The present invention provides a novel crystalline polymorphic form of clopidogrel hydrochloride, process for preparation and pharmaceutical compositions thereof. The novel crystalline polymorphic form has been designated as Form III. Further the present invention provides novel amorphous form of clopidogrel hydrochloride, process for preparation and pharmaceutical compositions thereof.
Methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate, 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.
(FORMULA REMOVED)

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.
The present inventors have surprisingly found hereto unknown a novel crystalline polymorphic form of clopidogrel hydrochloride (hereinafter referred to as Form III of clopidogrel hydrochloride). Further the present inventors have also prepared an amorphous form of clopidogrel hydrochloride.
A first aspect of the present invention provides Form III of clopidogrel hydrochloride having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1 of the accompanied drawing. The XRPD of Form III of clopidogrel hydrochloride exhibits characteristic 20 values 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 and 36.72. Form III of clopidogrel hydrochloride is further characterized by a XRPD pattern comprising 20 values at 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. The Fourier Transform Infrared (FTIR) spectrum of Form III of clopidogrel hydrochloride in potassium bromide is depicted in Figure 2 of the accompanied drawing. Form III of clopidogrel hydrochloride has characteristic DSC thermogram as depicted in Figure 3 of the accompanied drawing. The DSC thermogram shows a characteristic endothermic peak at120-142°C.
A second aspect of the present invention provides amorphous clopidogrel hydrochloride having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 4 of the accompanied drawing. The Fourier Transform Infrared (FTIR) spectrum of amorphous clopidogrel hydrochloride in potassium bromide is depicted in Figure 5 of the accompanied drawing. The amorphous clopidogrel hydrochloride has characteristic DSC thermogram as depicted in Figure 6 of the accompanied drawing. The DSC thermogram shows a characteristic endothermic peak at 125-135°C.
A third aspect of the present invention provides a process for the preparation of Form III of clopidogrel hydrochloride, which comprises of,
dissolving clopidogrel free base in non-polar organic solvent,
adding hydrogen chloride to the mixture obtained in step a),
isolating Form III of clopidogrel hydrochloride from the resultant mixture after stirring for sufficient time.
Clopidogrel free base to be used as starting material can be prepared by any process known in the literature. The so obtained clopidogrel free base is dissolved in non-polar solvent selected from group comprising of ether, alkane, cycloalkane or mixture thereof. To the mixture, hydrogen chloride is added as gas or as solution in the said non-polar solvent. The reaction mass is stirred for minimum of 1 hour to several days and filtered to collect the solids. The solids obtained are washed and dried to get Form III of clopidogrel hydrochloride.
A fourth aspect of the present invention provides a process for the preparation of amorphous clopidogrel hydrochloride, which comprises of,
dissolving clopidogrel free base in non-polar organic solvent,
adding hydrogen chloride to the mixture obtained in step a),
isolating amorphous clopidogrel hydrochloride from the resultant mixture after stirring for sufficient time.
Clopidogrel free base to be used as starting material can be prepared by any process known in the literature. The so obtained clopidogrel free base is non-polar solvent selected from group comprising of ether, alkane, cycloalkane or mixture thereof. To the mixture, hydrogen chloride is added as gas or as solution in the said non-polar solvent. The reaction mass is stirred for less than one hour, filtered and dried to get amorphous clopidogrel hydrochloride.
A fifth aspect of the present invention provides a pharmaceutical composition comprising Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride along with pharmaceutically acceptable carrier / excipient.
A sixth aspect of the invention provides a method of treating or inhibiting blood platelet aggregation and thrombosis which comprises administering to the patient in need of such treatment a therapeutically effective amount of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.
A seventh aspect of the present invention provides a method of 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, which comprises administering to the patients in need of such treatment a therapeutically effective amount of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.
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, 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 III OF CLOPIDOGREL HYDROCHLORIDE
Clopidogrel free base (51 g) was dissolved in ether (725 ml). The temperature was adjusted to 25-30°C and ethereal hydrogen chloride (5% solution, 216.6 g) was added over 30 minutes at 25-30°C. The reaction mass 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°C to yield the title compound. Yield: 54 g
EXAMPLE 2
PREPARATION OF FORM III OF CLOPIDOGREL HYDROCHLORIDE
Clopidogrel free base (25 g) was dissolved in diisopropyl ether (450 ml). The temperature was adjusted to about 15°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°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. Yield: 25 g
EXAMPLE 3
PREPARATION OF AMORPHOUS CLOPIDOGREL HYDROCHLORIDE
Clopidogrel free base (31 g) was dissolved in diisopropylether (620 ml) and the temperature was adjusted to 15°C. Ethereal hydrogen chloride (5% solution, 67 g) was added in about 7 minutes. The thick slurry was stirred for 20 minutes at 15-20°C, quickly filtered and vacuum dried at 35-38°C for 16 hours to yield the title compound. Yield: 33 g

WE CLAIM:
1. Form III of clopidogrel hydrochloride.
2. Form III of clopidogrel hydrochloride having X-Ray Powder Diffraction (XRPD) pattern wherein characteristic 20 values are obtained 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 and 36.72.
3. Form III of clopidogrel hydrochloride as claimed in claim 2, having characteristic 20 values at 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.
4. Amorphous clopidogrel hydrochloride having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 4 of the accompanied drawing.
5. A process for the preparation of Form III of clopidogrel hydrochloride, which comprises of,

a) dissolving clopidogrel free base in non-polar organic solvent,
b) adding hydrogen chloride to the mixture obtained in step a),
c) isolating Form III of clopidogrel hydrochloride from the resultant mixture after stirring for sufficient time.
6. A process for the preparation of amorphous clopidogrel hydrochloride, which comprises
of,
a) dissolving clopidogrel free base in non-polar organic solvent,
b) adding hydrogen chloride to the mixture obtained in step a),
c) isolating amorphous clopidogrel hydrochloride from the resultant mixture after stirring for sufficient time.
7. A process according to claims 5 and 6, wherein the non-polar organic solvent is selected from group comprising of ether, alkane, cycloalkane or mixture thereof.
8. A pharmaceutical composition comprising Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride along with pharmaceutically acceptable carrier / excipient.
9. A method of treating or inhibiting blood platelet aggregation and thrombosis which comprises administering to the patient in need of such treatment a therapeutically effective amount of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.
10. A method of 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, which comprises
administering to the patients in need of such treatment a therapeutically effective amount
of Form III of clopidogrel hydrochloride or amorphous clopidogrel hydrochloride.