WO2007029080A1 - Preparation of form i of clopidogrel hydrochloride - Google Patents

Preparation of form i of clopidogrel hydrochloride Download PDF

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Publication number
WO2007029080A1
WO2007029080A1 PCT/IB2006/002404 IB2006002404W WO2007029080A1 WO 2007029080 A1 WO2007029080 A1 WO 2007029080A1 IB 2006002404 W IB2006002404 W IB 2006002404W WO 2007029080 A1 WO2007029080 A1 WO 2007029080A1
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Prior art keywords
clopidogrel
crystalline form
clopidogrel hydrochloride
hydrochloride
solution
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PCT/IB2006/002404
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French (fr)
Inventor
Kiran Kumar Gangakhedkar
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Ranbaxy Laboratories Limited
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Publication of WO2007029080A1 publication Critical patent/WO2007029080A1/en

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    • 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

  • crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a XRPD having peaks at 13.09, 19.99, 22.98 and 23.22 2 ⁇ .
  • crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit XEiPD having peaks at 9.75, 13.09, 13.94, 19.99, 20.66, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.87 and 32.58 20.
  • crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit XRPD having peaks at 9.75, 11.31, 13.09, 13.94, 15.16, 16.16, 16.93, 17.28, 17.78, 19.68, 19.99, 20.66, 21.46, 21.72, 22.27, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.03, 28.87, 30.43, 31.67, 32.58, 36.09 and 36.8420.
  • crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a FTIR spectrum as depicted in Figure 2.
  • crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a DSC as depicted in Figure 3.
  • Clopidogrel base may be obtained by any methods known in the art including methods 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, each of which are incorporated herein by reference.
  • the hydrochloric acid used for preparing crystalline clopidogrel hydrochloride Form I may be added as a gas or as a solution in one or more organic solvents.
  • Suitable organic solvents may be selected from one or more ethers, alkanes, cycloalkanes or mixtures thereof.
  • Suitable ether solvents include, for example, diethyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, methyl tert-butyl ether, 1, 2-dioxane, 1,2- dimethoxyethane, dimethoxy methane, methoxy ethoxyethane, methoxy propoxymethane or mixtures thereof.
  • Suitable alkane solvents include, for example, pentane, isopentane, hexane, heptane, octane, nonane or mixtures thereof.
  • Suitable cycloalkane solvents include, for example, cyclopentane, cyclohexane or a mixture (s) thereof.
  • the solution obtained in step b) may be stirred at a temperature in the range of about 20 0 C to about 50°C.
  • the solution may also be stirred for about 30 minutes to about 4 hours, preferably about 2 hours.
  • Crystalline clopidogrel hydrochloride Form I may be isolated by cooling, filtration, centrifugation or a combination thereof.
  • Crystalline clopidogrel hydrochloride Form I prepared by present process may be characterized by an X-ray powder diffraction pattern (XRPD) having peaks at 13.09, 19.99, 22.98 and 23.22 20. Crystalline clopidogrel hydrochloride Form I prepared by present process may also be characterized by an X-ray powder diffraction pattern (XRPD) having peaks at 9.75, 13.09, 13.94, 19.99, 20.66, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.87 and 32.58 2 ⁇ .
  • XRPD X-ray powder diffraction pattern
  • Crystalline clopidogrel hydrochloride Form I prepared by present process may also be characterized by an X-ray powder diffraction pattern (XRPD) having one or more peaks at 9.75, 11.31, 13.09, 13.94, 15.16, 16.16, 16.93, 17.28, 17.78, 19.68, 19.99, 20.66, 21.46, 21.72, 22.27, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.03, 28.87, 30.43, 31.67, 32.58, 36.09 and 36.8421?.
  • XRPD X-ray powder diffraction pattern
  • Crystalline clopidogrel hydrochloride Form I prepared by present process may be further characterized by Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure 3.
  • DSC Differential Scanning Calorimetric
  • Figure 1 depicts XRPD of Form I of clopidogrel hydrochloride
  • Figure 2 depicts FTIR spectrum of Form I of clopidogrel hydrochloride
  • Figure 3 depicts DSC of Form I of clopidogrel hydrochloride Powder XRD of the samples were determined by using X-Ray Difractometer
  • FTIR of the samples were determined by using Instrument: Perkin Elmer, 16 PC, SCAN: l ⁇ scans, 4.0 cm “1 , according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
  • EXAMPLE 1 PREPARATION OF FORM I OF CLOPIDOGREL HYDROCHLORIDE Clopidogrel free base (22 g) was dissolved in 1,2-dimethoxyethane (220 mL).

Abstract

The present invention relates to a process for preparation of crystalline Form I of clopidogrel hydrochloride comprising dissolving clopidogrel free base in one or more solvents selected from 1,2-dimethoxyethane, dimethoxy methane, methoxy ethoxyethane, methoxy propoxymethane or mixtures thereof, adding hydrogen chloride to the mixture and isolating crystalline Form I of clopidogrel hydrochloride.

Description

PREPARATION OF FORM I OF
CLOPIDOGREL HYDROCHLORIDE
Field Of The Invention
The present invention relates to a process for preparation of crystalline Form I of clopidogrel hydrochloride comprising dissolving clopidogrel free base in one or more solvents selected from 1,2-dimethoxyethane, dimethoxy methane, methoxy ethoxyethane, methoxy propoxymethane or mixtures thereof, adding hydrogen chloride to the mixture and isolating crystalline Form I of clopidogrel hydrochloride.
Background Of The Invention Methyl (+)-(S)-α- (2-chloroρhenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate of Formula I, generally known as Clopidogrel, is an inhibitor of anteroposterior induced platelet aggregation and is indicated for reducing atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.
Figure imgf000002_0001
FORMULA I
U.S. Patent No. 4,529,596 discloses clopidogrel and a process for its preparation.
U.S. Patent No. 4,847,265 (the '265 patent) provides processes for preparing dextrorotatory enantiomer of clopidogrel and its salts. Li particular, the '265 discloses the hydrogen sulphate, the taurochloate, the hydrogen chloride and the hydrogen bromide salts of dextrarotatory enantiomer of clopidogrel which is prepared by dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing HCl. The resulting product clopidogrel hydrogen chloride is characterized by a melting point at 117 0C. The '265 patent, however, does not disclose the existence of any specific polymorphic forms of clopidogrel hydrochloride. 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 0C, which is prepared by dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing HCl. Like in the '265 patent, the '469 patent does not disclose the existence of any specific polymorphic forms of clopidogrel hydrochloride.
PCT Patent Application Nos. WO 99/65915; WO 04/106344; WO 04/26879; WO 04/52966; WO 04/72084; WO 04/74215; WO 04/81015; WO 04/81016; WO 05/26174; WO 05/16931 provide several salts and polymorphic forms of clopidogrel.
PCT Patent Application Nos. WO 98/51681, WO 98/51682, WO 98/51689, and WO 00/27840 provide a process for preparing clopidogrel hydrochloride, which utilizes a solution of clopidogrel free base in diethyl ether, introducing HCl gas into the solution and isolating the formed crystals by filtration. The hydrogen chloride salt is characterized by a melting point of 130-132 0C. These applications do not disclose the existence of any specific polymorphic forms of clopidogrel hydrochloride. PCT Patent Application No. WO 03/066637 (the '637 application) 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. It also provides another process for preparing crystalline form I of clopidogrel which involves recrystallizing clopidogrel hydrochloride from acetone and diisopropyl ether. The yield of crystalline form I of clopidogrel hydrochloride is reported to be about 65-85%. However, the process disclosed in the '637 application is not suitable for commercial scale and is not reproducible.
In view of the above, there remains a need for a process of preparing crystalline form I of clopidogrel hydrochloride, which is simple, reproducible and cost-effective.
Summary Qf The Invention Generally provided is a process for preparing crystalline form I of clopidogrel hydrochloride comprising the steps of: a) dissolving clopidogrel free base in one or more solvents selected from 1,2- dimethoxyethane, dimethoxy methane, methoxy ethoxyethane, methoxy propoxymethane or mixtures thereof to form a clopidogrel solution, b) adding hydrogen chloride to the mixture obtained in step a) to form a clopidogrel hydrochloride solution, and c) isolating crystalline Form I of clopidogrel hydrochloride.
The process can include one or more of the following embodiments. For example, the dissolution of clopidogrel free base can be carried out at a temperature of about 20 °C to about 82 0C. In another embodiment, hydrogen chloride can be added as a solution in an ether solvent, hi yet another embodiment, hydrogen chloride can be added as a gas.
In another embodiment, the clopidogrel hydrochloride solution obtained in step b) can be stirred at a temperature of about 20 °C to about 50 0C. hi another embodiment, the clopidogrel hydrochloride solution obtained in step b) can be stirred for about 30 minutes to about 4 hours. hi one embodiment, the crystalline form I of clopidogrel hydrochloride can be isolated by cooling, filtration, centrifugation, or a combination thereof. The crystalline form I of clopidogrel hydrochloride is washed with one or more ether solvents.
In another embodiment, the crystalline form I of clopidogrel hydrochloride can be dried under reduced pressure at a temperature of about 25 0C to about 50 0C for about 30 minutes to about 24 hours.
In another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a XRPD having peaks at 13.09, 19.99, 22.98 and 23.22 2Θ. hi another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit XEiPD having peaks at 9.75, 13.09, 13.94, 19.99, 20.66, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.87 and 32.58 20. hi another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit XRPD having peaks at 9.75, 11.31, 13.09, 13.94, 15.16, 16.16, 16.93, 17.28, 17.78, 19.68, 19.99, 20.66, 21.46, 21.72, 22.27, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.03, 28.87, 30.43, 31.67, 32.58, 36.09 and 36.8420. In another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a FTIR spectrum as depicted in Figure 2. hi another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a DSC as depicted in Figure 3.
Detailed Description Of The Invention
Clopidogrel base may be obtained by any methods known in the art including methods 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, each of which are incorporated herein by reference.
Clopidogrel base can be dissolved at a temperature of about 20 0C to about 82 °C. Preferably, clopidogrel base can be dissolved at about 30°C.
The hydrochloric acid used for preparing crystalline clopidogrel hydrochloride Form I may be added as a gas or as a solution in one or more organic solvents.
Suitable organic solvents may be selected from one or more ethers, alkanes, cycloalkanes or mixtures thereof.
Suitable ether solvents include, for example, diethyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, methyl tert-butyl ether, 1, 2-dioxane, 1,2- dimethoxyethane, dimethoxy methane, methoxy ethoxyethane, methoxy propoxymethane or mixtures thereof.
Suitable alkane solvents include, for example, pentane, isopentane, hexane, heptane, octane, nonane or mixtures thereof.
Suitable cycloalkane solvents include, for example, cyclopentane, cyclohexane or a mixture (s) thereof.
The solution obtained in step b) may be stirred at a temperature in the range of about 200C to about 50°C. The solution may also be stirred for about 30 minutes to about 4 hours, preferably about 2 hours.
Crystalline clopidogrel hydrochloride Form I may be isolated by cooling, filtration, centrifugation or a combination thereof.
The isolated crystalline clopidogrel hydrochloride Form I may be washed with one or more ether solvents.
The isolated crystalline clopidogrel hydrochloride Form I may be dried under reduced pressure at a temperature of about 25 0C to about 50 0C for about 30 minutes to about 24 hours. Preferably, the isolated crystalline clopidogrel may be dried at a temperature of about 35 °C to about 38 0C for about 16 hours.
Crystalline clopidogrel hydrochloride Form I prepared by present process may be characterized by an X-ray powder diffraction pattern (XRPD) having peaks at 13.09, 19.99, 22.98 and 23.22 20. Crystalline clopidogrel hydrochloride Form I prepared by present process may also be characterized by an X-ray powder diffraction pattern (XRPD) having peaks at 9.75, 13.09, 13.94, 19.99, 20.66, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.87 and 32.58 2Θ. Crystalline clopidogrel hydrochloride Form I prepared by present process may also be characterized by an X-ray powder diffraction pattern (XRPD) having one or more peaks at 9.75, 11.31, 13.09, 13.94, 15.16, 16.16, 16.93, 17.28, 17.78, 19.68, 19.99, 20.66, 21.46, 21.72, 22.27, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.03, 28.87, 30.43, 31.67, 32.58, 36.09 and 36.8421?. Crystalline clopidogrel hydrochloride Form I prepared by present process may also be characterized by an X-ray powder diffraction pattern (XRPD) as depicted in Figure 1. Crystalline clopidogrel hydrochloride Form I prepared by present process may be further characterized by Fourier Transform Infrared (FTIR) spectrum as depicted in Figure
2.
Crystalline clopidogrel hydrochloride Form I prepared by present process may be further characterized by Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure 3.
Brief Description Of The Drawings
Figure 1 depicts XRPD of Form I of clopidogrel hydrochloride Figure 2 depicts FTIR spectrum of Form I of clopidogrel hydrochloride
Figure 3 depicts DSC of Form I of clopidogrel hydrochloride Powder XRD of the samples were determined by using X-Ray Difractometer,
Rigaku 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.
FTIR of the samples were determined by using Instrument: Perkin Elmer, 16 PC, SCAN: lόscans, 4.0 cm"1, according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Examples
EXAMPLE 1: PREPARATION OF FORM I OF CLOPIDOGREL HYDROCHLORIDE Clopidogrel free base (22 g) was dissolved in 1,2-dimethoxyethane (220 mL).
Ethereal hydrogen chloride (5 % solution, 47.5 g) was added in about 5 minutes at 30-35 0C. The reaction mass was stirred at 30-35 0C for 2 hours and filtered. The solids collected were washed with ether (50 mL) and dried at 35-38 0C for 16 hours under vacuum to yield the title compound. Yield: 23 g

Claims

We Claim: 1. A process for preparing crystalline form I of clopidogrel hydrochloride comprising the steps of: d) dissolving clopidogrel free base in one or more solvents selected from 1,2- dimethoxyethane, dimethoxy methane, methoxy ethoxyethane, methoxy propoxymethane or mixtures thereof to form a clopidogrel solution, e) adding hydrogen chloride to the mixture obtained in step a) to form a clopidogrel hydrochloride solution, and f) isolating crystalline Form I of clopidogrel hydrochloride.
2. The process of claim 1, wherein the dissolution of clopidogrel free base is carried out at a temperature of about 20 0C to about 82 °C.
3. The process of claim 1, wherein hydrogen chloride is added as a solution in an ether solvent.
4. The process of claim 1, wherein hydrogen chloride is added as a gas.
5. The process of claim 1, wherein the clopidogrel hydrochloride solution obtained in step b) is stirred at a temperature of about 20 °C to about 50 °C.
6. The process of claim 1, wherein the clopidogrel hydrochloride solution obtained in step b) is stirred for about 30 minutes to about 4 hours.
7. The process of claim 1, wherein the crystalline form I of clopidogrel hydrochloride is isolated by cooling, filtration, centrifugation, or a combination thereof.
8. The process of claim 1 , wherein the crystalline form I of clopidogrel hydrochloride is washed with one or more ether solvents.
9. The process of claim 1, wherein the crystalline form I of clopidogrel hydrochloride is dried under reduced pressure at a temperature of about 25 0C to about 50 °C for about 30 minutes to about 24 hours.
10. The process of claim 1 , wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits a XRPD having peaks at 13.09, 19.99, 22.98 and 23.22 20.
11. The process of claim 1 , wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits a XRPD having peaks at 9.75, 13.09, 13.94, 19.99, 20.66, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.87 and 32.58 20 12. The process of claim 1, wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits a XRPD having peaks at 9.75, 11.31, 13.09, 13.94, 15.16, 16.16, 16.93, 17.28, 17.78, 19.68, 19.99, 20.66, 21.46, 21.72, 22.27, 22.98, 23.22, 24.84, 25.15, 25.48, 27.64, 28.03, 28.87, 30.43, 31.67, 32.58, 36.09 and 36.84 20. 13. The process of claim 1 , wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits a FTIR spectrum as depicted in Figure 2. 14. The process of claim 1 , wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits a DSC as depicted in Figure 3.
PCT/IB2006/002404 2005-09-05 2006-09-01 Preparation of form i of clopidogrel hydrochloride WO2007029080A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
CN102120745A (en) * 2011-01-31 2011-07-13 天津红日药业股份有限公司 Crystal form I of clopidogrel hydrochloride and preparation method and application thereof
CN102367257A (en) * 2011-11-21 2012-03-07 天津红日药业股份有限公司 Single-crystal crystal forms of clopidogrel hydrochloride and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529596A (en) * 1982-07-13 1985-07-16 Sanofi, S.A. Thieno [3,2-c] pyridine derivatives and their therapeutic application
WO2003066637A1 (en) * 2002-02-06 2003-08-14 EGIS Gyógyszergyár Rt. Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529596A (en) * 1982-07-13 1985-07-16 Sanofi, S.A. Thieno [3,2-c] pyridine derivatives and their therapeutic application
WO2003066637A1 (en) * 2002-02-06 2003-08-14 EGIS Gyógyszergyár Rt. Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
CN102120745A (en) * 2011-01-31 2011-07-13 天津红日药业股份有限公司 Crystal form I of clopidogrel hydrochloride and preparation method and application thereof
CN102120745B (en) * 2011-01-31 2013-04-10 天津红日药业股份有限公司 Crystal form I of clopidogrel hydrochloride and preparation method and application thereof
CN102367257A (en) * 2011-11-21 2012-03-07 天津红日药业股份有限公司 Single-crystal crystal forms of clopidogrel hydrochloride and preparation method and application thereof
CN102367257B (en) * 2011-11-21 2014-05-07 天津红日药业股份有限公司 Single-crystal crystal forms of clopidogrel hydrochloride and preparation method and application thereof

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