FORM 2
(39 of 1970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "An improved process for the preparation of Clopidogrel bisulfate crystalline Form 1"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.


AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE CRYSTALLINE FORM 1
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Clopidogrel bisulfate crystalline Form 1, which is devoid of any contamination of Clopidogrel bisulfate crystalline Form 2.
BACKGROUND OF THE INVENTION
Clopidogrel bisulfate is hydrogen sulfate salt of dextro-rotatory methyl alpha-5-(4, 5, 6, 7-tetrahydro (3, 2-c] thieno pyridyl) (2-chlorophenyl)-acetate and is represented by Formula I:

Clopidogrel bisulfate is an orally active inhibitor of platelet aggregation now marketed as Plavix, as an antithrombotic agent. It is an adenosine diphosphate (ADP) receptor antagonist indicated for the reduction of atherosclerotic events including myocardial infarction, ischemic stroke and vascular death in patients with atherosclerosis.
U.S. Patent No. 4,529,596 discloses Methyl alpha-5- (4, 5, 6, 7-tetrahydro [3, 2-c] thienopyridyl) (2 -chloropheny 1) -acetate.

U.S. Patent No. 4,847,265 (herein after "the '265 patent") discloses dextro-rotatory enantiomer of methyl alpha-5-(4, 5, 6, 7-tetrahydro [3, 2-c] thieno pyridyl) (2-chlorophenyl)-acetate and a pharmaceutically acceptable salts thereof. The hydrochloride, hydrogen sulfate, hydrobromide and taurocholate salts are specifically disclosed.
The '265 patent describes a process to prepare Clopidogrel bisulfate in acetone solvent. The synthetic process disclosed in this patent leads to the preparation of Clopidogrel bisulfate crystalline Form 1.
U.S. Patent publication nos. 20060041136; 20060047121; 20070082924; 20080188663 and 20090099363 and PCT application nos. 2004048385; 2005100364; 2006087226; 2007102037; 2007017886 and 2008118030 describe a processes for the preparation of Clopidogrel bisulfate crystalline Form 1.
The process hitherto reported for preparing Clopidogrel bisulfate crystalline Form 1 are producing inconsistence results at commercial scale and also contamination of Clopidogrel bisulfate Form 2 in Clopidogrel bisulfate crystalline Form 1 is encountered as Clopidogrel bisulfate crystalline Form 2 is thermodynamically favored over Clopidogrel bisulfate crystalline Form I.
Therefore, there was a need to develop an industrially suitable process for the preparation of Clopidogrel bisulfate crystalline Form 1, which is devoid of any contamination of Clopidogrel bisulfate crystalline Form 2.
Thus the present invention is to provide an industrially suitable process for preparation of Clopidogrel bisulfate crystalline Form 1, which is devoid of any contamination of Clopidogrel bisulfate crystalline Form 2.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide an industrially suitable process for the preparation of Clopidogrel bisulfate crystalline Form 1, which is devoid of any contamination of the Clopidogrel bisulfate crystalline Form 2, comprises the steps of:
a) providing a solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent,
b) adding Clopidogrel solution obtained in step a, into a sulphuric acid solution in n-butanol or vice versa.
c) isolating Clopidogrel bisulfate crystalline Form 1.
DETAILED DESCRIPTION OF THE INVENTION:
Clopidogrel base may be obtained by any of the methods known in the art including those 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 only.
Clopidogrel base may be obtained by treating Clopidogrel hydrobromide salt with inorganic base.
Clopidogrel hydrobromide salt may be obtained by any of the methods known in the art including those described in PCT publication nos. WO2005026174; WO2005068471; WO2005080890; WO2006034451 and WO2008108742, which are incorporated herein by reference only.
Examples of inorganic base may include sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

A solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent may be provided by dissolving Clopidogrel base in methyl tert-butyl ether (MTBE) solvent at a temperature in the range of -5°C to 0°C.
A solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent may be added into a sulphuric acid solution in n-butanol solvent at a temperature in the range of-5°C to 0°C for 45 minutes to 1.5 hours.
A sulphuric acid solution in n-butanol solvent may be added into a solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent at a temperature in the range of-5°C to 0°C for 45 minutes to 1.5 hours.
The resulting reaction mixture obtained after step b may be stirred for 1 hour at -5 to 0°C, 12 hours at 15 to 20°C and 24 hours at 25-30°C.
The resulting reaction mixture obtained after step b may be optionally seeded with Clopidogrel bisulfate crystalline Form 1 crystals.
Clopidogrel bisulfate crystalline Form 1 may be isolated by filtration, washing, centrifugation, drying and combination thereof.
Isolated Clopidogrel bisulfate crystalline Form 1 may be washed with metbhyl-tert butyl ether (MTBE) at an ambient temperature.
The ambient temperature is defined as a temperature in the range of 20°C to 30°C.
Isolated Clopidogrel bisulfate crystalline Form 1 may be dried under reduced pressure at a temperature in the range of 40°C to 60°C.

Clopidogrel bisulfate crystalline Form 1 obtained by the present invention is devoid of any contamination of Clopidogrel bisulfate crystalline Form 2.
Clopidogrel bisulfate crystalline Form 1 obtained by the present invention may contain Clopidogrel bisulfate crystalline Form 2 below detection thresholds (Limit of Detection).
The detection thresholds (Limit of Detection) of Clopidogrel bisulfate crystalline Form 2 in Clopidogrel bisulfate crystalline Form 1 is 1.00% w/w.
The limit of quantification of Clopidogrel bisulfate crystalline Form 2 in Clopidogrel bisulfate crystalline Form 1 is 2.00% w/w.
The LOD-LOQ studies were performed by using PXRD methodology.
Clopidogrel bisulfate crystalline Form 1 obtained by the present invention is stable and not converted into Clopidogrel bisulfate crystalline Form 2 over 6 months period during stability studies.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 shows a representative powder X-ray diffraction pattern of Clopidogrel bisulfate crystalline Form-1.
X-ray diffraction pattern were recorded using PANalytical X'Pert Pro Powder X-ray Diffractometer having 9- 8 configuration.

These and other specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are not intended to limit the scope of the appended claims in any manner.
EXAMPLES:
EXAMPLE-1: PREPARATION OF CLOPIDOGREL BISULFATE FORM 1
A solution of Clopidogrel base (988 gm, 3.07 mole) in methyl-tert butyl ether (MTBE, 6.4 litre) at -5 to 0°C was added slowly to a pre-cooled solution of concentrated sulphuric acid (300 gm, 3.06 mole) in n-butanol (1.48 lit) within the period of 1 hour. The resulting reaction mixture was stirred 1 hour at -5 to 0°C, 12 hours at 15 to 20°C and 24 hours at 25-30°C. Solid product obtained was filtered and washed with methyl-tert butyl ether (MTBE, I It). The product was dried at 40-50°C under reduced pressure to afford Clopidogrel bisulfate crystalline Form 1. Yield: 1.12 kg
EXAMPLE-2: PREPARATION OF CLOPIDOGREL BISULFATE FORM 1
A suspension of Clopidogrel hydrobromide (lOOOgm, 2.48 moles) in dichloromethane (3 lit) at 15-20°C was neutralized with sodium bicarbonate solution (~5 lit) to pH 7-8. Solvents were distilled after aqueous layer separation under reduced pressure at the temperature not exceeding to 35° C to get the corresponding base. To a solution of resulting base in methyl-tert butyl ether (MTBE, 5.2 lit) at -10 to -5 ° C was added slowly a pre-cooled solution of concentrated sulphuric acid (243 g, 2.48 moles) in n-butanol (1.2 lit) over a period of 2 hours. The resulting reaction mixture was stirred 3 hours. After stirring at 15-20 °C for 8 hours the resulting product was filtered and washed with methyl-Cert butyl ether (MTBE, 0.8 lit). The product was dried at 40-50°C under reduced pressure to afford Clopidogrel bisulfate crystalline Form 1. Yield: 0.8 Kg

WE CLAIM:
1.A process for the preparation of Clopidogrel bisulfate crystalline Form 1 comprising the steps of:
a) providing a solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent,
b) adding Clopidogrel solution obtained in step a, into a sulphuric acid solution in n-butanol or vice versa.
c) isolating Clopidogrel bisulfate crystalline Form 1.

2. The process according to claim 1, wherein solution of Clopidogrel base is provided by dissolving Clopidogrel base in methyl tert-butyl ether (MTBE) solvent at a temperature in the range of-5°C to 0°C.
3. The process according to claim 1, wherein solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent is added into a sulphuric acid solution in n-butanol solvent at a temperature in the range of-5°C to 0°C for 45 minutes to 1.5 hours.

4. The process according to claim 1, wherein sulphuric acid solution in n-butanol solvent is added into a solution of Clopidogrel base in methyl tert-butyl ether (MTBE) solvent at a temperature in the range of-5°C to 0°C for 45 minutes to 1.5 hours.
5. The process according to claim 1, wherein resulting reaction mixture obtained after step b is stirred for 1 hour at -5 to 0°C, 12 hours at 15 to 20°C and 24 hours at 25-30°C.
6. The process according to claim 1, wherein resulting reaction mixture obtained after step b is optionally seeded with Clopidogrel bisulfate crystalline Form 1 crystals.

7. The process according to claim 1, wherein Clopidogrel bisulfate crystalline Form 1 is isolated by filtration, washing, centrifugation, drying and combination thereof.
8. The process according to claim 1, wherein isolated Clopidogrel bisulfate crystalline Form 1 is washed with methyl-tert butyl ether (MTBE) at a temperature in the range of 20°C to 30°C.
9. The process according to claim 1, wherein isolated Clopidogrel bisulfate crystalline Form 1 is dried under reduced pressure at a temperature in the range of 40°C to 60°C.
10. The process according to claim 1, wherein isolated Clopidogrel bisulfate
crystalline Form 1 is devoid of any contamination of Clopidogrel bisulfate crystalline
Form 2.

Dated this 06th day of November 2009
Signature:
Name: Dr. Rajendra Agarwal