DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULPHATE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATERMARKBUILDING,
PLOT NO.11, SURVEY NO.9,
HITECHCITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a process for producing Clopidogrel bisulphate with reduced particle size by using sonocrystallization.

BACKGROUND OF THE INVENTION

Clopidogrel is chemically known as (+)-(S)-a-(2-Chlorophenyl)-6,7-dihydro thieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester is an inhibitor of platelet aggregation. It is marketed as an anti-anginal agent, antiplatelet agent and is found to decrease morbid events in people with established atherosclerotic cardiovascular disease and cerebrovascular diseases. Clopidogrel is administered as its hydrogen sulphate (bisulphate) salt and is marketed under the brand name PLAVIX®.

US 4,529,596 discloses the therapeutic application of Clopidogrel as blood-platelet aggregation inhibiting agent, antithrombotic agent and its preparation.

US 4,847,265 describes the process for the preparation of the Clopidogrel bisulphate by reacting Clopidogrel base with sulphuric acid in the presence of acetone.

US 6,429,210 first disclosed Clopidogrel bisulphate Form – II and disclosed that the process described in US ‘265 gives Form – I. These two crystalline polymorphic Form – I and Form – II differ in their stability, physical properties, spectral characteristics and their method of preparation. However, both the polymorphs have similar bioavailability, as shown in their bioequivalence in healthy human volunteers.
US 6,504,030 describes a process for the preparation of Clopidogrel bisulphate Form – II which involves the reaction of acetone solution of Clopidogrel with 94-96% sulfuric acid followed by seeding with Clopidogrel bisulphate Form – II.

US 7,629,465 discloses the preparation of Clopidogrel bisulphate Form – II by dissolving Clopidogrel free base in isopropyl alcohol followed by treating with concentrated sulfuric acid.

1176/CHE/2010 discloses the purification of Clopidogrel bisulphate Form – II by using a solvent mixture of isopropyl alcohol and water.

The major drawback associated with the above prior-art processes is the particle size of Clopidogrel bisulphate. The crystalline particles of Clopidogrel bisulphate Form – II obtained directly by the prior-art processes are having higher particle size and micronization is required to get the desired particle size. Hence, there is a need to develop an alternative improved process to obtain Clopidogrel bisulphate Form – II crystals with reduced particle size.

In view of the above, the instant invention describes a process, which produces Clopidogrel bisulphate Form – II with reduced particle size.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a simple and effective process for the preparation of Clopidogrel bisulphate Form – II with reduced particle size by using sonocrystallization.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides Clopidogrel bisulphate Form – II with reduced particle size d (0.9) of about from 15 to 50 microns.

In another embodiment, the present invention provides an improved process for the preparation of Clopidogrel bisulphate Form – II of Formula (I):

which comprises the steps of:
a) treating clopidogrel with sulfuric acid;
b) re-circulating the reaction mass through continuous tubular flow reactor with sonication;
c) seeding with Clopidogrel bisulphate Form – II;
d) isolating Clopidogrel bisulphate Form – II.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to Clopidogrel bisulphate Form – II with reduced particle size d (0.9) of about from 15 to 50 µm.

The process for the preparation of Clopidogrel bisulphate Form – II comprises adding dilute sulfuric acid solution to Clopidogrel, re-circulating the reaction mass through the continuous tubular flow reactor with sonication followed by seeding with Clopidogrel bisulphate Form – II and then isolating Clopidogrel Bisulphate Form – II.

Clopidogrel is prepared by using the processes disclosed in the prior art or by the process exemplified in the present invention.

The temperature maintained in the continuous tubular flow reactor with sonication is from about 15°C to 50°C without affecting the quality of product.

The flow rate of the continuous tubular flow reaction with sonication is about 150 – 250 ml/ min and an uniform flow rate should be maintained at step (b) for re-circulating the reaction mass.

The frequency range of sonocrystallization reactor at step (b) is about 10 – 50 KHz with the continuous provision.

The tubular reactor with sonication used at step (b) is selected from continuous mode reactor or batch reactor. The reaction mass is recirculated in the reactor through pump.

Isolation of Clopidogrel bisulphate Form – II at step (d) is carried out by continuous recirculation of reaction mass with the micro bubble generation with sonocrystallization followed by cooling the reaction mass and washing by using organic solvent.

The organic solvent used for washing in step (d) include but is not limited to alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Examples:

Example 1:
Preparation of Clopidogrel bisulfate Form – II
Chlorophenyl glycine methyl ester thiophene derivative hydrochloride (100 g, 0.289 moles) was added to a mixture of 37% aqueous formaldehyde solution (500 ml), DM water (500 ml) and methanol (100 ml) at 20-30°C and stirred for 32 hours at 25-30°C. The reaction mass was filtered to remove the undissolved material and extracted with methylene chloride (300 ml). Then butylated hydroxytoluene (0.3 g, 0.00136 moles) was added into the methylene chloride extract at 25-30°C and stirred for 10-15 min, then concentrated the methylene chloride solution followed by the addition of isopropyl alcohol (100 ml) and then again concentrated to obtain the residue of Clopidogrel free base. The above reaction mass containing (clopidogrel free base) was charged into the isopropyl alcohol (600 ml) and dilute sulphuric acid (47.17 g, 0.96 moles equivalent) was added at 25-30°C, then circulated the reaction mass through the continuous tubular flow reactor (200 ml/min) under the sonication (30±3 KHZ) for 4 hours at 15-30°C followed by cooling to 0-10°C and washing with isopropyl alcohol to obtain Clopidogrel bisulphate Form – II.

Particle size d (0.9): 37.35 microns
HPLC Purity: 99.93% ,CLAIMS:CLAIMS
We claim,

1. A process for the preparation of clopidogrel bisulphate form – II of formula (I),

which comprises the steps of:
a) treating clopidogrel with sulfuric acid;
b) re-circulating the reaction mass through tubular flow reactor with sonication;
c) seeding with clopidogrel bisulphate form – II;
d) isolating clopidogrel bisulphate form – II.

2. The process according to claim 1, wherein tubular flow reactor of step (b) is selected from continuous mode reactor or batch reactor.

3. The process according to claim 1, wherein the temperature maintained in the tubular flow reactor of step (b) is from 15°C to 50°C.

4. The process according to claim 1, wherein the flow rate of tubular flow reactor of step (b) is from 150 to 250 ml/min.

5. The process according to claim 1, wherein the frequency range of tubular flow reactor of step (b) is from 10 to 50 KHz.

6. The process according to claim 1, wherein the isolation of step (d) is carried out by cooling the reaction mixture.