WO2016177625A1 - Siméprévir potassique amorphe - Google Patents

Siméprévir potassique amorphe Download PDF

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Publication number
WO2016177625A1
WO2016177625A1 PCT/EP2016/059505 EP2016059505W WO2016177625A1 WO 2016177625 A1 WO2016177625 A1 WO 2016177625A1 EP 2016059505 W EP2016059505 W EP 2016059505W WO 2016177625 A1 WO2016177625 A1 WO 2016177625A1
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Prior art keywords
simeprevir
amorphous
potassium salt
potassium
alkali metal
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Ceased
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PCT/EP2016/059505
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English (en)
Inventor
Verena Adamer
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Sandoz AG
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Sandoz AG
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Publication date
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Publication of WO2016177625A1 publication Critical patent/WO2016177625A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention relates to amorphous simeprevir potassium salt and to a process for the preparation of amorphous simeprevir potassium salt.
  • the invention is further directed to pharmaceutical compositions comprising an effective amount of simeprevir potassium salt, especially in its amorphous form and to the use of said pharmaceutical compositions as medicament, in particular for the treatment of hepatitis C infections in human.
  • WO 2007/014926 Al discloses simeprevir in non-salt form for use in the treatment of hepatitis C virus (HCV) infections. It is mentioned that pharmaceutically acceptable base addition salts can also be used and that the preparations of these salts involve the reaction with an appropriate base.
  • WO 2008/092954 A2 discloses crystalline forms of simeprevir in non-salt form for use in the treatment of HCV infections.
  • WO 2010/097229 A2 discloses an amorphous sodium salt of simeprevir and its preparation via spray drying.
  • suitable solvents which may be applied in the spray drying process are halogenated hydrocarbons, such as chloroform or dichloromethane (dichloromethane is for example used in example 1 of WO 2010/097229 A2) and ethers such as diethylether or tetrahydrofuran (see page 5, lines 1-2).
  • a first objective of the invention was to provide an amorphous simeprevir salt, which overcomes aforementioned drawbacks associated with the physicochemical properties of the amorphous sodium salt, in particular with regards to its behavior upon contact with water and/or water vapor.
  • a further objective of the invention was to provide a process for the preparation of amorphous simeprevir salts avoiding the use of highly volatile, environmentally problematic and hazardous solvents such as halogenated hydrocarbons and ethers.
  • chemical impurities are by-products and/or synthetic intermediates used during simeprevir production, other than simeprevir itself.
  • Such chemical impurities may contain structural elements that they have in common with simeprevir, such as a methoxy-methylquinolin ring system or a trisubstituted cyclopropane ring system.
  • the invention relates to amorphous simeprevir potassium salt characterized by having a PXRD pattern comprising no reflection in the range of from 2 to 40 ° 2-Theta, when measured at room temperature with CuKalphai, 2 radiation having a wavelength of 0.15419 nm.
  • the invention relates to amorphous simeprevir potassium salt characterized by having a PXRD pattern essentially the same as displayed in figure 1 herein, when measured at room temperature with CuKalphai,2 radiation having a wavelength of 0.15419 nm.
  • the amorphous simeprevir potassium salt does not have any noticeable peak, especially not any peak characteristic of a crystalline form of simeprevir, in a powder X-ray diffraction pattern when measured after 96 hours storage at 40°C/75% relative humidity.
  • the amorphous simeprevir potassium salt has an PXRD pattern substantially as shown in Fig. 1 when measured after 96 hours storage at 40°C/75% relative humidity.
  • Amorphous simeprevir potassium salt of the present invention is preferably chemically pure. "Chemical purity" of the amorphous simeprevir potassium salt can for example be determined by HPLC analysis.
  • the amorphous simeprevir potassium salt of the present invention has a chemical purity of 95% w/w or more, preferably of 98%> w/w or more, more preferably of 99.5% w/w or more, based on the total weight of the amorphous simeprevir potassium salt.
  • the invention also relates to amorphous simeprevir potassium salt characterized by a GMS curve wherein the absolute difference in the water content between the sorption isotherm and the desorption isotherm at the same relative humidity is at most 1.3%, preferably at most 1.2%, more preferably at most 1.1%, even more preferably at most 1.0%, even more preferably at most 0.9% and most preferably at most 0.8%, in the range of from 40 to 90% relative humidity at room temperature, preferably at (25.0 ⁇ 0.1) °C, for example when measured according to method 2.
  • amorphous simeprevir potassium salt of the present invention is better suited to being used together with such excipients than amorphous simeprevir sodium.
  • the amorphous potassium salt of the invention is less hygroscopic compared to amorphous simeprevir sodium salt.
  • the adsorbed water is only weakly bound by the amorphous simeprevir potassium salt of the present invention, allowing a reproducible equilibration of the water content irrespective of the previous sample history. This is also in contrast to what could have been expected based on the behavior of the amorphous simeprevir sodium salt.
  • the effective amount of amorphous simeprevir potassium of the invention is in the range of from about 25 to 500 mg, more preferably from about 50 to 250 mg, even more preferably from about 100 to 200 mg and most preferably the effective amount is about 150 mg, calculated as simeprevir.
  • pharmaceutical compositions of the invention comprise an effective amount of amorphous simeprevir potassium of the invention and one or more pharmaceutically acceptable excipients selected from the group of wetting agents lubricants, glidants, disintegrants and fillers.
  • the invention relates to amorphous simeprevir potassium of the invention and to pharmaceutical compositions comprising an effective amount of amorphous simeprevir potassium of the invention, for use as medicament.
  • R represents branched or non-branched Ci-Cio alkyl and M + represents an alkali metal cation preferably selected from potassium, sodium and lithium, more preferably from potassium and sodium and most preferably the alkali metal cation is potassium.
  • suitable alkali metal alcoholates are sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propylate, potassium n-propylate, sodium z ' so-propylate, potassium z ' so-propylate, sodium n-butoxide, potassium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, potassium tert-amylate, sodium 3,7-dimethyl-3- octylate, potassium 3,7-dimethyl-3-octylate, whereat sodium methoxide, potassium methoxide, sodium tert-butoxide and potassium tert-butoxide are most preferred.
  • step (i) of the process a mixture of simeprevir and the applied alkali metal alcoholate in a suitable solvent is prepared.
  • the reaction mixture may be heated for example to a temperature of about 40 °C or more, preferably of about 50 °C or more, more preferably of about 60 °C or more, for example the mixture may be heated to reflux temperature.
  • the reaction mixture is kept, preferably under stirring, at the applied temperature for a period that is long enough to allow a complete acid-base reaction, for example a period in the range of from about 0.5 to 48 hours, preferably from about 1 to 24 hours, more preferably from about 2 to 12 hours.
  • Suitable antisolvents which may be used in step (ii) of the process are selected from alkanes such as n-pentane, n-hexane, cyclohexane, n-heptane or mixtures thereof, whereat n-heptane is most preferred.
  • the reaction mixture obtained in (i) is combined with an antisolvent by adding the antisolvent to the reaction mixture or vice versa.
  • the applied solvent/antisolvent ratio may be in the range of from about 1 : 2 to 10, preferably from about 1 : 2 to 8, more preferably from about 1 : 2 to 6 and most preferably from about 1 : 2 to 4.
  • the obtained suspension may optionally be cooled, for example to a temperature of about 10 °C or less, preferably of about 0 °C or less, more preferably of about - 10 °C or less, in order to improve the yield.
  • the suspension is optionally kept, preferably under stirring, at the applied temperature for a period in the range of from about 0.5 to 48 hours, preferably from about 1 to 24 hours, more preferably from about 2 to 12 hours.
  • the amorphous simeprevir salt obtained in step (iii) may be dried at a temperature of about 100 °C or less, preferably at a temperature of about 40 °C or less, for example at about room temperature. Drying may be performed at atmospheric or at reduced pressure for a period of about 72 hours or less.
  • reaction mixture obtained in (i) may be lyophilized. Lyophilization may for example be performed according to the procedures described in examples 3 and 4 herein.
  • the amorphous simeprevir potassium salt according to item 1 characterized by having a powder X-ray diffractogram comprising no reflection in the range of from 2 to 40 ° 2- Theta, when measured at 20 °C with CuKalphai,2 radiation having a wavelength of 0.15419 nm.
  • the amorphous simeprevir potassium salt according to item 2 characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 1 herein.
  • the amorphous simeprevir potassium salt according to any one of items 1 to 12 characterized by having a gravimetric moisture sorption curve, wherein the relative difference between the water content of the sorption isotherm and the desorption isotherm at same relative humidity is at most 20%, when measured in the range of from 40 to 80% relative humidity at (25.0 ⁇ 0.1) °C.
  • the amorphous simeprevir potassium salt according to any one of items 1 to 14 wherein the water content at 95% relative humidity and (25.0 ⁇ 0.1) °C is at most 30%.
  • a pharmaceutical composition comprising an effective amount of amorphous simeprevir potassium salt, and at least one pharmaceutically acceptable excipient.
  • amorphous simeprevir potassium salt according to any one of items 1 to 18 or the pharmaceutical composition according to any one of items 19 to 25 for use in the treatment of hepatitis C infections in human.
  • a process for the preparation of an amorphous simeprevir alkali metal salt comprising:
  • step (ii.1) combining the reaction mixture of (i) with an antisolvent or (ii.2) lyophilizing the reaction mixture of (i).
  • amorphous simeprevir alkali metal salt is selected from amorphous simeprevir potassium salt and amorphous simeprevir sodium salt.
  • step (i) simeprevir in non-salt form is used as the starting material.
  • step (i) simeprevir is dissolved to form a solution.
  • step (i) a clear solution free of any solid material is obtained.
  • step (i) the simeprevir concentration in the solvent is from 1 g/1 to 50g/l.
  • step (i) the molar ratio of simeprevir and alkali metal alcoholate is from 1 : 1 to 1 :6.
  • step 34 wherein the molar ration is from 1 : 1 to 1 :2.
  • step (i) the alkali metal alcoholate is a branched or non-branched alkali metal alkanolate comprising one to ten carbon atoms.
  • step (i) the alkali metal alcoholate is selected from the group of potassium methoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide.
  • the solvent is an alcohol
  • the alcohol is tert-butanol.
  • step (ii-1) the antisolvent is an alkane.
  • step (ii-1) the antisolvent is an alkane.
  • the alkane is n-heptane.
  • the solvent / antivolvent ratio (v/v) is from 1 :2 to 1 : 10.
  • Powder X-ray diffractograms were obtained with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • the diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions.
  • Method 2 Method 2:
  • Moisture sorption and desorption isotherms were recorded with an SPSx- ⁇ moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at 40% RH and first decreased to 3%) RH, then to 0%> RH. Subsequently, the relative humidity was increased to 5% and 10%>, then to 90%) in 10%> steps. It was further increased to 95%>. Then it was decreased back to 90%> and to 0% in 10% steps. Finally, it was increased again to 40% RH in 10% steps. The time per step was set to a minimum of 2 hours and a maximum of 10 hours. If an equilibrium condition with a constant mass of ⁇ 0.01% within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 10 hours.
  • Example 1 Preparation of amorphous simeprevir potassium by precipitation
  • Simeprevir in non-salt form (107 mg, 143 mmol; prepared according to the process disclosed in examples 1 and 2 of WO 2008/092954 A2) was suspended in tert-butanol (1 mL) and heated to 82 °C.
  • a suspension of potassium tert-butoxide (24 mg, 214 mmol) in tert-butanol (3.5 mL) was heated to 60 °C and added to the simeprevir suspension.
  • a slightly turbid solution was obtained.
  • After 0.5 h of stirring at 82 °C the solution was cooled to 25 °C over 2 h and subsequently n-heptane (15 mL) was added causing precipitation of a colorless solid.
  • the obtained suspension was further cooled to -10 °C over 2 h and stirred at this temperature for additional 15 h. Finally, the solid was collected by filtration and dried under vacuum at 20-30 mbar) for 28 h.
  • Amorphous simeprevir potassium salt from example 1 was analyzed by method 1 (figure 1) and method 2 (figure 2).
  • Simeprevir (107 mg, 143 mmol; prepared according to the process disclosed in examples 1 and 2 of WO 2008/092954 A2) was suspended in tert-butanol (1 mL) and heated to 82 °C.
  • a solution of simeprevir (65 mg, 87 mmol; prepared as described in example 1) and ethanolic potassium ethoxide solution (22 microL, 24% w/w) in tert-butanol (4mL) was prepared by heating to 82 °C.
  • the resulting clear solution was lyophilized using a Christ alpha 2 4 LSC plus freeze dryer and applying the settings according to table 2.
  • a solution of simeprevir (60 mg, 80 mmol; prepared as described in example 1) and ethanolic sodium ethoxide solution (30 microL, 21% w/w) in tert-butanol (4 mL) was prepared by heating to 82 °C.
  • the resulting clear solution was lyophilized using a Christ alpha 2 4 LSC plus freeze dryer and applying the same settings as outlined in table 2 of example 3.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne du siméprévir potassique amorphe et un procédé de préparation de sels de siméprévir amorphe. Des compositions pharmaceutiques comprenant une quantité efficace de siméprévir potassique, notamment sous sa forme amorphe, et l'utilisation desdites compositions pharmaceutiques à titre de médicament, en particulier pour le traitement des infections de type hépatite C chez l'homme sont en outre décrites.
PCT/EP2016/059505 2015-05-04 2016-04-28 Siméprévir potassique amorphe Ceased WO2016177625A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15166283.0 2015-05-04
EP15166283 2015-05-04

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WO2016177625A1 true WO2016177625A1 (fr) 2016-11-10

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014926A1 (fr) 2005-07-29 2007-02-08 Tibotec Pharmaceuticals Ltd. Inhibiteurs macrocycliques du virus de l'hépatite c
WO2008092954A2 (fr) 2007-02-01 2008-08-07 Tibotec Pharmaceuticals Ltd. Formes polymorphes d'un inhibiteur macrocyclique de hcv
WO2010097229A2 (fr) 2009-02-27 2010-09-02 Ortho-Mcneil-Janssen Pharmaceuticals Inc Sel amorphe d'un inhibiteur macrocyclique du vhc

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014926A1 (fr) 2005-07-29 2007-02-08 Tibotec Pharmaceuticals Ltd. Inhibiteurs macrocycliques du virus de l'hépatite c
WO2008092954A2 (fr) 2007-02-01 2008-08-07 Tibotec Pharmaceuticals Ltd. Formes polymorphes d'un inhibiteur macrocyclique de hcv
WO2010097229A2 (fr) 2009-02-27 2010-09-02 Ortho-Mcneil-Janssen Pharmaceuticals Inc Sel amorphe d'un inhibiteur macrocyclique du vhc

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VITALIJ K. PECHARSKY; PETER Y ZAVALIJ: "Fundamentals of Powder Diffraction and Structural Characterization ofmaterials", 2003, KLUWER ACADAMIC PUBLISHERS, pages: 3

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