Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/69—Benzenesulfonamido-pyrimidines

Definitions

• the present invention relates to multicomponent systems comprising bosentan and selected cocrystal formers, to pharmaceutical preparations comprising said systems, and specifically to homogenous crystalline phases (cocrystals) comprising bosentan and selected cocrystal formers.
• the invention also relates to processes for preparing said multicomponent systems and crystalline phases.
• the invention also relates to compositions comprising said multicomponent systems or crystalline phases and pharmaceutically acceptable carrier, and to methods of using said multicomponent systems or crystalline phases to treat a disease condition wherein competitive antagonism of endothelin receptors is beneficial.
• Bosentan is the synonym of N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2- pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide], specifically shown in formula (I)
• Bosentan It is known to act as competitive antagonist of endothelin receptors. Bosentan is useful in the treatment of cardiovascular disorders and its marketed product Tracleer® is indicated for the treatment of the pulmonary artery hypertension (PAH). Bosentan may form hydrates with a varying content of water.
• WO 08/135795 and WO 09/053748 are disclosed hydrate crystalline forms, hereafter referred to as form from 1 to 8 of N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2- pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide].
• An amorphous form is disclosed herein.
• WO 09/047637 and WO 09/093127 disclose further hydrate crystalline forms of bosentan, hereafter referred to as form from A1 to A5 .
• WO 09/083739 discloses crystalline anhydrous forms of N-[6-(2-Hydroxyethoxy)-5-(2- methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide], hereafter referred to as form from B and C.
• WO 10/032261 discloses a process for the preparation of bosentan and some further crystalline forms of N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl- pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide].
• the invention provides novel solid forms, especially crystalline forms, of bosentan comprising bosentan and cocrystal formers selected from gentisic acid (i.e. 2,5- dihydroxybenzoic acid) and maleic acid (i.e. cis-butenedioic acid), and processes for the manufacture thereof.
• gentisic acid i.e. 2,5- dihydroxybenzoic acid
• maleic acid i.e. cis-butenedioic acid
• Said crystalline forms show desired different physical and/or biological characteristics which may assist in the manufacture or formulation of the active compound, to the purity levels and uniformity required for regulatory approval.
• the said crystalline form may possess improved pharmacological characteristics, for example, improved bioavailability, thus offering enhanced possibilities to modulate and design improved drug products.
• the solid form of the invention especially provides a composite comprising two components, which are bosentan and maleic acid or gentisic acid, and especially gentisic acid, within one single anhydrous phase.
• the composition of the invention thus represents a crystalline material containing (A) bosentan and (B) a cocrystal former selected from maleic acid and gentisic acid, preferably gentisic acid.
• Components A and B are present in the same solid phase, preferably in the same crystalline phase, i.e. forming a cocrystal.
• the cocrystal of the invention may further comprise an organic solvent as an additional component (C), e.g.
• a low molecular ketone, ester or hydrocarbon such as acetone or ethylacetate or heptane thus constituting a solvate
• the solvate hereinafter is also referred to as the form S of the present cocrystal.
• Most preferred, however, is a cocrystal essentially consisting of the 2 main components A and B, and containing further components such as organic solvent and/or water, if any, only on the impurity level (e.g. less than 5%, preferably less than 1 % b.w.).
• the molar ratio of bosentan and acid i.e.
• maleic or especially gentisic acid is generally in the range from 2:1 to 1 :2, in particular from 1 .5:1 to 1 :1 .5 and especially about 1 :1 (i.e. from 1 .1 :1 to 1 :1.1 ).
• the invention thus includes i) a multicomponent molecular crystal containing N-[6-(2-Hydroxyethoxy)-5-(2- methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide] and maleic acid; ii) an essentially anydrous crystalline form as defined under i consisting essentially of N-[6-(2-Hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert- butyl-benzenesulfonamide] and maleic acid, having stoichiometric molar ratio of about 1 :1 ; iii) a multicomponent molecular crystal containing N-[6-(2-Hydroxyethoxy)-5-(2- methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl
• a preferred subject of the invention is a cocrystal comprising bosentan and gentisic acid, which is substantially free of any other constituents such as water or organic sol- vents (form A).
• This preferred cocrystal essentially as mentioned above under (iv), is characterized by its melting point higher than 158°C (e.g. from the range 158 - 168°C, especially from the range 160 - 166 °C; see Figure 5 or example 13).
• the preferred cocrystal is characterized by powder x-ray diffraction (PXRD) peaks corresponding to d-spacings of 14.7, 4.92, 4.1 1 , 3.60 and 3.39 A (1 Angstroem [A] is 10 "10 m).
• the cocrystal form A is characterized by powder x-ray diffraction (PXRD) peaks corresponding to d-spacings of 14.7 (vs), 5.08 (s), 4.92 (vs), 4.50 (s), 4.46 (s), 4.42 (s), 4.36 (s), 4.21 (s), 4.1 1 (vs), 3.95 (s), 3.88 (s), 3.70 (s), 3.60 (vs) and 3.39 A (vs), and especially by d-spacings as compiled in Table 101 further below and/or by a characteristic X-ray powder diffraction pattern as exhibited in Figure 4 (in brackets: peak intensities by visual assessment as explained above).
• PXRD powder x-ray diffraction
• the present invention further provides solvate forms of the cocrystal of bosentan and gentisic acid (solvate form S).
• current form S further comprises organic solvent molecules, e.g. a low molecular ketone, ester or hydrocarbon such as acetone or ethylacetate or heptane, as an additional component (C).
• Component C is contained in the present form S preferably in a molar ratio from the range 1 to 0.1 molar parts, in particular from 1 to 0.6 molar parts of component C on 1 molar part of bosentan.
• bosentan and gentisic acid are present in the same solid solvate phase, preferably in the same crystalline phase, i.e. forming a cocrystal.
• the solvate phases show similar x-ray diffraction patterns; the preferred novel crystalline solvate form generally exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (A): 16.4, 10.0, 5.5, 4.1 and 3.5 A.
• the present invention pertains to a solvate (form S) of N-[6-(2- Hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl- benzenesulfonamide] and gentisic acid and
• Preferred solid form defined under (i) and especially (ii) may be further characterized by its melting point of about 146°C (m.p. e.g. from the range 141 - 151 °C, especially from the range 143 - 149 °C .
• the present solid form provides better dissolution characteristic and hygroscopic behavior, when compared with the bosentan forms previously known.
• Bosentan and maleic acid are present in the same solid phase, preferably in the same crystalline phase, i.e. forming a cocrystal.
• the preferred novel crystalline form generally exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressed in d-values (A): 13.1 1 (vs), 9.80 (m), 9.53 (s), 6.84 (w), 6.58 (w), 5.71 (w), 5.22 (w), 4.91 (m), 4.78 (w), 4.16 (w), 4.00 (w), 3.94 (w), 3.72 (w), 3.44 (w), 3.18 (w). More specifically, the present invention comprises a crystalline form of N-[6-(2-
• Another object of the invention is a process for the preparation of crystalline form defined under i to iv which comprises the steps of
• bosentan e.g. bosentan hydrate or an anhydrous form of bosentan
• maleic acid and/or gentisic acid preferably gentisic acid
• a convenient variant of this preparation method comprises the steps of (subsequently) a) providing a solution of bosentan (e.g. bosentan hydrate or an anhydrous form of bosentan) and gentisic acid in a suitable solvent,
• bosentan e.g. bosentan hydrate or an anhydrous form of bosentan
• Step (c) usually includes drying.
• Solvent removal may be accomplished according to methods commonly known in the art such as applying reduced pressure (e.g. in a Ro- tavapor, or a suitable flask), filtration, distillation, or a combination of such methods.
• Suitable solvents used in this process are, for example, acetone, a mixture ace- tone/ethyl acetate (e.g. about 1 :1 ), acetonitrile.
• the solvent used in step (a) is typically acetone.
• Solutions according to steps (a) preferably are concentrated solutions.
• water miscible solvents like alcohols, esters and ethers, e.g. ethanol, ethyl acetate, or mixtures of these solvents.
• the concentration of bosentan may range from 0.1 to about 300 mg/ml of solvents (including water), preferably from 20 to 200 mg/ml.
• step (a) is carried out at a temperature from the range 30-60°C or the mixture is heated to a temperature from said range, e.g. about 50°C, especially in case that solid bosentan is provided in step (a), with forming a solution.
• the solution thus tempered is then preferably cooled before step (c).
• Ambient temperature means in the context of the invention a temperature range at room temperature, comprising 20 to 30 °C and preferably about 23 to 26 °C.
• an antisolvent may be added which facilitates the precipitation of the solid.
• a further object of the invention thus is a process for the preparation of crystalline form defined under i - iv which comprises the steps of
• bosentan e.g. bosentan hydrate or an anhydrous form of bosentan
• maleic acid and/or gentisic acid preferably gentisic acid
• Step (e) may be carried out at elevated temperature, e.g. as defined above for step (a).
• the solvent used in step (d) is typically an antisolvent (such as a non-polar hydrocarbon like heptane), or a mixture of ethylacetate and acetone.
• Suspensions according to step (d) preferably are concentrated suspensions.
• the addition of an antisolvent is further useful for transforming the solvate; thus, present form A (especially the 1 :1 cocrystal with gentisic acid) may be obtained according to the above process comprising steps (d) - (f) starting from a suspension of a solvate of the cocrystal (e.g. acetone solvate, ethyl acetate solvate etc.).
• the suspension in step (d) may be obtained by suspending solid powder of the educt(s) in the suitable solvent or solvent mixture described for step (d), or by adding an antisolvent as described for step (d) to a solution obtained in accordance with step (a) described further above, optionally with concentrating the suspension, e.g. by re- ducing the amount of solvent under reduced pressure and/or heating, e.g. up to 120°C, e.g. to 45-120°C, or 50-100°C.
• step (e) is typically performed by stirring for 0.1 -100 hours, preferably 1 to 24 hours.
• Step (e) is preferably performed at a temperature higher than room tem- perature, e.g. at temperatures up to 120°C, e.g. 95-120°C. Ultrasonication of the suspension can be additionally performed during step (e).
• Cocrystal defined above generally is isolated by filtering off the crystals and drying, e.g. in vacuum, an inert gas flow or both at ambient temperature, or elevated temperatures e.g. up to about 140°C.
• the present solvate forms (form S) is further useful for obtaining the present non- solvate form A;
• the transformation of the solvate form S, especially the solvate cocrystal forms of bosentan with gentisic acid, into form A may be achieved with intensified drying, e.g. by applying temperatures from the range 40 to 150°C, preferably 60 to
• the solid form of the invention enable to improve the dissolu- tion characteristics of bosentan, i.e. providing a better dissolution kinetic profile with respect to the previously known bosentan form.
• the aqueous solubility of the bosentan and maleic acid cocrystal is about 20 times higher than the free drug substance.
• Cocrystal defined above is thermodynamically stable and can be dried at elevated temperatures, as noted above, and is obtained as a fine powder with typical particle size distributions with the median size between 1 and 50 ⁇ , preferably between 1 to 10 ⁇ . This particle size range ensures a fast dissolution profile, while retaining the favourable handling properties in the formulation process.
• Cocrystal defined above is less prone to water uptake under humidity, and is easy to formulate.
• Solid forms defined above may contain minor amounts of water on the surface.
• the anhydrous form is especially preferred.
• the present solid forms, especially the present non-solvate forms such as the present cocrystal of bosentan with maleic acid, and especially the present form A containing gentisic acid, provide better dissolution characteristics, and better product stability especially with regard to hygroscopic behavior, than the bosentan forms previously known.
• the solid form of the invention may be used in pharmaceutical compositions in the same way as other forms of bosentan previously known.
• Oral formulations may be solid formulations such as capsules, tablets, pills and troches, or liquid formulations such as aqueous suspensions, elixirs and syrups.
• Solid and liquid formulations encompass also incorporation of the present solid form, especially cocrystal with maleic acid, into liquid application forms.
• the solid forms according to the invention may be directly used as powders (mi- cronized particles), granules, suspensions or solutions, or they may be combined together with other pharmaceutically acceptable ingredients in admixing the components and optionally finely divide them, and then filling capsules, composed for example from hard or soft gelatine, compressing tablets, pills or troches, or suspend or dissolve them in carriers for suspensions, elixirs and syrups. Coatings may be applied after compression to form pills.
• Pharmaceutically acceptable ingredients are well known for the various types of formulation and may be for example binders such as natural or synthetic polymers, excipi- ents, lubricants, surfactants, sweetening and flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents and carriers for the various formulation types.
• binders such as natural or synthetic polymers, excipi- ents, lubricants, surfactants, sweetening and flavouring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents and carriers for the various formulation types.
• binders are gum tragacanth, acacia, starch, gelatine, and biological de- gradable polymers such as homo- or co-polyesters of dicarboxylic acids, alkylene glycols, polyalkylene glycols and/or aliphatic hydroxyl carboxylic acids; homo- or co- polyamides of dicarboxylic acids, alkylene diamines, and/or aliphatic amino carboxylic acids; corresponding polyester-polyamide-co-polymers, polyanhydrides, polyortho- esters, polyphosphazene and polycarbonates.
• the biological degradable polymers may be linear, branched or crosslinked.
• polymers are poly-glycolic acid, poly-lactic acid, and poly-d,l-lactide/glycolide.
• Other examples for polymers are water-soluble polymers such as polyoxaalkylenes (polyoxaethylene, polyoxapropylene and mixed polymers thereof, poly-acrylamides and hydroxylalkylated polyacrylamides, poly-maleic acid and esters or -amides thereof, poly-acrylic acid and esters or -amides thereof, poly-vinylalcohol und esters or -ethers thereof, poly-vinylimidazole, poly-vinylpyrrolidon, und natural polymers like chitosan, carragenan or hyaluronic aid.
• excipients are phosphates such as dicalcium phosphate.
• examples for lubricants are natural or synthetic oils, fats, waxes, or fatty acid salts like magnesium stearate.
• Surfactants may be anionic, anionic, amphoteric or neutral.
• Examples for surfactants are lecithin, phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecyl sulfate, Na oleate or Na caprate, 1 - acylaminoethane-2-sulfonic acids, such as 1 -octanoylaminoethane-2-sulfonic acid, 1 - decanoylaminoethane-2-sulfonic acid, 1 -dodecanoylaminoethane-2-sulfonic acid, 1 - tetradecanoylaminoethane-2-sulfonic acid, 1 -hexadecanoylaminoethane-2-sulf
• sweetening agents are sucrose, fructose, lactose or aspartam.
• flavouring agents are peppermint, oil of wintergreen or fruit flavours like cherry or orange flavour.
• coating materials gelatine, wax, shellac, sugar or biological degradable polymers.
• preservatives examples include methyl or propylparabens, sorbic acid, chlorobutanol, phenol and thimerosal.
• Examples for adjuvants are fragrances.
• Examples for thickeners are synthetic polymers, fatty acids and fatty acid salts and esters and fatty alcohols.
• liquid carriers examples include water, alcohols such as ethanol, glycerol, propylene glycol, liquid polyethylene glycols, triacetin and oils.
• solid carriers examples include talc, clay, microcrystalline cellulose, silica, alumina and the like.
• the formulation according to the invention may also contain isotonic agents, such as sugars, buffers or sodium chloride.
• the solid forms according to the invention may also be formulated as effervescent tablet or powder, which disintegrate in an aqueous environment to provide a drinking solution.
• a syrup or elixir may contain the polymorph of the invention, sucrose or fructose as sweetening agent a preservative like methylparaben, a dye and a flavouring agent.
• the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration.
• parenteral including subcutaneous, intramuscular, and intravenous
• inhalant and ophthalmic administration are examples of the most suitable route in any given case.
• oral the most preferred route of the present invention is oral.
• the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
• Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is also not intended to pertain to true solutions of Rosuvastatin calcium whereupon the properties that distinguish the solid forms of Rosuvastatin calcium are lost. However, the use of the novel forms to prepare such solutions is considered to be within the contemplation of the invention.
• Capsule dosages will contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material.
• Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating.
• the enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carbox- ymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of meth- acrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
• a coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
• Slow release formulations may also be prepared from the crystal form according to the invention in order to achieve a controlled release of the active agent in contact with the body fluids in the gastro intestinal tract, and to provide a substantial constant and effective level of the active agent in the blood plasma.
• the crystal forms may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water-soluble polymer or a mixture of both, and optionally suitable surfactants. Embedding can mean in this context the incorporation of micro-particles in a matrix of polymers. Controlled release formulations are also obtained through encapsulation of dispersed micro- particles or emulsified micro-droplets via known dispersion or emulsion coating technologies.
• the solid forms, especially crystal forms, of the invention are also useful for administer- ing a combination of therapeutic effective agents to an animal. Such a combination therapy can be carried out in using at least one further therapeutic agent which can be additionally dispersed or dissolved in a formulation.
• the solid forms, especially crystal forms, of this invention and its formulations respectively can be also administered in combination with other therapeutic agents that are effective to treat a given condition to provide a combination therapy.
• the solid forms, especially crystal forms, and the pharmaceutical composition according to the invention are suitable for effective treatment of disorders in connection with need of inhibiting the endothelin receptors.
• the solid forms, especially crystal forms, and the pharmaceutical composition accord- ing to the invention are suitable for treatment of pulmonary artery hypertension (PAH).
• PAH pulmonary artery hypertension
• room temperature depicts a temperature from the range 18-23°C; over night denotes a time period in the range 12-16 hours. Percentages and ratios in the examples and elsewhere are by weight, if not indicated otherwise.
• One Angstroem [A] denotes the length of 10 "10 m
• the error of the calculated d-values is determined from the experimental error of the 2 ⁇ angle depends on the 2 ⁇ angle and is approximately ⁇ 2 within the last given digit, e.g. 14.7 ⁇ 0.2, or 3.39 ⁇ 0.02. Thus, all specifications of °2 ⁇ values are to be understood as including the experimental error margin of ⁇ 0.1 ° to ⁇ 0.2°, and all specifications of d-spacings are to be understood as including the experimental error margin of ⁇ 2 in the last digit given.
• Thermogravimetry The thermogravimetric measurements are carried out with a Mettler Toledo TGA/SDTA851 e module.
• the thermal behaviour is analysed in the range 30- 250 °C by using a heating rate of 5°C/min and a stream of nitrogen flowing at 150 ml/ during the experiment.
• DSC DSC is performed on a Mettler Toledo DSC 822e module. The sample is placed in crimped but vented aluminium pans (sample size was 10 mg). The thermal behaviour is analysed in the range 30 - 300 °C by using a heating rate of 5°C/min and a stream of nitrogen flowing at 150 ml/ during the experiment.
• 1 H-NMR The 1 H-NMR spectra are recorded on a Bruker DPX 300 spectrometer. Solvent: Acetone-d6.
• Example 1 a Preparation of a cocrystal of bosentan and maleic acid
• aqueous solubility is measured at room temperature and at pH 7 (phosphate buffer).
• the suspension are equilibrated in glass vials under stirring. After a time interval of 1 , 2, 4, 8, 15, 30 and 60 minutes a small sample of about 1.0 ml is recovered with a syringe and filtered through a 0.1 micrometer PVDF Millipore filtration unit. This sample is appropriately diluted and the concentration is determined by HPLC (Conditions: AC- QUITY Water system, equipped with PDA_230 nm UV detector and Sample Manager auto injector; Waters' Enpower software is used to record the chromatograms and to calculate the chromatographic parameters.
• Example 3 Preparation of a cocrystal of bosentan and maleic acid
• the PXRD shows no reflexes of educts.
• DSC confirms the formation of a pure phase of the non-solvate form A ( Figure 5).
• TG does not show any mass loss, indicating the formation of a non-solvate/anhydrous phase.
• 1 H-NMR (measured in acetone-d6) shows the spectrum of a 1 :1 mixture of bosentan and gentisic acid.
• DSC confirms the formation of a pure phase (as in Figure 5). TG does not show any mass loss, indicating the formation of an anhydrous phase.
• 1 H-NMR (measured in acetone-d6) shows the spectrum of a 1 :1 mixture of bosentan and gentisic acid.
• the dissolution test is performed at room temperature and at the physiologically relevant pH values of 1.2 (KCI/HCI buffer), 4.5 (KH-phthalate/NaOH buffer), 6.8 and 7.5 (KH2P04/NaOH buffer).
• the suspensions are equilibrated in glass vials under stirring. After interval of time of 10, 20, 30, 40, 50 and 60 minutes, a small sample of about 1 .0 ml is recovered with a syringe and filtered through a 0.1 micrometer PVDF Millipore filtration unit. This sample is appropriately diluted and the concentration is determined by HPLC.
• the liquid analysis is performed by HPLC (ACQUITY Water system, equipped with PDA_230 nm UV detector and Sample Manager auto injector; Waters' Enpower software used to record the chromatograms and to calculate the chromatographic parameters; gradient elution [ACN - 0,1 % H3P04] is achieved using C18 column, 50 x 2,1 mm, 1 ,7 ⁇ BEH; injection volume is set 1 ⁇ _ by auto injector; analysis performed with rate flux of 0,4 ml/min).
• the pH of the saturated solution is controlled by a Metrohm 713 pH meter.
• Tab. 2 Solubility of free drug and of cocrystals at physiologically relevant pH values
• Bosentan hydrate (comparison) 30 0
• Bosentan hydrate (comparison) 30 0
• the relative humidity (%r.h.) is scanned at a change rate of 5% r.h. from ambient to 0%r.h. and then to a high level (95-98 %r.h.) and finally back to ambient level.
• the adsorption/desorption profile provides useful information about the long-term stability of bosentan hydrate (Figure 8), bosentan and maleic acid cocrystal of Example 1 a ( Figure 9), and bosentan and gentisic acid cocrystal form A of Example 13 ( Figure 10) over a broad range of humidity in the surrounding atmosphere.
• Bosentan and maleic acid cocrystal does not exhib- it any moisture absorption over a broad humidity range (it takes place above the 90%RH).
• the present Bosentan / gentisic acid cocrystal does not exhibit any moisture absorption at all. This behaviour indicates that Bosentan and maleic acid cocrystal and especially the Bosentan and gentisic acid cocrystal (form A) is a very stable crystalline form over a broad humidity range.
• Example 8 Bosentan - gentisic acid cocrystal form S containing ethyl acetate.
• the PXRD pattern is shown in Figure 1 1 (solid line) and the corresponding peak positions are given in Table 103.
• 1 H-NMR shows the spectrum of bosentan and gentisic acid in a molar ratio of 1 :1 .2.
• TG-FTIR shows a mass loss of 4.5% m/m of ethyl acetate.
• Example 9 Bosentan - gentisic acid cocrystal form S containing n-heptane.
• the PXRD pattern is shown in Figure 1 1 (dashed line) and the corresponding peak positions are given in Table 102.
• 1 H-NMR shows the spectrum of bosentan and gentisic acid in a molar ratio of 1 :1.
• TG-FTIR shows a mass loss of 5.1 % m/m of n- heptane.
• Example 10 Production of bosentan - gentisic acid cocrystal form A.
• Example 1 1 Bosentan - gentisic acid cocrystal form A (seeding material).
• solvate form S (containing ethyl acetate) are suspended in 5 mL of n- heptane, heated to 90°C and sonicated for 1 minute. 5 mL of n-heptane are added. The suspension is sonicated for 1 minute, heated again to 90°C and stirred at 90°C to 93°C for 2 hours with several 1 -minute sonications. The suspension is cooled to room temperature, filtered and the obtained solid is dried under reduced pressure (about 30 mbar) at 120°C for one hour. Yield: 134 mg. PXRD shows the pattern of form A.
• Example 12 Production of bosentan - gentisic acid cocrystal form A.
• Example 13 Production of bosentan - gentisic acid cocrystal form A.
• the PXRD pattern corresponds to the one shown in Figure 4 and the corresponding peak positions are given in Table 101 .
• 1 H-NMR shows the spectrum of bosentan and gentisic acid in a molar ratio of 1 :1 .
• TG-FTIR shows that the obtained material is nei- ther a solvate, nor a hydrate.
• DVS investigation of the product shows that the obtained cocrystal is not hygroscopic as can be seen in Figure 10.
• DSC reveals a melting peak temperature of 164°C and an enthalpy of fusion of about 89 J/g.
• Example 14 Preparation of of bosentan - gentisic acid co-crystal form S containing acetonitrile and transformation to the non-solvate form A.
• Bosentan Hydrate 590 mg are dissolved in 10 ml of acetonitrile.
• Gentisic Acid (stoichiometry 1 :1 ) are added, and the solution is stirred at room temperature for 90 minutes.
• a clear yellow solution is obtained and it is stirred at 4 °C for 16 hours.
• the solvent is removed by Rotavapor and the obtained yellow material is identified as the 1 :1 cocrystal comprising bosentan and gentisic acid.
• a mixture of the non-solvate co- crystal form A and the acetonitrile solvate cocrystal form S is obtained.
• the XRPD pattern of the mixture is shown in Figure 6.
• the mixture containing the non-solvate and the acetonitrile solvate co-crystal is suspended in 10 ml of n-Heptan and stirred for 3 hours at 90 °C.
• the yellow powder is filtered, dried at room temperature for 2 hours and identified as the pure non-solvate 1 :1 co- crystal form A comprising bosentan and gentisic acid.
• the PXRD pattern is corresponding to the one shown in Figure 4 .
• DSC confirms the formation of a pure phase (corresponding to the one shown in Figure 5). TG does not show any mass loss, indicating the formation of an anhydrous phase.
• PEAK LISTS PEAK LISTS
• Table 101 PXRD peaklist for the bosentan - gentisic acid cocrystal form A. angle in °2-theta d-spacing in A qualitative intensity
• Table 102 PXRD peaklist for the bosentan - gentisic acid cocrystal form S according to example 9 (heptane) angle in °2-theta d-spacing in A qualitative intensity
• Table 103 PXRD peaklist for the bosentan - gentisic acid cocrystal form S according to example 8 (ethyl acetate) angle in °2-theta d-spacing in A qualitative intensity
• Figure 1 Powder X-Ray Diffraction pattern of bosentan and maleic acid 1 :1 cocrystal
• Figure 2 DSC trace of bosentan and maleic acid 1 :1 cocrystal
• Figure 3 Powder X-Ray Diffraction pattern of bosentan and gentisic acid 1 :1 acetone solvate cocrystal (form S)
• Figure 4 PXRD pattern of the cocrystal comprising bosentan and gentisic acid (pure non-solvate, form A)
• Figure 5 DSC trace of bosentan and gentisic acid 1 :1 non-solvate cocrystal form
• Figure 6 Powder X-Ray Diffraction pattern of the cocrystal comprising bosentan and gentisic acid 1 :1 cocrystal, mixture of form S and non-solvate cocryst. form
• FIG 8 Dynamic vapor sorption of bosentan hydrate
• Figure 9 Dynamic vapor sorption of the bosentan maleic acid cocrystal
• Figure 10 Dynamic vapor sorption of bosentan gentisic acid cocrystal form
• FIG 11 PXRD patterns of two variants of the bosentan - gentisic acid form S: The dashed line (bottom) shows form S containing heptane (Example 9); the solid line (top) shows form S containing ethyl acetate (Example 8).
• Figure 12 Plot of the API concentration vs equilibration time (buffer pH 6.8)
• Figure 13 Plot of the API concentration vs equilibration time (buffer pH 4.5)

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