The present invention relates to a simple process for the preparation of crystalline Form I of clopidogrel hydrochloride.
Methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, of Formula I, generically known as Clopidogrel is an inhibitor of anteroposterior induced platelet aggregation and is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.

US Patent No. 4,529,596 provides clopidogrel and a process for its preparation.
US Patent No. 4,847,265 (the '265 patent) provides processes for the preparation of dextrorotatory enantiomer of clopidogrel and its salts in particular the hydrogen sulphate, the taurochloate, the hydrogen chloride and the hydrogen bromide, which involves dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing hydrogen chloride in which the product clopidogrel hydrogen chloride is characterized by melting point at 117°C. The '265 patent however makes no reference to existence of the specific polymorphic forms of clopidogrel hydrochloride.
Further, 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 on clopidogrel.
US Patent No. 5,204,469 (the '469 patent) provides a process for the preparation of clopidogrel hydrochloride, having a characteristic melting point at 130-140°C, which also is prepared in the similar way by dissolving clopidogrel base in diethyl ether and precipitating the salt with diethyl ether containing hydrogen chloride. The '469 patent
also however makes no reference to existence of the 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 the preparation of clopidogrel hydrochloride, which involves clopidogrel free base in diethyl ether, and introducing hydrogen chloride gas into the solution and isolating the crystals formed by filtration. The hydrogen chloride salt is characterized by a melting point of 130-132°C. These applications also make no reference to existence of the 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 the preparation of 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%.
Crystalline form I of Clopidogrel hydrochloride exhibit specific X-Ray Diffraction (XRPD) pattern, Infra-red spectrum (FTIR) and differential scanning calorimetric thermogram depicted as Figure 1, 2 and 3 respectively of the accompanied drawings.
The present inventors have found that the process provided in the '637 application for preparation of crystalline form I of clopidogrel hydrochloride is not suitable at commercial scale and is not reproducible. It is now surprisingly found that crystalline form I of clopidogrel hydrochloride can be prepared by a process, which is simple, reproducible and cost-effective. The yield of crystalline form I of clopidogrel hydrochloride obtained by following the process of present invention is almost quantitative.
A first aspect of the present invention provides a process for the preparation of crystalline form I of ciopidogrel hydrochloride which comprises of,
dissolving ciopidogrel freebase in 1,2-dimethoxyethane,
adding hydrogen chloride to the mixture obtained in step a),
isolating crystalline Form I of ciopidogrel hydrochloride.
Ciopidogrel freebase to be used as starting material can be prepared by any process known in the literature. The so obtained ciopidogrel free base is dissolved in 1,2-dimethoxyethane. To the mixture, hydrogen chloride is added as gas or as solution. The reaction mass is stirred and filtered to collect the solids. The solids obtained are washed and dried to get crystalline Form I of ciopidogrel hydrochloride.
Figure 1 depicts XRPD of Form I of ciopidogrel hydrochloride
Figure 2 depicts FTIR spectrum of Form I of ciopidogrel hydrochloride
Figure 3 depicts DSC of Form I of ciopidogrel 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: 16scans, 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 intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF FORM I OF CLOPIDOGREL HYDROCHLORIDE
Ciopidogrel 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 the preparation of crystalline form I of clopidogrel hydrochloride which
comprises of,
a) dissolving clopidogrel freebase in 1,2-dimethoxyethane,
b) adding hydrogen chloride to the mixture obtained in step a),
c) isolating crystalline Form I of clopidogrel hydrochloride.

2. A process according to claim 1, wherein the salt formation is carried out at room temperature.
3. A process according to claim 1, wherein hydrogen chloride solution is added in step b).
4. A process according to claim 3, wherein hydrogen chloride in ether is added in step
b).
5. A process according to claim 2, wherein gaseous hydrogen chloride is added in step b).
6. A process according to claim 1, which comprises stirring the reaction mixture after step b) at 30-35°C for 2 hours.

7. A process according to claim 1, wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits XRPD as depicted in Figure 1.
8. A process according to claim 1, wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits FTIR spectrum as depicted in Figure 2.
9. A process according to claim 1, wherein crystalline Form I of clopidogrel hydrochloride obtained exhibits DSC as depicted in Figure 3.