PREPARATION OF FORM I OFCLOPIDOGREL 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 (-i-)-(S)-a-(2-chlorophenyl)-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.
CH3 O

Cl 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 HCI. The resulting product clopidogrel hydrogen chloride is characterized by a melting point at 117 °C. 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 °C, which is prepared by dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing HCI. 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 HCI gas into the solution and isolating the formed crystals by filtration. The hydrogen chloride salt is characterized by a melting point of 130-132 °C. 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 III 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 OF 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 °C. In another embodiment, hydrogen chloride can be added as a solution in an ether solvent. In 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 °C. In another embodiment, the clopidogrel hydrochloride solution obtained in step b) can be stirred for about 30 minutes to about 4 hours.
In 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 °C to about 50 °C 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 26. In another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit 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 26. In

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 36.84 26.
In another embodiment, crystalline Form I of clopidogrel hydrochloride obtained by the disclosed process can exhibit a FTIR spectrum as depicted in Figure 2. In 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 °C 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 20 °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.
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 °C to about 50 °C 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 °C 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 29. 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 26. 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 36.84 26. 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: loscans, 4.0 cm"1, according to the DSP 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.
EXAMPLE 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 °C. The reaction mass was stirred at 30-35 °C for 2 hours and filtered. The solids collected were washed with ether (50 ml) and dried at 35-38 °C for 16 hours under vacuum to yield the title compound.
Yield: 23 g

WE CLAIM:
1. 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.

2. The process of claim 1, wherein the dissolution of clopidogrel free base is carried
out at a temperature of about 20 °C 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 °C 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 XRPD, FTIR spectrum, DSC as depicted in Figure 1, Figure 2, Figure 3 respectively.