WO2007029096A2 - Nouvelles formes polymorphes de chlorhydrate de clopidogrel - Google Patents

Nouvelles formes polymorphes de chlorhydrate de clopidogrel Download PDF

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Publication number
WO2007029096A2
WO2007029096A2 PCT/IB2006/002443 IB2006002443W WO2007029096A2 WO 2007029096 A2 WO2007029096 A2 WO 2007029096A2 IB 2006002443 W IB2006002443 W IB 2006002443W WO 2007029096 A2 WO2007029096 A2 WO 2007029096A2
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WO
WIPO (PCT)
Prior art keywords
clopidogrel hydrochloride
clopidogrel
hydrochloride
form iii
mixtures
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PCT/IB2006/002443
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English (en)
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WO2007029096A3 (fr
Inventor
Kiran Kumar Gangakhedkar
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Ranbaxy Laboratories Limited
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2007029096A2 publication Critical patent/WO2007029096A2/fr
Publication of WO2007029096A3 publication Critical patent/WO2007029096A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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

Definitions

  • the present invention provides a novel crystalline polymorphic form of clopidogrel hydrochloride, process for its preparation and pharmaceutical compositions thereof.
  • the novel crystalline polymorphic form has been designated as Form III.
  • the present invention provides novel amorphous form of clopidogrel hydrochloride, process for preparation and pharmaceutical compositions thereof.
  • U.S. Patent No. 4,847,265 discloses processes for preparing dextrorotatory enantiomer of clopidogrel and its salts.
  • the '265 discloses the hydrogen sulphate, the taurochloate, the hydrogen chloride and the hydrogen bromide salts of dextrorotatory enantiomer of clopidogrel, which is prepared by dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing hydrogen chloride.
  • the resulting product clopidogrel hydrogen chloride is characterized by a melting point of 117 0 C.
  • U.S. Patent No. 5,204,469 (the '469 patent) provides a process for preparing clopidogrel hydrochloride, having a characteristic melting point of 130-140 0 C, which is prepared by dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing hydrogen chloride.
  • the '469 patent does not disclose the existence of any specific polymorphic forms of clopidogrel hydrochloride.
  • PCT Patent Application Nos. WO 98/51681, WO 98/51682, WO 98/51689, and WO 00/27840 provides process for preparing clopidogrel hydrochloride, which utilizes a solution of clopidogrel free base in diethyl ether, introducing hydrogen chloride gas into the solution and isolating the formed crystals by filtration.
  • the hydrogen chloride salt is characterized by a melting point of 130-132 0 C.
  • PCT Patent application No WO 03/066637 provides crystalline form I and II of clopidogrel hydrochloride characterized by the X-ray powder diffraction pattern and processes for their preparation.
  • the process involves dissolving clopidogrel free base in tetrahydrofuran or a mixture of acetone and ethyl acetate followed by adding hydrochloric acid in an organic solvent like tetrahydrofuran, propanol, ethyl acetate, stirring the mixture for 2 hours and thereafter allowing to stand in a refrigerator for 16 hours.
  • Crystalline form I of clopidogrel hydrochloride is then isolated from the reaction mass by filtration.
  • Form III of clopidogrel hydrochloride can have one or more of the following embodiments.
  • Form III of clopidogrel hydrochloride can have a X-Ray Powder Diffraction (XRPD) pattern wherein characteristic peaks are at about 12.92, 19.80, 22.96, 24.84 and 25.28.
  • XRPD X-Ray Powder Diffraction
  • Form III of clopidogrel hydrochloride can have a XRPD pattern wherein characteristic peaks are at about 9.40, 12.92, 13.70, 14.24, 16.00, 19.80, 20.30, 21.38, 22.00, 22.96, 23.92, 24.84, 25.28, 30.24, 31.52, 35.94 and 36.72 ⁇ 0.2 degrees two theta.
  • characteristic peaks are at about 9.40, 12.92, 13.70, 14.24, 16.00, 19.80, 20.30, 21.38, 22.00, 22.96, 23.92, 24.84, 25.28, 30.24, 31.52, 35.94 and 36.72 ⁇ 0.2 degrees two theta.
  • characteristic peaks are at about 9.40, 12.92, 13.70, 14.24, 16.00, 19.80, 20.30, 21.38, 22.00, 22.96, 23.92, 24.84, 25.28, 30.24, 31.52, 35.94 and 36.72 ⁇ 0.2 degrees two thet
  • Form III of clopidogrel hydrochloride can have a XRPD pattern wherein characteristic peaks are at about 9.40, 9.60, 12.92, 13.70, 14.24, 16.00, 16.74, 19.46, 19.80, 20.30, 20.66, 21.38, 21.52, 22.00, 22.96, 23.92, 24.84, 25.28, 26.10, 27.30, 28.80, 30.06, 30.24, 30.74, 31.20, 31.52, 32.52, 32.36, 35.94 and 36.72 ⁇ 0.2 degrees two theta.
  • XRPD X-Ray Powder Diffraction
  • a process for preparing Form III of clopidogrel hydrochloride comprising the steps of, a) dissolving clopidogrel free base in one or more non-polar organic solvents to form a solution, b) adding hydrochloric acid to the solution obtained in step a) to form a mixture, and c) stirring the mixture of step b) for more than about one hour to form Form III of clopidogrel hydrochloride and isolating Form III of clopidogrel hydrochloride from the mixture.
  • the process can include one or more of the following embodiments.
  • the mixture obtained after step b can be stirred for more than about 1 hour to 72 hours.
  • the one or more non-polar organic solvents are selected from one or more ethers, alkanes, cycloalkanes or mixtures thereof.
  • the one or more ethers are selected from diethyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, methyl tert-butyl ether, 1, 2-dioxane, 1,2-dimethoxyethane, tetrahydrofuran or mixtures thereof.
  • the one or more alkanes are selected from pentane, isopentane, hexane, heptane, octane, nonane or mixtures thereof.
  • the one or more cycloalkanes are selected from cyclopentane, cyclohexane or mixtures thereof.
  • a process for preparing amorphous clopidogrel hydrochloride which comprises of, a) dissolving clopidogrel free base in one or more non-polar organic solvents to form a solution, b) adding hydrochloric acid to the solution obtained in step a) to form a mixture, c) stirring the mixture of step b) for less than one hour to form amorphous clopidogrel hydrochloride and isolating amorphous clopidogrel hydrochloride from the mixture.
  • the process can include one or more of the following embodiments.
  • the mixture obtained after step b can be stirred for more than about 1 hour to 72 hours, hi another embodiment, the one or more non-polar organic solvents are selected from one or more ethers, alkanes, cycloalkanes or mixtures thereof.
  • the one or more ethers are selected from diethyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, methyl tert-butyl ether, 1, 2-dioxane, 1,2-dimethoxyethane, tetrahydrofuran or mixtures thereof.
  • the one or more alkanes are selected from pentane, isopentane, hexane, heptane, octane, nonane or mixtures thereof.
  • the one or more cycloalkanes are selected from cyclopentane, cyclohexane or mixtures thereof.
  • compositions comprising Form III of clopidogrel hydrochloride and one or more pharmaceutically acceptable carrier or excipients; or amorphous clopidogrel hydrochloride and one or more pharmaceutically acceptable carriers or excipients.
  • a method of treating or inhibiting blood platelet aggregation and thrombosis which comprises administering to a patient in need thereof a therapeutically effective amount of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.
  • a method of reducing atherosclerotic events in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease which comprises administering to a patient in need thereof a therapeutically effective amount of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.
  • the atherosclerotic events are selected from myocardial infarction, stroke, or vascular death.
  • amorphous clopidogrel hydrochloride in another aspect, provided is amorphous clopidogrel hydrochloride.
  • a process for preparing amorphous clopidogrel hydrochloride which comprises the steps of: a) dissolving clopidogrel free base in one or more non-polar organic solvents to form a solution, b) adding hydrochloric acid to the solution obtained in step a) to form a mixture, c) stirring the mixture of step b) for less than one hour to form amorphous clopidogrel hydrochloride and isolating amorphous clopidogrel hydrochloride from the mixture.
  • composition comprising Form III of clopidogrel hydrochloride and one or more pharmaceutically acceptable carriers or excipients.
  • a pharmaceutical composition comprising amorphous clopidogrel hydrochloride and one or more pharmaceutically acceptable carriers or excipients.
  • a method of treating or inhibiting blood platelet aggregation and thrombosis which comprises administering to a patient in need thereof a therapeutically effective amount of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.
  • Crystalline S-(+) Clopidogrel hydrochloride Form III may be characterized by an X-ray powder diffraction pattern (XRPD) comprising peaks at 12.92, 19.80, 22.96, 24.84 and 25.28. Crystalline S-(+) Clopidogrel hydrochloride Form III may also be characterized by an X-ray powder diffraction pattern (XRPD) comprising peaks at 9.40, 12.92, 13.70, 14.24, 16.00, 19.80, 20.30, 21.38, 22.00, 22.96, 23.92, 24.84, 25.28, 30.24, 31.52, 35.94 or 36.72 ⁇ 0.2 degrees two theta.
  • XRPD X-ray powder diffraction pattern
  • Crystalline S-(+) Clopidogrel hydrochloride Form III may be further characterized by Fourier Transform Infrared (FTIR) spectrum in potassium bromide as depicted in Figure 2.
  • FTIR Fourier Transform Infrared
  • Amorphous clopidogrel hydrochloride may be characterized by an X-Ray Powder Diffraction (XRPD) pattern comprising a halo pattern.
  • XRPD X-Ray Powder Diffraction
  • Amorphous clopidogrel hydrochloride may also be characterized by an XRPD pattern as depicted in Figure 4.
  • Amorphous clopidogrel hydrochloride may be further characterized by Fourier Transform
  • Clopidogrel free base to be used as starting material can be prepared by any process known in the literature, including for example processes described in U.S. Patent Nos. 4,847,265, 5,132,435, 5,189,170, 5,204,469, 6,495,691 and 6,635,763, which are incorporated herein by reference.
  • Suitable non-polar organic solvents used for preparing crystalline S-(+) Clopidogrel hydrochloride Form III or amorphous clopidogrel hydrochloride can be selected from one or more ethers, alkanes, cycloalkanes or mixtures thereof.
  • Suitable ether solvents include, for example, diethyl ether, dipropyl ether, diisopropyl ether, din-butyl ether, methyl tert-butyl ether, 1,2-dioxane, 1,2-dimethoxyethane, tetrahydrofuran or mixtures thereof.
  • Suitable alkanes include, for example, one or more of pentane, isopentane, hexane, heptane, octane, nonane or mixtures thereof.
  • Suitable cycloalkanes include, for example, cyclopentane, cyclohexane or mixtures thereof.
  • hydrochloric acid used for the preparation of crystalline S-(+) Clopidogrel hydrochloride Form III or amorphous clopidogrel hydrochloride may be added as gas or as solution in the one or more non-polar organic solvents as mentioned above.
  • Crystalline S-(+) Clopidogrel hydrochloride Form III may be isolated after stirring the mixture obtained after step b) for about 1 hour to several days (e.g., 48 hours or 72 hours).
  • Crystalline S-(+) Clopidogrel hydrochloride Form III may be isolated by filtration.
  • Isolated crystalline S-(+) Clopidogrel hydrochloride Form III may be washed with diethyl ether or diisopropyl ether.
  • Isolated crystalline S-(+) Clopidogrel hydrochloride Form III may be dried under reduced pressure at ambient temperature. Ambient temperature can be in a range of about 30 ⁇ 2 0 C. Isolated crystalline S-(+) Clopidogrel hydrochloride Form III may be dried for about 6 to 24 hours and preferably about 16 hours.
  • Amorphous clopidogrel hydrochloride may be isolated after the stirring of the mixture obtained after step b) for less than one hour.
  • Amorphous clopidogrel hydrochloride may be isolated by filtration.
  • Isolated amorphous clopidogrel hydrochloride Form III may be dried under reduced pressure at a temperature in a range of about 35-38 0 C.
  • Isolated amorphous clopidogrel hydrochloride may be dried for about 6 to 24 hours and preferably about 16 hours.
  • Figure 1 depicts XRPD of Form III of clopidogrel hydrochloride
  • Figure 2 depicts FTIR spectrum of Form III of clopidogrel hydrochloride
  • Figure 3 depicts DSC of Form III of clopidogrel hydrochloride
  • Figure 4 depicts XRPD of amorphous clopidogrel hydrochloride
  • Figure 5 depicts FTIR spectrum of amorphous clopidogrel hydrochloride
  • Figure 6 depicts DSC of amorphous clopidogrel hydrochloride
  • Powder XRD of the samples were determined by using X-Ray Difractometer, Rigalcu Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
  • Clopidogrel free base (51 g) was dissolved in ether (725 ml). The temperature was adjusted to 25-30 0 C and ethereal hydrogen chloride (5 % solution, 216.6 g) was added over 30 minutes at 25-30 0 C. The mixture was stirred for 1.5- 2 hours and filtered to collect the solids. The solids were washed twice with diethyl ether (100 ml) and vacuum dried for 16 hours at 30 ⁇ 2 0 C to yield the title compound.
  • Clopidogrel free base 25 g was dissolved in diisopropyl ether (450 ml). The temperature was adjusted to about 15 0 C and ethereal hydrogen chloride (7.1 % w/w hydrogen chloride in ether) was added over 5 minutes. The reaction mass was stirred at 30 ⁇ 2 0 C for 2 days and filtered to collect the solids. The solids were washed with diisopropyl ether and dried at 30 ⁇ 2 °C under vacuum to yield the title compound.

Abstract

L'invention porte sur une nouvelle forme polymorphe cristalline de chlorhydrate de clopidogrel, sur un procédé de préparation afférent et sur des compositions pharmaceutiques la renfermant. La nouvelle forme polymorphe cristalline est désignée comme forme III. L'invention porte également sur une nouvelle forme amorphe de chlorhydrate de clopidogrel, sur un procédé de préparation afférent et sur des compositions pharmaceutiques la renfermant.
PCT/IB2006/002443 2005-09-05 2006-09-05 Nouvelles formes polymorphes de chlorhydrate de clopidogrel WO2007029096A2 (fr)

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IN2365/DEL/2005 2005-09-05
IN2365DE2005 2005-09-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2107061A1 (fr) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
CN102120745A (zh) * 2011-01-31 2011-07-13 天津红日药业股份有限公司 一种盐酸氯吡格雷的晶型ⅰ及其制备方法和用途
CN102367257A (zh) * 2011-11-21 2012-03-07 天津红日药业股份有限公司 氯吡格雷盐酸盐的单晶晶型，它们的制备及应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802A1 (fr) * 1982-07-13 1984-02-01 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
WO2003066637A1 (fr) * 2002-02-06 2003-08-14 EGIS Gyógyszergyár Rt. Polymorphes d'hydrochlorure de clopidogrel et utilisation de ceux-ci en tant que composes antithrombotiques
WO2005117866A1 (fr) * 2004-06-01 2005-12-15 Ivax Pharmaceuticals S.R.O. Hydrochlorure de clopidogrel amorphe et son utilisation en tant qu'antithrombotique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802A1 (fr) * 1982-07-13 1984-02-01 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
WO2003066637A1 (fr) * 2002-02-06 2003-08-14 EGIS Gyógyszergyár Rt. Polymorphes d'hydrochlorure de clopidogrel et utilisation de ceux-ci en tant que composes antithrombotiques
WO2005117866A1 (fr) * 2004-06-01 2005-12-15 Ivax Pharmaceuticals S.R.O. Hydrochlorure de clopidogrel amorphe et son utilisation en tant qu'antithrombotique

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2107061A1 (fr) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
CN102120745A (zh) * 2011-01-31 2011-07-13 天津红日药业股份有限公司 一种盐酸氯吡格雷的晶型ⅰ及其制备方法和用途
CN102120745B (zh) * 2011-01-31 2013-04-10 天津红日药业股份有限公司 一种盐酸氯吡格雷的晶型ⅰ及其制备方法和用途
CN102367257A (zh) * 2011-11-21 2012-03-07 天津红日药业股份有限公司 氯吡格雷盐酸盐的单晶晶型，它们的制备及应用
CN102367257B (zh) * 2011-11-21 2014-05-07 天津红日药业股份有限公司 氯吡格雷盐酸盐的单晶晶型，它们的制备及应用

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