FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
AN IMPROVED PROCESS FOR PREPARATION OF CLOPIDOGREL BISULPHATE POLYMORPHIC FORM I
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD.
2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Clopidogrel bisulfate polymorphic form I from Clopidogrel base. An improved process of the present invention is consistently reproducible and provides stable and pure polymorphic form I of Clopidogrel bisulfate.
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 oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease and cerebrovascular disease. It is marketed under the trade name Plavix.
The racemic mixture of methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c] thieno pyridyl) (2-chlorophenyl)-acetate and pharmaceutically active salts thereof was first disclosed in United States patent No. US4529596.
In US4847265 dextrorotatory methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c] thieno pyridyl) (2-chlorophenyl)-acetate and pharmaceutically active salts thereof is

disclosed. US4847265 describes a process for preparing Clopidogrel bisulfate by using acetone as solvent. It was found that the process disclosed in US4847265 leads to Clopidogrel bisulfate polymorphic form I.
In US6429210 Clopidogrel bisulphate polymorphic form II is disclosed. In addition, a process for preparation of Clopidogrel bisulfate polymorphic form I and form II is also discussed wherein acetone is used as solvent. Initially form I is isolated from mother liquor and the same mother liquor kept for another 3 to 6 months below 40°C to yield Clopidogrel bisulfate polymorphic form II. However on further findings it was concluded that the process disclosed in US6429210 was not suitable for production of form I as it is thermodynamically unstable in solvents like acetone and invariably yielded form II without any need of keeping mother liquor for longer periods.
Thus, it is observed that the same solvent can be used for preparation of both polymorphic forms, form I and form II of Clopidogrel bisulfate.
Following is the table wherein the references for preparing polymorphic form I and form II of Clopidogrel bisulfate using same solvents are listed. It is clear from the given examples that the same solvent gives two different polymorphic forms under different experimental conditions.

Sr. Solvent used Patent reference for Patent reference for
No. Clopidogrel bisulfate Clopidogrel bisulfate
polymorphic form I polymorphic form II
1 Methyl ethyl ketone WO200893357 WO2003051362
Example 4 Example 1 and 2

2
Tert-butyl methyl ether WO2008019053 WO2003051362
Example 4, 5 and 6 Example 10
3 Methyl propyl ketone WO2005104663 1719/MUM/2008
Example 7 and 8 Example 1 and 2
4 Ethyl acetate WO2005104663 1719/MUM/2008
Example 9, 10 and 11 Example 3, 4 and 5
5 Isopropyl alcohol US7772398 1719/MUM/2008
Example 1 and 2 Example 6
6 Tetrahydrofuran WO2008019053 1719/MUM/2008
Example 2 Example 7
The problem observed in US6429210 became subject of International patent application No. WO2004020443. In WO2004020443 a process for preparation of Clopidogrel bisulfate polymorphic form I is disclosed. The process involves dissolving Clopidogrel base in solvent like C1-C5 alcohols or their esters with C1-C4 acids, or optionally mixture thereof, preferably isopropyl alcohol and/or butyl acetate, cooling the mixture, adding cone, sulphuric acid, inoculating the mixture with form I, stirring reaction mixture at -5 to 15°C to get Clopidogrel bisulfate polymorphic form I.
Another process for preparation of Clopidogrel bisulfate polymorphic form I is disclosed in WO2004020443 involves direct dissolution of Clopidogrel bisulfate at reflux in above mentioned solvents.
Even after using hazardous solvent like butyl acetate which affects central nervous system and have exposure limit of 150 ppm, the process failed to give pure form I and resulted in form II and form IV (form IV is solvate of Isopropyl alcohol) or their mixture with form I. The reasons comprised of form I being thermodynamically

unstable and hence its conversion to form II and use of Isopropyl alcohol which yielded form IV.
From the above prior arts it is clear that the method for producing Clopidogrel bisulfate polymorphic form I are poorly reproducible and results in inconsistence at production on commercial scale. Also contamination of Clopidogrel bisulfate polymorphic form II in form I is encountered as Clopidogrel bisulfate polymorphic form II is thermodynamically favored over form I. Hence, producing Clopidogrel bisulfate polymorphic form I requires specific temperature range and specific conditions for getting reproducible results as even a minor variation in condition appears to give form II or mixture instead of expected pure form I.
Further US7772398, WO200687226, WO2007125544, WO201183955, IN 2404/MUM/2008 also discloses process for preparation of Clopidogrel bisulfate polymorphic form I. However all these processes are time consuming and needs critical reaction conditions. The processes also resulted in inconsistency of the polymorphic form.
In majority of patents neat cone, sulphuric acid is added to the solution of Clopidogrel base to obtain bisulphate salt of Clopidogrel only in few patents solution of cone, sulphuric acid in solvent is used.WO201183955 provide a crystalline form (I) of Clopidogrel hydrogen sulphate which is prepared by a more convenient manufacturing method by using solution of cone, sulphuric acid in butanol and water mixture.
The inventors of the present invention have developed a simple and industrially scalable process for preparation of Clopidogrel bisulfate polymorphic form I which results consistency in formation of form I.

OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation Clopidogrel bisulfate polymorphic form I from Clopidogrel base where polymorphic form I are formed efficiently and reproducibly.
Another object of the present invention is to provide an improved process which results in consistency in formation of Clopidogrel bisulfate polymorphic form I.
Yet another object of the present invention is to provide an improved process for the preparation Clopidogrel bisulfate polymorphic form I with good yield and purity.
Yet another object of the present invention is to provide simple and industrially viable process for the preparation of Clopidogrel bisulfate polymorphic form I.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an improved process for preparation of Clopidogrel bisulfate polymorphic form I comprising steps of,
i) dissolving Clopidogrel base in an organic solvent A to form solution A ii) dissolving cone, sulfuric acid in an organic solvent B to form solution B iii) adding solution A and solution B simultaneously at -5 to 40°C to an organic solvent C wherein solvent C is optionally inoculated with seed of Clopidogrel bisulfate polymorphic form I followed by stirring for 8 to 24 hours iv) isolating precipitated Clopidogrel bisulfate polymorphic form I

In another aspect of the present invention, an improved process is consistently reproducible and provides stable and pure Clopidogrel bisulfate polymorphic form I using definite or minimum 7 volumes of the organic solvent with respect to Clopidogrel base.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparation of Clopidogrel bisulfate polymorphic form I from Clopidogrel base comprising steps of,
i) dissolving Clopidogrel base in an organic solvent A to form solution A ii) dissolving cone, sulfuric acid in an organic solvent B to form solution B iii) adding solution A and solution B simultaneously at -5 to 40°C to an organic solvent C wherein solvent C is optionally inoculated with seed of Clopidogrel bisulfate polymorphic form I followed by stirring for 8 to 24 hours iv) isolating precipitated Clopidogrel bisulfate polymorphic form I
The mode of addition of the solution A and solution B to solution C plays an important role in preparation of Clopidogrel bisulfate polymorphic form I. It was observed by inventors of the present invention that simultaneous addition of solution A and solution B to solution C precipitates stable Clopidogrel bisulfate polymorphic form I consistently.
Inventors of the present invention further found that the volumes of the solvents used in the process also play an important role. The total volume of solvent used in the process of present invention, is minimum of 7 volumes with respect to Clopidogrel base with which consistency in formation of polymorphic Form I is achieved. It has

observed that use of lesser volume of solvent produces polymorphic form II of Clopidogrel bisulfate.
Thus, an improved process of the present invention is consistently reproducible and provides stable and pure polymorphic form I of Clopidogrel bisulfate due to simultaneous addition of solution A and solution B to solution C and use of definite or minimum 7 volumes of total solvents.
In process of the present invention the organic solvent A, B and C used in steps i), ii) and iii) respectively are selected in such a way that
organic solvent A has a capacity to dissolve Clopidogrel base at lower or higher temperature. Organic solvent B has a capacity to dissolve cone, sulphuric acid at lower or higher temperature and organic solvent C in which Clopidogrel bisulfate has poor solubility or is insoluble.
According to an embodiment of the present invention, the organic solvent A and B are selected from ethers like 2-methyl tetrahydrofuran or isopropyl ether, alcohols like 2-butanol and esters like ethyl acetate or butyl acetate.
According to an embodiment of the present invention, the organic solvent C is selected from ethers like 2-methyl tetrahydrofuran, isopropyl ether or methyl tert-butyl ether, alcohols like 2-butanol, esters like ethyl acetate or butyl acetate and hydrocarbons like n-heptane or cyclohexane.
According to another embodiment of the present invention, the organic solvent A, B and C used in steps i), ii) and iii) respectively can be same or different.

In process of the present invention, when the organic solvent used in steps i), ii) and iii) is same then solvent A, B and C preferably is 2-methyl tetrahydrofuran.
Alternatively when, the organic solvent used in steps i) and ii) is same but solvent used in step iii) is different then the organic solvent A and B preferably is 2-butanol and the organic solvent C which is different is selected from ether like methyl tert-butyl ether and hydrocarbons like n-heptane or cyclohexane, preferably n-heptane is used.
According to another embodiment of the present invention, wherein the organic solvent A is 2-methyl tetrahydrofuran the moisture content of solution A obtained in step i) is not more than 0.5% preferably it is below 0.3% by KF.
According to yet another embodiment of the present invention, the molar ratio of cone, sulfuric acid used with respect to Clopidogrel base is in the range of 0.5 to 1.5, preferably in the range of 0.9 to 1.2.
Process of the present invention uses solution of cone, sulfuric acid in organic solvent B, as discussed above in step ii). Solution B of step ii) is prepared by dissolving cone. sulfuric acid at temperature ranging from 0-30°C based on the selection of organic solvent B.
Clopidogrel base used in step i) is Clopidogrel free base as available or Clopidogrel free base prepared from organic or inorganic salt of Clopidogrel such as sulphate, hydrochloride, camphor sulphonic acid etc. One of such method for preparation of Clopidogrel free base from its camphor sulfonate salt is as described in the example 1 of the present invention.

Clopidogrel bisulfate polymorphic form I obtained by process of the present invention is isolated in step iv) as per known methods. The obtained polymorphic form I is then characterized by known methods such as IR and XRD data. Values obtained for XRD and IR are compared with prior art data.
Comparison of IR data of Clopidogrel bisulfate polymorphic form I obtained by present invention against IR data of Clopidogrel bisulfate polymorphic form I and polymorphic form II as disclosed in US7291735 are tabulated as follows

Clopidogrel bisulfate 840.96 cm-1, 1774.65 cm-1, 1220.94 cm-1,
polymorphic form I 1753.29 cm-1 and 2985.81 cm-1
(as per present invention)
Clopidogrel bisulfate 841 cm-1, 1175 cm-1, 1222 cm-1, 1753 cm-1 and
polymorphic form I 2987 cm-1
(US7291735)
Clopidogrel bisulfate 1029 cm-1, 1189 cm-1, 1497 cm-1and 2551 cm-1
polymorphic form II
(US7291735)
The process for preparation of Clopidogrel bisulfate polymorphic form I can also be carried out by addition of concentrated sulfuric acid or sulfuric acid diluted with a solvent, to a solution of Clopidogrel base in a solvent which has poor/ low solubility of Clopidogrel bisulfate one of such solvent is 2-methyl tetrahydrofuran. However, our preference for consistency is as described in previous method of present invention.

The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1
Step 1: Preparation of Clopidogrel base from Clopidogrel camphor sulfonate
To 500 ml of 2-methyl tetrahydrofuran was added 100 gm of (+)-(S)-Clopidogrel camphor sulfonate to obtain a suspension. This suspension was then cooled to 5-10°C and pH was adjusted to 7.2 to 7.5 using 7 % sodium bicarbonate solution. The organic layer and the aqueous layer thus obtained were separated. The organic layer was washed with 100 ml of water followed by washing with 100 ml of brine solution. Then the organic solvent was subjected to distillation under vacuum below 45°C to obtain 58 gm of thick oil of Clopidogrel Base.
Step 2: Preparation of Clopidogrel bisulphate polymorphic form I from Clopidogrel base
Prepare solution A by dissolving 100 gm of Clopidogrel base in 400 ml of 2-methyl tetrahydrofuran. Prepare solution B by diluting 31 gm cone, sulphuric acid with 400 ml of pre-cooled 2-methyl tetrahydrofuran at 10°C. In 500 ml of 2-methyl tetrahydrofuran was added solution A and solution B simultaneously and drop wise at 20-25°C. The mixture was stirred at this temperature for 24 hours followed by filtering the solid and washing the product with 2-methyl tetrahydrofuran (2 X 150 ml). The product was dried at under vacuum 48-50°C for 6 to 8 hours to obtain yield of 124gm.
Example 2
Preparation of Clopidogrel bisulphate polymorphic form I

Prepare solution A by dissolving 60 gm of Clopidogrel base in 200 ml of 2-methyl tetrahydrofuran. Prepare solution B by diluting 18.5 gm cone, sulphuric acid with 200 ml of pre-cooled 2-methyl tetrahydrofuran at 0-5°C. In 300 ml of 2-methyl tetrahydrofuran was added solution A and solution B simultaneously and drop wise at 24-3 0°C through pressure equalizer in 1 hour. The mixture was maintained at this temperature for 24 hours followed by filtering the solid and washing the product with 2-methyl tetrahydrofuran (2 X 50 ml). The product was dried at under vacuum 40-45°C for 6 to 8 hours to obtain yield of 71 gm.
Example 3
Preparation of Clopidogrel bisulphate polymorphic form I
Prepare solution A by dissolving 60 gm of Clopidogrel base in 200 ml of 2-methyl tetrahydrofuran. Prepare solution B by diluting 18.5 gm cone, sulphuric acid with 200 ml of pre-cooled 2-methyl tetrahydrofuran at 0-10°C. In 300 ml of 2-methyl tetrahydrofuran was added solution A and solution B simultaneously and drop wise at 24-3 0°C through pressure equalizer in 1 hour. The mixture was maintained at this temperature for 12 hours followed by filtering the solid and washing the product with 2-methyl tetrahydrofuran (2 X 50 ml). The product was dried at under vacuum 40-45°C for 6 to 8 hours to obtain yield of 71 gm.
Example 4
Preparation of Clopidogrel bisulphate polymorphic form I
Prepare solution A by dissolving 50 gm of Clopidogrel base in 100 ml of butanol. Prepare solution B by diluting 16 gm cone, sulphuric acid with 50 ml of butanol. In 250 ml of heptane was added an inoculating seed of 25-50 mg of Clopidogrel bisulfate polymorphic form I. To this solution was added solution A and solution B simultaneously with equal ratio within 30 mins at 24-30°C. The mixture was maintained at this temperature for 20 to 24 hours followed by filtering the solid and

washing the product with 50 ml of heptane. The product was dried at under vacuum 70-75°C for 7 to 8 hours to obtain yield of 30 gm.
Advantages of an improved process of the present invention are
1. The process provides stable Clopidogrel bisulfate polymorphic form I
2. The process provides pure Clopidogrel bisulfate polymorphic form I, free from contamination of any other forms
3. The process provides consistency in producing Clopidogrel bisulfate polymorphic form I
4. The process is consistently reproducible on large scale as well. Thus, it is industrially feasible
5. The process is simple and commercially viable

We claim
1. An improved process for preparation of Clopidogrel bisulfate polymorphic form I
comprising steps of,
i) dissolving Clopidogrel base in an organic solvent A to form solution A ii) dissolving cone, sulfuric acid in an organic solvent B to form solution B iii) adding solution A and solution B simultaneously at -5 to 40°C to an organic solvent C wherein solvent C is optionally inoculated with seed of Clopidogrel bisulfate polymorphic form I followed by stirring for 8 to 24 hours iv) isolating precipitated Clopidogrel bisulfate polymorphic form I
2. The process as claimed claim 1 wherein, the organic solvent A, B and C can be same or different
3. The process as claimed claim 1 or 2 wherein the organic solvent A and B are selected from ethers like 2-methyl tetrahydrofuran or isopropyl ether, alcohols like 2-butanol and esters like ethyl acetate or butyl acetate and organic solvent C is selected from ethers like 2-methyl tetrahydrofuran, isopropyl ether or methyl tert-butyl ether, alcohols like 2-butanol, esters like ethyl acetate or butyl acetate and hydrocarbons like n-heptane or cyclohexane
4. The process as claimed in claim 1, 2 or 3 wherein, organic solvent A, B and C is same and preferably 2-methyl tetrahydrofuran
5. The process as claimed in claim 1, 2 or 3 wherein , organic solvent A and B used in step i) and ii) is same and preferably 2-butanol and organic solvent C used in step iii) is selected from ethers like methyl tert-butyl ether and hydrocarbons like n-heptane or cyclohexane, preferably n-heptane

6. The process as claimed claim 1 wherein, the molar ratio of cone, sulfuric acid used
with respect to Clopidogrel base is in the range of 0.5 to 1.5, preferably in the range
of 0.9 to 1.2
7. The process as claimed claim 1 wherein, the total volume of solvent used in the
steps i), ii) and iii) is minimum of 7 volumes with respect to Clopidogrel base