TECHNICAL FIELD OF INVENTION

The invention relates to the pharmaceutical field. More specifically, it relates to pharmaceutical compositions comprising prasugrel, sugar alcohol(s) and, optionally, one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Prasugrel is a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor and is indicated to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) as follows:

• Patients with unstable angina or non-ST-elevation myocardial infarction.

• Patients with ST-elevation myocardial infarction when managed with primary or delayed PCI.

Prasugrel is chemically designated as 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Its molecular formula is C2oH2oFN03S»HCl and its molecular weight is 409.90. Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.

In the U.S., Prasugrel is marketed by Eli Lilly under the brand name Effient® as an oral immediate release tablet containing either 5 mg or 10 mg prasugrel and the tablets are elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each 5 mg tablet contains 5.49 mg prasugrel hydrochloride, equivalent to 5 mg prasugrel and each 10 mg tablet contains 10.98 mg prasugrel hydrochloride, equivalent to 10 mg of prasugrel and the following inactive ingredients: mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10 mg tablet). During manufacture and storage, partial conversion from prasugrel hydrochloride to prasugrel free base may occur. Each 5mg Effient® tablet weighs around 95mg to 99mg and l0mg tablet weighs around 192mg tol96mg, containing approximately around 5% w/w of prasugrel HC1, which implies that it is a low dose drug in the tablet form.

U.S. Patent Application No. US2010/0004279 discloses tablet composition comprising prasugrel and mannitol or lactose having a specific 90% cumulative diameter (D90) value, preferably prepared by direct compression method. According to said patent application, use of mannitol or lactose having a particle size distribution in which D90 value between 80 to 300 micron provides excellent content uniformity with Relative Standard Deviation (RSD) less than 2%. Said patent application also discloses that tablets prepared using mannitol or lactose having a particle size distribution in which D90 value is more than 300 microns, does not comply with the content uniformity test. Poor content uniformity is a major problem for low dose formulation, and the variations in content uniformity may cause more problems in low dose drugs than high dose drugs, especially, if the drug is potent and has a narrow therapeutic index, it is therefore necessary for low dose formulation to strictly comply with content uniformity test. Hence from above, it was learned that, it is critical to have mannitol having a particle size distribution in which D90 value is in the range of 80 to 300 micron.

However, the prior art is not free of problems either. The inventors of the present invention found that tablets prepared using mannitol having a particle size distribution in which D90 value is 80 to 300 microns, shows capping and sticking problems during tablet compression.

The present inventors surprisingly found that prasugrel tablets prepared using:

(i) a sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(ii) optionally one or more pharmaceutically acceptable excipients(s), or

(a) a sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns;

(b) a sugar alcohol having D90 value of particle size distribution (PSD) less than 80 microns; and

(c) optionally one or more pharmaceutically acceptable excipients(s), has acceptable content uniformity.

Said tablet may be prepared by direct compression method or by dry granulation method.

Said tablet also demonstrated lack of capping and sticking phenomenon, when mannitol having a particle size distribution in which D90 value of greater than 300 microns or having D90 value of less than 80 microns was used.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to pharmaceutical compositions comprising prasugrel, sugar alcohol(s) and optionally one or more pharmaceutically acceptable excipient(s) and the process for preparing the same.

An objective of the invention is to prepare pharmaceutical composition comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(c) optionally one or more pharmaceutically acceptable excipient(s), wherein the pharmaceutical composition complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention is to prepare pharmaceutical composition comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns;

(c) sugar alcohol having D90 value of particle size distribution (PSD) less than 80 microns; and

(d) optionally one or more pharmaceutically acceptable excipient(s), wherein the pharmaceutical composition complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention is to prepare pharmaceutical composition comprising:

(a) prasugrel;

(b) sugar alcohol and/or saccharide having D90 value of particle size distribution
(PSD) greater than 300 microns;

(c) sugar alcohol and/or saccharide having D90 value of particle size distribution (PSD) less than 80 microns; and

(d) optionally one or more pharmaceutically acceptable excipient(s), wherein the pharmaceutical composition complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention is to prepare tablet comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(c) optionally one or more pharmaceutically acceptable excipient(s), wherein the tablet complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention is to prepare tablet comprising:

(a) prasugrel;

(b) sugar alcohol and/or saccharide having D90 value of particle size distribution (PSD) greater than 300 microns; and

(c) optionally one or more pharmaceutically acceptable excipient(s), wherein the tablet complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention is to prepare tablet comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns;

(c) sugar alcohol having D90 value of particle size distribution (PSD) less than 80 microns; and

(d) optionally one or more pharmaceutically acceptable excipient(s), wherein the tablet complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention relates to process for preparing a tablet comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(c) optionally one or more pharmaceutically acceptable excipient(s), wherein the tablet complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

Another objective of the invention relates to process for preparing tablet comprising

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns;

(c) sugar alcohol having D90 value of particle size distribution (PSD) less than 80 microns; and

(d) optionally one or more pharmaceutically acceptable excipient(s), wherein the tablet complies with content uniformity test having RSD < 2.5%, more preferably RSD < 2%.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

As discussed in the background of the invention, poor content uniformity is a major problem for low dose formulation, and the variations in content uniformity can cause more problems in low dose drugs than high dose drugs especially if the drug is potent and has a narrow therapeutic index. It is therefore necessary for low dose formulation to strictly comply with content uniformity test.

As contrary to the findings/ teachings of the prior art, the present inventors surprisingly found that, prasugrel tablets prepared using:

(i) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(ii) optionally one or more pharmaceutically acceptable excipient(s), or

(a) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns;

(b) sugar alcohol having D90 value of particle size distribution (PSD) less than 80 microns; and

(c) optionally one or more pharmaceutically acceptable excipient(s), complies with content uniformity test. Said tablet could be prepared by either direct compression method or by dry granulation method.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for prasugrel or its pharmaceutically acceptable salts or esters or derivatives thereof. Acceptable salts include but are not limited to hydrochloride, hydrobromide, sulphate, hemi sulphate, bi-sulphate, oxalate, mesylate, maleate, hydroiodide, besylate, cyclamate and the like.

According to the invention, prasugrel may be present in the amorphous or crystalline form. As used herein, the term "prasugrel" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof.

In the context of the invention, pharmaceutical composition of prasugrel preferably includes granules, pellets, mini-tablets, tablets or capsules.

According to an embodiment of the invention, the term "90% cumulative diameter or D90" as used herein, refers to the particle diameter at 90% of the cumulative particle size distribution.

According to an embodiment of the invention, the term "comply or complies or acceptable" when used in connection with the terms "tablet(s)" and "content uniformity test" refers to powder blend or tablets having the content uniformity result with Relative Standard Deviation (RSD) < 2.5%, more preferably <2%.

According to an embodiment of the invention, the term "low dose formulation" as used herein, relates to tablet containing less than 10% w/w of prasugrel.

According to an embodiment of the invention, the term "direct compression" as used herein, relates to a process for preparing tablet, wherein the blend comprising active ingredient and one or more pharmaceutically acceptable excipient(s) are directly subjected to compression-molding or compression process to get tablet(s).

According to an embodiment of the invention, the term "granulation" as used herein, relates to a process by which powder particles are made to adhere to each other to form agglomeration of particles to form granules.

According to an embodiment of the invention, the term "dry granulation" as used herein, relates to a process, wherein granules are prepared by crushing and dividing by an appropriate method, a compression-molded slug or sheet of blend comprising active ingredient and one or more pharmaceutically acceptable excipients are subjected to compression-molding or compression process to produce tablet.

According to an embodiment of the invention, the term "sugar alcohol" as used herein, relates to polyol or polyhydric alcohol or polyalcohol. Sugar alcohols according to the invention includes, but are not limited to mannitol, erythritol, xylitol, maltitol or mixture thereof. Preferred sugar alcohol is mannitol.

Mannitol is widely used as a diluent in tablet formulations. Use of mannitol improves compressibility and flowability of the powder blend or the granules therefore especially useful for direct-compression or dry granulation process for preparing tablets.

According to an embodiment of the invention, granular and spray-dried forms of mannitol are preferred. Roquette Pharma has developed a range of granular and spray-dried forms of mannitol and is sold under the brand name of Pearlitol®, which includes Pearlitol® 25 C, 50 C and 160 C, 300 DC, 400 DC and 500 DC, 100 SD and 200 SD.

Similarly, Merck has developed directly compressible mannitol range and is sold under the brand name of Parteck® M, available in two grades Parteck® 100MandParteck®200M.

According to an embodiment of the invention, prasugrel tablet(s) are prepared using:

(a) mannitol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(b) one or more pharmaceutically acceptable excipients, by direct compression or dry granulation method.

According to an embodiment of the invention, prasugrel tablets are prepared using:

(a) mannitol having D90 value of particle size distribution (PSD) greater than 300 microns;

(b) mannitol having D90 value of particle size distribution (PSD) less than 80 microns; and

(c) one or more pharmaceutically acceptable excipients, by direct compression or dry granulation method.

According to an embodiment of the invention, prasugrel tablets are prepared using:

(a) Pearlitol® having D90 value of particle size distribution (PSD) about 300 to 600 microns; and

(b) one or more pharmaceutically acceptable excipients, by direct compression method.

According to an embodiment of the invention, prasugrel tablets are prepared using:

(a) Pearlitol® having D90 value of particle size distribution (PSD) about 300 to 600 microns; and

(b) one or more pharmaceutically acceptable excipients, by dry granulation method.

According to an embodiment of the invention, prasugrel tablets are prepared by using:

(a) Pearlitol® having D90 value of particle size distribution (PSD) about 300 to 600 microns;

(b) Pearlitol® having D90 value of particle size distribution (PSD) about 25 to 80 microns; and

(c) one or more pharmaceutically acceptable excipients, by direct compression method.

According to an embodiment of the invention, prasugrel tablets are prepared by using:

(a) Pearlitol® having D90 value of particle size distribution (PSD) about 300 to 600 microns;

(b) Pearlitol® having D90 value of particle size distribution (PSD) about 25 to 80 microns; and

(c) one or more pharmaceutically acceptable excipients, by dry granulation method.

According to an embodiment of the invention, the term "saccharide(s)" as used herein, relates to carbohydrate(s). The saccharide(s) (carbohydrates) are divided into four chemical groupings: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Saccharide(s) according to the invention include, but are not limited to glucose, fructose, lactose, sucrose or mixture thereof.

According to an embodiment of the invention, prasugrel tablet are prepared using:

(a) saccharide(s) having D90 value of particle size distribution (PSD) greater than 300 microns; and

(b) one or more pharmaceutically acceptable excipients, by direct compression or dry granulation method.

According to an embodiment of the invention, prasugrel tablets are prepared using:

(a) saccharide(s) having D90 value of particle size distribution (PSD) greater than 300 microns;

(b) saccharide(s) having D90 value of particle size distribution (PSD) less than 80 microns by direct compression or dry granulation method.

According to an embodiment of the invention, prasugrel tablet are prepared using:

(a) lactose having D90 value of particle size distribution (PSD) greater than 300 microns; and

(b) one or more pharmaceutically acceptable excipients, by direct compression or dry granulation method.

According to an embodiment of the invention, prasugrel tablets are prepared using:

(a) lactose having D90 value of particle size distribution (PSD) greater than 300 microns;

(b) lactose having D90 value of particle size distribution (PSD) less than 80 microns; and

(c) one or more pharmaceutically acceptable excipients, by direct compression or dry granulation method.

The tablet dosage form according to an embodiment of the invention may be prepared using one or more pharmaceutically acceptable excipient(s) selected from a group consisting of diluent(s), binder(s), disintegrant(s), super-disintegrant(s), glidant(s), and/ or lubricant(s).

Suitable diluent(s) according to the invention include, but are not limited to, mannitol, xylitol, sorbitol, lactose, sucrose, cellulose, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, starch, calcium trisilicate, magnesium trisilicate, cellulose acetate, dextrose, or combinations thereof.

Suitable binder(s) according to the invention include, but are not limited to povidone, copovidone, pregelatinized starch, polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC, Hypromellose), starch, hydroxyethyl cellulose (HEC), ethyl cellulose (EC), chitosan, guar gum, methyl cellulose (MC), carbomer, acacia, sodium alginate, calcium alginate or combinations thereof.

Suitable disintegrant(s) according to the invention include, but are not limited to starch, microcrystalline cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, polacrilin potassium or combinations thereof.

Suitable superdisintegrant(s) according to the invention include, but are not limited to crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), pregelatinized starch or combinations thereof. Preferred superdisintegrant is crospovidone.

Suitable glidant(s) and lubricant(s) according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, sucrose stearate (sucrose stearic acid esters), glyceryl behenate or combinations thereof.

According to an embodiment of the invention, prasugrel tablets are preferably film coated and the film coating excipients may be selected from a group consisting of film formers, plasticizers, opacifiers, and coloring agents, etc.

Suitable film formers according to the invention include, but are not limited to, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), methyl cellulose (MC) and ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methacrylic acid copolymer, cellulose acetate phthalate, cellulose phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, and natural gums and resins such as zein, gelatin, shellac and acacia or combinations thereof.

Suitable plasticizers according to the invention include, but are not limited to, castor oil, polyethylene glycol, propylene glycol, glycerin, triacetin, polysorbates, phthalate esters, dibutyl sebacate, citrate esters, and monoglycerides or combinations thereof.

Suitable opacifiers according to the invention include, but are not limited to, titanium dioxide and talc or combinations thereof.

Suitable coloring agents according to the invention include, but are not limited to, FDA approved dyes and lakes such as sunset yellow, tartrazine, erythrosine, iron oxide yellow and natural colors such as carmine or combinations thereof.

According to the invention, ready-to-use film coating systems such as Opadry®, Instacoat™ may also be used for film coating of compressed tablets.

Particle Size Distribution Measurement:

According to the invention, particle size distribution of mannitol or Pearlitol® was measured by laser diffraction method using HELOS (HI326) & RODOS System (manufactured by Sympatec GmbH). RODOS Dry Dispersion System was used to disperse the sample and measurement was conducted under the following conditions.

Measurement was conducted by n=3, and the average value of the observed particle diameter at 90% were obtained.

HELOS (Laser Diffraction Unit):

Type: HELOS/KF

Lens: R5

Measurement range: 0.5 to 875 um

Trigger conditions: 2 s-100 ms-kl5-0.5%

Calculation mode: Fraunhofer HRLD (v3.2 Rel .2)

RODOS (Dispersing System):

Feeder: VIBRI

Dispersing pressure: 2.00 bar

Vacuum degree: 100.00 mbar

Rotation: 20.00%

Feed: 60.00%

Software: WINDOX Version 3.2 (manufactured by Sympatec GmbH) Content Uniformity Test:

According to an embodiment of the invention, the procedure used to determine the content uniformity test result is as follows:

Assay 10 tablets: Pass if both of the following criteria are met

1. Relative Standard Deviation (RSD) of < 2.5%, most preferably < 2%, and

2. No tablet assay value outside the range of 85% tol 15% w/w of the label claim.

The assay value for prasugrel tablets is determined by using following procedure.
Mobile phase-A: Degassed 0.02M - pH 2.65 buffer

Mobile phase-B: Mix 950 volumes of acetonitrile and 50 volumes of water and degas.
Diluent: Mix 650 volumes of acetonitrile and 350 volumes of 0.005M -pH 7.0 di-potassium hydrogen phosphate buffer and degas.

Diluent as blank: Filter a portion of diluent through 0.45pm PVDF syringe filter
Chromatographic conditions:

Column: Hypersil® GOLD (150mm x 4.6mm, 5um) (C-18, Part No-25005-
154630)

Flow rate: 1.2 ml/minute

Wavelength: 220 nm

Column temperature: 35°C ± 2°C

Sample tray temperature: 10°C ± 2°C

Injection Volume: l0uL

Run time: 10 minutes

Ratio of Mobile phase-A and Mobile phase-B from two different channels is 68:32
(v/v)

Needle wash : Use Acetonitrile and water in the ratio of 80:20 (v/v).

Standard stock solution:

Weigh accurately and transfer about 55 mg of prasugrel HC1 reference standard (or) working standard into a 100 ml volumetric flask, add about 80 ml of diluent sonicate to dissolve and dilute to volume with diluents and mix well.

Standard Solution:

1. Pipette 5.0 ml of the above standard stock solution into a 25 ml volumetric flask and dilute to volume with diluent and mix well.

2. Filter a portion of solution through 0.45 um PVDF syringe filter.

Test preparation for l0mg strength:

3. Transfer 1 tablet into a 100 ml dry volumetric flask, add about 4 ml of water and sonicate to disintegrate the tablets completely.

4. Add about 80 ml of diluent, sonicate for about 45 minutes with intermittent shaking, dilute to volume with diluent and mix well.

5. Centrifuge a portion of above solution at 5000 RPM, in a centrifuge tube with cap, for about 10 minutes.

6. Filter a portion of the above solution through 0.45 um PVDF syringe filter (Millipore).

Procedure:

Inject separately diluent as blank, standard solution (five times) and test solution into the chromatograph. Record the chromatograms and measure the responses for the major peak.

Calculation: For lOmg strength:

AT X Ws x 5 x 100 x P x lOOx 373.4

Amount of prasugrel = present as % of label claim As x 100 x 25 x Lc x 100 x 409.9
Where,

AT = Average peak area of Prasugrel from test preparation.

As = Average peak area of Prasugrel from standard preparation.

Ws = Weight of Prasugrel HCI reference standard (or) working standard taken, in mg, for standard preparation.

Lc = Label claim of Prasugrel in mg per unit.

P = Potency of Prasugrel HCI reference standard (or) working standard in %, on as is basis.

409.9 = Molecular weight of Prasugrel HCI.

373.4 = Molecular weight of Prasugrel

The Relative Standard deviation (RSD) was calculated from content values obtained for each individual tablet samples.

EXAMPLES:

Following Examples are illustrative of the embodiments of the invention, and do not limit the scope of this invention.

COMPARATIVE EXAMPLE 1: Prasugrel HC1 tablets prepared by direct compression using mannitol having D90 value in the range of 80 to 300 microns.

Unit Composition:

S. No. Ingredients rag/tablet

1. Prasugrel HC1 10.98

2. Pregelatinized Starch 30.00

3. Crospovidone 20.00

4. Hydroxypropylmethyl 10.00
cellulose

5. Mannitol (Pearlitol(g) SD 200)~~ 121.02

6. Sucrose stearic acid esters 6.00

7. I Glyceryl Behenate 2.00

Tablet weight 1 200.00~~

Brief manufacturing process:

1. Sifting together prasugrel HC1, crospovidone, hydroxypropylmethyl cellulose, mannitol and pregelatinized starch using suitable size sieve and mixing well.

2. Sifting sucrose stearic acid esters and glyceryl behenate using suitable size sieve.

3. Lubricating the blend obtained in step (1) with sifted material obtained in step (2)

4. Compressing the lubricated blend obtained in step (3) using rotary tablet compression machine in to tablets.

In-Process Quality Control Tests:

Tablets prepared according to Example 1 were subjected to in-process quality control tests and the resultant data are compiled in Table 1.

Table 1

Brief manufacturing process:

1. Sifting together prasugrel HC1, microcrystalline cellulose PH-113, crospovidone, hydroxypropylmethyl cellulose and pregelatinized starch through # 60 mesh.

2. Mixing Pearlitol® 400DC and microcrystalline cellulose PH-112 with sifted material obtained in step (1) in a blender.

3. Passing the blend obtained in step (2) through # 25 mesh.

4. Sifting sucrose stearate and glyceryl behenate through # 60 mesh.

5. Lubricating the blend obtained in step (3) using sifted sucrose stearate and glyceryl behenate obtained in step (4).

6. Compressing the lubricated blend of step (5) in to tablets.

In-Process Quality Control Tests:

Tablets prepared according to Example 2 were subjected to in-process quality control tests and the resultant data are compiled in Table 2.

Table 2

Test I Example 2

Weight variation (mg) 197.7-206.5

Hardness (Kp) 5.4 - 6.4

Thickness (mm) 4.08-4.1

Disintegration time in minutes 1.10- 1.19

Observation during compression No capping or sticking observed

Content Uniformity Test:

Content uniformity of prasugrel tablets prepared according to Example 2 was determined and the resultant data are compiled in Table 3.

EXAMPLE 3: Prasugrel HC1 tablets prepared by dry granulation method using mannitol having D90 value less than 80 microns and mannitol having D90 value greater than 300 microns.

Unit Composition:

Brief manufacturing process:

1. Sifting together prasugrel HC1, crospovidone (Part 1), hydroxypropylmethyl cellulose and pregelatinized starch (Part 1) using Quadro Comil or mechanical sifter fitted with suitable size screen.

2. Sifting Mannitol (Pearlitol® 25C) using Quadro® Comil® or mechanical sifter
fitted with suitable size screen.

3. Sifting Mannitol (Pearlitol® 400DC) (part 1) using Quadro® Comil® or mechanical sifter fitted with suitable size screen.

4. Sifting together blend obtained in step (1) and sifted Mannitol (Pearlitol® 25C) obtained in step (2) using Quadro® Comil® or mechanical sifter fitted with suitable size screen.

5. Blending material obtained in step (3) and step (4) in a bin blender for suitable period of time.

6. Sifting sucrose stearic acid esters (Part 1) using Quadro® Comil® or mechanical sifter fitted with suitable size screen.

7. Lubricating the blend of step (5) with sifted sucrose stearic acid esters obtained in step (6).

8. Compressing the lubricated blend obtained in step (7) using Roll compactor to gets compacts.

9. Milling the compacts obtained in step (8) using Quadro® Comil® fitted with suitable size screen to get granules of suitable size.

10. Sifting Mannitol (Pearlitol® 400 DC) (Part 2), Pregelatinized starch (Part 2) and Crospovidone (Part 2) using Quadro® Comil® fitted with suitable size screen.

11. Blending materials obtained in step (9) and (10) using bin blender for suitable period of time.

12. Sifting sucrose stearic acid esters (Part 2) and glyceryl behenate using Quadro® Comil® fitted with suitable size screen.

13. Lubricating the step (11) with sifted material obtained in step (12)

14. Compressing the lubricated blend obtained in step (13) using rotary tablet
compression machine.

In-Process Quality Control Tests:

Tablets prepared according to Example 3 were subjected to in-process quality control
tests and the resultant data are compiled in Table 4.

Table 4

Content Uniformity Test:

Content Uniformity of prasugrel tablets prepared according to Example 3 was determined and the resultant data are compiled in Table 5.

The content uniformity test data of tablets prepared acceding to Example 2 comprising mannitol (Pearlitol® 400 DC) and Example 3 comprising mixture of mannitol (Pearlitol® 400 DC) and (Pearlitol® 25C), shows acceptable content uniformity with RSD less than 2%.

Dissolution Data:

Tablets prepared according to Example 2, Example 3 and marketed Effient® 10 mg tablets were subjected to in-vitro dissolution test in 900ml of pH 4.0 citrate buffer, using USP Type I (Basket) dissolution apparatus at 75 rpm and the resultant data is compiled in Table 6.

Above in-vitro dissolution data also shows that the tablets prepared according to Example 2 and Example 3 has similar in-vitro dissolution profile as that of marketed Effient® 10 mg tablets.

Stability Data:

Prasugrel tablets prepared according to Example 3 were packed in HDPE containers and subjected to stability study for 12 weeks at 40 °C ± 2 °C/75% RH ± 5% RH and the resultant data is compiled in Table 7.

Table 7

Above stability data shows that the tablets prepared according to Example 3 are stable for 12 weeks at 40°C ± 2°C / 75% RH ± 5% RH.

WE CLAIM:

1. A pharmaceutical composition comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(c) optionally one or more pharmaceutically acceptable excipient(s), wherein said pharmaceutical composition has content uniformity of RSD<2%.

2. A pharmaceutical composition comprising:

(a) prasugrel;

(b) sugar alcohol having D90 value of particle size distribution (PSD) greater than 300 microns;

(c) sugar alcohol having D90 value of particle size distribution (PSD) less than 80 microns; and

(d) optionally one or more pharmaceutically acceptable excipient(s), wherein said pharmaceutical composition has content uniformity of RSD<2%.

3. A tablet comprising:

(a) prasugrel;

(b) crospovidone;

(c) mannitol having D90 value of particle size distribution (PSD) greater than 300 microns; and

(d) optionally one or more pharmaceutically acceptable excipient(s), wherein said tablet has content uniformity of RSD < 2%.

4. A tablet comprising:

(a) prasugrel;

(b) crospovidone;

(c) mannitol having D90 value of particle size distribution (PSD) greater than 300 microns;

(d) mannitol having D90 value of particle size distribution (PSD) less than 80 microns; and

(e) optionally one or more pharmaceutically acceptable excipient(s), wherein said tablet has content uniformity of RSD < 2%.

5. A pharmaceutical composition according to any of the preceding claims, wherein said sugar alcohol is selected from a group comprising of mannitol, erythritol, xylitol, maltitol or mixture thereof.

6. A tablet/ pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutically acceptable excipient is selected form a group consisting of diluent(s), binder(s), disintegrant(s), super-disintegrant(s), glidant(s), and/or lubricant(s).

7. A tablet comprising prasugrel having following unit composition:

8. A dry granulation process for preparing tablet/pharmaceutical composition comprising prasugrel and one or more pharmaceutically acceptable excipient(s) according to any of the preceding claims, comprises the following steps:

a) Sifting prasugrel and intragranular part of one or more pharmaceutically acceptable excipient(s) using Quadro® Comil® fitted with suitable size screen.

b) Blending sifted material obtained in step (a) in a blender for suitable period of time.

c) Sifting intragranular part of lubricant using Quadro® Comil® fitted with suitable size screen.

d) Lubricating the blend of step (b) with sifted lubricant obtained in step (c).

e) Compressing the lubricated blend obtained in step (d) using Roll compactor to gets compacts.

f) Milling the compacts obtained in step (e) using Quadro® Comil® fitted with suitable size screen to get granules of suitable size.

g) Sifting extragranular part of one or more pharmaceutically acceptable excipient(s) using Quadro® Comil® fitted with suitable size screen.
h) Blending material obtained in step (f) and (g) in a blender for suitable period of time.

i) Sifting extragranular part of lubricant using Quadro® Comil® fitted with suitable size screen.

j) Lubricating the step (h) with sifted lubricant obtained in step (i)

k) Compressing the lubricated blend obtained in step (j) using rotary tablet compression machine.

9. A pharmaceutical composition comprising prasugrel and one or more pharmaceutically acceptable excipient(s) as herein described and exemplified.