FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULPHATE FORM I


Applicant
Name:
Nationality:
Address:

Torrent Pharmaceuticals Limited
Indian
Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmadabad 380 009.
Gujarat, India

The following specification describes the invention:"


FIELD OF THE INVENTION
This invention relates to a process for the preparation of clopidogrel bisulphate Form I.
BACKGROUND OF THE INVENTION
(+)-(S)-alpha-2-(chlorophenyl)-6,7- dihydrothieno - [3,2-c]- pyridine- 5- (4-H)- acetic acid methyl ester known as clopidogrel under the International Non-Proprietary Name is marketed as a hydrogen sulphate salt. Clopidogrel is known for its platelet aggregating and anti-thrombotic properties and finds medicinal applications in this field. It can be represented by Formula-1, and was disclosed in U.S. Pat. No. 4,529,596 ('596 patent) in its racemic form for the first time.

The pure enantiomeric forms of clopidogrel (dextro and levo isomers) were disclosed in EP281459 ('459 patent) which teaches the isolation of the dextro rotatory isomer of clopidogrel by diasteriomeric salt formation of racemic clopidogrel base using an optically active acid, such as L-camphor-10-sulfonic acid. The clopidogrel free base was then converted into its hydrogen sulfate salt 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 clopidogrel hydrogen sulfate in the form of white crystals whose melting point was 184 °C and optical rotation was +55.1.degree. (c=1.891/MeOH). But '459 patent did not characterize or suggest any name to the crystal (polymorph) of clopidogrel hydrogen sulfate.
Clopidogrel bisulphate Form I and II was disclosed in International Publication No. WO 99/65915 (the '915 application).
U.S. Pat. Nos. 6,429,210 and 6,504,030 and US patent application 2002/019829 A1 discloses the manufacturing process of Clopidogrel hydrogen sulfate Form-I and II. These
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polymorphs are prepared by dissolving Clopidogrel camphor sulfonate in acetone followed by addition of conc, sulfuric acid at an ambient temperature. Excess of acetone is distilled and residue is cooled down to 0-5 °C. followed by filtration to get Clopidogrel Form-I. The Form-ll of Clopidogrel is obtained from residual mother liquor after 3-6 months period.
US patent application 2003/0114479 discloses the manufacturing processes for Clopidogrel hydrogen sulfate Form-I, II, III, IV, V and amorphous forms. The application also claims the preparation of Clopidogrel hydrogen sulfate Form I from amorphous Clopidogrel hydrogen sulfate. Specification of the US patent application 2003/0114479 discloses the preparation method of Clopidogrel hydrogen sulfate Form I using different combinations of alcohol and ether in 56-88% yield.
The process for obtaining crystalline Form I of clopidogrel hydrogen sulfate according to example 1A of the '915 application discloses the introduction of clopidogrel camphor sulfonate in methylene dichloride (MDC) and transformation of this salt into clopidogrel base with potassium carbonate solution. Clopidogrel base 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 clopidogrel hydrogen sulfate Form I.
The process described in above application is difficult to follow on industrial scale for the production of Form I of clopidogrel hydrogen sulphate, due to thermodynamic instability of Form I in solvents like acetone. This problem became the subject of many future patent applications which reveal that the manufacture of Form I of clopidogrel hydrogen sulphate is challenging to process chemists.
US Patent No. 6767913 discloses a process which illustrate that the amorphous form of clopidogrel bisulphate is converted into clopidogrel bisulphate Form I In an ether solvent, particularly in the time period from about 45 minutes to one hour. In order to obtain substantially pure Form I, amorphous clopidogrel bisulphate was suspended in ether for four to eight hours. This patent also discloses that the transformation time may be longer if the starting material is clopidogrel free base rather than its bisulphate salt.
International Publication No. WO 05/100364 teaches the preparation of Clopidogrel bisulphate Form I by neutralizing clopidogrel salt like clopidogrel hydrochloride,
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clopidogrel hydrogen sulphate in inert atmosphere by a base like potassium carbonate, extracting the base with an organic solvent and treating the base with Conc, sulfuric acid at -5 to 20 °C, stirring the reaction mixture for 10 hours at -20 to 20 °C. However, the process is not optimal for the large scale production of clopidogrel bisulphate Form I as the yield is only 50 %.
Although most of the general class of organic solvents are said to be used for the preparation of Form I polymorph, it appears from the literature and the experimental studies that these solvents result in a mixture of Form II and Form I. The presence of Form II in Form I can lead to instability of Form I which is a cause of concern for the production of stable formulations without polymorphic conversion, Moreover, the processes disclosed for the preparation of substantially pure Form I are not reliably reproducible on commercial scale,
It has been surprisingly observed that using ether solvent selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane and optionally Form I clopidogrel bisulphate as seeding material results into clopidogrel bisulphate Form I substantially pure. The process is simple, industrially feasible and economical.
SUMMARY OF THE INVENTION
In one embodiment, the specification discloses a process for the preparation of crystalline Form I of clopidogrel bisulphate comprising the steps of:
(a) mixing clopidogrel base in ether selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane;
(b) optionally seeding with clopidogrel bisulphate Form I;
(c) adding the mixture of sulfuric acid and ether solvent;
(d) raising the temperature of reaction mixture of step (c) upto about 40 °C;
(e) isolating Form I of clopidogrel bisulphate; and
(f) optionally drying the isolated material of step (e).
In another embodiment, the specification discloses a process for the preparation of clopidogrel bisulphate Form I having X-ray powder diffraction substantially the same as
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shown in Figure 1, using ether solvent selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane.
The Form I of clopidogrel bisulphate obtained by the process of this invention is substantially pure.
DESCRIPTION OF THE DRAWINGS
Figure 1: An X-ray powder diffraction pattern of crystalline clopidogrel bisulphate Form I. DETAILED DESCRIPTION OF THE INVENTION
The term 'substantially pure' as used herein means that clopidogrel bisulphate Form I isolated by the process is substantially free from any other polymorph of clopidogrel bisulphate as well as other impurities.
In one embodiment, the specification discloses a process for the preparation of crystalline Form I clopidogrel bisulphate comprising the steps of:
(a) mixing clopidogrel base in ether selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane;
(b) optionally seeding with clopidogrel bisulphate Form I;
(c) adding the mixture of sulfuric acid and ether solvent;
(d) raising the temperature of reaction mixture of step (c) upto about 40 °C;
(e) isolating Form I of clopidogrel bisulphate; and
(f) optionally drying the isolated material of step (e).
The clopidogrel base can be prepared according to EP 281459.
The process comprises mixing clopidogrel base in ether selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane to obtain a solution which was optionally seeded with clopidogrel bisulphate Form I. The ratio of 1-15 % by weight of clopidogrel bisulphate Form I with respect to clopidogrel base was preferred. After seeding the solution with clopidogrel bisulphate Form l, the mixture may be kept at 0-15°C temperature, preferably at 4-5 °C temperature under stirring.
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Sulfuric acid solution in ether solvent was added to the above mixture at 0-15 °C temperature, preferably at 5 °C temperature to form clopidogrel bisulphate. The reaction mixture was maintained at this temperature and then increased up to 20-40 °C intermittently, at a rate of 1-2 °C per min. The mixture was then stirred for 16 hours at 30-40°C. The process was carried out under inert atmosphere. The inert atmosphere was created in the reaction mixture by bubbling an inert gas (nitrogen or argon) through the reaction mixture. The ether solvent is selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane.
The Form I of clopidogrel bisulphate may be isolated by filtration or any well known techniques in the art and can be dried under vacuum at 20-60 °C, preferably at 25-40 °C.
The yieid of Form f of clopidogrel bisulphate obtained by the process is about 90 %.
In another embodiment, the specification discloses a process for the preparation of clopidogrel bisulphate Form I having X-ray powder diffraction substantially the same as shown in Figure 1, using ether solvent selected from the group consisting of diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and methoxy ethane.
The X-ray powder diffraction pattern of clopidogrel bisulphate Form I is given in Table 1 and Fig. 1.
Table 1:

[°28] d-spacing [°A] Relative Intensity [%]
9.1813 9.62433 17.23
9.5343 9.26879 3.24
10.8356 8.15843 17.13
10.9818 8.0512 9.01
11.5087 7.68277 15.77
13.8107 6.4068S 5.10
14.3482 6.16808 10.03
14.8659 5.95440 11.96
15.2135 5,81914 9.36
15.4623 5.72607 17.97
16.2786 5.44072 3.97
17.9125 4.94797 7.69
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18.1917 4.87263 5.23
18.4361 4.80860 11.93
18.9269 4.68500 16.07
19.6171 4.52169 9.22
20,5269 4.32329 29.59
21.5317 _ 4.12375 8.54
21.8334 4.06744 12.44
22.0397 4.02984 3.58
22.5639 3.93738 5.78
23.1277 3.84265 100.00
23.3657 3.80406 15.75
23.8153 3.73325 16.26
24.3959 3.64569 4.01
25.0011 3.55880 4.37
25.4599 3.49571 28.04
25.8865 3.43905 7.31
26.5891 3.34975 6.28
27.1808 3.27816 4.12
27.3949 3.25302 5.88
27.8420 3.20179 2.66
28.4507 3.13465 5.18
28.9214 3.08470 9.46
30.7220 2.90789 7.52
31.2478 2.86014 2.40
32.9284 2.71790 4.34
33.4201 2.67904 1.53
33.9242 2.64037 2.44
34.6870 2.58403 1.81
35.5141 2.52572 1.99
36.0735 2.48783 2.08
36.5194 2.45847 1.97
36.9209 2.43265 2.26
37.4089 2.40203 1.62
The Form I of clopidogrel bisulphate is substantially free of other polymorphs and may be formulated into a dosage form, like tablet, capsule, etc., by combining with one or more pharmaceutically acceptable excipients. The dosage form may be oral or parenteral.
The following example illustrates one way of preparation of clopidogrel bisulphate Form I, and is not intended to limit the scope of the invention.
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EXAMPLE 1
PREPARATION OF CLOPIDOGREL BISULPHATE FORM I
Clopidogrel base (50 gm; 0.156 mole) was dissolved in diisopropyl ether (500 ml_). Clopidogrel bisulphate Form I (5 gm) was added to the above clear solution and the reaction mixture was cooled to 5 °C. A solution of concentrated sulfuric acid (15.27 gm; 0.156 mole) in diisopropyl ether (40 mL) was added drop wise to the reaction mixture with stirring. After the addition was substantially complete, the temperature of the reaction mixture was raised to about 10 °C followed by 20 to 40 °C at a rate of 1-2 °C per min. and stirred for 16 hours. The reaction mixture was filtered and the solid obtained was dried under vacuum at 30-35°C to obtain the crystal of clopidogrel bisulphate Form I. The yield of clopidogrel bisulphate Form I was found to be about 90 %.


Dated this 20thday of February, 2009

u
for Torrent Pharmaceuticals Ltd, Praveen Chand Gandhi

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