Title of Invention

A NOVEL PROCESS FOR PREPARATION OF CLOPIDOGREL BISULFATE POLYMORPH - FORM I

Abstract The present invention discloses aprocess for making Clopidogrel Bisulfate Form I which comprises dissolving Clopidogrel Bisulfate Form II in a solublizing solvent at room temperature to form a solution; adding an anti-solvent to the said solution till turbid; stirring the said turbid solution; collecting the precipitated solid and drying the final solid product, form I..
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]
"A Novel Process for Preparation of Clopidogrel Bisulfate
Polymorph - Form I"
(a) USV LIMITED
(b) B.S.D. Marg, Station Road, Govandi, Mumbai - 400 088, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in . which it is to be performed:


Technical Field of the Invention :
The present invention relates to a novel process for preparation of crystalline Form I of Antithrombotic agent [Methyl (s)-(+)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-acetate hydrogen sulfate] commonly known as Clopidogrel Bisulfate (Formula I), from Form II.

Background and Prior Art
Clopidogrel is administrated as its hydrogensulfate (syn. Bisulfate) salt and its Antiplatelet activity makes it effective drug for reducing ischemic strokes, heart attacks and in atherosclerosis a vascular disease causing claudication. Atherosclerosis is a buildup of plaque in the walls of arteries, which leads to thickening, and the reduction in the elasticity of the arteries. High Cholesterol, high blood pressure, smoking and infection also causes an injury to the inner walls of the arteries, which leads to the atherosclerosis. The plaque formation leads to blood clotting which is due to the platelet aggregation at the site of the injury. This clotting becomes an obstacle for the flow of the blood to the organs causing heart attacks. Clopidogrel, binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting against the atherosclerosis.

Solid state properties of the material like flowability affect the ease with which the material is handled during the formulation. Another important property is the rate of dissolution, which imposes an upper limit on the rate at which an orally administrated active ingredient can reach the blood stream. The solid state form of the compound can also affect its compaction behaviour and storage stability.
US Patent no US 4,847,265 describes the formation of the dextrorotatory isomer of clopidogrel by salt formation using racemic compoimd and an optically active acid such as 10-L-camphorsulfonic acid in acetone, followed by successive recrystallisation until a product with constant rotatory power was obtained, followed by the release of the dextro rotatory isomer from its salt by a base. The hydrogen sulfate salt is then obtained by dissolution of the base in cold acetone, cooled in ice and addition of concentrated sulphuric acid to precipitate the bisulphate salt. The precipitate thus obtained is crystalline Form I.
US 6,429,210 describes process for preparation of the dextrorotatory S enantiomer of Clopidogrel bisulfate in the crystalline Form, Form II. US2003114479 describes the novel crystalline forms, Form III, IV and V along with the process for preparation of Form I. In this patent, polymorphic Form I is prepared by suspending amorphous clopidogrel hydrogen sulphate in ether.
International patent application WO2004020443 describes process for preparation of Clopidogrel bisulfate Form I, which comprises separating out crystalline Form I from the solution of clopidogrel in the form of free base or salt in a solvent selected from the series of the primary, secondary or tertiary C1-C5 alcohols or their Esters with C1-C4 carboxylic acids or optionally of mixtures thereof.
International patent application WO 2004048385 describes a process for the preparation of crystalline Form I of S-Clopidogrel hydrogen sulphate by reacting the optically active base, (S)-(+) clopidogrel with concentrated sulfuric acid, wherein the salt formed by the

said reaction in the reaction medium is precipitated with the precipitating solvent such as aliphatic or cyclic ethers and/or their mixture or isobutyl methyl ketone.
Form II of Clopidogrel Bisulfate is thermodynamically more stable and henca e sfnalis, change in conditioj;! during the preparation of Form I can result in Form 11.
The present invention relates to the process for preparation oi me crystalline Form I of Clopidogrel bisulfate from Form II. The present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is reproducible. The present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is cost effective and economical. The present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is commercially viable.
SUMMARY OF THE INVENTION
This invention discloses a process for manufacturing crystalline Form I of Clopidogrel Bisulfate, comprising crystallization of Form I from Form II by dissolving Form II in a solvent such as acetic acid and adding antisolvent such as di-isopropyl ether.
DETAILED DESCRIPTION OF THE INVENTION
This invention discloses a process for manufacturing crystalline Form I of Clopidogrel Bisulfate, comprising crystallization or precipitation of Form I from Form II using solvent such as a C1 to C4 carboxylic acid and antisolvent such as aliphatic ethers. The present invention also relates to the solid-state form. Form I of Clopidogrel Bisulfate.
The manufacturing process described in this invention involves crystallization of Form I from Form II in a reproducible way.

Dissolving the Clopidogrel Bisulfate Form II in glacial acetic acid at room temperature; Regenerating the clopidogrel bisulfate from the solution by adding an antisolvent to the solution at room temperature;
Stirring the reaction mixture for 24 hours at room temperature, filtering and drying the crystals to obtain Form I of Clopidogrel Bisulfate.
As used herein, a solvent is any liquid substance, which has capacity to dissolve the organic compound, Clopidogrel Bisulfate, either at room tempperature„or_. higher temperature. Antisolvent is an organic solvent in which organic compound such as Clopidogrel Bisulfate has poor solubility.
As used herein, room temperature means a temperature from about 10°C to 45°C, preferably 25°C to 30°C
The Form II required for the preparation of Form I was prepared by the method described in Patent US 4, 847,265.
The quality of clopidogrel bisulfate of Form I without detectable contamination by Form II, obtained in accordance with this invention, is documented by the following measurements:
X-ray powder diffraction pattern has been obtained on D 8 -Advance, Bruker AXE, Germany, diffiactometer equipped with Scintillation detector using Copper Kα (λ = 1.5406 A) radiation with scanning range between 2-50 ǿ at scanning speed of 2°/min.
Differential Scanning Calorimeter was performed on Mettler DSC 20 instrument. Samples of 2 mg to 3 mg weighed in aluminium crucibles with holes were scanned at a heating rate of 10°C per minute under nitrogen atmosphere at rate of 35 ml/min.

The Fourier-transform infrared (FT-IR) spectrum of Form I was obtained on a FT-IR 8300, Shimadzu instrument, in the range of 400-4000 cm' with a resolution of 4 m',
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 Shows the X-ray Diffraction Diagram of Clopidogrel Bisulfate Form I Fig. 2 Shows the DSC Thermogram of Clopidogrel Bisulfate Form I Fig. 3 Shows the FT-IR Spectrum of Clopidogrel Bisulfate Form I
Fig 1 of the polymorphic form obtained by this method, Form I shows an X-ray powder diffraction pattern which is characterized by having peaks at about 9.21, 9.56, 14.85, 15.53, 15.23, 20.62, 21.59, 23.19, 23.85, 25.52, ± 0.2 degrees. Fig 2 shows the DSC thermogram of Form I which is characterized by having sharp endotherm at 187°C followed by another sharp endotherm at 212°C. The FT-IR spectrum of Form I shows absorption at 2987, 2952, 1751, 1477, 1436, 1220, 1191, 867, 841, 766, 592 cm which is shown in Fig 3.
The following examples are provided to illustrate the invention and are not limiting the scope of the complete disclosure.
Example 1
5g. of crude Clopidogrel Bisulfate Form II was dissolved in 25 mL Glacial acetic acid at room temperature. The solution was filtered to remove any suspended particles. To the resultant clear solution 100 ml of Diethyl ether was added dropwise at the same temperature. The solution was stirred for 24 hrs. at the same temperature. The solid was filtered, washed v^dth Diethyl ether and dried to get Form I.

Example 2
5g. of crude Clopidogrel Bisulfate Form II was dissolved in 25 ml Glacial acetic acid at room temperature. The solution was filtered to remove any suspended particles. To the resultant clear solution 100 ml of Di isopropyl ether was added drop wise at the same temperature. The solution was stirred for 24 hrs. at the same temperature. The solid was filtered, washed with Di isopropyl ether and dried to get Form I.




We claim A process for making Clopidogrel Bisulfate Form I wherem the said process
comprises dissolving Clopidogrel Bisulfate Form II in a solublizing solvent at




room temperature to form a solution; adding an anti-solvent to the said solution
till turbid; stirring the said turbid solution; collecting the precipitated solid and
drying.
The process as claimed in claim I wherein the said solubilizing solvent is a C1-C4
carboxylic acid, preferably acetic acid.
The process as claimed in claim I wherein the said room temperature is between
10°C to 45°C preferably 25°C to 30°C.
process as claimed in claim 1 wherein the said antisolvent is selected from the group of aliphatic ethers such as-Dimethyl ether, Diethyl ether, Di-isopropyl ether, preferably Di-isopropyl ether.

The process as claimed in claim 1 wherein the said antisolvent is selected from the group of aliphatic Cyclic ethers sucli as Dioxane. Tetrahydrofuran. The process as claimed in claim 1 wherein the said drying may be carried out between 50°C to 70°C.
A Clopidogrel Bisulfate Form I prepared by the process as claimed in any of the claims 1 to 6.
A process for making Clopidogrel Bisulfate Form I as substantially described herein with reference to foregoing examples 1 to 2.

Dated this the 1st day of September 2004

Dr. Gopakumar G. Nair Gopakumar Nair Associates

Documents:

945-mum-2004-abstract(1-9-2004).doc

945-mum-2004-abstract(1-9-2004).pdf

945-mum-2004-abstract(granted)-(20-8-2010).pdf

945-mum-2004-cancelled pages(30-3-2010).pdf

945-mum-2004-claims(1-9-2004).doc

945-mum-2004-claims(1-9-2004).pdf

945-MUM-2004-CLAIMS(AMENDED)-(30-3-2010).pdf

945-mum-2004-claims(granted)-(20-8-2010).pdf

945-mum-2004-correspondence 1(23-11-2006).pdf

945-mum-2004-correspondence 2(19-2-2009).pdf

945-MUM-2004-CORRESPONDENCE 3-7-2008.pdf

945-MUM-2004-CORRESPONDENCE(19-2-2009).pdf

945-MUM-2004-CORRESPONDENCE(27-10-2009).pdf

945-mum-2004-correspondence(3-7-2008).pdf

945-mum-2004-correspondence(ipo)-(18-5-2009).pdf

945-mum-2004-correspondence(ipo)-(25-8-2010).pdf

945-mum-2004-description(complete)-(1-9-2004).pdf

945-mum-2004-description(granted)-(20-8-2010).pdf

945-mum-2004-drawing(1-9-2004).pdf

945-mum-2004-drawing(granted)-(20-8-2010).pdf

945-mum-2004-form 1(1-9-2004).pdf

945-mum-2004-form 1(10-9-2004).pdf

945-mum-2004-form 13(19-2-2009).pdf

945-MUM-2004-FORM 18(18-9-2007).pdf

945-mum-2004-form 2(1-9-2004).doc

945-mum-2004-form 2(1-9-2004).pdf

945-mum-2004-form 2(granted)-(20-8-2010).pdf

945-mum-2004-form 2(title page)-(1-9-2004).pdf

945-mum-2004-form 2(title page)-(granted)-(20-8-2010).pdf

945-mum-2004-form 26(1-9-2004).pdf

945-mum-2004-form 26(6-12-2003).pdf

945-mum-2004-form 3(1-9-2004).pdf

945-mum-2004-form 3(23-11-2006).pdf

945-MUM-2004-FORM 3(27-10-2009).pdf

945-MUM-2004-FORM 3(30-3-2010).pdf

945-MUM-2004-REPLY TO EXAMINATION REPORT(30-3-2010).pdf


Patent Number 242279
Indian Patent Application Number 945/MUM/2004
PG Journal Number 35/2010
Publication Date 27-Aug-2010
Grant Date 20-Aug-2010
Date of Filing 01-Sep-2004
Name of Patentee USV LIMITED
Applicant Address B.S.D. MARG, STATION ROAD, GOVANDI, MUMBAI-400 088,
Inventors:
# Inventor's Name Inventor's Address
1 TARUR VENKATASUBRAMANIAN RADHAKRISHNAN USV LIMITED B.S.D. MARG, STATION ROAD, GOVANDI, MUMBAI-400 088,
2 SATHE DHANANJAY GOVIND USV LIMITED B.S.D. MARG, STATION ROAD, GOVANDI, MUMBAI-400 088, MAHARASHTRA,INDIA
3 SAWANT KAMLESH DIGAMBAR 4/4, N.S.E. BLDG, WORLI VILLAGE, MUMBAI-400 030, MAHARASHTRA, INDIA
PCT International Classification Number C07D495/04 C07D495/00 A01K31/4793
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA