EP2121704A2 - Polymorphic forms of clopidogrel hydrobromide - Google Patents

Polymorphic forms of clopidogrel hydrobromide

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Publication number
EP2121704A2
EP2121704A2 EP08724381A EP08724381A EP2121704A2 EP 2121704 A2 EP2121704 A2 EP 2121704A2 EP 08724381 A EP08724381 A EP 08724381A EP 08724381 A EP08724381 A EP 08724381A EP 2121704 A2 EP2121704 A2 EP 2121704A2
Authority
EP
European Patent Office
Prior art keywords
clopidogrel hydrobromide
clopidogrel
hydrobromide
polymorphic form
amorphous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08724381A
Other languages
German (de)
French (fr)
Inventor
Miroslav Veverka
Eva Veverkova
Stefan Vodny
Janez Smodis
Matej Smrkolj
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA Tovarna Zdravil dd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KRKA Tovarna Zdravil dd filed Critical KRKA Tovarna Zdravil dd
Publication of EP2121704A2 publication Critical patent/EP2121704A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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

Definitions

  • the present invention relates to amorphous form of methyl (+)-(S)-(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrobromide and to novel polymorphic forms alpha, beta and gama of methyl (+)-(S)-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrobromide. Further, the present invention relates to the preparation of new forms, the pharmaceutical compositions comprising such forms and to the method of use such forms for inhibiting platelet aggregation.
  • Clopidogrel is a well known inhibitor of induced platelet aggregation. It acts by inhibiting the binding of adenosine phosphate to its receptor.
  • the chemical name of clopidogrel is methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate. It is represented by the following formula (I):
  • Clopidogrel is administered as its hydrogensulfate salt. It is currently being marketed as Plavix ® tablets.
  • U.S. Patent Nos. 4,847,265, 5,132,435, 6,258,961, 6,215,005 and 6,180,793 disclose methods of the preparation of clopidogrel hydrogensulfate. Different polymorphic forms of clopidogrel hydrogensulfate has been disclosed in the prior art.
  • Clopidogrel hydrobromide is known from U. S. Patent No 4,847,265 wherein after the crystallization from mixture of isopropylether and ispropanol the material with melting point 140 0 C was obtained.
  • the patent is completely silent about the crystal form of the product and IR and/or X-ray diffraction pattern data.
  • Cystalline forms of clopidogrel hydrobromide are disclosed in WO 2005026174, US 2006154957, EP 1674468 Al, WO 2005/068471, WO 2005/080890, WO 2005/068471 and WO 2006/034451.
  • the compounds according to the inventions are characterized by X-ray diffraction pattern (XRPD), differential scanning calorimetric (DSC) thermogram, TGA and FT Raman.
  • New crystalline forms B, C and D of methyl (+)-(S)-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridene-5(4H)-acetate hydrobromide and processes for their preparation are described in WO 2005/103058. All forms are characterized by FTIR and XRPD. The precipitate obtained in example 2 was dried to afford the form D named as an amorphous solid in example 4. The obtained form D was characterized in FT-IR spectrum with peaks at about 456, 723, 756, 1647 and 1748 cm '1 and by an XRPD pattern as depicted in Figure ID of aforesaid patent.
  • amorphous form of clopidogrel hydrobromide does not disclose and not even suggest the existence of an amorphous form of clopidogrel hydrobromide.
  • Form D of clopidogrel hydrobromide named in WO 2005/103058 as an amorphous solid and characterized by XRPD does not show a good halo shape pattern typical of amorphous form that is substantially free of crystalline material.
  • amorphous form of clopidogrel hydrobromide according to the present invention shows significant different FTIR spectrum.
  • a first aspect of the present invention provides clopidogrel hydrobromide in amorphous form.
  • Amorphous clopidogrel hydrobromide according to the present invention is characterized by an XRPD spectrum as substantially shown in Figure 1 and/or by FT-IR as substantially shown in Figure 2.
  • a second aspect of the present invention provides clopidogrel hydrobromide in polymorphic form alpha.
  • Polymorphic form alpha of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 3 and/or by FT- IR as substantially shown in Figure 4.
  • a third aspect of the present invention provides clopidogrel hydrobromide in polymorphic form beta.
  • Polymorphic form beta of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 5 and/or by FT- IR as substantially shown in Figure 6.
  • a forth aspect of the present invention provides clopidogrel hydrobromide in polymorphic form gama.
  • Polymorphic form gama of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 7.
  • the present invention also provides a process for preparing clopidogrel hydrobromide in amorphous form, in polymorphic form alpha, beta and gama.
  • the present invention also provides pharmaceutical compositions and their method of administration to inhibit platelet aggregation.
  • FIG. 1 is a powder X-ray diffraction (XRPD) pattern of the amorphous form of clopidogrel hydrobromide according to the present invention.
  • FIG. 2 is a FTIR spectrum of the amorphous form of clopidogrel hydrobromide according to the present invention.
  • FIG. 3 is a powder X-ray diffraction (XRPD) pattern of form alpha of clopidogrel hydrobromide according to the present invention.
  • FIG. 4 is a FTIR spectrum of form alpha of clopidogrel hydrobromide according to the present invention in 2000-700 cm '1 region.
  • FIG. 5 is a powder X-ray diffraction (XRPD) pattern of form beta of clopidogrel hydrobromide according to the present invention.
  • FIG. 6 is a FTIR spectrum of form beta of clopidogrel hydrobromide according to the present invention.
  • FIG. 7 is a powder X-ray diffraction (XRPD) pattern of form gama of clopidogrel hydrobromide according to the present invention.
  • the present invention provides a novel amorphous form of clopidogrel hydrobromide.
  • the new form is characterized by powder X-ray diffraction pattern as substantially depicted in Figure 1.
  • the pattern is without intense focused reflections with typical amorphous halo.
  • the novel amorphous form of clopidogrel hydrobromide exhibits a FTIR spectrum as substantially depicted in Figure 2 with the following characteristic absorption bands at about
  • the amorphous form is highly pure. Preferably, it is essentially free of any crystalline clopidogrel hydrobromide.
  • amorphous as used in the context of the present application denotes a physical state which is not crystalline and may be verified by X-ray diffraction and other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry. More preferably the amorphous clopidogrel hydrobromide is free of crystalline clopidogrel hydrobromide within the detection limit of a powder X-ray diffractometer comparable to the instrumentation described. The purity of clopidogrel hydrobromide can be assessed by a comparison of the XRPD pattern of an unknown sample with those of mixtures of authentic pure amorphous and pure crystalline clopidogrel hydrobromide.
  • the term highly pure amorphous clopidogrel hydrobromide also means that the amorphous clopidogrel hydrobromide according to the present invention comprises less than about 3% of other impurities, preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other impurities.
  • the present invention further provides a process for preparing the novel amorphous form of clopidogrel hydrobromide according to the present invention comprising the steps of preparing a solution of clopidogrel hydrobromide in a polar, dipolar or a less polar aprotic solvent, removing the solvent from the solution to obtain a residue, admixing the residue with an antisolvent to precipitate clopidogrel hydrobromide and separating the clopidogrel hydrobromide.
  • the solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent may be heated to increase the solubility of the clopidogrel hydrobromide.
  • the polar, dipolar or less polar aprotic solvent may be selected from the group consisting of ketones preferably acetone, C 1 to C 4 alcohols, tetrahydrofuran, acetonitrile, C 3 to C 6 ketones, dimethylformamide, water and mixtures thereof.
  • the solution may be cooled, preferably to room temperature.
  • the aforementioned polar, dipolar or less polar aprotic solvent may optionally be removed from the solution to obtain a foam residue.
  • the removal of the solvent is carried out in the processes of the present invention by evaporation.
  • the solvent/solvents are removed be evaporation under ambient or reduced pressure. The antisolvent in such a case is then added to the foam residue.
  • a solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent may be slowly added to the antisolvent in order to precipitate amorphous clopidogrel hydrobromide according to the present invention.
  • Preferred antisolvents are selected from the group consisting of C 2 to C 4 dialkyl ethers such as for example dimethylether, diethyl ether, butyl ether and methyl tert. -butyl ether, C 1 to C 4 acetates, cyclohexane and toluene.
  • the precipitate should be separated from the reaction mixture at early stage, preferably within a few hours.
  • the precipitate may be collected by techniques well-known in the art such as for example filtration or centrifugation.
  • the precipitate may be dried under ambient or reduced pressure.
  • the present invention also provides a process for the preparation of amorphous clopidogrel hydrobromide comprising the steps of preparing a solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent as defined above, admixing the solution with an antisolvent, removing the polar, dipolar or less polar aprotic solvent from the solution to precipitate clopidogrel hydrobromide and separating the clopidogrel hydrobromide.
  • the antisolvent is toluene or cyclohexane.
  • the antisolvent is heated to a temperature of about room temperature to reflux so that the clopidogrel hydrobromide becomes more soluble in the antisolvent, with temperatures at or near reflux being preferred.
  • the resulting mixture is preferably cooled to about room temperature.
  • the polar, dipolar or less polar aprotic solvent and antisolvent are removed, preferably by evaporation, to leave amorphous form.
  • the present invention provides a process for the preparation of the amorphous form of clopidogrel hydrobromide comprising the steps of preparing a solution of clopidogrel hydrobromide in a solvent selected from the group consisting of Cj to C 4 alcohols, tetrahydrofuran, acetonitrile, ketones as for example acetone, dimethylformamide, water and mixtures thereof and removing solvent to obtain the amorphous form.
  • the mixture of clopidogrel hydrobromide and solvent is heated to form a solution. In a preferred embodiment a mixture is heated to reflux for a few hours. After heating, the solution is preferably cooled to about room temperature. The solution may be stirred for a few hours. After stirring, the solvent is removed to obtain a powder, which is the amorphous form of clopidogrel hydrobromide.
  • the solvent may be evaporated and temperature may be increased.
  • the present invention also provides a process for the preparation of clopidogrel hydrobromide in amorphous form, which comprises adding hydrogen bromide to a solution of clopidogrel in a solvent selected from the group consisting of ethers, preferably butylether, alcohols, preferably methanol, C 4 -C 8 dialkyl ether as for example diethyl ether, propyl ether and tert-butyl methyl ether, C 5 -C 8 linear, branched or cyclic hydrocarbon, as for example alkane, n-hexane, 2-methylhexane, cyclohexane and methylcyclohexane, toluene and tetrahydrofurane and mixtures thereof, to precipitate clopidogrel hydrobromide and separating the precipitated clopidogrel hydrobromide from the solvent.
  • a solvent selected from the group consisting of ethers, preferably butylether, alcohols,
  • the hydrogen bromide is conveniently added to the solution of clopidogrel at a temperature in the range of from about -15°C to reflux of the solvent.
  • the mixture of the solvent and precipitate of clopidogrel hydrobromide is suitably maintained at a temperature of from about -15 0 C to about 80 0 C, preferably from about -5 to 40 0 C for from about 20 to about 120 minutes prior to separating the clopidogrel hydrobromide from the solvent.
  • the hydrogen bromide may be added to the solution as a gas or as a solution of hydrogen bromide in a solvent selected from the group consisting of alcohols, C 4 -C 8 dialkyl ether, a C 5 -C 8 linear, branched or cyclic hydrocarbon and any mixtures thereof.
  • concentration of clopidogrel in the solvent is conveniently in the range of from about 5 to about 55 g/1.
  • the hydrogen bromide may, for example, be added to the solution of clopidogrel over a period of few seconds in rapid stream or in one portion as a solution thereof. In one embodiment, from about 0.9 to about 1.5 molar equivalents of hydrogen bromide are added to the solution of clopidogrel.
  • the separated clopidogrel hydrobromide may easily be dried in a vacuum at a temperature below 30 0 C.
  • the above disclosed processes according to the present invention also comprises the step of drying the precipitate to provide an amorphous form of clopidogrel hydrobromide.
  • the compound can be dried under conventional vacuum drying conditions, as for example, under a vacuum of down to about 50 or 15 mmHg, preferably about 30 mmHg, and at a temperature of up to about 20 to about 60 0 C, preferably about 30 0 C.
  • a second aspect of the present invention provides clopidogrel hydrobromide in polymorphic form alpha.
  • Polymorphic form alpha of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 3 and by FT-IR as substantially shown in Figure 4.
  • Polymorphic form alpha of clopidogrel hydrobromide is characterized by a powder X- ray diffraction pattern with the following peaks:
  • a third aspect of the present invention provides clopidogrel hydrobromide in polymorphic form beta.
  • Polymorphic form beta of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 5 and by FT-IR as substantially shown in Figure 6.
  • a forth aspect of the present invention provides clopidogrel hydrobromide in polymorphic form gama.
  • Polymorphic form gama of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 7.
  • Polymorphic form gama of clopidogrel hydrobromide is characterized by a powder X- ray diffraction pattern with the following peaks:
  • the clopidogrel hydrobromide in polymorphic forms alpha, beta and gama according to the present invention is substantially pure.
  • substantially pure clopidogrel hydrobromide means that the clopidogrel hydrobromide according to the present invention comprises less than about 20% of other crystalline or amorphous forms of clopidogrel hydrobromide, preferably less than about 15%, more preferably less than about 10%, more preferably less than about 5%, more preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other crystalline or amorphous form.
  • the term "substantially pure" clopidogrel hydrobromide also means that the clopidogrel hydrobromide according to the present invention comprises less than about 3% of other impurities, preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other impurities.
  • the present invention also provides a process for the preparing of clopidogrel hydrobromide form alpha, beta and gama according to the present invention.
  • the compounds of the present invention may be prepared by a process comprising crystallization of clopidogrel hydrobromide from a solution in one or more organic solvents.
  • the organic solvent may be polar compound, miscible with water, dipolar, and/or aprotic compound.
  • the organic solvent comprises a plurality or mixture of solvent compounds.
  • the organic solvent may be C 3 to C 6 ketones such as for example acetone, pentanone, cyclopentanone and 4-methyl-2-pentanone, a C 1 -C 4 alcohol, such as for examplemethanol, ethanol and 2-propanol, ethers such as for example tetrahydrofuran, diisopropyl ether, butyl ether, anisole, dimethoxyethane, and diethylenglycol-dimethylether, substituted C 2 to C 4 alkanes such as for example chlorinated C 2 to C 4 alkanes, C 1 to C 4 acetates such as for example ethylacetate and buthylacetate, C 5 -C 8 linear, branched or cyclic hydrocarbon such as for example hexane and cyclohex
  • polymorphic form alpha of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is ether, more preferably diglyme .
  • polymorphic form beta of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is C 3 to C 6 ketone, more preferably cyclopentanone.
  • polymorphic form gama of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is halogenated C 2 to C 4 alkanes, more preferably dichloroformate.
  • the crystallisation is carried out at temperature of about 20 to 35 0 C for about 1 to 6 hours followed by cooling at temperature of about 0 to 15°C for about 0.1 to 4 hours; preferably the crystallization is carried out at temperature of about 25 to 30 0 C for about 1.5 to 3 hours followed by cooling at temperature of about 5 to 10 0 C for about 0.5 to 1.5 hours.
  • the present invention also provides a process for the preparation of clopidogrel hydrobromide in forms alpha, beta and gama which comprises adding hydrogen bromide to a solution of clopidogrel in an organic solvent. Hydrogen bromide may be used also as its water solution.
  • the organic solvent may be C 3 to C 6 ketones such as for example acetone, pentanone, cyclopentanone and 4-methyl-2-pentanone, a C 1 -C 4 alcohol, such as for example methanol, ethanol and 2-propanol, or ethers such as for example diglyme, tetrahydrofuran, diisopropyl ether, butyl ether, anisole, dimethoxyethane, and diethylenglycol-dimethylether, substituted C 2 to C 4 alkanes such as for example chlorinated C 2 to C 4 alkanes, C 1 to C 4 acetates such as for example ethylacetate, buthylacetate, C 5 -C 8 linear, branched or cyclic hydrocarbon such as for example hexane, cyclohexane or aromatic hydrocarbon such as for example toluene and any mixtures thereof and separating the precipitated clopidogrel hydrobromide from the solvent
  • polymorphic form alpha of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is ether, more preferably diglyme.
  • polymorphic form beta of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is C 3 to C 6 ketone, more preferably cyclopentanone.
  • polymorphic form gama of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is halogenated C 2 to C 4 alkanes, more preferably dichloroformate.
  • the above disclosed processes according to the present invention also comprises the step of drying the precipitate to provide the polymorphic form alpha or beta or gama of clopidogrel hydrobromide.
  • the compound can be dried under conventional vacuum drying conditions, as for example, under a vacuum of down to about 50 or 15 mmHg, preferably about 30 mmHg, and at a temperature of up to about 20 to about 6O 0 C, preferably about 30 0 C.
  • clopidogrel hydrobromide according the present invention exists in solvated forms.
  • polymorphic form alpha and/or beta and/or gama of clopidogrel hydrobromide according to the present invention may be used in the preparation of other known crystalline forms of clopidogrel hydrobromide.
  • compositions of the present invention contain clopidogrel hydrobromide in polymorphic forms alpha, beta, gama or in amorphous form, optionally in mixture with other form(s) and active ingredients. Excipients are added to the composition for variety of purposes. Diluents (as for example microcrystalline cellulose, talc, calcium carbonate, magnesium oxide) increased the bulk of solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for patient and care give to handle. Binders for solid pharmaceutical compositions may include dextrin, gelatin, povidone, maltodextrin. Disintegrants may include colloidal silicon dioxide, crospovidone, starch.
  • Glidants also can be added to improve the flowability of a non-compacted solid composition and improve the accuracy of dosing. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and references works in the field the art.
  • Dosage forms of the present invention may include solid dosage forms such as for example tablets, pills, powders, granules and capsules.
  • Liquid dosage forms may include liquid syrups, suspensions, emulsions, solutions and elixirs.
  • Dosage forms of the present invention may include parenteral administration such as for example sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions.
  • Topical administration or aerosol inhalation may include water, alcohol, glycol, oil solution or oil-water emulsion. Rectal administration may include suppositories.
  • the active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
  • compositions of the present invention is useful in inhibition of platelet aggregation which means in reducing atherosclerotic events, such as for example myocardial infarction, stroke and vascular death.
  • Clopidogrel base and/or clopidogrel hydrobromide reffered to in examples can be prepared according to any known processes.
  • Clopidogrel base (0.63g) was dissolved in cyclohexane (60ml) at a temperature of 33 0 C, and then filtered. A brisk stream of hydrogen bromide gas was passed into reaction solution to keep the temperature at about 33 0 C; a wide gas-inlet tube is used. The separation of white material commences almost immediately then the gas stream has been discontinued and the reaction mixture was then stirred at temperature 33 °C for 0.5 hour. The solid, which had formed, was then collected by filtration, washed with cyclohexane and dried at 25 0 C in a vacuum oven for 12 hours to afford 0.6g of amorphous clopidogrel hydrobromide.
  • Clopidogrel base (0.38g) was dissolved in diglyme (4ml) at a temperature of 45 0 C.
  • the mixture was then cooled to 25 C and stream of hydrogen bromide was added at vigorous stirring.
  • the reaction mixture was stirred at a temperature of 25 0 C for 0.25 hours and then 8 hour at temperature 0 0 C.
  • the solidified material which was formed was then collected by filtration and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.25g of polymorphic form alpha of clopidogrel hydrobromide.
  • Clopidogrel base (0.35 g) was dissolved in acetone (3 ml) and ethanol (0.32 ml) containing hydrogen bromide was added. The reaction mixture was stirred at room temperature for 2 hours and poured with stirring onto toluene (50 ml) at a temperature of 105 0 C. The mixture was cooled and then the volume was reduced to 20 ml with the stirring at temperature 35 0 C. The solid was collected by filtration, washed with diethyl ether and dried at 30 0 C in a vacuum oven for 12 hours to obtain 0.2 g of amorphous form of clopidogrel hydrobromide.
  • Clopidogrel base (0.3 g) was dissolved in diglyme (5 ml) and butyl acetate (0.25 ml) containing hydrogen bromide was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was cooled to a temperature - 15 0 C with stirring. The solid was collected by filtration, washed with diethyl ether and then dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.15 g of polymorphic form alpha of clopidogrel hydrobromide.
  • Clopidogrel hydrobromide (0.25g) was dissolved in cyclopentanone (5ml) at a temperature of 85 0 C. The mixture was filtered and then diethyl ether (1.5ml) was added in one portion at vigorous stirring at cooling to -5 C. The reaction mixture was stirred at a temperature of -5 0 C for 0.25 hours. The solidified material which was formed was then collected by filtration and dried at 45 0 C in a vacuum oven for 12 hours to obtain 0.15g of polymorphic form beta of clopidogrel hydrobromide as cyclopentanone solvate.
  • Clopidogrel hydrobromide m.p .of about 140 0 C was dissolved in acetone (3 ml) and butanol (0.3 ml) at a temperature of 55-56 0 C.
  • the reaction mixture was stirred at reflux temperature for 6 hours and then filtered.
  • the solvent was evaporated to dryness under reduced pressure at a temperature of 55-56 0 C.
  • the foam was collected, washed with diethyl ether and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.2 g of amorphous form of clopidogrel hydrobromide.
  • Clopidogrel base (0.3 g) was dissolved in methanol (3 ml) and methanol (0.3 ml) containing hydrogen bromide is added. The reaction mixture was cooled to -5°C and the solvent was evaporated to dryness under reduced pressure. Then, diethyl ether (20 ml) was added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with diethyl ether and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.3 g of amorphous form of clopidogrel hydrobromide.
  • Clopidogrel base (0.23g) was dissolved in butyl ether (200ml) and hydrogen bromide gas was introduced at 75 0 C with vigorous stirring. The reaction mixture was cooled down and precipitated material was collected by filtration, washed with dimethyl ether and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.05g of amorphous clopidogrel hydrobromide.
  • Clopidogrel base (0.8 g) was dissolved in tetrahydrofuran (8 ml) and cone, hydrobromic acid (0.22 ml) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated to dryness under reduced pressure. Residue was dissolved in THF (4ml) and then added to diethyl ether (20 ml) with stirring at temperature 30 0 C in one portion. The solid was collected by filtration, washed with diethyl ether and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.82 g of amorphous form of clopidogrel hydrobromide.
  • Clopidogrel base (0.2g) was dissolved in n-hexane (25ml) at a temperature of 45 0 C.
  • the mixture was then cooled to -15 C and diethyl ether (1.5ml) containing hydrogen bromide was added in one portion at vigorous stirring.
  • the reaction mixture was stirred at a temperature of 25 0 C for 0.25 hours.
  • the solidified material which was formed was then collected by filtration and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.15g of the amorphous form of clopidogrel hydrobromide.
  • clopidogrel base (0.76g) was dissolved in toluene : cyclohexane mixture (90 ml, 1 : 1).
  • a vigorous stream of hydrogen bromide gas was introduced to the reaction mixture with rapid stirring at temperature 60 0 C.
  • the reaction mixture was stirred at a temperature of 60 0 C for 0.25 hours.
  • the solid which has formed was collected by filtration, washed with tert. butyl methyl ether and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.65g of the amorphous form of clopidogrel hydrobromide
  • Clopidogrel hydrobromide m.p of about 140 0 C (0.2g) was dissolved in acetone (2 ml) at a temperature of 55 0 C.
  • the reaction mixture was poured with stirring onto toluene (17 ml) at a temperature of 105 0 C.
  • the mixture was cooled to a temperature of 25-30 0 C and filtered.
  • the filtrate was evaporated to dryness.
  • the solid was collected, washed with diethyl ether and dried at 35 0 C in a vacuum oven for 12 hours to obtain 0.08 g of amorphous form of clopidogrel hydrobromide.
  • Clopidogrel hydrobromide of any polymorph form (Ig) was dissolved in dichloroformate (7.8 ml). Then heptane (8.7ml) is slowly added. The obtained solution is concentrated under nitrogen atmosphere. The obtained crystals are filtered. The obtained substance is polymorphic form gama of clopidogrel hydrobromide.
  • compositions comprising amorphous form of clopidogrel hydrobromide according to the present invention or polymorphic form alpha or polymorphic form beta of clopidogrel hydrobromide according to the present invention
  • Film coating a)
  • Titanium dioxide (E 171) 1.46mg
  • Granulate is prepared in a process of thermoplastic granulation, followed by, but not limited to, two above described formulations of compression mixtures. After compression process, cores are film coated, using either hypromellose or polyvinyl alcohol based film coating.
  • the manufacturing process is performed in a low moisture environment (relative humidity below 40%, temperature below 25°C).
  • the manufactured tablets are packed in aluminum blisters (OPA/ALU/PVC).

Abstract

The present invention relates to amorphous form of methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrobromide and to novel polymorphic forms alpha, beta and gama of methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrobromide. Further, the present invention relates to the preparation of new forms, the pharmaceutical compositions comprising such forms and to the method of use such forms for inhibiting platelet aggregation.

Description

POLYMORPHIC FORMS OF CLOPIDOGREL HYDROBROMIDE
FIELD OF THE INVENTION
The present invention relates to amorphous form of methyl (+)-(S)-(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrobromide and to novel polymorphic forms alpha, beta and gama of methyl (+)-(S)-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrobromide. Further, the present invention relates to the preparation of new forms, the pharmaceutical compositions comprising such forms and to the method of use such forms for inhibiting platelet aggregation.
TECHNICAL BACKGROUND
Clopidogrel is a well known inhibitor of induced platelet aggregation. It acts by inhibiting the binding of adenosine phosphate to its receptor. The chemical name of clopidogrel is methyl (+)-(S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate. It is represented by the following formula (I):
(I)
Clopidogrel is administered as its hydrogensulfate salt. It is currently being marketed as Plavix® tablets. U.S. Patent Nos. 4,847,265, 5,132,435, 6,258,961, 6,215,005 and 6,180,793 disclose methods of the preparation of clopidogrel hydrogensulfate. Different polymorphic forms of clopidogrel hydrogensulfate has been disclosed in the prior art.
Clopidogrel hydrobromide is known from U. S. Patent No 4,847,265 wherein after the crystallization from mixture of isopropylether and ispropanol the material with melting point 1400C was obtained. The patent is completely silent about the crystal form of the product and IR and/or X-ray diffraction pattern data.
Cystalline forms of clopidogrel hydrobromide are disclosed in WO 2005026174, US 2006154957, EP 1674468 Al, WO 2005/068471, WO 2005/080890, WO 2005/068471 and WO 2006/034451. The compounds according to the inventions are characterized by X-ray diffraction pattern (XRPD), differential scanning calorimetric (DSC) thermogram, TGA and FT Raman.
New crystalline forms B, C and D of methyl (+)-(S)-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridene-5(4H)-acetate hydrobromide and processes for their preparation are described in WO 2005/103058. All forms are characterized by FTIR and XRPD. The precipitate obtained in example 2 was dried to afford the form D named as an amorphous solid in example 4. The obtained form D was characterized in FT-IR spectrum with peaks at about 456, 723, 756, 1647 and 1748 cm'1 and by an XRPD pattern as depicted in Figure ID of aforesaid patent.
However, aforementioned patent literature do not disclose and not even suggest the existence of an amorphous form of clopidogrel hydrobromide. Moreover, Form D of clopidogrel hydrobromide named in WO 2005/103058 as an amorphous solid and characterized by XRPD does not show a good halo shape pattern typical of amorphous form that is substantially free of crystalline material. In addition, amorphous form of clopidogrel hydrobromide according to the present invention shows significant different FTIR spectrum.
It is well known that one of the most important physical properties of pharmaceuticals (amorphous versus crystalline form) is their solubility. (Konno T., Chem. Pharm. Bull., 1990, 38, 2003). In some therapeutic indications, the bioavailability is one of the key parameters determining the form of the substance to be used in pharmaceutical formulation. There can be many advantages mediated by using the amorphous form of a drug. The most important are enhanced solubility and bioavailability. It has been found that the crystalline form is less readily soluble than the amorphous one; therefore processes have been developed for the production of amorphous forms.
Summary of the invention
Accordingly, a first aspect of the present invention provides clopidogrel hydrobromide in amorphous form. Amorphous clopidogrel hydrobromide according to the present invention is characterized by an XRPD spectrum as substantially shown in Figure 1 and/or by FT-IR as substantially shown in Figure 2.
A second aspect of the present invention provides clopidogrel hydrobromide in polymorphic form alpha. Polymorphic form alpha of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 3 and/or by FT- IR as substantially shown in Figure 4.
A third aspect of the present invention provides clopidogrel hydrobromide in polymorphic form beta. Polymorphic form beta of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 5 and/or by FT- IR as substantially shown in Figure 6.
A forth aspect of the present invention provides clopidogrel hydrobromide in polymorphic form gama. Polymorphic form gama of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 7.
The present invention also provides a process for preparing clopidogrel hydrobromide in amorphous form, in polymorphic form alpha, beta and gama.
The present invention also provides pharmaceutical compositions and their method of administration to inhibit platelet aggregation.
Brief Description of the figures
X-ray powder diffraction patterns were obtained by a Phillips PW3040/60 X'Pert PRO diffractometer using CuKa radiation of 1,541874 L
FT-IR spectra were recorded on a FT-IR spectrometer Spectrum 100 and System GX Perkin Elmer at a resolution of 4 cm"1
FIG. 1 is a powder X-ray diffraction (XRPD) pattern of the amorphous form of clopidogrel hydrobromide according to the present invention.
FIG. 2 is a FTIR spectrum of the amorphous form of clopidogrel hydrobromide according to the present invention. FIG. 3 is a powder X-ray diffraction (XRPD) pattern of form alpha of clopidogrel hydrobromide according to the present invention.
FIG. 4 is a FTIR spectrum of form alpha of clopidogrel hydrobromide according to the present invention in 2000-700 cm'1 region.
FIG. 5 is a powder X-ray diffraction (XRPD) pattern of form beta of clopidogrel hydrobromide according to the present invention.
FIG. 6 is a FTIR spectrum of form beta of clopidogrel hydrobromide according to the present invention.
FIG. 7 is a powder X-ray diffraction (XRPD) pattern of form gama of clopidogrel hydrobromide according to the present invention.
Detailed Description of the invention
In a first aspect, the present invention provides a novel amorphous form of clopidogrel hydrobromide. The new form is characterized by powder X-ray diffraction pattern as substantially depicted in Figure 1. The pattern is without intense focused reflections with typical amorphous halo.
The novel amorphous form of clopidogrel hydrobromide exhibits a FTIR spectrum as substantially depicted in Figure 2 with the following characteristic absorption bands at about
In accordance with the invention, the amorphous form is highly pure. Preferably, it is essentially free of any crystalline clopidogrel hydrobromide. The phrase "amorphous" as used in the context of the present application denotes a physical state which is not crystalline and may be verified by X-ray diffraction and other means including but not limited to observation with a polarized light microscope and differential scanning calorimetry. More preferably the amorphous clopidogrel hydrobromide is free of crystalline clopidogrel hydrobromide within the detection limit of a powder X-ray diffractometer comparable to the instrumentation described. The purity of clopidogrel hydrobromide can be assessed by a comparison of the XRPD pattern of an unknown sample with those of mixtures of authentic pure amorphous and pure crystalline clopidogrel hydrobromide.
In the context of the present application, the term highly pure amorphous clopidogrel hydrobromide also means that the amorphous clopidogrel hydrobromide according to the present invention comprises less than about 3% of other impurities, preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other impurities.
The present invention further provides a process for preparing the novel amorphous form of clopidogrel hydrobromide according to the present invention comprising the steps of preparing a solution of clopidogrel hydrobromide in a polar, dipolar or a less polar aprotic solvent, removing the solvent from the solution to obtain a residue, admixing the residue with an antisolvent to precipitate clopidogrel hydrobromide and separating the clopidogrel hydrobromide. The solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent may be heated to increase the solubility of the clopidogrel hydrobromide. The polar, dipolar or less polar aprotic solvent may be selected from the group consisting of ketones preferably acetone, C1 to C4 alcohols, tetrahydrofuran, acetonitrile, C3 to C6 ketones, dimethylformamide, water and mixtures thereof. After dissolution, the solution may be cooled, preferably to room temperature. The aforementioned polar, dipolar or less polar aprotic solvent may optionally be removed from the solution to obtain a foam residue. Preferably, the removal of the solvent is carried out in the processes of the present invention by evaporation. Preferably, the solvent/solvents are removed be evaporation under ambient or reduced pressure. The antisolvent in such a case is then added to the foam residue. Alternatively, a solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent may be slowly added to the antisolvent in order to precipitate amorphous clopidogrel hydrobromide according to the present invention. Preferred antisolvents are selected from the group consisting of C2 to C4 dialkyl ethers such as for example dimethylether, diethyl ether, butyl ether and methyl tert. -butyl ether, C1 to C4 acetates, cyclohexane and toluene. The precipitate should be separated from the reaction mixture at early stage, preferably within a few hours. The precipitate may be collected by techniques well-known in the art such as for example filtration or centrifugation. The precipitate may be dried under ambient or reduced pressure.
The present invention also provides a process for the preparation of amorphous clopidogrel hydrobromide comprising the steps of preparing a solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent as defined above, admixing the solution with an antisolvent, removing the polar, dipolar or less polar aprotic solvent from the solution to precipitate clopidogrel hydrobromide and separating the clopidogrel hydrobromide. In a preferred embodiment, the antisolvent is toluene or cyclohexane. Preferably, the antisolvent is heated to a temperature of about room temperature to reflux so that the clopidogrel hydrobromide becomes more soluble in the antisolvent, with temperatures at or near reflux being preferred. After addition of the mixture to the solvent, the resulting mixture is preferably cooled to about room temperature. To obtain the amorphous form, the polar, dipolar or less polar aprotic solvent and antisolvent are removed, preferably by evaporation, to leave amorphous form.
Further, the present invention provides a process for the preparation of the amorphous form of clopidogrel hydrobromide comprising the steps of preparing a solution of clopidogrel hydrobromide in a solvent selected from the group consisting of Cj to C4 alcohols, tetrahydrofuran, acetonitrile, ketones as for example acetone, dimethylformamide, water and mixtures thereof and removing solvent to obtain the amorphous form. The mixture of clopidogrel hydrobromide and solvent is heated to form a solution. In a preferred embodiment a mixture is heated to reflux for a few hours. After heating, the solution is preferably cooled to about room temperature. The solution may be stirred for a few hours. After stirring, the solvent is removed to obtain a powder, which is the amorphous form of clopidogrel hydrobromide. The solvent may be evaporated and temperature may be increased.
The present invention also provides a process for the preparation of clopidogrel hydrobromide in amorphous form, which comprises adding hydrogen bromide to a solution of clopidogrel in a solvent selected from the group consisting of ethers, preferably butylether, alcohols, preferably methanol, C4-C8 dialkyl ether as for example diethyl ether, propyl ether and tert-butyl methyl ether, C5-C8 linear, branched or cyclic hydrocarbon, as for example alkane, n-hexane, 2-methylhexane, cyclohexane and methylcyclohexane, toluene and tetrahydrofurane and mixtures thereof, to precipitate clopidogrel hydrobromide and separating the precipitated clopidogrel hydrobromide from the solvent. The hydrogen bromide is conveniently added to the solution of clopidogrel at a temperature in the range of from about -15°C to reflux of the solvent. The mixture of the solvent and precipitate of clopidogrel hydrobromide is suitably maintained at a temperature of from about -15 0C to about 80 0C, preferably from about -5 to 40 0C for from about 20 to about 120 minutes prior to separating the clopidogrel hydrobromide from the solvent. The hydrogen bromide may be added to the solution as a gas or as a solution of hydrogen bromide in a solvent selected from the group consisting of alcohols, C4-C8 dialkyl ether, a C5-C8 linear, branched or cyclic hydrocarbon and any mixtures thereof. The concentration of clopidogrel in the solvent is conveniently in the range of from about 5 to about 55 g/1. The hydrogen bromide may, for example, be added to the solution of clopidogrel over a period of few seconds in rapid stream or in one portion as a solution thereof. In one embodiment, from about 0.9 to about 1.5 molar equivalents of hydrogen bromide are added to the solution of clopidogrel. The separated clopidogrel hydrobromide may easily be dried in a vacuum at a temperature below 30 0C.
The above disclosed processes according to the present invention also comprises the step of drying the precipitate to provide an amorphous form of clopidogrel hydrobromide. The compound can be dried under conventional vacuum drying conditions, as for example, under a vacuum of down to about 50 or 15 mmHg, preferably about 30 mmHg, and at a temperature of up to about 20 to about 600C, preferably about 300C.
A second aspect of the present invention provides clopidogrel hydrobromide in polymorphic form alpha. Polymorphic form alpha of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 3 and by FT-IR as substantially shown in Figure 4. Polymorphic form alpha of clopidogrel hydrobromide is characterized by a powder X- ray diffraction pattern with the following peaks:
Pos. d-spacing ReI. Int. [°2Th.] [A] ™
8.7 10.20 100
13.8 6.40 63
21.1 4.22 32
24.1 3.70 83
25.3 3.52 32
26.2 3.40 53
Polymorphic form alpha of clopidogrel hydrobromide exhibits a FTIR spectrum with the following characteristic absorption bands at about
A third aspect of the present invention provides clopidogrel hydrobromide in polymorphic form beta. Polymorphic form beta of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 5 and by FT-IR as substantially shown in Figure 6.
Polymorphic form beta of clopidogrel hydrobromide is characterized by a powder X- ray diffraction pattern with the following peaks:
Pos. d-spacing ReI. Int.
[°2Th.] [A] [%]
10.4 8.48 51
11.6 7.62 38
16.4 5.40 28
20.1 4.42 11
24.6 3.62 21
25.6 3.48 74
Polymorphic form beta of clopidogrel hydrobromide exhibits a FTIR spectrum with the following characteristic absorption bands at about
A forth aspect of the present invention provides clopidogrel hydrobromide in polymorphic form gama. Polymorphic form gama of clopidogrel hydrobromide is characterized by an XRPD spectrum as substantially shown in Figure 7. Polymorphic form gama of clopidogrel hydrobromide is characterized by a powder X- ray diffraction pattern with the following peaks:
Pos. d-spacmg ReI. I
[°2Th.] [A] [%]
7.7 11.50 28
10.2 8.70 11
15.3 5.79 9
17.9 4.95 13
20.2 4.39 29
23.1 3.86 29
25.1 3.54 12
26.2 3..40 100
The clopidogrel hydrobromide in polymorphic forms alpha, beta and gama according to the present invention is substantially pure.
In the context of the present application, the term "substantially pure" clopidogrel hydrobromide means that the clopidogrel hydrobromide according to the present invention comprises less than about 20% of other crystalline or amorphous forms of clopidogrel hydrobromide, preferably less than about 15%, more preferably less than about 10%, more preferably less than about 5%, more preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other crystalline or amorphous form.
In the context of the present application, the term "substantially pure" clopidogrel hydrobromide also means that the clopidogrel hydrobromide according to the present invention comprises less than about 3% of other impurities, preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other impurities. The present invention also provides a process for the preparing of clopidogrel hydrobromide form alpha, beta and gama according to the present invention. The compounds of the present invention may be prepared by a process comprising crystallization of clopidogrel hydrobromide from a solution in one or more organic solvents. The organic solvent may be polar compound, miscible with water, dipolar, and/or aprotic compound. Optionally the organic solvent comprises a plurality or mixture of solvent compounds. The organic solvent may be C3 to C6 ketones such as for example acetone, pentanone, cyclopentanone and 4-methyl-2-pentanone, a C1-C4 alcohol, such as for examplemethanol, ethanol and 2-propanol, ethers such as for example tetrahydrofuran, diisopropyl ether, butyl ether, anisole, dimethoxyethane, and diethylenglycol-dimethylether, substituted C2 to C4 alkanes such as for example chlorinated C2 to C4 alkanes, C1 to C4 acetates such as for example ethylacetate and buthylacetate, C5-C8 linear, branched or cyclic hydrocarbon such as for example hexane and cyclohexane, aromatic hydrocarbon such as for example toluene and mixtures thereof,. Preferably polymorphic form alpha of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is ether, more preferably diglyme . Preferably polymorphic form beta of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is C3 to C6 ketone, more preferably cyclopentanone. Preferably polymorphic form gama of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is halogenated C2 to C4 alkanes, more preferably dichloroformate.
The crystallisation is carried out at temperature of about 20 to 35 0C for about 1 to 6 hours followed by cooling at temperature of about 0 to 15°C for about 0.1 to 4 hours; preferably the crystallization is carried out at temperature of about 25 to 300C for about 1.5 to 3 hours followed by cooling at temperature of about 5 to 10 0C for about 0.5 to 1.5 hours. The present invention also provides a process for the preparation of clopidogrel hydrobromide in forms alpha, beta and gama which comprises adding hydrogen bromide to a solution of clopidogrel in an organic solvent. Hydrogen bromide may be used also as its water solution. The organic solvent may be C3 to C6 ketones such as for example acetone, pentanone, cyclopentanone and 4-methyl-2-pentanone, a C1-C4 alcohol, such as for example methanol, ethanol and 2-propanol, or ethers such as for example diglyme, tetrahydrofuran, diisopropyl ether, butyl ether, anisole, dimethoxyethane, and diethylenglycol-dimethylether, substituted C2 to C4 alkanes such as for example chlorinated C2 to C4 alkanes, C1 to C4 acetates such as for example ethylacetate, buthylacetate, C5-C8 linear, branched or cyclic hydrocarbon such as for example hexane, cyclohexane or aromatic hydrocarbon such as for example toluene and any mixtures thereof and separating the precipitated clopidogrel hydrobromide from the solvent. Preferably polymorphic form alpha of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is ether, more preferably diglyme. Preferably polymorphic form beta of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is C3 to C6 ketone, more preferably cyclopentanone. Preferably polymorphic form gama of clopidogrel hydrobromide according to the present invention is obtained when the organic solvent is halogenated C2 to C4 alkanes, more preferably dichloroformate.
The above disclosed processes according to the present invention also comprises the step of drying the precipitate to provide the polymorphic form alpha or beta or gama of clopidogrel hydrobromide. The compound can be dried under conventional vacuum drying conditions, as for example, under a vacuum of down to about 50 or 15 mmHg, preferably about 30 mmHg, and at a temperature of up to about 20 to about 6O0C, preferably about 300C. Furthermore it was unexpectedly found that clopidogrel hydrobromide according the present invention exists in solvated forms.
The polymorphic form alpha and/or beta and/or gama of clopidogrel hydrobromide according to the present invention may be used in the preparation of other known crystalline forms of clopidogrel hydrobromide.
Pharmaceutical compositions of the present invention contain clopidogrel hydrobromide in polymorphic forms alpha, beta, gama or in amorphous form, optionally in mixture with other form(s) and active ingredients. Excipients are added to the composition for variety of purposes. Diluents (as for example microcrystalline cellulose, talc, calcium carbonate, magnesium oxide) increased the bulk of solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for patient and care give to handle. Binders for solid pharmaceutical compositions may include dextrin, gelatin, povidone, maltodextrin. Disintegrants may include colloidal silicon dioxide, crospovidone, starch. Glidants also can be added to improve the flowability of a non-compacted solid composition and improve the accuracy of dosing. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and references works in the field the art.
Dosage forms of the present invention may include solid dosage forms such as for example tablets, pills, powders, granules and capsules. Liquid dosage forms may include liquid syrups, suspensions, emulsions, solutions and elixirs. Dosage forms of the present invention may include parenteral administration such as for example sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Topical administration or aerosol inhalation may include water, alcohol, glycol, oil solution or oil-water emulsion. Rectal administration may include suppositories. The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
The pharmaceutical compositions of the present invention is useful in inhibition of platelet aggregation which means in reducing atherosclerotic events, such as for example myocardial infarction, stroke and vascular death.
The invention is illustrated by reference to the following examples. However, the examples are not intended to limit any scope of the claim anyway. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.
Clopidogrel base and/or clopidogrel hydrobromide reffered to in examples can be prepared according to any known processes.
EXAMPLE l
Clopidogrel base (0.63g) was dissolved in cyclohexane (60ml) at a temperature of 33 0C, and then filtered. A brisk stream of hydrogen bromide gas was passed into reaction solution to keep the temperature at about 33 0C; a wide gas-inlet tube is used. The separation of white material commences almost immediately then the gas stream has been discontinued and the reaction mixture was then stirred at temperature 33 °C for 0.5 hour. The solid, which had formed, was then collected by filtration, washed with cyclohexane and dried at 25 0C in a vacuum oven for 12 hours to afford 0.6g of amorphous clopidogrel hydrobromide. EXAMPLE 2
Clopidogrel base (0.38g) was dissolved in diglyme (4ml) at a temperature of 45 0C.
The mixture was then cooled to 25 C and stream of hydrogen bromide was added at vigorous stirring. The reaction mixture was stirred at a temperature of 25 0C for 0.25 hours and then 8 hour at temperature 00C. The solidified material which was formed was then collected by filtration and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.25g of polymorphic form alpha of clopidogrel hydrobromide.
EXAMPLE 3
Clopidogrel base (0.35 g) was dissolved in acetone (3 ml) and ethanol (0.32 ml) containing hydrogen bromide was added. The reaction mixture was stirred at room temperature for 2 hours and poured with stirring onto toluene (50 ml) at a temperature of 105 0C. The mixture was cooled and then the volume was reduced to 20 ml with the stirring at temperature 350C. The solid was collected by filtration, washed with diethyl ether and dried at 30 0C in a vacuum oven for 12 hours to obtain 0.2 g of amorphous form of clopidogrel hydrobromide.
EXAMPLE 4
Clopidogrel base (0.3 g) was dissolved in diglyme (5 ml) and butyl acetate (0.25 ml) containing hydrogen bromide was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was cooled to a temperature - 15 0C with stirring. The solid was collected by filtration, washed with diethyl ether and then dried at 35 0C in a vacuum oven for 12 hours to obtain 0.15 g of polymorphic form alpha of clopidogrel hydrobromide. EXAMPLE 5
Clopidogrel hydrobromide (0.25g) was dissolved in cyclopentanone (5ml) at a temperature of 85 0C. The mixture was filtered and then diethyl ether (1.5ml) was added in one portion at vigorous stirring at cooling to -5 C. The reaction mixture was stirred at a temperature of -5 0C for 0.25 hours. The solidified material which was formed was then collected by filtration and dried at 45 0C in a vacuum oven for 12 hours to obtain 0.15g of polymorphic form beta of clopidogrel hydrobromide as cyclopentanone solvate.
EXAMPLE 6
Clopidogrel hydrobromide m.p .of about 140 0C (0.2g) was dissolved in acetone (3 ml) and butanol (0.3 ml) at a temperature of 55-56 0C. The reaction mixture was stirred at reflux temperature for 6 hours and then filtered. The solvent was evaporated to dryness under reduced pressure at a temperature of 55-56 0C. The foam was collected, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.2 g of amorphous form of clopidogrel hydrobromide.
EXAMPLE 7
Clopidogrel base (0.3 g) was dissolved in methanol (3 ml) and methanol (0.3 ml) containing hydrogen bromide is added. The reaction mixture was cooled to -5°C and the solvent was evaporated to dryness under reduced pressure. Then, diethyl ether (20 ml) was added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.3 g of amorphous form of clopidogrel hydrobromide. EXAMPLE 8
Clopidogrel base (0.23g) was dissolved in butyl ether (200ml) and hydrogen bromide gas was introduced at 75 0C with vigorous stirring. The reaction mixture was cooled down and precipitated material was collected by filtration, washed with dimethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.05g of amorphous clopidogrel hydrobromide.
EXAMPLE 9
Clopidogrel base (0.8 g) was dissolved in tetrahydrofuran (8 ml) and cone, hydrobromic acid (0.22 ml) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated to dryness under reduced pressure. Residue was dissolved in THF (4ml) and then added to diethyl ether (20 ml) with stirring at temperature 300C in one portion. The solid was collected by filtration, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.82 g of amorphous form of clopidogrel hydrobromide.
EXAMPLE 10
Clopidogrel base (0.2g) was dissolved in n-hexane (25ml) at a temperature of 45 0C.
The mixture was then cooled to -15 C and diethyl ether (1.5ml) containing hydrogen bromide was added in one portion at vigorous stirring. The reaction mixture was stirred at a temperature of 25 0C for 0.25 hours. The solidified material which was formed was then collected by filtration and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.15g of the amorphous form of clopidogrel hydrobromide.
EXAMPLE 11
In 100ml 3 -necked flat bottom flask equipped with a thermometer, magnetic stirrer and two inlet tubes, clopidogrel base (0.76g) was dissolved in toluene : cyclohexane mixture (90 ml, 1 : 1). A vigorous stream of hydrogen bromide gas was introduced to the reaction mixture with rapid stirring at temperature 600C. The reaction mixture was stirred at a temperature of 60 0C for 0.25 hours. The solid which has formed was collected by filtration, washed with tert. butyl methyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.65g of the amorphous form of clopidogrel hydrobromide
EXAMPLE 12
Clopidogrel hydrobromide m.p of about 140 0C (0.2g) was dissolved in acetone (2 ml) at a temperature of 55 0C. The reaction mixture was poured with stirring onto toluene (17 ml) at a temperature of 105 0C. The mixture was cooled to a temperature of 25-30 0C and filtered. The filtrate was evaporated to dryness. The solid was collected, washed with diethyl ether and dried at 35 0C in a vacuum oven for 12 hours to obtain 0.08 g of amorphous form of clopidogrel hydrobromide.
EXAMPLE 13
Clopidogrel hydrobromide of any polymorph form (Ig) was dissolved in dichloroformate (7.8 ml). Then heptane (8.7ml) is slowly added. The obtained solution is concentrated under nitrogen atmosphere. The obtained crystals are filtered. The obtained substance is polymorphic form gama of clopidogrel hydrobromide.
EXAMPLE 14
Examples of pharmaceutical formulations, comprising amorphous form of clopidogrel hydrobromide according to the present invention or polymorphic form alpha or polymorphic form beta of clopidogrel hydrobromide according to the present invention Film coating: a)
Hypromellose 5.6 mg
Titanium dioxide (E 171) 1.46mg
Talc 0.5mg
Colour sicopharm rot (E 172) q.s.
Propylene glycol q.s.
b)
Opadry II HP 7.96mg
(ready to use mixture of polyvinyl alcohol, titanium dioxide, propylene glycol and talc)
Colour sicopharm rot (E 172) q.s.
(colour may be added seperately or included in the above mentioned ready to use mixture)
Granulate is prepared in a process of thermoplastic granulation, followed by, but not limited to, two above described formulations of compression mixtures. After compression process, cores are film coated, using either hypromellose or polyvinyl alcohol based film coating.
The manufacturing process is performed in a low moisture environment (relative humidity below 40%, temperature below 25°C). The manufactured tablets are packed in aluminum blisters (OPA/ALU/PVC).

Claims

1. Amorphous clopidogrel hydrobromide having halo shape X-ray powder diffraction pattern.
2. The amorphous clopidogrel hydrobromide of claim 1 characterized by a powder X- ray diffraction pattern as substantially depicted in Figure 1.
3. The amorphous clopidogrel hydrobromide characterized by a FTIR spectrum as substantially depicted in Figure 2.
4. The amorphous clopidogrel hydrobromide characterized by a FTIR spectrum peaks at about 3008, 2926, 1134, 1039, 886 and 762 cm'1.
5. The amorphous clopidogrel hydrobromide of any of preceding claims characterized by being essentially free of crystalline clopidogrel hydrobromide.
6. The amorphous clopidogrel hydrobromide of any of preceding claims characterized by containing less than about 3% of impurities, preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other impurities.
7. A process for preparing amorphous clopidogrel hydrobromide according to any of the preceding claims comprising steps of
a) preparing a solution of clopidogrel hydrobromide in a polar, dipolar or less polar aprotic solvent, preferably selected from a group consisting of ketones, more preferably acetone, C1 to C4 alcohols, more preferably butanol, tetrahydrofuran, acetonitrile, C3 to C6 ketones, dimethylformamide, water and mixtures thereof, and bl) optionally removing the solvent from the solution to obtain a residue and admixing the residue with an antisolvent selected from the group consisting of C2 to C4 dialkyl ethers, preferably dimethylether, diethyl ether, butyl ether and methyl tert.-butyl ether, Cj to C4 acetates, toluene and cyclohexane, to precipitate clopidogrel hydrobromide; or b2) optionally admixing the solution with an antisolvent, selected from the group consisting of C2 to C4 dialkyl ethers, preferably dimethylether, diethyl ether, butyl ether and methyl tert.-butyl ether, C1 to C4 acetates, toluene and cyclohexane, most preferably diethylether, cyclohexane and toluene, removing the polar, dipolar or less polar aprotic solvent from the solution to precipitate clopidogrel hydrobromide; and c) separating the precipitated clopidogrel hydrobromide from the solvent.
8. A process for preparing amorphous clopidogrel hydrobromide of any of the preceding claims 1-6, comprising the steps of: a) adding hydrogen bromide to a solution of clopidogrel in one or more solvents selected from the group consisting of ketones, preferably acetone, alcohols, preferably methanol, ethers, preferably butylether, Cs-C8 linear, branched or cyclic hydrocarbon, preferably n-hexane and cyclohexane, toluene and tetrahydrofurane and any mixtures thereof, to precipitate clopidogrel hydrobromide b) separating the precipitated clopidogrel hydrobromide from the solvent.
9. A process for preparing amorphous clopidogrel hydrobromide according to claim 8, characterized in that hydrogen bromide may be added to the solution as a gas or as a solution of hydrogen bromide in a solvent selected from the group consisting of alcohols, C4-Cg dialkyl ether, a C5-C8 linear, branched or cyclic hydrocarbon and any mixtures thereof.
10. The process for preparing amorphous clopidogrel hydrobromide according to claims 7 to 8 further comprising the step of drying.
11. Polymorphic form alpha of clopidogrel hydrobromide characterized by a powder X-ray diffraction pattern as substantially depicted in Figure 3.
12. Polymorphic form alpha of clopidogrel hydrobromide characterized by a powder X-ray diffraction peaks at about 8.7, 13.8, 21.1, 24.1, 25.3 and 26.2 degrees two theta.
13. Polymorphic form alpha of clopidogrel hydrobromide characterized by a FTIR spectrum as substantially depicted in Figure 4.
14. Polymorphic form alpha of clopidogrel hydrobromide characterized by a FTIR spectrum peaks at about 2896, 1446, 1412, 1333, 1128, 972 and 949 cm"1.
15. Polymorphic form beta of clopidogrel hydrobromide characterized by a powder X-ray diffraction pattern as substantially depicted in Figure 5.
16. Polymorphic form beta of clopidogrel hydrobromide characterized by a powder X-ray diffraction peaks at about 10.4, 11.6, 16.4, 20.1, 24.6 and 25.6 degrees two theta.
17. Polymorphic form beta of clopidogrel hydrobromide characterized by a FTIR spectrum as substantially depicted in Figure 6.
18. Polymorphic form beta of clopidogrel hydrobromide characterized by a FTIR spectrum peaks at about 3026, 1450, 1399, 1189, 1156, 945 and 903 cm"1.
19. Polymorphic form gama of clopidogrel hydrobromide characterized by a powder X-ray diffraction pattern as substantially depicted in Figure 7.
20. Polymorphic form gama of clopidogrel hydrobromide characterized by a powder X-ray diffraction peaks at about 7.7, 20.2, 23.1, 26.2 degrees two theta.
21. The polymorphic form alpha of clopidogrel bromide according to claims 11 to 14 characterized by comprising less than about 20% of other crystalline or amorphous forms of clopidogrel hydrobromide, preferably less than about 10%, more preferably less than about 1%, more preferably less than about 0.5%.
22. The polymorphic form beta of clopidogrel bromide according to claims 15 to 18 characterized by comprising less than about 20% of other crystalline or amorphous forms of clopidogrel hydrobromide, preferably less than about 10%, more preferably less than about 1%, more preferably less than about 0.5%.
23. The polymorphic form gama of clopidogrel bromide according to claims 19 to 20 characterized by comprising less than about 20% of other crystalline or amorphous forms of clopidogrel hydrobromide, preferably less than about 10%, more preferably less than about 1%, more preferably less than about 0.5%.
24. The polymorphic form of clopidogrel hydrobromide according to claims 11 to 23 characterized by containing less than about 3% of impurities, preferably less than about 2%, more preferably less than about 1%, and even more preferably less than about 0.5% of other impurities.
25. A process for preparing the polymorphic form alpha of clopidogrel hydrobromide of claims 11 to 14, 21 and 24 comprising the steps of: a) adding hydrogen bromide to a solution of clopidogrel in organic solvents selected from ethers, preferably diglyme, b) separating the precipitated clopidogrel hydrobromide from the solvent.
26. A process for preparing the polymorphic form beta of clopidogrel hydrobromide of claims 15 to 18, 22 and 24 comprising the steps of: a) adding hydrogen bromide to a solution of clopidogrel in organic solvents selected from ketones, preferably cyclopentanone, b) separating the precipitated clopidogrel hydrobromide from the solvent.
27. A process for preparing the polymorphic form alpha of clopidogrel hydrobromide of claims 11 to 14, 21 and 24 comprising the steps of: a) crystallization from a solution of clopidogrel hydrobromide in one or more organic solvents selected from ethers, preferably diglyme, b) separating the precipitated clopidogrel hydrobromide from the solvent.
28. A process for preparing the polymorphic form beta of clopidogrel hydrobromide of claims 15 to 18, 22 and 24 comprising the steps of: a) crystallization from a solution of clopidogrel hydrobromide in one or more organic solvents selected from ketones, preferably cyclopentanone, b) separating the precipitated clopidogrel hydrobromide from the solvent.
29. A process for preparing the polymorphic form gama of clopidogrel hydrobromide of claims 19-20 and 23-24 comprising the steps of: a) dissolving clopidogrel hydrobromide in organic solvents selected from halogenated C2 to C4 alkanes, preferably dichloroformate, b) concentration under nitrogen atmosphere c) isolation.
30. Use of polymorphic form alpha of clopidogrel hydrobromide of claims 11 to 14,
21 and 24 in the preparation of other polymorphic forms of clopidogrel hydrobromide.
31. Use of polymorphic form beta of clopidogrel hydrobromide of claims 15 to 18,
22 and 24 in the preparation of other polymorphic forms of clopidogrel hydrobromide.
32. Use of polymorphic form gama of clopidogrel hydrobromide of claims 19 to 20, and 23-24 in the preparation of other polymorphic forms of clopidogrel hydrobromide.
33. A pharmaceutical composition comprising a compound according to any one of the preceding claims 1-6 and 11-24 together with pharmaceutically acceptable excipients.
34. Use of an effective amount of a compound according to any of the claims 1-6 and 11-24 for the preparation of a pharmaceutical composition for the inhibition of platelet aggregation in a patient in need thereof.
35. A method of inhibiting platelet aggregation which comprises administering to a patient in need thereof an effective amount of a compound according to any one of the preceding claims.
EP08724381A 2007-03-08 2008-03-07 Polymorphic forms of clopidogrel hydrobromide Withdrawn EP2121704A2 (en)

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CN1997648A (en) * 2004-04-20 2007-07-11 赛诺菲-安万特 Polymorphic forms of methyl(+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H) acetate hydrobromide, clopidrogel hydrobromide
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