TECHNICAL FIELD OF THE INVENTION
The present invention relates to a clopidogrel bisulphate tablet and process for the preparation thereof, wherein the tablet does not exhibit sticking during the compression process. Said tablet has improved tabletting properties such as processability and compressibility.
BACKGROUND OF THE INVENTION
Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/llla complex. Currently, it is marketed as bisulphate salt under the trade name PLAVIX® by Sanofi Synthelabo/ Bristol Myers Squibb partnership. PLAVIX® is indicated for the reduction of atherothrombotic events such as recent myocardial infarction (Ml), recent stroke, or established peripheral arterial disease and acute coronary syndrome. Chemically, clopidogrel bisulphate is designated as methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5 (4H)-acetate sulphate (1:1) with the following structural formula:
(Formula Removed)
tablet contains
hydrogenated castor oil, hydroxypropylcellulose, mannitol, microcrystalline cellulose, polyethylene glycol 6000, ferric oxide, hypromellose, lactose monohydrate, titanium dioxide, and triacetin as inactive ingredients. The tablets are polished with carnauba wax.
U.S. Patent No. 4,529,596 describes racemic clopidogrel, its pharmaceutically acceptable mineral and organic acid salts, its blood platelet aggregation inhibiting and anti-thrombotic activities. U.S. Patent No. 4,847,265 discloses dextrorotatory isomer of clopidogrel, pharmaceutical salts and formulation of the same. US 5,576,328 describes

method of preventing the occurrence of a secondary ischemic event by administration of clopidogrel.
U.S. Patent No's. 6,429,210 and 6,504,030 disclose crystalline polymorph (Form 2) of (+)-(S) clopidogrel hydrogen sulphate, its process of preparation and pharmaceutical compositions containing it.
Several references disclose pharmaceutical compositions comprising different polymorphic forms of clopidogrel hydrogen sulphate and pharmaceutically acceptable excipients. For example, U.S. Patent No's. 6,767,913; 7,074,928; European Patent Application No's. EP 1467735; U.S. Patent Application No's. 20030225129 and International Publication No. WO 04/052966.
Although tablet compositions of clopidogrel bisulphate are known and commercially available, problems of sticking, poor tablet compression and difficult technical handling persist and are well documented.
U.S. Patent No. 6,914,141 and European Patent No. EP 1310245B1 disclose pharmaceutical tablets comprising clopidogrel bisulphate and a lubricant selected from zinc stearate, stearic acid, and sodium stearyl fumarate.
International Publication No. WO 05/070464 discloses clopidogrel bisulphate tablets containing hydrogenated vegetable oils and sodium carboxymethyl starch to solve problems occurring in tablet compression and provide suitable tablet formulation.
International Publication No. WO 04/098593 discloses compositions comprising amorphous clopidogrel hydrogen sulphate; either or both of calcium stearate and magnesium stearate; a non-hygroscopic additive; and at least one excipient.
International Publication No. WO 07/008045 describes compositions containing clopidogrel bisulphate and pregelatinized starch.
International Publication No. WO 07/049868 describes stabilized pharmaceutical composition comprising clopidogrel bisulphate along with specified quantities of starch and cellulose.

Clopidogrel bisulphate being a fine powder and hygroscopic in nature, absorbs moisture and is therefore, difficult to compress into tablets as such using conventional tabletting techniques. The tablet material adheres to the punch and/or die surfaces resulting in defects such as sticking, capping and lamination during tabletting. Usually, lubricants are added to keep the tablets from sticking to the punches and die walls during or after compaction. Commercially marketed PLAVIX® tablets do not contain commonly used magnesium stearate as a lubricant, but instead contain hydrogenated castor oil and polyethylene glycol as lubricants since magnesium stearate causes degradation of clopidogrel bisulphate. Both these ingredients are occasionally used as lubricants, since they are not as effective as magnesium stearate and their use results in sticking to the punches and die walls during or after the compression process.
The present invention addresses and overcomes these commonly encountered problems. It has been found that clopidogrel bisulphate tablets of the present invention resolves the problem of sticking, flow well and have good compression performance.
SUMMARY OF THE INVENTION
In one general aspect, it relates to a clopidogrel bisulphate tablet comprising a therapeutically effective amount of clopidogrel bisulphate; lactose monohydrate and other pharmaceutically acceptable excipients, wherein clopidogrel bisulphate has a particle size distribution such that it has a D90 value of not less than 50 urn and the said tablet does not exhibit sticking during the compression process.
In another general aspect, it relates to a clopidogrel bisulphate tablet comprising a therapeutically effective amount of clopidogrel bisulphate; lactose monohydrate, microcrystalline cellulose, low substituted hydroxypropylcellulose, polyethylene glycol 6000 and hydrogenated castor oil, wherein clopidogrel bisulphate has a particle size distribution such that it has a D90 value of not less than 50 urn and the said tablet does not exhibit sticking during the compression process.
In another general aspect, it relates to a process for preparing clopidogrel bisulphate tablet comprising a therapeutically effective amount of clopidogrel bisulphate having a

particle size distribution such that it has a Dgo value of not less than 50 urn comprising the steps of:
a) blending said clopidogrel bisulphate with lactose monohydrate and other
pharmaceutically acceptable excipients in a suitable blender;
b) mixing one or more of lubricants with the blend of step (a);
c) compressing the final blend of step (b) into tablets.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a clopidogrel bisulphate tablet, wherein the said tablet does not exhibit sticking during the compression process.
The term "therapeutically effective amount" as used herein, refers to the dose of clopidogrel bisulphate with respect to the free base which produces the desired therapeutic response upon oral administration. The dose may range from about 1mg to about SOOmg of clopidogrel, particularly in an amount of from about 50mg to about 100mg.
The term "sticking" as described herein is intended for a defect encountered during tabletting procedure wherein the tablet material and/or tablet adheres to the punch surfaces and/or die walls during and after the compaction process.
As used herein, the D9o value corresponds to the 90th percentile of the particle size distribution i.e. 90% of the particles have the size equal to or below the quoted limit.
In a tableting procedure, the choice of excipients is critical to achieve suitable physical characteristics and to produce formulations with acceptable handling and processing characteristics. This is more so, in case of tablets containing hygroscopic drugs such as clopidogrel salts. For such drugs, it is generally necessary to include a lubricant in the mix of ingredients to resolve the problems of sticking. Lubricant prevents adhesion of the tablet material to the surface of dies and/or punches, reduce interparticulate friction and facilitate the ejection of tablets from the die cavities. Suitable lubricants may be selected from the group comprising of hydrogenated vegetable oils, polyethylene glycols, mineral oils, wax having a high melting point, glyceryl fatty acid esters, light anhydrous silicic acid, zinc stearate, stearic acid, sodium stearyl fumarate and

combinations thereof. Lubricants may comprise from about 1% to about 10% by weight of the tablet.
The inherent sticking problem associated with clopidogrel bisulphate cannot be overcome by an increasing amount of conventional lubricants alone. It is found that the problem can be successfully resolved by the selection of suitable diluents in conjunction with appropriate lubricants. We have found that the formulation prepared in accordance with the innovator's formulation i.e. containing mannitol as one of the excipients showed excessive sticking during compression process. Sticking problem persisted when mannitol was replaced with anhydrous lactose. However, when lactose monohydrate was used in place of mannitol, the resultant tablets were free of the tendency of sticking to the punch surfaces and/or die walls and at the same time, were easily compressed into integral, cohesive tablets. The preferred diluent in the present invention is therefore, lactose monohydrate and may comprise from about 10% to about 90% by weight of the tablet. It may also be used in combination with one or more of other diluents such as microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate and combinations thereof.
In addition, to the requirement for selection of appropriate excipients, we have found that the particle size of clopidogrel bisulphate significantly affects the processing behavior and characteristics of the tablet during the compression process. Use of clopidogrel bisulphate having particle size distribution i.e. Dgo value of equal to or less than 50 urn resulted in significant sticking during compression even when lactose monohydrate was used. It is therefore, observed that tablets having adequate compressibility, flowability and devoid of problems of sticking may be obtained using a specific particle size of clopidogrel bisulphate in conjunction with suitable excipients. The tablets may, without limitation, include other pharmaceutically acceptable excipients selected from one or more of binders, disintegrants and glidants.
Suitable binders may be selected from the group comprising of microcrystalline cellulose, hydroxypropylcellulose, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethyl cellulose, starch, polyvinylpyrrolidone, polyethylene glycol, polyvinylalcohols, pectins, gelatin and combinations thereof. Binders may comprise from about 1% to about 20% by weight of the tablet.

Suitable disintegrants may be selected from the group comprising of hydroxypropylcellulose, microcrystalline cellulose, starch, pregelatinized starch, carboxymethyl starches, croscarmellose, sodium starch glycolate, crospovidone, alginates and combinations thereof. Disintegrants may comprise from about 1% to about 20% by weight of the tablet.
Suitable glidants may be selected from talc, colloidal silicon dioxide and the like and may comprise from about 0.1% to about 3% by weight of the tablet.
Clopidogrel bisulphate tablets free of the tendency of sticking during the compression process as described herein may be prepared by conventional direct compression method.
In one embodiment, the tablets are prepared by the process comprising the steps of:
(a) blending said clopidogrel bisulphate with lactose monohydrate and other
pharmaceutically acceptable excipients in a suitable blender;
(b) mixing one or more of the lubricants with the blend of step (a);
(c) compressing the final blend of step (b) into tablets.
In a preferred embodiment, the tablets are prepared by the process comprising the steps of:
(a) blending said clopidogrel bisulphate with lactose monohydrate, microcrystalline
cellulose and low substituted hydroxypropylcellulose in a suitable blender;
(b) mixing polyethylene glycol 6000 and hydrogenated castor oil with the blend of
step (a);
(c) compressing the final blend of step (b) into tablets.
Tablets may, optionally, be coated with film forming agents and/or other pharmaceutically acceptable excipients. Particularly suitable for use are commercially available coating compositions comprising film forming polymers marketed under various trade names such as Opadry®.
The invention described herein is further illustrated by the following examples but it should not be construed as limiting the scope of the invention.

EXAMPLES A-E

(Formula Removed)
** Particle size distribution i.e. Dao value is not less than 50 um
Procedure for Example A:
All the ingredients were sifted through Quadro Co-mill using specified sieves. Clopidogrel bisulphate, lactose monohydrate, microcrystalline cellulose and low substituted hydroxypropyl cellulose were blended together in a non-shear blender to attain a homogeneous distribution. The above blend was further mixed with polyethylene glycol 6000 and hydrogenated castor oil to prepare the final blend. The final blend was compressed into suitably sized tablets using conventional tabletting machine. No sticking on the tablet punches and dies was observed.
Procedure for Example B:
All the ingredients were sifted through Quadro Co-mill using specified sieves. Clopidogrel bisulphate, mannitol, microcrystalline cellulose and low substituted hydroxypropyl cellulose were blended together in a non-shear blender to attain a homogeneous distribution. The above
blend was further mixed with polyethylene glycol 6000 and hydrogenated castor oil to prepare the final blend. The final blend was compressed into suitably sized tablets using conventional tabletting machine. Significant sticking during compression was observed in these tablets.
Procedure for Example C:
All the ingredients were sifted through Quadro Co-mill using specified sieves. Clopidogrel bisulphate, anhydrous lactose, microcrystalline cellulose and low substituted hydroxypropyl cellulose were blended together in a non-shear blender to attain a homogeneous distribution. The above blend was further mixed with polyethylene glycol 6000 and hydrogenated castor oil to prepare the final blend. The final blend was compressed into suitably sized tablets using conventional tabletting machine. Significant sticking during compression was observed in these tablets.
Procedure for Examples D.
All the ingredients were sifted through Quadro Co-mill using specified sieves. Clopidogrel bisulphate, anhydrous lactose, microcrystalline cellulose and pregelatinized starch were blended together in a non-shear blender to attain a homogeneous distribution. The above blend was further mixed with polyethylene glycol 6000 and hydrogenated castor oil to prepare the final blend. The final blend was compressed into suitably sized tablets using conventional tabletting machine. Significant sticking during compression was observed in these tablets.
Procedure for Example E:
All the ingredients were sifted through Quadro Co-mill using specified sieves. Clopidogrel bisulphate, mannitol, microcrystalline cellulose and pregelatinized starch were blended together in a non-shear blender to attain a homogeneous distribution. The above blend was further mixed with polyethylene glycol 6000, stearic acid and anhydrous colloidal silica to prepare the final blend. The final blend was compressed into suitably sized tablets using conventional tabletting machine. Significant sticking during compression was observed in these tablets.
EFFECT OF PARTICLE SIZE OF CLOPIDOGREL BISULPHATE ON STICKING IN TABLETS PREPARED IN ACCORDANCE WITH EXAMPLE A ABOVE

(Table Removed)Clopidogrel bisulphate tablets were prepared in accordance with the Example A above. It was found that when Clopidogrel bisulphate having D90 value equal to or less than 50 urn was used, significant sticking was observed during the compression process.

WE CLAIM:
1) A clopidogrel bisulphate tablet comprising a therapeutically effective amount of
clopidogrel bisulphate; lactose monohydrate and other pharmaceutically
acceptable excipients; wherein clopidogrel bisulphate has a particle size
distribution such that it has a Dgo value of not less than 50 urn and the said tablet
does not exhibit sticking during the compression process.
2) The clopidogrel bisulphate tablet according to Claim 1, wherein the other
pharmaceutically acceptable excipients are selected from one or more of
diluents, binders, disintegrants and lubricants.
3) The clopidogrel bisulphate tablet according to Claim 2, wherein the diluent is
selected from the group comprising of microcrystalline cellulose, powdered
cellulose, starch, pregelatinized starch, calcium carbonate, calcium sulphate,
dibasic calcium phosphate, tribasic calcium phosphate and combinations
thereof.
4) The clopidogrel bisulphate tablet according to Claim 2, wherein the binder is
selected from the group comprising of microcrystalline cellulose,
hydroxypropylcellulose, methyl cellulose, cellulose ethers, sodium
carboxymethylcellulose, ethyl cellulose, starch, polyvinylpyrrolidone,
polyethylene glycol, polyvinylalcohols, pectins, gelatin and combinations thereof.
5) The clopidogrel bisulphate tablet according to Claim 2, wherein the disintegrant
is selected from the group comprising of hydroxypropylcellulose, microcrystalline
cellulose, starch, pregelatinized starch, carboxymethyl starches, croscarmellose,
sodium starch glycolate, crospovidone, alginates and combinations thereof.
6) The clopidogrel bisulphate tablet according to Claim 2, wherein the lubricant is
selected from the group comprising of hydrogenated vegetable oils, polyethylene
glycols, mineral oils, wax having a high melting point, glyceryl fatty acid esters,
light anhydrous silicic acid, zinc stearate, stearic acid, sodium stearyl fumarate
and combinations thereof.
7) The clopidogrel bisulphate tablet according to Claim 1, wherein the tablet further
comprises microcrystalline cellulose, low substituted hydroxypropyl cellulose,
polyethylene glycol 6000 and hydrogenated castor oil.
8) A process for the preparation of clopidogrel bisulphate tablet according to Claim
1, wherein the process comprises the steps of:

a) blending said clopidogrel bisulphate with lactose monohydrate and other
pharmaceutically acceptable excipients in a suitable blender;
b) mixing one or more of the lubricants with the blend of step (a);
c) compressing the final blend of step (b) into tablets.
9) A clopidogrel bisulphate tablet and process for the preparation thereof
substantially as described and illustrated by the examples herein.