FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of crystalline Form I of (5)-(+)-2-(2-chIorophenyI)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-yi)acetic acid methylester hydrogen sulphate of Formula I.

(5)-(+)-2-(2-Chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-yl)acetic acid methylester hydrogen sulphate is generically known as (S)-(+)-Clopidogrel bisulfate.
Clopidogrel is an inhibitor of platelet aggregation. Clopidogrel's platelet inhibiting activity makes it an effective drug for reducing the induce of ischemic strokes or heart attacks. By inhibiting platelet aggregation, Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. Recent studies have shown that Clopidogrel is more effective in blocking platelet aggregation than Asprin. Clopidogrel is much effective than Aspirin even at much lower dosage. In addition to being more effective, Clopidogrel produces much less gastrointestinal bleeding than Asprin.
Clopidogrel is marketed under the name Plavix® in the US. It has been approved for the treatment of atherothrombotic events such as Recent Stroke or Established Peripheral Arterial Disease and Acute Coronary Syndrome.
Sanofi disclosed generically Clopidogrel and its pharmaceutically acceptable salts in US 4,529,596 and disclosed dextro rotatory enantiomer, (S)-(+)-Clopidogrel bisulfate specifically in US 4,847,265.

us '265 describes a process for the preparation of (S)-(+)-Clopidogrel bisulfate by diasteriomeric salt formation of racemic Clopidogrel base using an optically active acid, such as Ievo-camphor-10-suifonic acid, which is further treated with aqueous base in a solvent to produce (S)-(+)-Clopidogrel free base, which is then converted into its hydrogen sulfate sah by dissolving in acetone, cooling and mixing with concentrated sulfuric acid to precipitation. The precipitate thus obtained is then isolated by filtration, washed and dried to give (S)-(+)-Clopidogrel bisulfate in the form of white crystals whose melting point was 184°C and optical rotation is +55.1° (c=1.891/CH30H). However, US '265 patent did not characterize or suggest any name to these crystals (polymorph) of (S)-(+)-Clopidogrel bisulfate.

Subsequently US 6,429,210 disclosed two polymorphic forms of (S)-(-i-)-Clopidogrel bisulfate referred to as Form I and Form II. US '210 identified that the precipitation method described in '265 patent had led to crystalline Form-I. Further, US '210 also relates to a new crystalline form called Form-II of (S)-(+)-Clopidogrel bisulfate. This Form II is suggested to be thermodynamically most stable crystalline form. According to '210 patent both polymorphs, namely Form I and Form II, were prepared from the same solvent selected from acetone.

The process for producing crystalline Form I of (S)-(+)-Clopidogrel bisulfate according to example IC of the US '210 involves treating Clopidogrel camphor sulfonate with potassium carbonate solution in methylene dichloride (MDC) to produce (S)-(+)-Clopidogrel free base, which is extracted in MDC, and the solvent is evaporated. Residue obtained is then dissolved in acetone and cooled. Addition of sulfuric acid is said to precipitate out (S)-(+)-Clopidogrel bisulfate in Form I. Further, this patent also described to obtain Form II either by keeping the mother liquor of Form I for prolonged periods or by seeding the acetone solution containing the base after addition of sulfuric acid with Form II or by subjecting the suspension to mechanical shearing using a shearing device.
Further, there are many latter patent applications such as US2006/074242,
US2006/0205766, WO2005/117866, WO2005/100364, US2005/059696,
WO2005/063708, WO2005/016931, WO2005/003139, ■WO2004/026879,
WO2004/08I015, WO 2004/02 044 3, WO2004/081016, WO2004/048385,
WO2004/081016, WO2004/0024012, WO2006/087226, US2003/0114479,
US2003/225129, & WO2002/059128, which disclose processes for the preparation of Form I of (S)-(+)-Clopidogrel bisulfate using different class of organic solvents. After a detailed study of the above various patent publications clearly indicating that the manufacture of pure Form I of (S)-(+)-Clopidogrel bisulfate without the contamination Form II is difficult.
The presence of Form II in Form I can lead to instability of Form I which results in inconsistency in formulations and ultimately leading to varying drug bioavailability. Moreover, among all these, most processes are not reliably reproducible on large scale.
We have also noted that, the process variants of dissolving (S)-(+)-Clopidogrel bisulfate salt in conventional solvents at higher temperature and cooling to precipitate Form I resulted in Form II or its mixture with Form I. Moreover, the poor solubility of (S)-(+)-Clopidogrel bisulfate (whereas the free base possess good solubility) in most of the known solvents did not allow us to use this crystallization process variant to be practiced.

So, it is evident from the prior art that the methods to produce Form I of (S)-(+)-Clopidogrel bisulfate from known solvents are poorly reproducible, and needed optimization of experimental conditions and/or the selection of suitable solvents. Since Form I is kinetically controlled and Form II is thermodynamically controlled form, they require very specific temperature range and specific conditions for getting reproducible results in conventional solvents. Also, in these solvents a minor variation in condition appears to give Form II instead of expected Form I or a mixture of Form I & Form II.
Further, the use of most of the solvents used in the prior-art are not safe from handling point of view on commercial scale, as some of these are toxic and difficult to separate after the reaction and therefore encounters the problem of spent and disposal.
Hence, there is a need to develop a process, by using eco-friendly and safer solvents, which provides (S)-(+)-Ciopidogrel bisulfate Form I with without contamination of Form II or other polymorphs.
The present invention is specifically directed towards a process, wherein (S)-(+)-Clopidogrel free base is treated with sulfuric acid in a solvent selected from alkyl carbonates to produce (S)-(+)-Clopidogrel bisulfate Form I with high polymorph purity.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple and effective process for the preparation of (S)-(+)-Clopidogrel bisulfate Form I with high purity and good yields on a commercial scale.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of crystalline Form I of (S)-(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-yl)acetic acid methylester hydrogen sulphate of Formula I,

COOCH3


H,SO, P°™"'" ■

which comprises:
(i) preparing a solution of (S)-(+)-Clopidogrel free base in a solvent selected
from alkyl carbonate, (ii) optionally, seeding the resulting solution with (S)-(+)-Clopidogrel bisulfate
Form I, (iii) adding concentrated sulfuric acid, (iv) optionally, heating the solution, (v) isolating (S)-(+)-Clopidogrel bisulfate Form I.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 represents Powder X-Ray diffraction pattern (PXRD) of (S)-(+)-Clopidogrel bisulfate Form I prepared according to example 1 of the present invention.
FIG. 2 represents the spectrogram obtained by Fourier Transform Infra Red spectrometry (FTIR) of (S)-(+)-Clopidogrel bisulfate Form 1 prepared according to example 1 of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of crystalline Form I of (5)-(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-yl)acetic acid methylester hydrogen sulphate of Formula I.
The process comprises dissolving (S)-(+)-Clopidogrel free base in a solvent selected from alkyl carbonate such as dimethyl carbonate, diethyl carbonate, ethyl methyl carbonate, ethyl propyl carbonate, methyl propyl carbonate, isopropyl methyl carbonate, isopropyl

ethyl carbonate or mixtures thereof. Dissolution may be carried out by adding Clopidogrel free base to the alkyl carbonate solvent to obtain a clear solution. The resulting clear solution is optionally treated with carbon, followed by filtration to remove insoluble material. The resulting clear solution is optionally seeded with (S)-(+)-Clopidogrel bisulfate Form 1. Concentrated sulfuric acid alone or in a solvent selected from alkyl carbonate is added to the reaction. The preferred concentration of sulphuric acid is in the range of 80% to 98% and the molar ratio of the sulfuric acid to the (S)--(+)-Clopidogrel free base is in the range of about 0.5:1 to about 1.2:1. The most preferred concentration of sulphuric acid used in the salt formation is 90-98%. The sulphuric acid may be employed directly or may be employed as a solution in a carrier solvent. In a preferred embodiment of the process, the exotherm of sulphuric acid addition is controlled by cooling and maintaining the temperature in between -10 to 30°C.
The reaction mass is optionally heated to a temperature of about 30 to 100°C, followed by cooling at a temperature of from about 20 to about 30°C.
The isolation of (S)-(+)-Clopidogrel bisulfate Form I obtained by the present invention may then be recovered by techniques well known in the art, such as filtration, followed by washing with a solvent selected from acetone, ethyl acetate, butyl acetate or mixtures thereof and optionally dried.
(S)-(+)-Clopidogrel bisulfate Form 1 obtained by the process described above in the form of white crystals whose melting point was about 182°C and optical rotation is +55.1° (c=1.89]/CH30H).
(S)-(+)-Clopidogrel bisulfate Form 1 so obtained was characterized by PXRD, DSC and FTIR without any detectable quantity of Form II or other polymorphic Forms with respect to the standard PXRD pattern of Form I as described in US '210 patent. The Form-I obtained by the process of the present invention does not contain any detectable

Form-II polymorph and therefore it is stable to storage and handling.
The (S)-(+)-ClopidogreI free base used in the present invention may be prepared by the procedure disclosed in US 4,847,265. The process disclosed in US '265 involves treating racemic Clopidogrel base with levo-camphor-10-sulfonic acid, to produce levo-camphor-10-sulfonic acid salt of (S)-(+)-Clopidogrel, which is further treated with aqueous base in a solvent selected from dichloromethane to produce Clopidogrel free base. The Clopidogrel free base, used in the present invention may or may not be isolated as a solid.
The stable (S)-(+)-Clopidogrel bisulfate Form I obtained by the process of the present invention may be formulated into a dosage form, e.g., tablet, capsule, etc., by combining with one or more pharmaceutically acceptable excipients using known techniques. The resulting dosage form may include a suitable amount of the active ingredient required for the desired action. Further, the dosage form may be immediate release or extended release.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLE!
Preparation of S)-(+)-Clopidogrel bisulfate Form I
(S)-(+)-Clopidogrel free base (50 g, 0.155 moles) was dissolved in diethyl carbonate (250 ml) at 20-30°C and seeded with S-(+)-Clopidogrel hydrogen sulfate Form-I (2.5 g). Concentrated sulfriric acid (15.24 g, 0.155 moles) was added to the mixture in I hr at 20-SO^C and stirring was continued at 20-30°C for 1 hr. Further, the slurry was heated to 80-85°C and maintained for 1 hr. The resulting reaction mixture was cooled to 20-25*'C, filtered, washed with acetone (100 ml) and dried at 40-45°C under reduced pressure to yield S-(+)-Clopidogrel hydrogen sulfate Form-I (64.50 g, 98.86%). HPLC Purity: 99,62% by HPLC. Optical rotation: +55.7° (c=2/CH30H).

EXAMPLE-2:
Preparation of (S)-(+)-CIopidogreI bisulfate Form I
(S)-(+)-Clopidogrel free base (100 g, 0.311 moles) was dissolved in diethyl carbonate (500 ml) at 20-30°C and seeded with S-(+)-Clopidogrel hydrogen sulfate Form-I (5 g). Concentrated sulfuric acid (30.50 g, 0.311 moles) was added to the mixture in 1 hr 30 min at 20-30°C and stirring was continued at 20-30°C for 1 hr. Further, the slurry was heated to 80-85°C and maintained for 1 hr. The resulting reaction mixture was cooled to 20-25''C, filtered, washed with acetone (200 ml) and dried at 40-45°C under reduced pressure to yield S-(+)-Clopidogrel hydrogen sulfate Form-I (128.50 g, 98.5%). HPLC Purity: 99.60%by HPLC. Optical rotation: +56.2° (c=2/CH30H).
EXAMPLE-3:
Preparation of (S)-(+)-Clopidogrel bisulfate Form I
Clopidogrel base (25g, 0.0778 moles) was dissolved in diethyl carbonate (125 ml) at 20-30° C and seeded with S-(+)-Clopidogrel bisulfate Form-I (1.25g). Concentrated sulfuric acid (7.7g, 0.0778 moles) was added to the mixture. The resulting slurry was stirred at 20-30° C till complete conversion of Form-I.
EXAMPLE-4:
Preparation of (S)-(+)-CIopidogrel bisulfate Form I
Cfopidogrel base (20g, 0.0622 moles) was dissolved in dimethyl carbonate (100 mi) at 20-30° C, seeded with S-(+)-Clopidogrel bisulfate Form-I (1 g) and cooled to 0-10° C. Concentrated sulfuric acid (6.1g, 0.0622 moles) was added to the mixture at 0-10° C. The resulting mixture temperature was slowly rised to 20-30°C in 30 min and stirred for another 2h. The resulting product was filtered, washed with acetone (20 ml) and dried at 40-44°C under reduced pressure to yield S-(+)-Ciopidogrel bisulfate Form-I (21 g).

WE CLAIM
1. A process for the preparation of crystalline Form 1 of (S)-(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-yi)acetic acid methyiester hydrogen sulphate of Formula I,

The process according to claim 1, wherein alkyl carbonate used in step (i) is selected from dimethyl carbonate, diethyl carbonate, ethyl methyl carbonate, ethyl propyl carbonate, methyl propyl carbonate, isopropyl methyl carbonate, isopropyl ethy] carbonate or mixtures thereof.
The process according to claim 2, wherein alkyl carbonate is diethyl carbonate.
The process according to claim 1, wherein concentrated sulfuric in a solvent is added to the reaction.
The process according to claim 1, wherein concentration of sulphuric acid is in the range of 80% to 98%.

The process according to claim 1, wherein the molar ratio of the sulfuric acid to the (S)-(+)-Clopidogrel free base is in the range of about 0.5:1 to about 1.2:1.
A process according to claim 1, isolation of (S)-(+)-Clopidogrel bisulfate Form I, comprises:
(i) cooling the reaction mass to about 20 to 25°C,
(ii) filtering the (S)-(+)-Clopidogrei bisulphate Form I,
(iii) isolating the pure (S)-(+)-Clopidogrel bisulfate Form I by filtration and optionally washing the crystals with organic solvents.
A process according to claim 7, wherein solvent used in washing (S)-(+)-Clopidogrel bisulfate Form I is selected from acetone, ethyl acetate, butyl acetate or mixtures thereof.