WO2011092720A2

WO2011092720A2 - Pharmaceutical composition of prasugrel and its pharmaceutically acceptable salts

Info

Publication number: WO2011092720A2
Application number: PCT/IN2011/000066
Authority: WO
Inventors: Manne Satyanarayana Reddy; Srinivasan Thirumalai Rajan; Madhu Elevathingal Nicholas; Karamala Rama Subba Reddy
Original assignee: Msn Laboratories Limited
Priority date: 2010-02-01
Filing date: 2011-01-31
Publication date: 2011-08-04
Also published as: WO2011092720A3

Abstract

A pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts, especially hydrochloride salts as well as process for their preparation are provided. The pharmaceutical composition comprises: a) prasugrel hydrochloride, b) a water insoluble dry binder, c) at least one diluent, d )at least one disintegrant and e) at least one lubricant. The pharmaceutical composition is optionally coated with a film. An improved process for preparing of prasugrel and its pharmaceutically acceptable salts, a process for purifying 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2 -one hydrochloride compound, a process for preparing crystalline form-B2 of prasugrel hydrochloride and a process for preparing a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound are provided.

Description

Pharmaceutical Composition of Prasugrel and its Pharmaceutically

Acceptable Salts

Related Applications:

This application claims the benefit of priority of our Indian complete specification number: 244/CHE/2010, filed on 1^st February 2010, which is incorporated herein by reference.

Field of the invention:

The present invention relates to a pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts thereof, especially hydrochloride salt as well as process for its preparation. Prasugrel is chemically known as 2-acetoxy-5-cyclopropylcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and is represented by the following structural formula- 1.

Formula- 1

The present invention also relates to an improved process for the preparation of prasugrel and its pharmaceutically acceptable salts.

Background of the invention:

Prasugrel is a thienopyridine derivative, and an ADP receptor antagonist. Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. It produces more potent platelet inhibition, a rapid onset of action and may provide a superior therapeutic alternative to clopidogrel.

Prasugrel hydrochloride is marketed in Europe as Efient and in US as Effient for the treatment of patients with acute coronary syndrome who are managed with percutaneous coronary intervention. US 5,288,726 disclose tetrahydrothienopyridine derivatives including prasugrel. This patent document discloses the use of these compounds for the treatment and prophylaxis of thrombosis and embolisms. US 6,693,115 disclose the hydrochloric acid and maleic acid salts of prasugrel.

The hydrochloride and maleate salt forms provide unexpected and unobvious improvements in their efficacy and stability profiles compared to other salts and also compared to free base molecule. However, prolonged exposure of prasugrel to air and moisture results in degradation. Hence, there is a need to develop a composition, which improves the stability, shelf life and therefore long term efficacy of individual doses of prasugrel.

International publication number WO 2006/135605 describes a formulation comprising a therapeutically effective amount of prasugrel hydrochloride packaged in an air and moisture impervious blister package, with an inert gas like nitrogen, argon, neon, carbondioxide and carbon monoxide atmosphere, to improve the stability and shelf life of prasugrel.

International publication number WO 2008/073759 describes a formulation comprising packaging prasugrel tablet, capsule, caplet or other solid form of prasugrel in an air and/or moisture impervious container under a positive liquid gas pressure, to enhance the stability and shelf life of prasugrel.

The above said processes of packing of prasugrel hydrochloride is not easy to handle at industrial level as it involves the packing under inert gas atmosphere/liquid gas pressure. Hence there is a need in the art for an improved packing which avoids the usage of such gases.

European patent application number EP 2,100,607 describes a pharmaceutical composition comprising prasugrel or pharmaceutically acceptable salt thereof; and a water-soluble polymer selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose and polyvinyl pyrrolidone. European patent application number EP 2,100,608 describes a method for producing a solid preparation containing prasugrel or pharmaceutically acceptable salt thereof is mixed, while applying mechanical stress to the composition. European patent application number EP 2,100,609 describes a solid medicinal preparation, which comprises prasugrel or pharmaceutically acceptable salt thereof; and mannitol or lactose which, when examined under conditions, has a particle size distribution in which the 90% cumulative diameter is 80 to 300 μιη. European patent application number EP 2,100,610 describes a pharmaceutical composition comprising prasugrel or pharmaceutically acceptable salt thereof; and a low- substituted hydroxypropyl cellulose.

U.S. patent application number 2009/0281136 describes a pharmaceutical formulation comprising prasugrel or pharmaceutically acceptable salt thereof; and at least one stabilizing agent.

According to the invention, the pharmaceutical composition is in the form of a tablet, in which pregelatinized starch is used as a binder enhancing the crushing strength and dissolution profile. The use of ethyl cellulose, a hydrophobic polymer in the coating material, provides a protective layer against absorption of moisture. Further, the tablets are packed in alu-alu cold packing which has no air gap in the pocket of aluminium blister preventing any moisture being present in the atmosphere around the tablet. The present invention there by avoided the usage of inert gases/liquid pressure in packing which is difficult to handle as used in the art to increase the stability.

Brief Description of Invention:

The first aspect of the present invention is to provide a pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts, which comprises of; a) Prasugrel hydrochloride,

b) a water insoluble dry binder,

c) at least one diluent,

d) at least one disintegrant, e) at least one lubricant, and

f) optionally coated with a film.

Further embodiment, the pharmaceutical composition of the present invention is in the form of a tablet which is coated with a film impregnated with ethyl cellulose, which protects the pharmaceutical composition from moisture. The composition is prepared by dry granulation method.

The tablets prepared according to the present invention are packed in alu-alu cold packing in order to avoid the pharmaceutical composition from being exposed to moisture.

The second aspect of the present invention is to provide a process for purification of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one hydrochloride compound of formula-3, which comprises of;

a) Suspending the compound of formula-3 in a suitable solvents or mixture of solvents,

b) heating the suspension to reflux,

c) cooling the suspension,

d) filtering the solid to get the compound of formula-3.

The third aspect of the present invention is to provide an improved process for the preparation of prasugrel and its pharmaceutically acceptable salts, which comprises of; a) Removing the protecting group on nitrogen from N-trityl 5,6,7,7a-tetrahydro-4H- thieno[3,2-c] pyridine-2-one compound of formula-2, by treating with hydrochloric acid in acetone to provide 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one hydrochloride, which on purification from a mixture of dichloromethane and methanol provides highly pure compound of formula-3,

b) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one hydrochloride compound of formula-3 with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4, in the presence of potassium carbonate in acetonitrile,

( followed by treatment with hydrobromic acid to provide the compound of formula- acetylating the compound of formula-5 with acetic anhydride in the presence of triethylamine to provide prasugrel compound of formula- 1,

converting the prasugrel into its hydrochloride by treating prasugrel with ethyl acetate hydrochloride in a suitable solvent to provide prasugrel hydrochloride the compound of formula- la.

The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-B₂ of prasugrel hydrochloride.

The fifth aspect of the present invention is to provide an improved process for the preparation of a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4. Detailed description of the invention :

The first aspect of the present invention provides a pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts, which comprises of;

a) Prasugrel hydrochloride,

b) a water insoluble dry binder,

c) at least one diluent,

d) at least one disintegrant,

e) at least one lubricant, and

f) optionally coated with a film. In one embodiment the pharmaceutical composition of the present invention is in the form of a tablet which is prepared by dry granulation and direct compression method. The tablet is coated with a film which protects the pharmaceutical composition form coming into contact with moisture avoiding degradation of the active pharmaceutical ingredient. Further the tablets are packed in alu-alu cold packing without leaving an air gap in the pockets of aluminium blister, which prevents the pharmaceutical composition from being exposed to air which may contain moisture, thereby avoids the formation of impurities and increase stability and shelf life of prasugrel. Further embodiment, the pharmaceutical composition of the present invention is in the form of a tablet which is coated with a film impregnated with ethyl cellulose, which protects the pharmaceutical composition from moisture. The composition is prepared by dry granulation method.

Further the pharmaceutical composition of the present invention involves the usage of micronized prasugrel hydrochloride which further enhances the solubility. The micronized prasugrel hydrochloride having D90 and D₅₀ particles is not more than 10 microns. The composition comprising micronized prasugrel hydrochloride has superior solubility when compared with the non-micronized composition.

As used herein the term "Prasugrel" means a compound including, but not limited to, the drug compound prasugrel, its pharmaceutical acceptable salts and their polymorphs and hydrates thereof.

The term "pharmaceutically acceptable salts" refers to salts including but not limited to, hydrohalides like hydrochloride, hydrobromide and hydroiodide; inorganic acids such as nitrate, perchloric acid salt, sulfate or phosphate; lower-alkyl sulfonic acid salts such as methanesulfonate, or ethanesulfonate; arylsulfonic acid salts such as benzene sulfonate or p-toluenesulfoante; organic acid salts such as .acteate, malate, fumerate, succinate, citrate, ascorbate, tartarate, oxalate or maleate; or an amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt, preferably hydrohalides or organic acid salts, more preferably hydrochloride or maleate and most preferably hydrochloride.

In a preferred embodiment of the present invention provides a pharmaceutical composition of prasugrel, which comprises of;

a) Prasugrel hydrochloride,

b) pregelatinized starch,

c) microcrystalline cellulose,

d) croscarmellose sodium,

e) magnesium stearate and f) coated with a film comprising of hydroxypropyl cellulose, polyethylene glycol, titanium dioxide, color with or with out ethylcellulose.

The present invention further provides a process for preparing pharmaceutical composition of prasugrel hydrochloride, which comprises of the following steps:

a) Mixing prasugrel hydrochloride with diluent,

b) adding water insoluble dry binder and disintegrant,

c) blending diluent and lubricant,

d) optionally milling or seiving granules,

e) compressing to tablets,

f) applying a coat on the compressed tablets.

The formulation according to the invention preferably comprises from 2 to 20%, most preferably from 5 to 10%, of prasugrel or its salts and/or hydrates thereof (all the percentages are % by weight based on the weight of the pharmaceutical preparation).

The pharmaceutical composition of the present invention contains binders, diluents, disintegrants, lubricants and/or coating materials. The "diluents" that may be used include but are not limited to, cellulose derivatives such as microcrystalline cellulose, phosphates such as dibasic calcium phosphate anhydrous, tricalcium phosphate anhydrous, sulfates such as calcium sulfate and silicified microcrystalline cellulose. According to the invention, the diluent preferably used is microcrystalline cellulose having the diameter in the range of 420 microns to 105 microns, which increases greater compressibility and more resistance towards crushing strength. The pharmaceutical preparation advantageously comprises from 50 to 96%, preferably from 60 to 95%, most preferably from 70 to 90% of the diluents. The "binders" that may be used include but are not limited to, starch derivatives such as pregelatized starch, polymers such as carbomer, chitosan. According to the invention, the binder preferably used is pregelatinized starch. The pharmaceutical preparation advantageously comprises from 1 to 25%, preferably from 1.5 to 20%, more preferably from 2 to 16% of the binders.

The "disintegrants" that may be used may be, selected from the group consisting of starch, starch glycolates, crosslinked polyvinylpyrrolidone and sodium carboxymethylcellulose (croscarmellose sodium). According to the invention, the disintegrant preferably used is croscarmellose sodium. The pharmaceutical preparation advantageously comprises from 1 to 10%, preferably from 1.5 to 8%, more preferably from 2 to 6% of the disintegrant.

The "lubricants" that may be used include but are not limited to, stearic acid, stearic acid metal salts such as magnesium stearate or calcium stearate; talc; colloidal silica; waxes such as bee's wax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate glycol; tumeric acid; sodium steryl fumerate. According to the invention, the lubricant preferably used is magnesium stearate. The pharmaceutical preparation advantageously comprises from 0.05 to 1.5%, preferably from 0.2 to 1.2%, more preferably from 0.5 to 1% of the lubricant.

As the "coating agents" used, may be selected from hydroxypropyl cellulose, hydroxymethyl cellulose, ethyl cellulose, talc, polyethylene glycol, titanium dioxide and color.

The pharmaceutical composition of the present invention is preferably in the form of a solid for example tablets, capsules, granules, fine granules, powders, pills, chewables or troches. Preferably, it is in the form of powders, granules, fine granules, capsules or tablets and most preferably tablets.

As the prasugrel and its salts are moisture sensitive, the present invention utilizes the dry method for formulation which is more advantageous. The dry method of the present invention involves dry granulation and the direct compression method. The "dry granulation method" is a method in which a preparation is produced by using granules prepared by crushing and dividing by an appropriate method by compress- molded slug or sheet of raw material powders. The "direct compression method" is a method wherein the raw material powders are directly subjected to compression-molding to produce a preparation.

The tablets are packed in alu-alu cold packing which has no air gap in the pocket of aluminium blister preventing any moisture being present in the atmosphere around the tablet.

The dosage of the compound represented by the aforementioned general formula- 1 or pharmacologically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, may vary depending on various conditions such as the activity of the drug, symptoms, age or body weight of a patient. The daily dosage amount for an adult human has a lower limit of 0.01 mg (preferably 1 mg) and an upper limit of 200 mg in the case of oral administration (preferably 100 mg).

Prasugrel and its pharmaceutically acceptable salts used in the present invention can be prepared by the processes known in the art or by the process illustrated in the present invention.

The second aspect of the present invention provides a process for the purification of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one hydrochloride compound of formula-3, which comprises of:

a) Suspending the compound of formula-3 in a suitable solvent selected from chloro solvents like dichloromethane, chloroform and 1 ,2-dichloroethane; alcoholic solvents like methanol, ethanol,l-propanol, isopropyl alcohol and n-butanol or mixtures thereof, preferably in a mixture of dichloromethane and methanol, b) heating the suspension to reflux,

c) cooling the suspension,

d) filtering the solid to get highly pure compound of formula-3. Formula-3 is an important intermediate used in the preparation of important drug like prasugrel. Almost all the reported processes for the preparation of prasugrel proceeds through the compound of formula-3, which is having very low quality and hence lead to the formation of corresponding impurities in final compounds. Hence it is necessary to have a highly pure compound of formula-3. Till date there is no purification technique has been reported for the compound of formula-3. While working to resolve this issue it was surprisingly found that the purification of compound of formula-3 in a mixture of dichloromethane and methanol provided the compound of formula-3 with very high quality in terms of its assay. Here highly pure compound means, a compound having purity greater than 95%, preferably greater than 98%, more preferably 99.00% by HPLC and having assay greater than 95%, preferably greater than 98%, more preferably 99%.

When the highly pure compound of formula-3 prepared by the present invention is used in the preparation of prasugrel or its pharmaceutically acceptable salts which provides the final compounds with high yields and purity. In particular, the yield of the condensed product obtained by the condensation of the compound of formula-3 with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4 has substantially increased. The third aspect of the present invention provides an improved; process for the preparation of prasugrel and its pharmaceutically acceptable salts, which comprises of; a) Removing the protecting group on nitrogen from N-trityl 5,6,7,7a-tetrahydro-4H thieno[3,2-c] pyridine-2-one com ound of formula-2,

Formula-2

by treating with hydrochloric acid in acetone to provide 5,6,7,7a-tetrahydro-4H- thieno[3,2-c] pyridine-2-one hydrochloride, which on purification in a mixture of dichloromethane and methanol provides a highly pure compound of formula-3,

Formula -3

b) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one hydrochloride compound of formula-3 with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4,

Formula-4

in the presence of potassium carbonate in a acetonitrile, followed by treatment with hydrobromic acid provides a compound of formula-5,

' Formula-5

c) acetylating the compound of formula-5 with acetic anhydride in the presence of triethylamine provides la- 1,

Formula- 1

d) converting the prasugrel into its hydrochloride salt by treating prasugrel with ethylacetate hydrochloride in acetone to provide the prasugrel hydrochloride compound of formula- 1 a.

The fourth aspect of the present invention provides a process for the preparation of crystalline form-B₂ of prasugrel hydrochloride, which comprises of; a) Dissolving the prasugrel in acetone,

b) heating the solution and subjected to carbon treatment,

c) cooling the solution,

d) adding ethylacetate hydrochloride,

e) filtering the solid to get the crystalline form-B₂ of prasugrel hydrochloride,

The obtained prasugrel hydrochloride is packed using clear and block polyethylene bags under vacuum packing to increase the self life of the product.

Three different crystalline forms A, Bi and B₂ of prasugrel hydrochloride are known in the art. The disclosed process involves the usage of acetone and aqueous hydrochloric acid for the preparation of said crystalline forms. When the reported process was repeated with the exception that dry hydrochloric acid in ethylacetate was used in place of aqueous hydrochloric acid it provided prasugrel hydrochloride with the physical characteristics of known crystalline form B₂ of prasugrel hydrochloride.

The fifth aspect of the present invention is an improved process for the preparation of a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4,

Formula-4

which comprises of reacting the -cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-6

Formula-6

with aqueous hydrobromic acid in the presence of hydrogen peroxide in suitable protic solvents preferably water to provide a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4. The results of dissolution test of tablets prepared by the present invention in comparison with innovator's tablet is shown in the following tables.

Table-l

The dissolution profile conducted in four different media indicates that 0.0 IN HCl has got more discriminatory power comparative with other dissolution mediums. The formulation prepared according to the present invention is equivalent to the in-vitro studies of the innovator's drug. The present invention is schematically represented by the following scheme- 1 :

Scheme-1

Formula-5

triethyl amine

acetic anhydride

isopropyl alcohol

dichloromethane

Formula-1 a Formula-1

PRASUGREL HYDROCHLORIDE PRASUGREL Stability study of the pharmaceutical composition of the present invention as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Examples-l, 2 and 3:

•Equivalent to 5 mg of prasugrel.

**Equivalent to 10 mg of prasugrel.

Manufacturing process:

Prasugrel hydrochloride and all excipients were shifted through #40 mesh sieve and mixed thoroughly. Prasugrel hydrochloride was mixed with 1 :1 proportion microcrystalline cellulose, mixed pregelatinized starch and croscarmellose sodium by using blender. Then blend with remaining microcrystalline cellulose followed by magnesium stearate. The blend was then subjected to compression on machine to make tablets.

The cores were aqueous coated in a coating pan with hydroxypropyl cellulose, polyethylene glycol, titanium dioxide and color. ExampIe-4:

^*Equivalent to 5 mg of prasugrel.

* "Equivalent to 10 mg of prasugrel.

(

Manufacturing process:

The cores were aqueous coated in a coating pan with hydroxypropyl cellulose, polyethylene glycol, ethyl cellulose, titanium dioxide and color.

Example-5: Purification of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one- hydrochloride

A mixture of dichloromethane (425 ml), methanol (75 ml) and 5 , 6, 7, 7a-tetrahydro-4H- thieno[3,2-c]-pyridin-2-one-hydrochloride (100 grams) was heated to reflux. The reaction mixture was stirred for 30 minutes and cooled to 25-30°C and further stirred for 1 hour. The solid obtained was filtered, washed with dichloromethane and dried to get the title compound.

Yield: 88 grams; Assay: 98.5%. Example-6: Preparation of 5-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a- tetrahydrothieno[3,2-c]pyridine-2(4H)-one hydrobromide

A mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one-hydrochloride (100 grams), potassium carbonate (215 grams) and acetonitrile (1750 ml) was stirred for 30 minutes at 25-30°C. a-cyclopropylcarbonyl-2-fluorobenzyl bromide (85.5 grams) in acetonitrile (50 ml) was added to the reaction mixture and stirred for 6 hours at 25-30°C. The precipitated solid was removed by filtration. Silica gel (200 grams) was added to the filtrate and stirred for 30 minutes and filtered. The filtrate was distilled off completely under reduced pressure and ethyl acetate followed by cyclohexane was added to it. The reaction mixture was stirred for 25 minutes at 25-30°C. Added silica gel (150 grams) to the reaction mixture and stirred for 30 minutes at 25-30°C. The reaction mixture was filtered and solvent form the filtrate was distilled off completely under reduced pressure. Acetone (300 ml) was added to the obtained residue, stirred for 30 minutes and then cooled to 0-5°C. Aqueous hydrobromide (102 grams) was added to the reaction mixture at 0-5 °C and stirred the reaction mixture at 25-30°C for 5 hours. The reaction mixture was cooled to 0°C and stirred for 2 hours. The solid formed was filtered, washed with acetone and dried to get the title compound.

Yield: 84 grams;

M.R.: 188-198°C. Example-7: Preparation of a-cyclopropylcarbonyl-2-fluorobenzyI bromide compound of formula-4:

142 ml of aqueous HBr was added to the solution of water (500 ml) and l-cyclopropyl-2- (2-fluorophenyl)ethanone (100 grams) at 25-30°C and stirred for 15 minutes at the same temperature. 30% hydrogen peroxide solution (127 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 2 hours at 25-30°C and raised the temperature of the reaction mixture to 35-40°C. Stirred the reaction mixture for 4 hours at the same temperature. After completion of the reaction mixture, the reaction mixture was cooled to 10-20°C. The reaction mixture was poured into pre-cooled water at below 25°C and cyclohexane was added to the reaction mixture. Both the organic and aqueous layers were separated. The organic layer was washed with 5% sodium thiosulphite solution followed by 5% potassium iodide solution and water. The solvent was distilled off under reduced pressure completely from the organic layer and then get the title compound.

Yield: 140 grams.

Example-8: Preparation of prasugrel compound of formula-1:

Triethylamine (98 grams) was added to the solution of 5-(2-cyclopropyl-l-(2-fluoro phenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrobromide (100 grams) in dichloromethane (1000 ml) and stirred for 15 minutes at 25-30°C and then cooled to 0-5 °C. Acetic anhydride (62 grams) was added to the reaction mixture and stirred for 6 hours at 0-5°C. The reaction mixture was quenched with water at 20-25°C and separated both the aqueous and organic layers. Organic layer was washed with aqueous sodium bicarbonate followed by water and then the solvent from the organic layer was distilled off under reduced pressure and isopropyl alcohol (125 ml) was added to the obtained residue and stirred for 45 min at 40-50°C. The reaction mixture was cooled to 10-15°C and stirred for 60 minutes. The solid obtained was filtered, washed with isopropyl alcohol and then dried to get the title compound.

Yield: 84 grams. Example-9: Preparation of Prasugrel hydrochloride crystalline form-B₂:

Dissolved the 5-(2-cyclopropyl-l -(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl acetate (100 grams) in acetone (800 ml) and then heated to 35-40°C. Carbon (5 grams) was added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture and filtrate was cooled to 0-5°C and then ethyl acetate hydrochloric acid (500 ml) was added to it. Then the reaction mixture was stirred for 45 minutes at 0- 5°C. The precipitated solid was filtered and washed with acetone. To the wet material added acetone (800 ml) and stirred for 45 minutes at 25-30°C. Filtered the reaction mixture, washed with acetone and dried the compound to get the title compound. The obtained prasugrel hydrochloride is packed using clear and block polyethylene bags under vacuum.

Yield: 89 grams; Purity: 99.65 % by HPLC

Example-10: Preparation of Prasugrel hydrochloride crystalline form-B2:

Dissolved the 5-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl acetate (100 grams) in acetone (800 ml) and then heated to 35-40°C. Carbon (5 grams) was added to the reaction mixture and stirred for 15 minutes. Filtered ^■ the reaction mixture and filtrate was cooled to 0-5°C and ethyl acetate (500 ml) was added to it. Then hydrochloric acid gas was bubbled through it. The precipitated solid was filtered and washed with acetone. To the wet material added acetone (800 ml) and stirred for 45 minutes at 25-30°C. Filtered the reaction mixture, washed with acetone and^■" dried the compound to get the title compound.

Yield: 85grams; Purity: 99.5 % by HPLC

Packing conditions for prasugrel hydrochloride:

Pack the prasugrel hydrochloride in clear low-density polyethylene bag and seal the bag with vacuum sealer. Place this bag in black color low-density polyethylene bag and seal the bag with vacuum sealer. Place the bag in triple laminated bag and seal the bag with vacuum sealer. Place this bag in HDPE container and seal the container. Store the container at control room temperature. If vacuum sealing is not available, pack the material under nitrogen atmosphere with normal sealing and store at 2-8°C to increase the self life of prasugrel hydrochloride

Claims

We Claim:

1. A pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts, which comprises of;

a) Prasugrel hydrochloride,

b) a water insoluble dry binder,

c) at least one diluent,

d) at least one disintegrant ,

e) at least one lubricant, and

f) optionally coated with a film.

2. A pharmaceutical composition according to claim 1, wherein the water insoluble dry binder is selected from starches, carbomer, and chitosan.

3. A pharmaceutical composition according to claims 1 to 2, wherein the water insoluble dry binder is starch, most preferably pregelatinized starch.

4. A pharmaceutical composition according to claim 1, wherein the diluent is selected from microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate and calcium sulphate.

5. A pharmaceutical composition according to claim 1, wherein the disintegrant is selected from croscarmellose sodium, starch glycolates and crosslinked polyvinylpyrrolidone and the lubricant is selected from magnesium stearate and calcium stearate.

6. A pharmaceutical composition according to claim 1, wherein the film containing hydroxyl propyl methyl cellulose, poly ethylene glycol, titanium dioxide, color with/ without ethyl cellulose.

7. A pharmaceutical composition according to claim 1, wherein the film containing hydroxyl propyl methyl cellulose, poly ethylene glycol, titanium dioxide, color.

8. A pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts, which comprises of; a) Prasugrel hydrochloride,

b) microcrystalline cellulose,

c) pregelatinizsed starch,

d) croscarmellose sodium,

e) magnesium stearate and

f) coating consisting of hydroxyl propyl methyl cellulose, poly ethylene glycol, titanium dioxide, color.

9. A pharmaceutical composition according to the preceding claims, wherein the pharmaceutical composition is in the form of a tablet, which is prepared by dry granulation and direct compression method.

10. A solid pharmaceutical composition in the form of a tablet comprising prasugrel hydrochloride, characterized in that tablet coated by film containing ethyl cellulose.

11. A pharmaceutical composition of prasugrel or its pharmaceutically acceptable salts, which comprises of;

a) Prasugrel hydrochloride,

b) microcrystalline cellulose,

c) pregelatinizsed starch,

d) croscarmellose sodium,

e) magnesium stearate and

f) coating consisting of hydroxyl propyl methyl cellulose, poly ethylene glycol, titanium dioxide, color and ethyl cellulose.

12. A process for preparing pharmaceutical composition of prasugrel hydrochloride according to the preceding claims comprising:

g) Mixing prasugrel hydrochloride with diluent,

h) adding water insoluble dry binder and disintegrant,

i) blending diluent and lubricant,

j) optionally milling or seiving granules,

k) compressing to tablets, 1) applying a coat on the compressed tablets.

13. The pharmaceutical preparation according to the preceding claims, wherein the binder present in the range from 1 to 25%, preferably from 1.5 to 20%, more preferably from

2 to 16%.

14. A pharmaceutical composition according to the preceding claims, prasugrel hydrochloride tablets are packed in alu-alu cold packing with no air gap in the pocket of aluminium blister pack.

15. A process for the purification of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one hydrochloride compound of formula-3 comprise,

a) Suspending the compound of formula-3 in dichloromethane and methanol, b) heating the suspension to reflux,

c) cooling the suspension,

d) filtering the solid to get highly pure compound of formula-3.

16. The process according to claim 15, wherein the purified thienopyridine compound of formula-3 is having purity greater than 98%.

17. An improved process for the preparation of prasugrel and its pharmaceutically acceptable salts, which comprises of;

a) Removing the protecting group on nitrogen from N-trityl 5,6,7,7a-tetrahydro-4H- thieno[3,2-c] pyridine-2-one compound of formula-2,

Formula-2

by treating with an hydrochloric acid in acetone to provide 5,6,7,7a-tetrahydro- 4H-thieno[3,2-c] pyridine-2-one hydrochloride, which on purification using dichloromethane and methanol to obtain a highly pure compound of formula-3,

Formula -3

Formula-4

in the presence of potassium carbonate in acetonitrile, followed by treatment with hydrobromic acid to provide a compound of formula-5,

Formula-5

c) acetylating the compound of formula-5 with acetic anhydride in the presence of triethylamine provides the prasugrel compound of formula- 1,

Formula- 1

d) converting the prasugrel into its hydrochloride salt by treating prasugrel with ethylacetate hydrochloride in acetone to provide prasugrel hydrochloride compound of formula- la.

18. A process for the preparation of crystalline form-B₂ of prasugrel hydrochloride, which comprises of;

a) Dissolving the prasugrel in acetone,

b) heating the solution and subjected to carbon treatment, c) cooling the solution,

d) adding ethylacetate hydrochloride,

e) filtering the solid to get the crystalline form-B₂ of prasugrel hydrochloride.

19. A process for the preparation of a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4

Formula-4

comprises of reacting the -cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-6

Formula-6

with aqueous hydrobromic acid in the presence of hydrogen peroxide in suitable polar protic solvents to provide a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-4.

20. A process according to claim 19, wherein the polar protic solvent is water.

Dated this day 2-1 of January 2011

(Manne Satyanarayana Reddy)

MSN Laboratories Limited.