forms of (pseudo)polymorphic forms Hydrate 2 and Hydrate 3 as well as Pattern 4 and 5 of the benzenesulfonate salt of elinzanetant
Example 11
Sorption and Desorption Stability
DVS was conducted as described above to analyse the water sorption and desorption behaviour of Hydrate 2 form of the benzenesulfonate salt of elinzanetant prepared according to Example 2. The following mass-changes were identified in the second cycle, and the results for the first and the second cycle are shown in Figure 5(a). The shape of the sorption isotherm is characteristic for non-stoichiometric hydrates which are known from the literature (cp. Jean-Rene Authelin, Thermodynamics of non- stoichiometric pharmaceutical hydrates, International 1-2 Journal of Pharmaceutics, Volume 303, Issues, 2005, Pages 37-53, htps://doi.Org/10.1016/i.iipharm.2Us s ). As can be seen in Figure 5(a), the mass changes throughout the different sorption cycles remains similar, showing a stable and predictable mass ratio at specific ambient humidities.
Table 6: Mass changes in sorption-desorption test
Target Change in mass (%) - ref
% P/Po Sorption Desorption
0 0.109 0.000
10 0.669 0.709
20 0.827 0.895
30 0.967 1.059
40 1.118 1.215
50 1.296 1.399
60 1.507 1.627
70 1.790 1.910
80 2.191 2.336
90 2.829 3.031
98 4.224 4.224
This translal es in a molar ratio (n of the Formulas disclosed herein above) for the different humidities as follows:
Table 7: Molar water ratios in sorption-desorption test
Target
Change in mole ratio of H2O - ref
% P/Po Sorption Desorption
0 0.1 0.0
10 0.3 0.3
20 0.4 0.4
30 0.4 0.5
40 0.5 0.6
50 0.6 0.7
60 0.7 0.8
70 0.8 0.9
80 1.0 1.1
90 1.3 1.4
98,0 2.0 2.0
DVS was also performed with the Hydrate 3 form of the benzenesulfonate salt of elinzanetant prepared according to Example 4. The results are shown in Figure 5(b). As can be seen, repeated sorption and desorption results in a different ratio of comolecule uptake into the crystal structure and differing sorption isotherm shape in different cycles.
TGA
Thermogravimetric Analyses (TGA) were conducted for the isolated polymorphs and/or (pseudo)polymorphs to identify mass loss phenomena that would indicate formation of a hydrate or a solvate. The results are shown in Figure 3 (Hydrate 2), Figure 8 (Pattern 4), Figure 13 (Hydrate 3), Figure 18 (Pattern 5), Figure 22 (Pattern 6), Figure 25 (Pattern 8), Figure 45 (Hydrate 6), Figure 50 (Hydrate 7), Figure 54 (Pattern 7).
NMR
1 H Nuclear Magnetic Resonance (NMR) was conducted to exclude presence of solvents in the analyzed polymorphs and/or (pseudo)polymorphs. Results are shown in Figure 32 (Hydrate 2) and Figure 33 (Hydrate 3) showing no organic solvents, therefore confirming that the mass loss observed in TGA analyses corresponds to water and the (pseudo)polymorphic forms are hydrates. XRPD of Hydrate 2 at different ambient humidities
X-Ray Powder Diffraction (XRPD) analysis was conducted for Hydrate 2 form at different relative humidity conditions, to further confirm the non-stoichiometric hydrate assignment. As can be seen in Figures 29, 30 and 31 , the crystal structure is stable between 20%, 50% and 80% relative humidity (as seen by marginal changes in the XRPDs), confirming that Hydrate 2 form is a non-stoichiometric hydrate, structure of which does not depend on the amount of water molecules in the crystal, in the range of 20% to 80% relative humidity.
Example 12
Mechanical Stability
To test the mechanical stability of the Hydrate 2 and the Hydrate 3 forms of the benzenesulfonate salt of elinzanetant, XRPD analysis using Method B, supra, were conducted before and after micronization of the respective (pseudo)polymorphic forms.
The Hydrate 2 form of the benzenesulfonate salt of elinzanetant was produced by dissolving 10 g of elinzanetant in 75 mL of ethyl acetate. The solution was heated to 70 °C within 30 minutes and a solution of 2.6 g of benzenesulfonic acid in 13.8 mL of water was added to that solution during 20 minutes. The resulting mixture was cooled down to 5 °C and the resulting suspension was stirred at 5 °C overnight. The crystallized solid was isolated by filtration, washed with 20 mL ethyl acetate, and dried in vacuum at 45 °C to yield 10.5 g (84.91 %) of solid of the Hydrate 2 form of the benzenesulfonate salt of elinzanetant.
The Hydrate 3 form of the benzenesulfonate salt of elinzanetant was produced by dissolving 10 g of elinzanetant in 100 mL of MtBE. The solution was heated to 50 °C within 30 minutes and a solution of 2.6 g of benzenesulfonic acid in 13.8 mL of water was added to that solution during 15 minutes. The resulting mixture was stirred at 50 °C for 60 minutes and subsequently cooled down to 5 °C within 300 minutes. The resulting suspension was stirred at 5 °C overnight and the solid was isolated by filtration, washed with 20 mL MtBE and dried in vacuum at room temperature to yield 11.1 g (89.77%) of solid of the Hydrate 3 form of the benzenesulfonate salt of elinzanetant. XRPD analysis using Method B were conducted before and after micronization of the respective solid hydrate forms in a spiral jet mill. The results are shown in Figure 34.
The Hydrate 2 form shows advantageous crystallinity and mechanical stability over the Hydrate 3 form. This can be seen in the Figure 34, where the Hydrate 2 form shows more intensive and sharp reflections compared to Hydrate 3 form. Moreover, after micronizing the Hydrate 2 form and the Hydrate 3 form using a spiral jet-mill, it can be seen that the diffraction pattern of micron ized Hydrate 2 form shows conserved crystallinity (intensity of reflections is the same as before micronization), whereas the diffraction pattern of micronized Hydrate 3 shows a significant reduction of crystallinity (amorphization), typically leading to issues with physical properties, water content, wettability, reproducibility and physical stability (e.g. through slow re-crystallization). Those issues are present for the more stable Hydrate 2 form.
PHARMACEUTICAL COMPOSITIONS CONTAINING A SALT OF ELINZANETANT
Production of crystalline form of the isopropanol solvate of the di-hydrochloride salt of elinzanetant
30.0 g of elinzanetant was mixed with 105.0 g of isopropanol, at room temperature, to obtain a clear solution. The solution was heated to 70 °C and 26.1 g of 5-6N solution of HCI in isopropanol was added. To the resulting solution, 0.30 g of seeds of the 2HCI isopropanol solvate seeds were added. Crystallization was complete after 1 hour of stirring at 70 °C and the suspension was cooled down to room temperature in 2 hours. After overnight stirring at room temperature, the solid was isolated by filtration, washed with 90 mL of isopropanol and dried in vacuum at 45 °C, to obtain 35.7 g (99.3% yield) of the product. XRPD is shown in Figure 35. Isopropanol (by gas chromatography): 8.7%; chloride ion content (by ion chromatography): 8.4%
The crystalline form was analyzed by XRPD Method B. The result is shown in Figure 35 and the reflections are shown in Table 8:
Table 8: Reflections of XRPD of crystalline form of the isopropanol solvate of the dihydrochloride salt of elinzanetant
Production of Tablets
Tablets with a dose of 120 mg elinzanetant related to the free base were investigated. Tablets were produced by compressing the respective composition below using either a compression simulator ((StylOne Evolution, Medelpharm) or a conventional rotary die press (Fette 102i, Fette compacting). Oval tablets with a length of 16 mm and a width of 7 mm were produced targeting a resistance to crushing of 150 N. Example 13: Comparative Examples
The Following compositions were manufactured as comparative examples.
Example 13.1 : Wet Granulation
Example 13.1.1 : Elinzanetant di-HCI salt sodium dodecyl sulfate composition
2.04 g lactose, 2.76 g microcrystalline cellulose and 0.41 g croscarmellose sodium were blended in a mortar with a pestle. 0.02 g sodium dodecyl sulfate, 0.26 g hydroxypropyl methylcellulose were dissolved in water and 2.63 g crystalline elinzanetant di-HCI salt isopropanol solvate (see WO 2021/094247 A1 , Example 7) suspended.
The blend was wet granulated by adding the elinzanetant di-HCI salt suspension dropwise in the mortar and blending it manually. Wet granules were afterwards dried within an oven for 2 h and the dried granules manually crushed with the pistil. The granules were blended with 0.043 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.1.2: Elinzanetant benzenesulfonate salt sodium dodecyl sulfate composition
0.72 g lactose, 0.99 g microcrystalline cellulose and 0.14 g croscarmellose sodium were blended in a mortar with a pestle. 0.007 g sodium dodecyl sulfate, 0.09 g hydroxypropyl methylcellulose were dissolved in water and 0.92 g elinzanetant benzenesulfonate salt prepared according to Example 3suspended.
The blend was wet granulated by adding the elinzanetant benzenesulfonate suspension dropwise in the mortar and blending it. Wet granules were afterwards dried within an oven for 2 h and the dried granules crushed with the pistil. The granules were blended with 0.043 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg. Example 13.1.3: Elinzanetant di-HCI salt sodium dodecyl sulfate composition
1.56 g Hydroxypropylmethylcellulose 3 Centipoise (HPMC 3 cp) and 0.12 g sodium dodecyl sulfate were dissolved within 75.92 demineralized water. Within this solution 16.09 g elinzanetant di-HCI salt isopropanol solvate were suspended. 12.48 g lactose and 16.91 g microcrystalline cellulose were blended within a fluid bed granulator and granulated with the prepared elinzanetant di-HCI salt suspension. The granules were dried afterwards directly within the granulator and sieved trough an 800 pm sieve.
The granules were post-blended with 0.26 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.1.4: Elinzanetant di-HCI salt Polysorbate 20 composition
1.56 g HPMC 3 cp and 0.12 g Polysorbate 20 were dissolved within 75.92 demineralized water. Within this solution 16.09 g elinzanetant di-HCI salt isopropanol solvate were suspended. 12.48 g lactose and 16.91 g microcrystalline cellulose were blended within a fluid bed granulator and granulated with the prepared elinzanetant di- HCI salt suspension. The granules were dried afterwards directly within the granulator and sieved trough an 800 pm sieve.
The granules were post-blended with 0.26 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.1.5: Elinzanetant benzenesulfonate salt composition without surfactant
0.86 g HPMC 3 cp was dissolved within 41.64g demineralized water. Within this solution 8.83 g elinzanetant benzenesulfonate salt prepared according to Example 3were suspended. 6.86 g lactose and 9.33 g microcrystalline cellulose were blended within a fluid bed granulator and granulated with the prepared elinzanetant benzenesulfonate salt suspension. The granules were dried afterwards directly within the granulator and sieved trough an 800 pm sieve. 9 g of granules were post-blended with 0.047 g sieved magnesium stearate (500 pm) for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2: Direct Compression
Example 13.2.1 : Direct Compression without surfactants
Example 13.2.1.1 Elinzanetant di-HCI salt crospovidone composition
2.32 g of elinzanetant di-HCI salt isopropanol solvate were mixed for 5 min within a turbula blender with 4.47 g of microcrystalline cellulose and 0.38 g of crospovidone. 0.038 g sieved (500 pm sieve) magnesium stearate was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.1.2 Elinzanetant benzenesulfonate salt crospovidone composition
2.29 g of elinzanetant benzenesulfonate salt prepared according to Example 3 were mixed for 5 min within a turbula blender with 4.49 g of microcrystalline cellulose and 0.38 g of crospovidone. 0.038 g sieved (500 pm sieve) magnesium stearate was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.1.3 Elinzanetant di-HCI salt croscarmellose sodium composition
3.25 g elinzanetant di-HCI salt isopropanol solvate, 6.25 g microcrystalline cellulose and 0.53 g croscarmellose sodium were rubbed within a mortar and afterwards blended for 2 min in a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.1.4 Elinzanetant benzenesulfonate salt croscarmellose sodium composition
3.21 g elinzanetant benzenesulfonate salt prepared according to Example 3, 6.29 g microcrystalline cellulose and 0.53 g croscarmellose sodium were rubbed within a mortar and afterwards blended for 2 min in a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.2: Direct Compression without surfactants
Example 13.2.2.1. elinzanetant di-HCI salt isopropanol solvate lactose com posi ti on
3.25 g elinzanetant di-HCI salt isopropanol solvate, 3.26 g lactose, 3 g microcrystalline cellulose and 0.53 g croscarmellose sodium were rubbed within a mortar and afterwards blended for 2 min in a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.2.2 elinzanetant benzenesulfonate salt lactose composition
3.18 g elinzanetant benzenesulfonate salt prepared according to Example 3, 3.26 g lactose, 3.08 g microcrystalline cellulose and 0.53 g croscarmellose sodium were blended within a mortar and afterwards blended for 2 min in a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.2.3 elinzanetant di-HCI salt isopropanol solvate PEG6000 composition
3.24 g polyethylene glycol 6000 was rubbed within a mortar, afterwards 3.25 g elinzanetant di-HCI salt isopropanol solvate, 2.99 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added and rubbed again. The mixture was afterwards blended for 2 min in a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.2.4 elinzanetant benzenesulfonate salt PEG6000 composition
3.21 g elinzanetant benzenesulfonate salt prepared according to Example 3, 3.25 g polyethylene glycol, 3.05 g microcrystalline cellulose and 0.53 g croscarmellose sodium were blended within a mortar and afterwards blended for 2 min in a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed again for 2 min. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.3: Direct compression with ionic surfactants
Example 13.2.3.1 elinzanetant benzenesulfonate salt sodium dodecyl sulfate composition
3.21 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.64 g sodium dodecyl sulfate were rubbed with a mortar and pestle. 5.66 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 13.2.3.2 elinzanetant di-HCI salt sodium dodecyl sulfate composition
3.25 g elinzanetant di-HCI salt isopropanol solvate, and 0.63 g sodium dodecyl sulfate were blended with a mortar and pestle. 5.66 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added and all ingredients first blended with the mortar and pestle and afterwards for 5 min within a turbula mixer. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14: Compositions in accordance with the present disclosure
Example 14.1 Direct compression with non-ionic surfactants
Example 14.1.1 polysorbate 20
Example 14.1.1.1 elinzanetant di-HCI salt polysorbate 20 composition
3.26 g elinzanetant di-HCI salt isopropanol solvate and 0.63 g Polysorbate 20 were blended with a mortar and pestle. 5.63 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre- blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.1.2 elinzanetant benzenesulfonate salt polysorbate 20 composition
3.22 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.63 g Polysorbate 20 were blended with a mortar and pestle. 5.66 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.2 macrogol-15-hydroxystearate
Example 14.1.2.1 elinzanetant di-HCI salt macrogol-15-hydroxystearate composition
3.25 g elinzanetant di-HCI salt isopropanol solvate and 0.63 g macrogol-15- hydroxystearate were blended with a mortar and pestle. 5.62 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.2.2 elinzanetant benzenesulfonate salt macrogol-15- hydroxystearate composition
3.21 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.63 g Macrogol-15-hydroxystearate were blended with a mortar and pestle. 5.66 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg. Example 14.1.2.3 elinzanetant benzenesulfonate salt macrogol-15- hydroxystearate composition
7.65 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.76 g Macrogol-15-hydroxystearate were blended with a mortar and pestle. 14.23 g microcrystalline cellulose and 1.25 g croscarmellose sodium were added and all ingredients first blended with the mortar and pestle and afterwards for 3 min within a turbula mixer. 0.07 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 3 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.2.4 elinzanetant di-HCI salt macrogol-15-hydroxystearate composition
7.74 g elinzanetant di-HCI salt isopropanol solvate and 0.75 g macrogol-15- hydroxystearate were blended with a mortar and pestle. 14.14 g microcrystalline cellulose and 1.25 g croscarmellose sodium were added and all ingredients first manually blended with the mortar and pestle and afterwards for 3 min within a turbula mixer. 0.07 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 3 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.2.5 elinzanetant benzenesulfonate salt macrogol-15- hydroxystearate composition
9.94 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.32 g macrogol-15-hydroxystearate were blended with a mortar and pestle. 19.15 g microcrystalline cellulose and 1.63 g croscarmellose sodium were added and all ingredients first manually blended with the mortar and pestle and afterwards for 3 min within a turbula mixer. 0.07 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 3 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg. Example 14.1.3 Macrogolglycerolricinoleate
Example 14.1.3.1 elinzanetant di-HCI salt macrogolglycerolricinoleate composition
3.25 g elinzanetant di-HCI salt isopropanol solvate and 0.64 g macrogolglycerolricinoleate were blended with a mortar and pestle. 5.63 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.3.2 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
3.21 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.63 g Macrogolglycerolricinoleate were blended with a mortar and pestle. 5.66 g microcrystalline cellulose and 0.53 g croscarmellose sodium were added, and all ingredients manually blended with the mortar and pestle. 0.05 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.3.3 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
4.61 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.47 g Macrogolglycerolricinoleate were blended with a mortar and pestle. 8.51 g microcrystalline cellulose and 0.73 g croscarmellose sodium were added and all ingredients first manually blended with the mortar and pestle and afterwards blended for 5 min within a turbula mixer. 0.07 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg. Example 14.1.3.4 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
4.63 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.3 g Macrogolglycerolricinoleate were blended with a mortar and pestle. 8.58 g microcrystalline cellulose and 0.74 g croscarmellose sodium were added and all ingredients first manually blended with the mortar and pestle and afterwards blended for 5 min within a turbula mixer. 0.07 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.3.5 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
4.62 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 0.17 g Macrogolglycerolricinoleate were blended with a mortar and pestle. 8.88 g microcrystalline cellulose and 0.77 g croscarmellose sodium were added and all ingredients first manually blended with the mortar and pestle and afterwards blended for 5 min within a turbula mixer. 0.08 g sieved magnesium stearate (500 pm) was added to the pre-blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator using 16x7 mm oval punches with a weight of 480 mg.
Example 14.1.3.6 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
156.14 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 10.42 g macrogolglycerolricinoleate were blended with a mortar and pestle. 304.94 g microcrystalline cellulose (MCC) and 26.05 g croscarmellose sodium were blended in a free fall mixer for 10 min. Microcrystalline cellulose-croscarmellose sodium blend was split and the first part was mixed for 10 min on a free fall blender with the elinzanetant benzenesulfonate salt/surfactant blend. This pre-blend was manually sieved through an 800 pm sieve and blended again for 10 min. Afterwards the second part of the microcrystalline cellulose-croscarmellose sodium blend was added and the mixture blended again for 10 min. The blend was manually sieved trough an 800 pm sieve and blended again for further 10 min. One half of the resulting blend was mixed with 2.59 g of sieved magnesium stearate for 5 min in a free fall blender. Afterwards one half of the blend was mixed with 1.98 g silicon dioxide for 5 min within a turbula mixer and sieved manually through an 800 pm mesh. Afterwards the sieved material was blended again for 5 min. 0.71 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator (StylOne Evolution, Medelpharm) using 16x7 mm oval punches with a weight of 483.5 mg.
Example 14.2 Dry Granulation with non-ionic surfactants
Example 14.2.1 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
157.05 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 10.48 g macrogolglycerolricinoleate were blended with a mortar and pestle. 306.7 g microcrystalline cellulose and 26.2 g croscarmellose sodium were blended in a free fall mixer for 10 min. Microcrystalline cellulose-croscarmellose blend was split in two parts and one part was mixed for 10 min on a free fall blender with the elinzanetant benzenesulfonate salt/macrogolglycerolricinoleate blend. This pre-blend was manually sieved through an 800 pm sieve and blended again for 10 min. Afterwards the other part of the microcrystalline cellulose-croscarmellose sodium blend was added and the mixture blended again for 10 min. The blend was manually sieved trough an 800 pm sieve and blended again for further 10 min. This blend was roller compacted and dry granulated. 0.59 g silicon dioxide and 5.85 g microcrystalline cellulose were mixed for 5 min within a turbula mixer. This blend and 93.12 g of the dry granules were mixed for 5 min on a turbula mixer and sieved manually through a 1 mm sieve. Afterwards the sieved material was blended again for 5 min. 0.49 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 2 min within a turbula mixer. The final blend was tableted on a compression simulator (StylOne Evolution, Medelpharm) using 16x7 mm oval punches with a weight of 513 mg.
Example 14.2.2 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
314.07 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 21.34 g macrogolglycerolricinoleate were blended with a mortar and pestle. 633.66 g microcrystalline cellulose and 31.45 g croscarmellose sodium were blended in a free fall mixer for 10 min. This blend was split in two parts and one part was mixed for 10 min on a free fall blender with the elinzanetant benzenesulfonate salt /surfactant blend. This pre-blend was manually sieved through an 800 pm sieve and blended again for 10 min. Afterwards another part of the microcrystalline cellulose-croscarmellose sodium blend was added and the mixture blended again for 10 min. The blend was manually sieved trough an 800 pm sieve and blended again for further 10 min. This blend was roller compacted and dry granulated. 5.94 g silicon dioxide and 59.42 g microcrystalline cellulose were mixed for 5 min within a freefall blender and sieved manually through a 1 mm sieve. The sieved blend and the dry granules were mixed for 10 min. 7.62 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 5 min. The ready-to-press blend was tableted on a rotary die press (Fette 102i, Fette Compacting) using 16x7 mm oval punches with a weight of 514 mg. Tablets were coated within a drum coater with a yellow HPMC-based lacquer.
Example 14.2.3 elinzanetant benzenesulfonate salt macrogolglycerolricinoleate composition
872.89 g elinzanetant benzenesulfonate salt prepared according to Example 3 and 58.25 g macrogolglycerolricinoleate were blended with a mortar and pestle in three sub portions. 1760 g microcrystalline cellulose and 87.39 g croscarmellose sodium were blended in a free fall mixer for 10 min. This blend was split, and the first part was mixed for 10 min on a free fall blender with the API/surfactant blend. This pre-blend was manually sieved through an 800 pm sieve and blended again for 10 min. Afterwards the second part of the microcrystalline cellulose-croscarmellose sodium blend was added and the mixture blended again for 10 min. The blend was manually sieved trough an 800 pm sieve and blended again for further 10 min. This blend was roller compacted and dry granulated. 13.78 g silicon dioxide and 137.78 g microcrystalline cellulose were mixed for 5 min within a freefall blender and sieved manually through a 1 mm sieve. The sieved blend and 2.19 kg of the dry granules were mixed for 10 min. 23.65 g sieved magnesium stearate (500 pm) was added to the blend and mixed for 5 min. The ready-to-press blend was tableted on a rotary die press (Fette 102i, Fette Compacting) using 16x7 mm oval punches with a weight of 515 mg. Tablets were coated within a drum coater with a yellow HPMC-based lacquer. 97 able 9: Overview of Examples of elinzanetant benzenesulfonate salt tablet composition according to the present disclosure ompositions containing 152.9 mg elinzanetant salt were produced with a different salt correction factor. The salt correction factor was dapted for the variable occupancy hydrate, resulting in a correction factor of 148.8 mg for an equivalent of 120 mg elinzanetant free ase and the amount of MCC was increased accordingly.
able 10: Overview comparative elinzanetant benzenesulfonate salt tablet composition able 11: Overview of Examples of elinzanetant di-HCI salt isopropanol solvate tablet compositions according to the present disclosure
able 12: Overview comparative elinzanetant di-HCI salt isopropanol solvate tablet compositions ll amounts in Tables 9 to 12 are in mg; MCC: microcrystalline cellulose; CCS: croscarmellose sodium; SDS: sodium dodecyl su fate; 15HS: macrogol-15-hydroxy-stearate; MGR: macrogol-glycerol-ricinoleate; MS: magnesium stearate
EXAMPLE 15 Dissolution behavior of different compositions
Preparation of HPMC Suspensions
For suspension experiments a 0.5% hydroxypropylmethylcellulose 15 Centipoise (HPMC 15 cp) aqueous solution was prepared. For elinzanetant free base experiments a suspension with 12.5 mg/mL elinzanetant in a 0.5 % w/w HPMC 15 cp aqueous solution was prepared by stirring. For elinzanetant salts a suspension with a content based on elinzanetant free base of 12.5 mg/ml were used as well, which resulted in a concentration of a suspension with 15.84 mg/mL for elinzanetant 4- methylbenzenesulfonate (tosylate) salt, 14.99 mg/ml for elinzanetant di-HCI salt isopropanol solvate and 15.72 for elinzanetant benzenesulfonate salt.
Tablet in-process controls
Resistance to crushing of the tablets was tested on a conventional hardness tester (Sotax MT50 und UTS4.1 -12FSr Kraemer).
Soft gelatin capsule
When referring to soft gelatin capsules herein, the soft gelatin capsules having a gelatin shell and the following composition as a filling are meant. Soft gelatin capsules formulation (fill mass) was as follows: elinzanetant 5.00% w/w; Glycerol Monocaprylocaprate (Capmul MCM) 37.05% w/w; Caprylocaproyl polyoxyl-8 glycerides (Labrasol ALF) 9.50% w/w; Polysorbate 80 (Tween 80) 9.50% w/w; Glyceryl Monooleate (Peceol) 38.00% w/w; and DL-Alpha tocopherol (Vitamin E) 0.95% w/w; with a total amount of 60 mg elinzanetant per capsule. The soft gelatin capsules and manufacture of the same are disclosed in WO 2019/175253 A1 in particular as Example 1 a. WO 2019/175253 A1 is incorporated herein by reference.
Disintegration
Disintegration was tested in water according to Ph. Eur.2.9.1 , 11th edition. Results for the different compositions are shown in Table 13 and 14.
Dissolution testing in biorelevant media
Fasted State Simulated Intestinal Fluid (Double concentrated FaSSIF; herein referred to as FaSSIF)
Powder (biorelevant.com Ltd) sodium taurocholate 3.0 mM, lecithin 0.75 mM, sodium chloride 106 mM, monobasic sodium phosphate 28.4 mM, sodium hydroxide 8.7 mM
Buffer
In about 0.9 L of purified water 0.84 g of sodium hydroxide, 7.9 g of monobasic sodium phosphate monohydrate, and 12.38 g sodium chloride was dissolved, and adjust the pH to 6.5 with 1 N sodium hydroxide or 1 N hydrochloride acid. Purified water was added to gain a final volume of 1 L at room temperature.
Preparation
4.48 g of Powder was added to about 0.5 L of Buffer, and stirred until powder was completely dissolved. Buffer was added to gain a final volume 1 L with buffer at room temperature and stored at ambient conditions for at least 2 hours.
Fasted State Simulated Gastric Fluid (herein referred to as FaSSGF)
Powder (biorelevant.com Ltd)
Sodium taurocholate 0.08 mM, lecithin 0.02 mM, -sodium chloride 34.2 mM, hydrochloride acid 25.1 mM
Buffer
In about 0.9L of purified water 2.00g sodium chloride was dissolved and adjust the pH to 2.4 with 1 N hydrochloride acid. Purified water was added to gain a final volume of 1 L at room temperature.
Preparation:
Add 0.06 g of Powder was added to about 0.5 L of Buffer, stirred until powder was completely dissolved. Buffer was added to gain a final volume of 1 L at room temperature.
Dissolution was tested using USP XXIII Paddle Method II in 500 mL vessels at 37±0.5°C. Rotation speed of the paddles was 75 rpm for tablets and suspension, in case of soft gelatin capsules 100 rpm was used to enable a homogenous distribution of the fill mass. For the 2-stage dissolution set-up for the first 30 min 250 mL Fasted State Simulated Gastric Fluid (FaSSGF) pH 2.4 was used as media and afterward 250 mL double-concentrated Fasted State Simulated Intestinal Fluid (FaSSIF), tempered at 37°C, added. Samples of 5 mL were taken at each sampling point and refilled directly with fresh media. Prior to HPLC analytics, samples were filtered and diluted 1 :1 V/V with isopropanol.
For the experiments with suspensions, a down scaled setup was used, and experiments performed within 60 mL vessels, using 50 mL of media (25 mL FaSSGF, 25 ml FaSSIF).
Results and Discussion
The dissolution profile for the HPMC suspensions of the 4-methyl benzenesulfonate salt, the Hydrate 2 form of the benzenesulfonate salt of elinzanetant and the dihydrochloride salt of elinzanetant showed good and much faster release profiles for all salt suspensions as compared to the suspension of the free base (FIG. 36).
A simple direct compression composition (Example 13.2.1 .1 , Examplel 3.2.1 .2) for the elinzanetant di-hydrochloride salt as well as for the elinzanetant benzenesulfonate salt showed a disintegration of below 15 min (Table 13 and 14), but the dissolution was slowed down with an incomplete release as compared to the suspension. Micron ization of the salts showed no improvement on the profile and API release was comparable for micro and macro quality of the salts (Data not shown).
To mimic the pre-wetted state within the HPMC suspension, wet granulation processes were used wherein the salts were suspended in a HPMC binder solution. These suspensions were afterwards used as granulation liquids. For a small-scale process produced tablets showed a long disintegration time and did not disintegrate within 30 min. Due to this, just a small amount of elinzanetant was released within the dissolution test (Figure 38A and Figure 37A). In addition, a fluid bed granulation process was used and again the salts suspended within a HPMC solution as granulation liquid. This process is not scalable for the salts, as amorphization of the salts was observed within the granulation suspension. Elinzanetant di-HCI salt compositions Example 13.1 .3 and 13.1.4 have already amorphous parts ( Table 14) and comparable compositions with benzenesulfonate were not producible due to full amorphization of the API within the suspension. With controlled stirring time for the suspension, amorphization could be avoided (Example 13.1.5). Overall, tablets obtained using fluid bed granulation (crystalline or with amorphous parts) did not improve the dissolution behavior for both salts, even if the salt was pre-wetted in an
HPMC solution before converting into a dry and solid composition (Figure 38A and Figure 37 A).
Wet processing lead to amorphization, while dry processing (direct compression (DC) and roller compaction (RC) did not influence the crystalline structure of the elinzanetant salts.
Table 13: Disintegration and dissolution characteristics of tablets containing the benzenesulfonate salt of elinzanetant Table 14: Disintegration and dissolution characteristics of tablets containing the dihydrochloride salt of elinzanetant
Embedment of the salts in hydrophilic carriers (e.g. polyethylene glycol, lactose) (Example 13.2.2.1 , Example 13.2.2.2, Example 13.2.2.3, Example 13.2.2.4) and change of disintegrant (Example 13.2.1.3, Example 13.2.1.4) did as well not change the observed release of less than 50% after 210 minutes (FIG. 37A, and 38A or Table13, 14).
Surprisingly, the addition of non-ionic surfactants (e.g. macrogol-15-hydroxystearate, polysorbate 20, macrogolglycerolricinoleate) (Example 14.1.1.1 to Example 14.2.3) resulted in an enhancement of the tablet release profile and led to similar, desirable results as for the suspension (Figure 38B and Figure 37B). The use of ionic surfactants, such as sodium dodecyl sulphate (SDS) (Example 13.2.3.1 , Example 13.2.3.2), showed a drastically lowered and prolonged release profile. EXAMPLE 16: CLINICAL STUDIES
Relative Bioavailability between Soft Gelatin Capsule and Tablet according to the present disclosure
Study Design and Method
A combined single- and multiple-dose, open-label, fixed sequence, crossover study was conducted in healthy female and male participants to investigate the relative bioavailability of elinzanetant using soft gelatin capsules as disclosed herein above and used in phase iii clinical studies with a composition according to the present disclosure.
The above disclosed soft gelatin capsules (Reference) were compared to a tablet according to Example 14.2.3, supra, (Tablet).
Twenty-four (24) participants received a single dose of two capsules (60 mg elinzanetant in each capsule) of Reference (total dose 120 mg elinzanetant) on Day 1 . After a washout phase of 7 days in which frequent blood samples were collected for analyses of concentration of elinzanetant in plasma, all 24 participants received a second single dose of one Tablet (120 mg elinzanetant) followed by a washout phase of 7 days during that frequent blood samples for pharmacokinetic analyses (PK) of elinzanetant were collected. Maximum concentration (Cmax) and total systemic exposure (total AUC) after administration were calculated for Reference and Tablet to determine relative oral bioavailability.
Results
The geometric mean and standard deviation (SD) concentration-time profiles of elinzanetant for Reference and Tablet are shown in Figure 39. The geometric mean plasma concentrations and coefficient of variation (CV%) of elinzanetant for Cmax and AUC after single dose administration of Reference and Tablet are presented in Table 15:
Table 15 Conclusions
After administration of Reference, mean AUC of elinzanetant was 6793 pg*h/L, and after administration of Tablet mean AUC was 7248 pg*h/L Tablet showing surprisingly higher oral bioavailability of the Tablet compared to the Reference.
EXAMPLE 17: Dissolution of crystalline hydrate of the benzenesulfonate salt of elinzanetant compared to 4-methyl benzenesulfonate salt of elinzanetant and free base of elinzanetant
The crystalline elinzanetant free base was prepared in its anhydrate form in analogy to Example 8 disclosed in WO 2021/094247 A1 with heptane instead of iso-octane as anti-solvent: The dihydrochloride salt mono-isopropanol solvate (WO 2021/094247 A1 ; Example 7) was free based in methyl-terf-butylether (MTBE) using aqueous sodium hydroxide and the layers were separated. The organic layer is washed with aqueous sodium N-acetylcysteine solution, then aqueous sodium bicarbonate solution and then water. MTBE was removed by distillation, n-heptane was added, and part of the solvent was removed by distillation. Isopropanol was added, the solution was heated and the solution then filtered to remove any particulates. The product was crystallized by addition of n- heptane, isolated, washed and dried to give elinzanetant free base. It was either micronized using jet milling (“free base, micronized”) under nitrogen or used as the crystalline free base without micronization (“free base, macro”). The amorphous form of elinzanetant (“free base, amorphous”) was produced by quench-cooling. The quench-cooling was performed by heating the powdered sample of crystalline elinzanetant in an aluminum pan 5°C above its melting point, following an isothermal period of 5 minutes to ensure full liquefication. Afterwards the aluminum pan was transferred on top of an ice block to cool the melt forming a stable glass. Amorphous solid state was confirmed via XRPD Method C.
The amorphous form of 4-methylbenzenesulfonate salt of elinzanetant (“Tosylate”) was produced by suspending 200mg of crystalline elinzanetant free base in 2m L water and adding 658 pL of a 1 mol/L p-toluenesulfonic acid solution. The suspension was inoculated with Tosylate (see WO 2010/015626 A1 ) and stirred for 10 days at room temperature. Afterwards it was vacuumed off and washed three times with 0.5mL water each and air dried at room temperature for three days. The resulting batch was characterized via XRPD Method C as amorphous with crystalline amounts. The crystalline form of 4-methylbenzenesulfonate salt of elinzanetant (“Tosylate, crystalline”) was produced by suspending 16.0 g of the anhydrate Form 1 compound of formula (I) (elinzanetant) (see WO 2011/023733 A1 ) in 72 g butyl-acetate, 28 g heptane, 4.62 g p-toluenesulfonic acid, and 16 g H2O at room temperature. The resulting biphasic system was heated up to 70°C. The solution was cooled down to room temperature. The crystals were isolated by filtration. The wet filter cake was dried in vacuum at 60 °C to yield 19.0 g of dry Tosylate, crystalline (94.4% yield).
The crystalline hydrate of the benzenesulfonate salt of elinzanetant (“Besylate”) was produced by suspending 280mg of crystalline elinzanetant free base in 2.8mL water and adding 921 pL of a 1 mol/L benzenesulfonic acid solution. The suspension was inoculated with Hydrate 3 and stirred for 5 days at room temperature. Afterwards it was vacuumed off and washed three times with 0.5mL water each and air dried at room temperature for three days. The resulting batch was characterized via XRPD Method C as crystalline (pseudo)polymorphic form Hydrate 3 of the benzenesulfonate salt of elinzanetant.
High-resolution small-scale powder dissolution profiling was performed with the PION pDiss Profiler™. The Tosylate, free base (micro, macro or amorphous) and Besylate were provided in vessels and Fasted State Simulated Intestinal Fluid (FaSSIF) was added with the start of the experiment, minimum drug substance weigh in was set at 1 .5 mg in 6 mL FaSSIF respectively. FaSSIF was prepared by weighing 0.42 g NaOH, 4.47 g NaH2PO4* 2 H2O and 6.186 g NaCI in 0.9 L water. The pH was adjusted to 6.50 ± 0.05 with 1 N sodium hydroxide or 1 N hydrochloric acid. The flask was filled up to 1 L with water and 2.24 g SIF powder (Biorelevant Ltd) was added. The dissolution was recorded as the amount dissolved per volume (pg/mL) during a time interval of 0 min to 350 min. During the duration a crossbar stirrer at 100 rpm was used.
The comparison in Figure 40 shows a slow dissolution rate for the crystalline free base, which is slightly improved by particle size reduction (micronization) and by use of the tosylate salt, whereby the provision of the crystalline form of the tosylate salt further improves the dissolution. The amorphous free base shows improved dissolution profile as compared to the crystalline free base, but a slower dissolution as compared to crystalline tosylate. Surprisingly, the crystalline hydrate of the benzenesulfonate salt of elinzanetant shows a massive improvement with a very fast dissolution rate, clearly outperforming all other forms.
EXAMPLE 18: Dissolution of crystalline hydrate of the benzenesulfonate salt of elinzanetant compared to the amorphous form of the benzenesulfonate salt of elinzanetant
The crystalline benzenesulfonate salt of elinzanetant was prepared as in Example 17, and was hence the (pseudo)polymorphic form Hydrate 3 (“crystalline”).
The amorphous benzenesulfonate salt of elinzanetant (“amorphous Besylate”) was produced by suspending 200mg of crystalline elinzanetant free base in 2mL water and adding 658 pL of a 1 mol/L benzenesulfonic acid solution. The suspension was inoculated with a hydrate form of the benzenesulfonate salt of elinzanetant and stirred for one week at room temperature. Afterwards it was vacuumed off and washed three times with 0.5mL water each and air dried at room temperature for two days. The resulting batch was characterized via XRPD Method C as amorphous.
High-resolution small-scale powder dissolution profiling was performed with the PION pDiss Profiler™ as described in Example 17. The dissolution was measured as the amount dissolved per volume (pg/mL) during a time interval of 0 min to 90 min.
The results are shown in Figure 41 . The amorphous form of the benzenesulfonate salt of elinzanetant surprisingly showed a lower (e.g. at the plateau) dissolution profile than the crystalline hydrate of the benzenesulfonate salt of elinzanetant.
This shows that the dissolution rate of a crystalline hydrate form of the benzenesulfonate salt of elinzanetant is surprisingly not only magnitudes faster than the other solid forms shown in Example 17, but also higher than for its amorphous form, further underlying the besylate counter-ion as main driver for fast dissolution.
EXAMPLE 19: Intrinsic dissolution rate (IDR) comparison of crystalline and amorphous benzenesulfonate salt of elinzanetant and amorphous elinzanetant
Crystalline hydrate of the benzenesulfonate salt of elinzanetant (“besylate crystalline”) was prepared as disclosed in Example 3 using butyl acetate instead of ethyl acetate. XRPD confirmed crystalline (pseudo)polymorphic form Hydrate 2. The amorphous form of the free base (“free base amorphous”) was prepared by rotary evaporation ( 50°C, <20mbar) of a solution of 5g of crystalline free base in 30g acetone. XRPD confirmed the amorphous solid state.
The amorphous form of the benzenesulfonate salt of elinzanetant (“besylate amorphous”) was prepared by rotary evaporation ( 50°C, <20mbar) of a solution of 5g of crystalline Besylate hydrate 2 in 50g acetone. XRPD confirmed the amorphous solid state.
Crystalline tosylate of elinzanetant (“Tosylate, crystalline”) was prepared as disclosed in Example 17. The IDR profiling was performed with the PION pDiss Profiler™, equipped with the intrinsic dissolution rate kit from the same manufacturer. The kit uses hollow metal cylinders and a manual tablet press to produce tablets with a surface of 0.0707cm2. The tablets were manufactured with 5mg of crystalline or amorphous benzenesulfonate salt of elinzanetant, or amorphous elinzanetant free base pressed under 100psi. The respective samples were released in phosphate buffer pH 6.8 + 0.1 % sodium dodecyl sulfate (SDS). Each measurement was performed as a duplicate (n=2).
Results are shown in Table 16 and Figure 42.
Table 16: Measured values for IDR
Slope given in pg/ml/min; IDR given in pg/min/cm2; Mean IDR given in pg/min/cm2
The intrinsic dissolution rate levels off the factor of particle size and allows a comparison based on the intrinsic properties of the samples. The results further confirm the surprising results obtained from Example 17 and 18 and show the greatly enhanced dissolution rate as an intrinsic feature of the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant as compared to the free base and the crystalline tosylate salt of elinzanetant. The dissolution is surprisingly further enhanced in the crystalline hydrate forms of the benzenesulfonate salt of elinzanetant as compared to the amorphous form of the salt. Example 20: Preparation of (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant
5.0g of the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant (Hydrate 2) was suspended in 50g water. The suspension was stirred and heated to 60°C. The suspension was chilled to room temperature and stirred for 0.5h. Solid crystals were isolated and dried at 25°C and <100 mbar in a drying chamber. Thereafter, they were stored open on the bench for 4 hours. The crystals being platelike under the microscope were analyzed by XRPD Method C. The XPRD is shown in Figure 43 and Table 17. Infrared Spectra Bands are shown in Figure 44 and Table 18.
Table 17: Reflections of XRPD of crystalline form of the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant
Table 18: Infrared Spectra Bands of crystalline (pseudo)polymorphic form Hydrate 6 Thermogravimetric analysis is shown in Figure 45 and the Differential Scanning Calorimetry analysis in Figure 46. They showed: 2.4% mass loss, 1.2% residual moisture and 1.2% loss during melting (onset 142°C and peak at 158°C).
Furthermore, a DVS test was conducted with the (pseudo)polymorphic form Hydrate 6 in accordance with Example 11 . The results are shown in Table 19 and Figure 47.
Table 19: Mass changes in sorption-desorption test
%RH: re ative ambient humidity; % d.b. :[dry base]
The (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant, like Hydrate form 2 exhibits good stability after sorption and desorption. Solubility in water was tested to compare Hydrate 2 form, Hydrate 3 form, and Hydrate 6 form. Solubilities were recorded by suspending 25 mg of the respective drug substance in 2 ml water in glass vials with magnetic stirrer bars. The suspensions were stirred at 25 °C± 2 °C for 24 h ± 4 h prior to filtration and analysis via HPLC-UV.
Table 20: Solubility of different (pseudo)polymorphic Hydrate forms of the benzenesulfonate salt of elinzanetant This shows that the Hydrate 2 form has the best solubility in water of the tested Hydrate forms.
Example 21 : Preparation of (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant A further crystalline (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant was obtained as follows.
5.0g the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant (Hydrate 2) was stirred in 50 ml water at RT. White suspension formed. After 3h XRPD Method B was performed showed the presence of Hydrate 2. After 6 days XRPD showed a mixture of amorphous form and (Hydrate 2). The suspension was seeded with crystals of the (pseudo)polymorphic Hydrate 3 form of the benzenesulfonate salt of elinzanetant. After 21 days predominantly small rod-shaped crystals were observed. The crystals were analyzed by XRPD Method B. The results are shown in Figure 48, and the reflections are shown in Table 20. Infrared Spectra Bands are shown in Figure 49 and Table 21 .
Table 20: Reflections of XRPD of crystalline form of the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant Table 21: Infrared Spectra Bands of crystalline (pseudo)polymorphic form Hydrate 7
The Thermogravimetric analysis is shown in Figure 50 showing a 2.5% mass loss and the Differential Scanning Calorimetry analysis is seen in Figure 51 . Furthermore, a DVS test was conducted with the (pseudo)polymorphic form Hydrate 6 in accordance with Example 11 . The results are shown in Table 22 and Figure 52.
Table 22: Mass changes in sorption-desorption test
%RH: re ative ambient humidity; % d.b. : dry base
Example 22 (pseudo)polymorphic form Pattern 7 of the benzenesulfonate salt of elinzanetant
20g of the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant was combined with 72g nBuOAc, 28g n-Heptane and 5,4g water, resulting in a light suspension. The suspension was heated to 70°C and stirred until dissolved. A yellow solution was obtained. Residual turbidity was removed via Nutsche filtration. Sample washed with a solution of 7g nBUOAc and 2.8g Heptane (2:1 vol). Heated to 70°C and stirred until dissolved and then cooled to 45°C. The solution was then seeded with 0.1 g crystals of (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant and stirred for 2h at 45°C. Solution was cooled overnight to 20°C, a white suspension was obtained. 16.2g water was added and stirred for 15 minutes. Powder was isolated and washed with 20ml of water. Sample was further washed with 2 times 40ml nBuOAc / Heptane 2:1 (vol). The sample was mixed with ethanol and stirred for 5 days at RT -> Eddy 4-101 -2 XRPD: Hydrate ii | Microscope: Unknown Structure. EDDY 4-101-4 and EDDY 4-101 -5 combined as EDDY 4-101-6 Wet filter cake was dried at 60°C below 100 mbar with a dry nitrogen purge gas for 2 days. Additionally, a cold pack (precooled to -20 °C) was placed below the crystallization dish at start. A subsequent drying step at 60°C below 100 mbar with conditioned (water) nitrogen was performed for 4 hours. XRPD: Named as Pattern 7.
The crystals were analyzed by XRPD Method B. The results are shown in Figure 53, and the reflections are shown in Table 23.
Table 23: Reflections of XRPD of crystalline form of the benzenesulfonate salt of elinzanetant Pattern 7
The Thermogravimetric analysis is shown in Figure 54 showing a mass loss of 2.4% and the Differential Scanning Calorimetry analysis in Figure 55.
In particular embodiments, the present disclosure relates to the following items.
Items
1 . A crystalline hydrate of the benzenesulfonate salt of elinzanetant, preferably a variable occupancy hydrate.
2. The crystalline hydrate of item 1 , wherein the crystalline hydrate of the benzenesulfonate salt is the (pseudo)polymorphic form Hydrate 2, the (pseudo)polymorphic form Hydrate 3, the (pseudo)polymorphic form Hydrate 6 of the benzenesulfonate salt of elinzanetant, or the (pseudo)polymorphic form Hydrate 7 of the benzenesulfonate salt of elinzanetant.
3. The crystalline hydrate of item 2, wherein the (pseudo)polymorphic form Hydrate 2 is characterized by an X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 20 value ± 0.2°: 8.8, 14.2, 3.9.
4. The crystalline hydrate of item 2, wherein the (pseudo)polymorphic form Hydrate 3 is characterized by an X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 20 value ± 0.2°: 2.7, 18.5, 12.2.
5. The crystalline hydrate of item 2, wherein the (pseudo)polymorphic form Hydrate 2 is characterized by infrared spectroscopy displaying at least the following values of the band maxima (cm-1): 1121 , 1185, 1282.
6. The crystalline hydrate of item 2, wherein the (pseudo)polymorphic form Hydrate 3 is characterized by infrared spectroscopy displaying at least the following values of the band maxima (cm-1): 1122, 683, 1278.
7. A Method for preparing the crystalline hydrate according to any one of item 1 to 6 comprising: i) providing elinzanetant, preferably in a solvent; ii) adding benzenesulfonic acid; and iii) isolating the crystalline form of the benzenesulfonate salt of elinzanetant.
8. The method according to item 7, wherein the solvent is ethyl acetate or n-butyl acetate.
9. The method according to item 7 or 8, wherein the compound of formula (I) is provided in ethyl acetate or n-butyl acetate as a solvent and added to a biphasic system, the biphasic system comprising water and n-heptane.
10. The method according to any one of items 7 to 9, wherein the crystalline hydrate obtained is the (pseudo)polymorphic form Hydrate 2.
11. A pharmaceutical composition comprising a crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of items 1 to 6 and optionally one or more further pharmaceutically acceptable excipients.
12. A solid pharmaceutical composition comprising a crystalline salt of elinzanetant and a non-ionic surfactant.
13. The solid pharmaceutical composition according to item 12, wherein the nonionic surfactant is selected from the group consisting of macrogolglycerolricinoleate (Kolliphor EL), Tween 20, macrogol-15- hydroxystearate (Kolliphor HS 15), Polyoxyethylensorbitan-fatty acid esters (e.g. Polyoxyethylen (20) sorbitanmonolaurate, Polyoxyethylen (4) sorbitanmonolaurate, Polyoxyethylen(20)sorbitanmonostearate,
Polyoxyethylen(20)sorbitanmonooleate), glycol fatty acid esters, fatty alcohols (Cetyl-alcohol, stearyl alcohol), polyoxyethylen fatty acid esters (e.g. polyoxyethylenstearate, polyoxyethylen-400-monostearate,
Polyoxyethylenrizinoleat), polyoxythelen fatty alcohol ethers (e.g. Polyoxyethylnelaurylether, and Polyocyethylensteralether), saccharose fatty acid esters (e.g. saccharosedistearate, saccharosemonopalmitate).
14. The solid pharmaceutical composition according to any one of items 12 or 13, wherein the solid pharmaceutical composition is selected from the group consisting of granules, mixture, pellets, tablets, dragees, sachets, pills, and melts. The solid pharmaceutical composition according to any one of items 12 to 14, wherein the in vitro dissolution of elinzanetant is such that at least 50% is dissolved within 30 minutes, as determined by USP XXIII Paddle Method II using Fasted State Simulated Gastric Fluid (FaSSGF) at pH 2.4 as a medium at 37° and 75 rpm as the stirring rate. The solid pharmaceutical composition according to any one of items 12 to 15, wherein the in vitro dissolution of elinzanetant is that at least 60% is dissolved within 35 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37° and 75 rpm as stirring rate for 30 min and then rebuffering to Fasted State Simulated Intestinal Fluid (FaSSIF) at a pH 6.5 as a medium at 37° and 75 rpm as stirring rate. The solid pharmaceutical composition according to any one of items 12 or 16, wherein the in vitro dissolution of elinzanetant is that at least 80% is dissolved within 210 minutes, as determined by USP XXIII Paddle Method II first using FaSSGF at pH 2.4 as a medium at 37° and 75 rpm as stirring rate for 30 min and then rebuffering to FaSSIF at a pH 6.5 as a medium at 37° and 75 rpm as stirring rate. The solid pharmaceutical composition according to any one of items 12 to 17 obtainable by blending the salt of elinzanetant or a hydrate or solvate thereof with a non-ionic surfactant, and optionally one or more further pharmaceutically acceptable excipients to obtain a blend. The solid pharmaceutical composition according to any one of items 12 to 18, wherein the salt of elinzanetant is selected from the group consisting of benzenesulfonate salt, di-hydrochloride salt, and 4-methylbenzesulfonate salt. The solid pharmaceutical composition according to any one of items 12 to 19, wherein the salt of elinzanetant is a crystalline hydrate form of the benzenesulfonate salt of elinzanetant. The solid pharmaceutical composition according to item 20, wherein the crystalline hydrate form of the benzenesulfonate salt is the (pseudo)polymorphic form Hydrate 2 or the (pseudo)polymorphic form Hydrate 3. 22. The solid pharmaceutical composition according to any one of items 12 to 21 , wherein the pharmaceutical composition comprises:
5% w/w to 50% w/w of the crystalline salt of elinzanetant, such as from 10% w/w to 40% w/w; or from 20 % w/w to 35% w/w; and
0.5% w/w to 10% w/w of the non-ionic surfactant, preferably about 1 % w/w to 7% w/w.
23. The solid pharmaceutical composition according to any one of items 12 to 22, wherein the solid pharmaceutical composition further comprises one or more pharmaceutical acceptable binder.
24. The solid pharmaceutical composition according to item 23, wherein the one or more pharmaceutical acceptable binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof.
25. The solid pharmaceutical composition according to item 23 or 24, wherein the one or more pharmaceutical acceptable binder is present at a total concentration of 20% w/w to 75% w/w, preferably 50% w/w to 70%, more preferably about 64.67% w/w.
26. The solid pharmaceutical composition according to any one of items 12 to 25, wherein the solid pharmaceutical composition further comprises one or more disintegrant.
27. The solid pharmaceutical composition according to item 26, wherein the one or more disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof. The solid pharmaceutical composition according to item 26 or 27, wherein the one or more disintegrant is present at a concentration of 1 % w/w to 10% w/w, preferably 2% w/w to 6%, more preferably about 2.91 % w/w. The solid pharmaceutical composition according to any one of items 12 to 28, wherein the solid pharmaceutical composition further comprises one or more lubricant. The solid pharmaceutical composition according to item 29, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or mixtures thereof. The solid pharmaceutical composition according to item 28 or 29, wherein the one or more lubricant is present at a concentration of 0.1 % w/w to 5% w/w, preferably 0.3% w/w to 1 .5%, more preferably about 1 % w/w. The solid pharmaceutical composition according to any one of items 12 to 31 and 22 to 31 , wherein the solid pharmaceutical composition form comprises:
(a) a crystalline salt of elinzanetant at a concentration of between 20% w/w and 40% w/w, wherein the salt is selected from the group consisting of benzenesulfonate salt, 4-methylbenzenesulfonate salt, and dihydrochloride salt, or hydrates or solvates thereof;
(b) a non-ionic surfactant at a concentration of between 0.5% w/w and 7% w/w, wherein the non-ionic surfactant is selected from the group consisting of macrogolglycerolricinoleate, macrogol- glycerolhydroxystearate, polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 80 (Tween 80), and macrogol-15- hydroxystearate; or mixtures thereof;
(c) a binder at a concentration of between 40% w/w and 75% w/w; wherein the binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone, hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof;
(d) a lubricant at a concentration of between 0.5% w/w and 9% w/w; wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or a mixture thereof;
(e) a disintegrant at a concentration of between 1 % w/w and 10% w/w; wherein the disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof; and
(f) optionally a flow regulator at a concentration of between 0.2% w/w and 1 % w/w. The solid pharmaceutical composition according to any one of items 11 to 32, wherein the solid pharmaceutical composition is a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 28.89% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 1 .94% w/w;
(c) microcrystalline cellulose at a concentration of 64.67% w/w;
(d) magnesium stearate at a concentration of about 1 .00% w/w;
(e) croscarmellose sodium at a concentration of about 2.91 % w/w; and
(f) silicon dioxide at a concentration of about 0.58% w/w. A crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of items 1 to 6, or a pharmaceutical composition according to item 11 , or a solid pharmaceutical composition according to any of items 12 to 33 for use in the treatment and/or prophylaxis of a sex hormone-dependent disease. Use of a crystalline hydrate of the benzenesulfonate salt of elinzanetant as defined in any of items 1 to 6 or a pharmaceutical composition as defined in item 11 or a solid pharmaceutical composition as defined any one of items 12 to 32 for the manufacture medicament for the treatment or prevention of a sex hormone-dependent disease. A method of treating or preventing of a sex hormone-dependent disease, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of items 1 to 6, or a pharmaceutical composition of item 11 , or a sold pharmaceutical composition according to any one of items 12 to 32. A method for preparing the solid pharmaceutical composition according to any one of items 12 to 33 comprising the steps of:
(i) blending the crystalline salt of elinzanetant, and the at least one nonionic surfactant, and optionally one or more excipient to obtain a blend; and
(ii) optionally subsequently adding and blending one or more further excipients to the blend. The method according to item 37, wherein after step (ii) the blend is subjected to dry granulation. The method according to item 38, wherein the pharmaceutical composition is subjected to compression after granulation. The method according to item 37, wherein after step (ii) the blend is subjected to direct compression. The method according to item 37, wherein all excipients of the pharmaceutical composition are blended with the crystalline salt of elinzanetant or hydrate or solvate thereof and the at least one non-ionic surfactant in step (i). The method according to item 41 , wherein the blend is subjected to dry granulation. The method according to item 42, wherein the obtained blend is subjected to compression after granulation. The method according to item 41 , wherein the obtained blend is subjected to direct compression. 45. The solid pharmaceutical composition according to any one of items 12 to 33 obtainable by a method according to any one of items 37 to 39.

Claims

Claims
1 . A crystalline hydrate of the benzenesulfonate salt of elinzanetant.
2. The crystalline hydrate of claim 1 , wherein the crystalline hydrate of the benzenesulfonate salt is a variable occupancy hydrate.
3. The crystalline hydrate of claim 1 or 2, wherein the crystalline hydrate of the benzenesulfonate salt is the (pseudo)polymorphic form Hydrate 2.
4. The crystalline hydrate of claim 3, wherein the (pseudo)polymorphic form Hydrate 2 is characterized by an X-ray powder diffractogram measured at 25°C and with Cu-K alpha 1 as radiation source displaying at least the following reflections, quoted as 20 value ± 0.2°: 8.8, 14.2, 3.9.
5. The crystalline hydrate of claim 3, wherein the (pseudo)polymorphic form Hydrate 2 is characterized by infrared spectroscopy displaying at least the following values of the band maxima (cm-1): 1121 , 1185, 1282.
6. A pharmaceutical composition comprising a crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of claims 1 to 5 and optionally one or more further pharmaceutically acceptable excipients.
7. A solid pharmaceutical composition comprising a crystalline salt of elinzanetant and a non-ionic surfactant.
8. The solid pharmaceutical composition according to claim 7, wherein the nonionic surfactant is selected from the group consisting of macrogolglycerolricinoleate (Kolliphor EL), Tween 20, macrogol-15- hydroxystearate (Kolliphor HS 15), Polyoxyethylensorbitan-fatty acid esters (e.g. Polyoxyethylen (20)sorbitanmonolaurate, Polyoxyethylen (4) sorbitanmonolaurate, Polyoxyethylen(20)sorbitanmonostearate,
Polyoxyethylen(20)sorbitanmonooleate), glycol fatty acid esters, fatty alcohols (Cetyl-alcohol, stearyl alcohol), polyoxyethylen fatty acid esters (e.g. polyoxyethylenstearate, polyoxyethylen-400-monostearate, Polyoxyethylenrizinoleat), polyoxythelen fatty alcohol ethers (e.g. Polyoxyethylnelaurylether, and Polyocyethylensteralether), saccharose fatty acid esters (e.g. saccharosedistearate, saccharosemonopalmitate).
9. The solid pharmaceutical composition according to any one of claims 7 or 8, wherein the solid pharmaceutical composition is selected from the group consisting of tablets, granules, mixture, pellets, dragees, sachets, pills, and melts.
10. The solid pharmaceutical composition according to any one of claims 7 to 9, wherein the salt of elinzanetant is selected from the group consisting of benzenesulfonate salt, di-hydrochloride salt, and 4-methylbenzesulfonate salt.
11. The solid pharmaceutical composition according to any one of claims 7 to 10, wherein the salt of elinzanetant is a crystalline hydrate form of the benzenesulfonate salt of elinzanetant.
12. The solid pharmaceutical composition according to claim 11 , wherein the crystalline hydrate form of the benzenesulfonate salt is the (pseudo)polymorphic form Hydrate 2.
13. The solid pharmaceutical composition according to any one of claims 7 to 12, wherein the pharmaceutical composition comprises:
5% w/w to 50% w/w of the crystalline salt of elinzanetant; and
0.5% w/w to 10% w/w of the non-ionic surfactant.
14. The solid pharmaceutical composition according to any one of claims 7 to 13, wherein the solid pharmaceutical composition further comprises one or more pharmaceutical acceptable binder.
15. The solid pharmaceutical composition according to claim 14, wherein the one or more pharmaceutical acceptable binder is selected from the group consisting of cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), dextrose, maltose, sucrose, glucose, fructose, maltodextrins, polyvinylpyrrolidone (PVP), hydroxypropylcellulose or hypromellose (e.g. hypromellose 3 cP); or a mixture thereof.
16. The solid pharmaceutical composition according to claim 14 or 15, wherein the one or more pharmaceutical acceptable binder is present at a concentration of 20% w/w to 75% w/w.
17. The solid pharmaceutical composition according to any one of claims 7 to 16, wherein the solid pharmaceutical composition further comprises one or more disintegrant.
18. The solid pharmaceutical composition according to claim 17, wherein the one or more disintegrant is selected from the group consisting of croscarmellose sodium and cross-linked polyvinylpyrrolidone; or a mixture thereof.
19. The solid pharmaceutical composition according to claim 17 or 18, wherein the one or more disintegrant is present at a concentration of 1 % w/w to 10% w/w.
20. The solid pharmaceutical composition according to any one of claims 7 to 19, wherein the solid pharmaceutical composition further comprises one or more lubricant.
21 . The solid pharmaceutical composition according to claim 20, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fat or oil, polyethylenglycol and talcum; or mixtures thereof.
22. The solid pharmaceutical composition according to claim 20 or 21 , wherein the one or more lubricant is present at a concentration of 0.1 % w/w to 5% w/w.
23. The solid pharmaceutical composition according to any one of claims 7 to 22, wherein the solid pharmaceutical composition is a tablet comprising:
(a) the (pseudo)polymorphic Hydrate 2 form of the benzenesulfonate salt of elinzanetant at a concentration of about 28.89% w/w;
(b) macrogolglycerolricinoleate at a concentration of about 1 .94% w/w;
(c) microcrystalline cellulose at a concentration of 64.67% w/w; (d) magnesium stearate at a concentration of about 1 .00% w/w;
(e) croscarmellose sodium at a concentration of about 2.91 % w/w; and
(f) silicon dioxide at a concentration of about 0.58% w/w.
24. A crystalline hydrate of the benzenesulfonate salt of elinzanetant according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 5, or a solid pharmaceutical composition according to any of claims 7 to 23 for use in the treatment and/or prophylaxis of a sex hormone-dependent disease.
PCT/EP2025/063650 2024-05-24 2025-05-19 Crystalline forms of salts of elinzanetant and compositions containing salts of elinzanetant Pending WO2025242585A1 (en)

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