WO2010070677A2

WO2010070677A2 - A process for the preparation of prasugrel and its pharmaceutically acceptable salts thereof

Info

Publication number: WO2010070677A2
Application number: PCT/IN2009/000714
Authority: WO
Inventors: Khan Mubeen Ahmed; Srinivas Reddy Sanikommu; Bhaskar Rao Antyakula Pydi; Shankar Sanganabhatla
Original assignee: Glenmark Generics Limited
Priority date: 2008-12-15
Filing date: 2009-12-09
Publication date: 2010-06-24
Also published as: WO2010070677A3

Abstract

The present invention relates to processes for the preparation of prasugrel and its pharmaceutically acceptable salts, including novel crystalline forms of prasugrel hydrochloride, and pharmaceutical compositions thereof. The present invention also relates to solid state properties of prasugrel or a pharmaceutically acceptable salt thereof.

Description

A PROCESS FOR THE PREPARATION OF PRASUGREL AND ITS PHARMACEUTICALLY

ACCEPTABLE SALTS THEREOF PRIORITY

This application claims the benefit to Indian Provisional Applications 2609/MUM/2008, filed on December 15, 2008; 343/MUM/2009, filed on February 17, 2009; and 1248/MUM/2009, filed on May 14, 2009, the contents of each of which are incorporated by reference herein. BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to novel crystalline forms of prasugrel hydrochloride, solid state properties of prasugrel, processes for the preparation of prasugrel and its pharmaceutically acceptable salts and pharmaceutical compositions thereof.

2. Description of the Related Art

Prasugrel is a P2Y12 (P2T) antagonist which has been approved as hydrochloride salt in the U.S. and EU for the secondary prevention of thrombotic cardiovascular complications. Prasugrel hydrochloride is chemically described as 2-acetoxy-5-(. alpha. -cyclopropyl-carbonyl-2-fluorobenzyl)-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine hydrochloride and is represented by structural formula (I):

(I) U.S. Patent No. 5,288,726 describes tetrahydrothienopyridine derivatives, including prasugrel and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment, a process for the preparation of prasugrel, which is illustrated below:

Prasugrel

U.S. Patent No. 5,874,581 describes a process for the preparation of prasugrel using alkyl-silyl protected tetrahydrothienopyridine intermediate, illustrated by the scheme below:

TEA

S

Prasugrel

U.S. Patent No. 6693115 discloses crystal A₁ crystal B1 and crystal B2 of prasugrel hydrochloride and processes for the preparation thereof.

European Patent Application EP2003136 describes crystal A, crystal B1 and crystal B2 of prasugrel hydrochloride and processes for the preparation thereof.

International Application Publication No. WO2008108291 discloses a process for the preparation of prasugrel comprising reaction of cyclopropyl-2-fluorobenzyl ketone with chlorinating agent to give cyclopropyl -2-fluorobenzylcarbonyl chloride followed by condensation with O-protected 5,6,7,7a-tetrahydro- thieno[3,2-c] pyridin-2(4H)-one to afford O-protected 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]- 5,6,7, 7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one which is finally acetylated to give prasugrel. International Application Publication No. WO2007/114526 discloses the process for the preparation of high purity prasugrel or its hydrochloride salt having reduced 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2- oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (OXTP)content.

International Application Publication No. WO2008/108291 discloses a process for the preparation of prasugrel hydrochloride having reduced 2-acetoxy-5-[5-chloro-1-(2-fluorophenyl)-2-oxopentyl]-4, 5,6,7- tetrahydrothieno[3,2-c]pyrιdine (CATP) content.

International application publication WO09/62044 (WO^'044) describes a process for the preparation of prasugrel or a pharmaceutically acceptable salt thereof comprising acetylating N-trityl-5,6,7,7a- tetrahydro-thieno[3,2-c] pyridin-2(4H)-one followed by deprotection and reacting with cyclopropyl -2- fluorobenzylcarbonyl bromide to afford prasugrel.

WO'044 also describes crystalline Forms C, D₁ E and amorphous form of prasugrel hydrochloride and processes thereof.

International Application Publication No. WO09/66326 describes a process for the preparation of prasugrel comprising reacting acid addition salt of N-trityl-5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one with cyclopropyl^-fluorobenzylcarbonyl followed by deprotection to afford prasugrel.

International Application Publication WO09/122440 describes a process for the preparation of prasugrel or a pharmaceutically acceptable salt thereof comprising acetylating N-trityl-5,6,7,7a-tetrahydro- thieno[3,2-c] pyridin-2(4H)-one followed by deprotection and reacting with cyclopropyl -2- fluorobenzylcarbonyl bromide to afford prasugrel. The aforementioned processes have certain drawbacks. These processes either involve time- consuming processes, such as, column purifications or tedious separations to reduce the impurity levels. These processes may also involve the use of high solvent quantities. Hence, there remains a need for industrially viable processes to prepare prasugrel or its salts.

SUMMARY OF THE INVENTION The present invention relates to processes for the preparation of prasugrel and its pharmaceutically acceptable salts, including novel crystalline forms of prasugrel hydrochloride, and pharmaceutical compositions thereof. The present invention also relates to solid state properties of prasugrel or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention particularly provides a process for preparing prasugrel of formula Ia or a pharmaceutically acceptable salt thereof

Ia comprising: reacting a compound 2-(triphenylmethyl)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula Il

with an acetylating agent in the presence of a base and an organic solvent.

In a second aspect, the present invention relates to a process for preparing the compound of formula Il comprising: reacting a compound 2-(triphenylmethyl)-5-(α-bromo-2-fluorobenzyl)-4,5, 6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula IV

IV with a cyclopropane carbonitrile of formula

in the presence of magnesium or derivative thereof and an organic solvent.

In a third aspect, the present invention relates to a process for preparing the compound of formula IV comprising: a) reaction of the compound 5,6,7,7a-tetrahydro-4H-thieno-[3,2-c]pyridin-2-one or a salt thereof of formula IX

IX with a compound trityl halide of structural formula VIII

where X = F, Cl, Br or I in the presence of a base and an organic solvent to afford the compound 4,5,6,7-tetrahydrothieno- 5-(triphenylmethyl)[3,2-c]pyridine-2(3H)-one of formula VII

VII b) reaction of the compound of formula VII with a compound 1-(bromomethyl)-2- fluorobenzene of formula Vl

in the presence of a base and an organic solvent to afford the compound 2-(triphenylmethyl)-2~ fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula V

V c) reaction of the compound of formula V with bromine or its derivative in the presence of organic solvent to afford the compound of formula IV

IV In a fourth aspect, the present invention provides 4, 5, 6,7-tetrahydrothieno-5- (triphenylmethyl)[3,2-c]pyridine-2(3H)-one a compound of formula VII or a salt thereof.

VIl

In a fifth aspect, the present invention provides 2-(triphenylmethyl)-2fluorobenzyl)-4, 5,6,7- tetrahydrothieno[3,2-c]pyridine-2(3H)one a compound of formula V or a salt thereof.

V

In a sixth aspect, the present invention provides 2-(triphenylιmethyl)-5-(α-bromo-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one a compound of formula IV or a salt thereof.

IV In a seventh aspect, the present invention provides 2-(triphenylmethyl)-5-(α- cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula Il or a salt thereof.

In an eighth aspect, the present invention provides the preparation of prasugrel or pharmaceutically acceptable salts thereof, wherein the novel compounds of formulae II, IV, V and VII are used as intermediates

In a ninth aspect, the present invention provides a crystalline form of prasugrel hydrochloride 5 characterized by an X- ray powder diffraction pattern with characteristic peaks at about 6.4, 8.1, 8.4, 12.0, 12.6, 12. 8, 13.3, 15.2, 15.6, 18.6, 20.5, 23.6, 24.4, 25.5, 26.9, 27.4, and 28.5 ± 0.2 degrees two-theta, which is substantially in accordance with Figure 2.

The above crystalline form of prasugrel hydrochloride is designated as G1 and hereinafter referred by this designation.

10 The crystalline form G1 is further characterized by differential scanning calorimetry with an endotherm curve at about 145.71⁰C with an onset at about 141.31⁰C and an endset at about 149.33°C, which is substantially in accordance with Figure 3.

In a tenth aspect, the present invention provides another crystalline form of prasugrel hydrochloride characterized by an X- ray powder diffraction pattern with characteristic peaks at about 8.3, 11.9, 12.5, 12.8, 15 13.2, 15.5, 18.5, 20.3, 20.7, 23.4, 24.4, 25.2, 26.6, 27.2 and 28.3 ± 0.2 degrees two-theta, which is substantially in accordance with Figure 4.

The above crystalline form of prasugrel hydrochloride is designated as G2 and hereinafter referred by this designation.

The crystalline form G2 is further characterized by differential scanning calorimetry with an 0 endotherm curve at about 166.07⁰C with an onset at about 151.78⁰C and an endset at about 194.94°C, which is substantially in accordance with Figure 5.

In another aspect, the present invention provides a process for the preparation of crystalline forms, G1 and G2, of prasugrel HCI comprising: a) providing a solution of prasugrel hydrochloride in a solvent or mixture of solvents or aqueous 5 mixtures thereof; and b) precipitating the solid in a) by adding an antisolvent to obtain a substantially pure desired crystalline form of prasugrel HCI.

In another aspect, the present invention provides prasugrel having a mean particle size less than about 90 μm, wherein the prasugrel crystal particles have a specific surface area from about 0.1 m²/g to 0 about 1nrr/g, as measured by B.E.T. (Brunauer-Emmett-Teller) and flake shape as observed by SEM, which is substantially in accordance with Fig.8

In another aspect, the present invention provides prasugrel hydrochloride having a mean particle size less than about 10μm, wherein the prasugrel hydrochloride crystal particles have a specific surface area from about 1 m²/g to about 5 m²/g, as measured by B.E.T. and the crystal particles have a 5 condensation floe shape as observed by SEM which is substantially in accordance with Fig. 9. In a yet further aspect, the present invention provides a pharmaceutical composition comprising prasugrel or its pharmaceutically acceptable salts, obtained by the process of the present invention and at least a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1: is a schematic representation of the process of the present invention. Fig. 2: is an X-ray powder diffraction pattern of prasugrel HCI crystalline form Gl Fig. 3: is a Differential scanning calorimetry endotherm of prasugrel HCI crystalline form Gl Fig. 4: is an X-ray powder diffraction pattern of prasugrel HCI crystalline form G2.

Fig. 5: is a Differential scanning calorimetry endotherm of prasugrel HCI crystalline form G2. Fig. 6: is an X-ray powder diffraction pattern of prasugrel HCI amorphous form. Fig. 7: is a Differential scanning calorimetry glass transition of prasugrel HCI amorphous form. Fig. 8: Scanning Electron Microscope (SEM) photograph of prasugrel crystal particles. Fig. 9: Scanning Electron Microscope (SEM) photograph of prasugrel hydrochloride crystal particles.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to processes for the preparation of prasugrel and its pharmaceutically acceptable salts, including novel crystalline forms of prasugrel hydrochloride, and the solid state properties of prasugrel or a pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof.

In one embodiment, the present invention, provides a process for preparing prasugrel of formula Ia or a pharmaceutically acceptable salt thereof

Ia

comprising : reacting a compound 2-(triphenylmethyl)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula Il

Il with an acetylating agent in the presence of a base and an inert organic solvent.

The base is selected from, but is not limited to organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Preferably, triethylamine. The amount of base employed is an equimolar amount to 5 times the equimolar amount of the starting material of formula II. When an excess of an organic amine is employed as the base, this may optionally serve as the solvent.

The acetylating agent is selected from, but is not limited to acetyl chloride, acetic anhydride, ethyl acetate, acetic acid and the like and mixtures thereof, preferably acetic anhydride.

The reaction is normally and preferably effected in the presence of a solvent. The solvent is selected from, halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; aprotic polar solvents, such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; hydrocarbon solvents, such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof, preferably dichloromethane.

In general, the reaction temperature is from about-10°C to about 100° C, preferably from about 25 ⁰C to 30 ⁰C. The time required for the reaction to complete is a period of from about 30 minutes to about 20 hours. Preferably from 30 minutes to 5 hours.

In another embodiment, the present invention provides a process for preparation of the compound of formula Il comprising: reacting a compound 2-(triphenylmethyl)-5-(α-bromo-2-fluorobenzyl)-4,5, 6,7- tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula IV or a salt thereof

IV with a cyclopropane carbonitrile of formula III

in the presence of magnesium or derivative thereof and an inert organic solvent.

The inert solvent is selected from, but not limited to ether, such as diethyl ether, 1,4-dioxane, tetrahydrofuran. Preferably, tetrahydrofuran.

The reaction temperature can range from about 0⁰C to about 100° C. Preferably from about 40°C to about 50° C.

The time required for the reaction can be a period of from about 30 minutes to about 24 hours. Preferably, from about 1 hour to 5 hours. The resulting Grignard reagent complex, from the reaction of magnesium with a compound of formula IV, is then reacted with a compound of formula III to afford the compound of formula II.

Typically, the molar amount of compound of formula III may be 1 to 2 times the molar amount of the compound of formula IV. Preferably, 2 molar amounts. While the molar amount of base may be 1 to 4 times the molar amount of the compound of formula IV. Preferably, 2 molar amounts. In a further embodiment, the present invention provides a process for the preparation of compound of formula IV or salt thereof comprising: a) reacting a compound 5,6,7,7a-tetrahydro-4 H-thieno-[3,2-c]pyπdin-2-one or a salt thereof of formula IX

IX with a compound trityl halide of formula VIII

VIII where X = F, Cl, Br or I in the presence of a base and an organic solvent to afford the compound 4,5,6,7-tetrahydthieno-5-

(triphenylmethyl)[3,2-c]pyridine-2(3H)-one of formula VII

VlI b) reacting a compound of formula VII with a compound 1 -(bromomethyl)-2- fluorobenzene of formula Vl

Vl in the presence of a base and an organic solvent to afford the compound 2-(triphenylmethyl)-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula V.

V

The reaction solvent, which can be used in reaction of a compound of formula IX and a compound of formula VIII may include an ether, such as tetrahydrofuran, diethyl ether, dioxane and the like; a chlorinated solvent, such as methylene chloride, ethylene dichloride, chloroform, and the like; an aromatic hydrocarbon solvent, such as toluene, xylene and the like; a nitrile solvent, such as acetonitrile, propionitrile, benzonitrile and the like; an amide type solvent such as dimethylformamide, dimethylacetamide, dimethylimidazolidone, or mixtures thereof. Preferably, acetonitrile.

The base may be inorganic or organic, for example alkali metal carbonates such sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; or their aqueous or alcoholic mixtures thereof; organic bases such as triethylamine, diisopropyl ethyl amine, pyridine and the like, preferably diisopropyl ethyl amine.

The reaction of a compound of formula IX and a compound of formula VIII optionally can be carried out neat, i.e., in the absence of solvent.

The reaction temperature generally can range from about -20 ⁰C to about 100°C, preferably at temperatures of about 25⁰C to about 30⁰C. The molar ratio of the reaction substrates is generally, the oxothienopyridine of formula IX: the base : the trityl halide of formula VIII may be about 1 :0.5: ϊ to about 1.0:3: 2, preferably 1:1:0.5.

The isolation of the desired compound of formula VII from the reaction mixture can be carried out using a single method or combination of methods known in the art, such as, crystallization, extraction, washing, column chromatography, etc.

The substituted benzyl halide of formula Vl is reacted with a condensed hydropyridyl compound of formula VII, to give the compound of formula V. This reaction can be carried out in the presence or absence of an inert solvent, herein, preferably in the presence of an inert solvent) and in the presence or absence of a base, herein, preferably in the presence of a base. In an embodiment of the present invention, the compounds of formulae VII and V optionally can be obtained by a one pot reaction.

The base that can be used is selected from, but not limited to organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo-[4.3.0]non-5-ene; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Preferably, potassium carbonate.

The amount of base employed is from an equimolar amount to 5 times the equimolar amount with respect to the starting material of formula Vl₁ preferably an equimolar amount. Optionally, when an excess of an organic amine is employed as the base, this may additionally serve as the solvent.

The reaction of a compound of formula Vl and a compound of formula VII is effected in the presence of a solvent. The solvent is preferably inert to the reaction. The solvent is selected from, but not limited to ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethyl acetamide, N- methyl-2-pyrrolidone or hexamethyl phosphoric triamide; and sulfoxides, such as dimethyl sulfoxide. Preferably, acetonitrile.

The temperature of the reaction can be from about 25°C to about 100° C or reflux temperatures of the solvent(s) used. Preferably, from about 45°C to about 50°C. The time required for the reaction can be a period of from about 1 hour to about 15 hours. Preferably, from about 9 hours to about 10 hours.

In an embodiment of the present invention, the reaction of a compound of formula Vl and a compound of formula VII can be optionally accelerated in the presence of an ammonium salt, for example, a quaternary ammonium salt, like tetramethylammonium halide,tetraethylammonium- halide,tetrabutylammoniumhalide, trialkylmonobenzylammonium halide such as trimethylbenzyl-ammonium chloride and/or an alkali metal halide such as potassium bromide, sodium iodide and the like, preferably a quaternary ammonium salt. After completion of the reaction, the desired compound of formula V can be recovered from the reaction mixture by conventional means known to one of skilled in the art. Alternatively, a suitable recovery procedure optionally comprises: adding water; neutralizing the mixture, if necessary; extracting the mixture with a water-immiscible organic solvent; drying the extract; and distilling the solvent off. Preferably, the recovery of compound of formula V is by distillation followed by addition of cosolvent or antisolvent. The product thus obtained, optionally can be further purified by conventional means, such as recrystallization or chromatographic separation techniques, for example preparative thin layer chromatography or column chromatography, notably column chromatography.

In a yet further embodiment, the present invention provides a process for the preparation of a compound of formula IV or a salt thereof

IV comprising: reacting a compound of formula V with bromine or its derivative in the presence of an organic solvent.

V

The bromine or bromo derivative is selected from, but not limited to bromine, hydrobromic acid

(aqueous or cone), ammonium bromide, N-bromosuccinamide, N-bromosuccinamide in benzoyl peroxide and the like; N-bromosuccinamide (NBS) in the presence of radical initiator, like p-toluene sulfonic acid or azobis(isobutyronitrile) (AIBN). Preferably, N-bromosuccinamide (NBS)in the presence of radical initiator azobis (isobutyronitrile) (AIBN).

Suitable organic solvents that can be used, include but are not limited to, alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like; nitriles such acetonitrile, propionitrile and the like; halogenated hydrocarbons such as methylene chloride, chloroform, chorobenzene and the like; preferably methylene chloride.

The reaction temperature can be from about 5°C to about 100°C or reflux temperatures of the solvent(s) used, preferably at a temperature from about 25°C to about 50°C. The time required for the bromination reaction can be a period of from 30 minutes to 15 hours, preferably from 5 to 10 hours.

The oxopyridyl compound of formula IX, a tautomer thereof and salts thereof used as one of the starting materials can be prepared according to the method described in Japanese Provisional Patent Publication No. 246187/1986, which is incorporated herein by reference.

In an embodiment of the present invention, the process is optionally carried out in situ; or by one pot synthesis.

In a further embodiment of the present invention, a continuous process for preparing a compound of formula I can be obtained from the above intermediate reaction processes (the process for preparing a compound of formula II, the process for preparing a compound of formula IV, the process for preparing a compound of formula V, the process for preparing a compound of formula VII) whereupon interdependently combined with the intermediates of compounds of formulae IX and VIII.

In another embodiment of the present invention, a compound of formulae Ia or I is optionally purified by re-crystallization using a solvent or mixture of solvents. In a further embodiment of the present invention, a compound of formulae Ia or I is optionally converted into a pharmaceutically acceptable salt.

In still another embodiment of the present invention, the acid addition salt of a compound of formula

Ia is prepared by addition of a compound of formula Ia to an acid, preferably hydrochloric acid, hydrogen chloride (gas) in the presence or absence of an inert solvent, preferably in the presence of an inert solvent, or by dropwise addition of an acid (preferably hydrochloric acid), or by addition of hydrogen chloride (gas).

Optionally, the seed crystals of said salt can be added.

The acid addition salts that may be used are selected from, but not limited to salts of mineral acids, in particular, hydrohalogenic acids (including hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid); nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts of lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts of arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; and salts of organic carboxylic acids, such as acetic acid, propionic acid, butyric acid, fumaric acid, tartaric acid, oxalic acid, malonic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid. The acid moiety of acid addition salts of 2-acetoxy-5-(. alpha. -cyclopropylcarbonyl-2-fluorobenzyl)-

4,5,6,7-tetrahydr othieno[3,2-c]pyridine is, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid. Preferably, hydrochloric acid or maleic acid.

The solvent used can be any liquid which has no adverse effect on the reaction and it can dissolve the starting material to some extent. The solvents that can be used include aliphatic hydrocarbons such as hexane, cyclohexane, heptane; aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol)dimethyl ether; ketones such as acetone, methyl ethyl ketone or diethyl ketone; esters such as ethyl acetate, propyl acetate or butyl acetate; nitriles such as acetonitrile or propionitrile or mixtures thereof or their aqueous mixtures. The preferred solvents are tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, cyclohexane, toluene or acetonitrile.

The temperatures that can be used range from about -2O⁰C to about 100⁰C. Preferably, from about 0°C to about 3O⁰C. The time period for carrying out the reaction can be from 5 minutes to 10 hours. Preferably, from about 10 minutes to about 5 hours. The precipitated salt of a compound of formula (Ia) can be isolated from the reaction mixture by conventional methods, for example, by filtration or by evaporation of the solvent(s).The total purity of the prasugrel or a pharmaceutically acceptable salt thereof obtained by the above described processes has the purity by HPLC of at least about 98%, more preferably, at least about 99% and most preferably at least about 99.5%. Preferably, the chemical purity of the prasugrel or a pharmaceutically acceptable salt thereof is about 99% or more, more preferably about 99.5% or more, more preferably about 99.8% or more, more preferably about 99.9% or more, as measured by area under high performance liquid chromatography (HPLC). In one embodiment, the present invention encompasses prasugrel or a pharmaceutically acceptable salt thereof having less than about 0.20% of any single impurity as measured by area under HPLC peaks. Preferably, the prasugrel or a pharmaceutically acceptable salt thereof has less than about 0.15% of any single chemical impurity as measured by the area under HPLC peaks. In another embodiment, the present invention provides 4, 5, 6,7-tetrahydrothieno-5-

(triphenylmethyl)[3,2-c]pyridine-2(3H)-one a compound of formula VII or a salt thereof.

VlI In yet another embodiment, the present invention provides 2-(triphenylmethyl)-2-fluorobenzyl)-

4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one a compound of formula V or a salt thereof.

v

In still one other embodiment, the present invention provides 2-(triphenylmethyl)-5-(α-bromo-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one a compound of formula IV or a salt thereof.

(IV)

In yet another embodiment, the present invention provides 2-(triphenylmethyl)-5-(α- cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula Il or a salt thereof

The present invention relates to polymorphs of prasugrel hydrochloride and processes for the preparation thereof. More particularly the present invention relates to novel crystalline and amorphous forms of prasugrel hydrochloride.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.

The discovery of new amorphous forms of active pharmaceutical ingredients (API's) provides opportunities to improve the performance characteristics of a pharmaceutical product. Such discoveries enlarge the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Generally, amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.

Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

Generally, amorphous materials do not exhibit the three dimensional long-range order ordinarily found in crystalline material and are structurally more similar to liquids where the arrangement of molecules is random. Additionally, amorphous solids are not crystalline and therefore do not give a definitive x-ray diffraction pattern (XPD). They also do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point.

The present invention provides crystalline and amorphous forms of prasugrel HCI and process for preparation thereof, which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.

The present invention provides a crystalline form G1 of prasugrel hydrochloride characterized by an X- ray powder diffraction pattern with characteristic peaks at about 6.4, 8.1 , 8.4, 12.0, 12.6, 12.8, 13.3, 15.2, 15 6, 18.6, 20.5, 23.6, 24.4, 25.5, 26.9, 27.4, and 28.5 ± 0.2 degrees two-theta, which is substantially in accordance with Figure 2.

The crystalline form G1 is further characterized by differential scanning calorimetry with an endotherm curve at about 145.71⁰C with an onset at about 141.31⁰C and an endset at about 149.33°C, which is substantially in accordance with Figure 3.

The present invention provides a crystalline form G2 of prasugrel hydrochloride characterized by an X- ray powder diffraction pattern with characteristic peaks at about 8.3, 11.9, 12.5, 12.8, 13.2, 15.5, 18.5, 20 3, 20.7, 23.4, 24.4, 25.2, 26.6, 27.2 and 28.3 ± 0.2 degrees two-theta which is substantially in accordance with Figure 4. The crystalline form G2 is further characterized by differential scanning calorimetry with endotherm curve at about 166.07⁰C with onset at about 151.78⁰C and endset at about 194.94⁰C, which is substantially in accordance with the figure 5.

The present invention provides process for the preparation of crystalline form G1 and G2 of prasugrel HCI comprising: a) providing a solution of prasugrel hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof ; and b) precipitating the solid by adding an anti solvent to obtain the substantially pure desired crystalline form of prasugrel HCI.

As used herein, a solvent is any liquid substance capable of dissolving prasugrel hydrochloride. As used herein, the term "antisolvent" means a liquid in which a compound is poorly soluble. The addition of an antisolvent to a solvent reduces the solubility of a compound.

As used herein a mixture of solvents refers to a composition comprising more than one solvent. In (a) above, the solution of prasugrel HCI salt can be obtained by dissolving prasugrel HCI salt in a solvent or mixture of solvents or their aqueous mixtures.

The solvents that can be used include, but are not limited to water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; halogenated solvents such as dichloromethane, ethylene dichloride , chloroform and the like; nitrite solvents such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, isopropyl acetate and the like: aprotic polar solvents may include N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N- dimethylacetamide (DMA) and the like; or mixtures thereof in various proportions without limitation.

Preferably, dichloromethane is the solvent for crystalline form G1, while isopropyl alcohol is for crystalline form G2.

The temperature for obtaining a clear and homogenous salt solution can range from about 25°C to about 75°C or at the boiling point of the solvent/s used, preferably from about 25⁰C to about 40°C.

The solution obtained is optionally filtered through celite or diatomaceous earth to separate the extraneous matter present or formed in the solution by using conventional filtration techniques known in the art.

In (b) above, the precipitation of the solid is accomplished by adding an antisolvent to the solution. The antisolvents include, but are not limited to, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene and the like or mixtures thereof in various proportions without limitation. Preferably, cyclohexane is the antisolvent for crystalline Form G1 , while, n-hexane is for crystalline Form G2.

In a preferred embodiment, the class of solvents that can be used for solubilizing or dissolving the prasugrel hydrochloride in (a) above, for obtaining the crystalline form G1 include, but are not limited to, halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like or mixtures thereof in various combinations without limitation. And the antisolvents in (b) above that can be used for precipitating the crystalline form G1 include but are limited to hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like or mixtures thereof in various proportions without limitation.

In a preferred embodiment the class of solvents that can be used for solubilizing or dissolving the prasugrel hydrochloride in (a) above, for obtaining the crystalline form G2 include, but are not limited to, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like or mixtures thereof in various combinations without limitation.

And the antisolvents in (b) above that can be used for precipitating the crystalline form G2 include but are limited to hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene and the like or mixtures thereof in various proportions without limitation. The solvents and the antisolvents used for the preparation of crystalline forms G1 and G2 of prasugrel hydrochloride can be of any combination, in various proportions or ratios without limitations; while preferably in ratios that would afford high yield and purity of the desired crystalline forms. Advantageously the volume of antisolvent used to precipitate the solid can range from about 5 to about 100 volumes with reference to volume of the solvent used for solubilizing prasugrel hydrochloride.

In one embodiment, the range of solvent to antisolvent is from about 1:7. Preferably, about 1:4.

The order of addition is immaterial, where the solution of prasugrel hydrochloride may be added to the antisolvent or the antisolvent may be added to the solution of prasugrel hydrochloride to precipitate the solid.

The temperature for precipitation of solid can range from about -10 °C to about 35°C. Preferably, from about 25⁰C to about 35°C.

Recovery of the separated solid can be achieved by any conventional methods known in the art, for example filtration.

The process optionally may include further drying of the product obtained from the solution by any method known in the art.

The substantially pure solid prasugrel HCI can be dried at temperatures from about 25⁰C to about 75° C, preferably from about 25 to about 50⁰C and at reduced pressure of about 5 mbar to about 20 mbar, preferably about 5 mbar to about 10 mbar, for about 1 hour to about 48 hours, preferably about 10 hours to about 15hours. Preferably about 50⁰C and at reduced pressure of about 5 mbar for about 30 minutes to about 2 hours.

The present invention provides an amorphous form of prasugrel HCI, characterized by X- ray powder diffraction pattern, which is substantially in accordance with Figure 6. The present invention provides a process for the preparation of amorphous prasugrel HCI, comprising: a) providing a solution of prasugrel hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof; and b) removing the solvents to obtain the substantially pure amorphous prasugrel HCI. In (a) above, the process provides a solution of prasugrel hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof; and

The solution of prasugrel HCI salt can be obtained by dissolving prasugrel HCI salt in a solvent or mixture of solvents or their aqueous mixtures thereof.

The solvents that can be used include, but are not limited to water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone and the like; halogenated solvents such as dichloromethane, ethylene dichloride , chloroform and the like; nitrite solvents such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, isopropyl acetate and the like; aprotic polar solvents may include N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N₁N- dimethylacetamide (DMA) and the like; or mixtures thereof in various proportions without limitation.

Preferably, dichloromethane. The temperature for obtaining a clear and homogenous solution can range from about 25°C to about 75°C or the boiling point of the solvent/s used, preferably from about 25⁰C to about 40°C.

Removal of solvent is accomplished by, for example, substantially complete evaporation of the solvent, concentrating the solution, cooling to obtain amorphous form and filtering the solid under inert atmosphere. Alternatively, the solvent may also be removed by evaporation. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique. The solution may also be completely evaporated in, for example, a pilot plant rota vapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer (ATFD), or evaporated by spray drying to obtain a dry amorphous powder. Preferably, the methods for drying are spray drying or vertical agitated thin-film drying (or evaporation).

In the preferred spray drying technique, a solution of prasugrel HCI in (b) is sprayed into the spray drier at the flow rate ranging from about 10 ml/hr to about 300 ml/hr, preferably at flow rate of about 40 ml/hr to about 200ml/hr. The air inlet temperature to the spray drier used may range from about 25°C to about

150⁰C, preferably from about 6O⁰C to about 11O⁰C and the outlet air temperature used may range from about 3O⁰C to about 9O⁰C preferably from about 35⁰C to about 50°C.

Agitated thin film evaporation technology, on the other hand, involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition. In vertical agitated thin-film drying (or evaporation) (ATFD-V)₁ the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it.

Recovery of prasugrel HCI can be achieved by any conventional methods known in the art, for example filtration.

The prasugrel HCI substantially in an amorphous form obtained by the above processes may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents. When implemented, the preferred instrument is a vacuum tray dryer. The characterization of the crystalline forms G1 and G2 and the amorphous form of prasugrel hydrochloride by X-ray powder diffraction, previously described, were performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu Kα1=1.54O6θA). The X-ray source is operated at 45 kV and 4OmA. Spectra are recorded at start angle from 2° to 50° 2Θ, a step size 0.0167° with a time per step of 1000 seconds. The crystalline forms G1 , G2 and the amorphous form of prasugrel hydrochloride were further characterized by differential scanning calorimetry by the method as follows: Approximately 1-5mg of sample was accurately weighed into an aluminum DSC pan with lid. The sample was placed then into a Mettler Toledo DSC822^e equipped with a liquid nitrogen cooling unit and allowed to equilibrate at 30⁰C until stable heat flow response was seen. A dry nitrogen purge gas at a flow rate of 50ml/min was used to produce the inert atmosphere and prevent oxidation of the sample during heating. The sample was scanned from 50-250⁰C at rate of 10°C/min and resulting heat flow response was measured against temperature.

Specifically, substantially pure crystalline Form G1 of prasugrel hydrochloride may have less than

20%, more preferably less than 10%, even more preferably less than about 5%, and most preferably less than 1 %, of any one of crystalline Forms A, B1 , B2, C, D, E, G2 and amorphous form of prasugrel hydrochloride. In one example, the PXRD pattern of the substantially pure crystalline Form G1 of prasugrel hydrochloride can be depicted substantially as Figure 2.

Specifically, substantially pure crystalline form G2 of prasugrel hydrochloride may have less than

20%, more preferably less than 10%, even more preferably less than about 5%, and most preferably less than 1 %, of any one of crystalline Forms A, B1, B2, C, D, E, G1 and amorphous form of prasugrel hydrochloride. In one example, the PXRD pattern of the substantially pure crystalline form G2 of prasugrel hydrochloride can be depicted substantially as Figure 4.

Specifically, substantially pure amorphous form of prasugrel hydrochloride may have less than

20%, more preferably less than 10%, even more preferably less than about 5%, and most preferably less than 1 %, of any one of crystalline forms A, B1, B2, C, D, E, G1 and G2 of prasugrel hydrochloride. In one example, the PXRD pattern of the substantially pure amorphous prasugrel hydrochloride can be depicted substantially as Figure 6.

Optionally seeding of the corresponding polymorph is used to obtain the desired polymorph by adding to the solution of prasugrel hydrochloride to afford the desired polymorph of prasugrel hydrochloride.

The term "pharmaceutically acceptable salt" refers to salts including, but not limited to: hydrohalogen acid salts such as the hydrofluoride, hydrochloride, hydrobromide and hydroiodide; the nitrate; the perchlorate; the sulfate; the phosphate; a C₁-C₄ alkanesulfonate, optionally substituted by halogens, such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; a C₆-C₁₀ arylsulfonate, optionally substituted by C₁-C₄ alkyl groups, such as benzenesulfonate and p- toluenesulfonate; a C₁-C₆ aliphatic acid salt such as acetate, malate, fumarate, succinate, citrate, tartarate, oxalate and maleate; and an amino acid salt such as the glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt and aspartic acid salt. Preferably, hydrochloric acid salt.

The prasugrel or an acid addition salt thereof according to the present invention has an asymmetric carbon atom in the molecule; there are stereoisomers having R and S configurations. The stereoisomers and a compound containing these in any proportion are both encompassed within the present invention. The stereoisomers, for example, can be' synthesized by using optically resolved raw material compounds or can be obtained by subjecting synthesized prasugrel or an acid addition salt thereof to optical resolution, if desired, using a conventional optical resolution or separation method. The prasugrel or an acid addition salt thereof according to the present invention may be allowed to stand in the air or recrystallized to absorb water, thereby having adsorbed water or becoming a hydrate. The water-containing compounds are encompassed within the present invention. In addition, solvates thereof each containing any amount of a solvent are also encompassed within the present invention. According to the present invention, the prasugrel or an acid addition salt thereof or their-hydrates or solvates can form crystals (crystal polymorphism) having a plurality of different inner structures and physicochemical properties, depending on reaction and crystallization conditions. The crystals and a mixture thereof in any proportion are encompassed within the present invention. Crystalline and amorphous solids thereof may be present as a mixture. A mixture thereof in any proportion is encompassed within the present invention. Specifically, the content of a specific crystal form according to the present invention is preferably 50% or more, more preferably 80% or more, still more preferably 90% or more, particularly preferably 95% or more, most preferably 97% or more.

According to the present invention, a crystal refers to a solid whose inner structure is three- dimensionally composed of a regular repetition of constituent atoms (or a group thereof), and is distinguished from an amorphous solid which does not have such a regular inner structure. Whether or not a solid is a crystal can be examined by a crystallographically known method (for example, powder X-ray crystallography or differential scanning calorimetry). By way of example, a solid is subjected to powder X- ray crystallography using X-rays obtained by irradiation with copper K.alpha radiation. A solid is determined to be a crystal when distinct peaks are observed in the X-ray diffraction pattern, while a solid is determined to be amorphous when no distinct peaks are observed. A solid is determined to be a crystal whose crystallinity is low when the peaks can be read but are not distinct (e.g., broad). A crystal whose crystallinity is low is encompassed within a crystal of the present invention.

In yet another embodiment, prasugrel or its pharmaceutically acceptable salts obtained by the processes described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 600ppm of dichloromethane, less than 410 ppm of acetonitrile, less than 3000ppm of cyclohexane, ethyl acetate, isopropyl alcohol, di-isopropyl ether, diethyl ether, and tetrahydrofuran (THF), less than about 890 ppm of toluene, less than 290ppm of n-hexane.

According to the present invention, prasugrel and its salts can be used in any crystalline form, or in amorphous form, or in combinations thereof.

The different physicochemical properties of the active ingredient and as well as of excipients are to be considered, as these properties affect the process and formulation properties of the compound. Various important physicochemical properties include but are not limited to particle sizes, density (bulk density and tapped density), compressibility index, Hausner's ratio, angle of repose, etc. Particle sizes of active pharmaceutical ingredient can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle size and size distribution. This will be even more critical for low-dose drugs and satisfactory dosage units of low doses cannot be

T> manufactured from a drug that does not meet certain particle size and size distribution specifications. Also particle sizes play an important role in dissolution of active ingredient form the final dosage form for certain drugs like prasugrel because of their poor solubility.

Hence, these physicochemical properties not only affect the processes of the preparing the pharmaceutical formulations but also affect the performance of the pharmaceutical product both in vitro and in vivo.

The D₁₀, D₅₀, and D₉₀ values are useful ways for indicating a particle size distribution. D₉₀ is a size value where at least 90 percent of the particles have a size smaller than the stated value. Likewise D₁₀ refers to 10 percent of the particles having a size smaller than the stated value. D₅₀ refers to at least 50 percent of the particles having a size smaller than the stated value and D [4,3] value refers to a mean particle size. Methods for determining D₁₀, D₅₀, D₉₀ and D [4,3] include those using laser light diffraction with equipment sold by Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom.

In the field of pharmaceutical formulation, it is notable that particle size plays a pivotal role in the solubility properties of an API, like prasugrel hydrochloride. Particle size reduction techniques are employed to increase a compound's solubility. Particle size reduction increases the surface area of the solid phase that is in contact with the liquid medium. However, particle size reduction cannot alter the solubility of the compound in a solvent, which is a thermodynamic quantity. At instances where the rate of dissolution of a poorly soluble drug is the rate limiting factor in its rate of absorption by the body, it is recognized that the bioavailability of such drugs may be enhanced when administration occurs in a finely divided state. Further, particle size can also affect how freely crystals or a powdered form of a drug will flow past each other, which in turn, has consequences in the production process of pharmaceutical products containing the drug

The specific surface area of an active pharmaceutical ingredient may be affected by various factors. It is recognized that there is an inverse relationship between surface area and particle size; where the smaller the particle size, the higher the surface area. Whereupon, the available surface area for drug dissolution correlates to the rate of dissolution and solubility. A greater surface area enhances both the solubility and the rate of dissolution of a drug, which in turn, may improve its bioavailability and potentially its toxicity profiles.

The lack of solubility of prasugrel poses a challenge since the bioavailability of a water insoluble active ingredient, like prasugrel hydrochloride, is usually poor. Thus there is a need in the art to prepare active pharmaceutical ingredients, such as prasugrel, with a high surface area to obtain formulations with greater bioavailability, and to compensate for any loss of surface area before formulation.

Prasugrel hydrochloride of defined particle size may be produced by precipitation from appropriate solvents. Particle size may be adjusted by customary methods such as cooling, pH adjustment, pouring a concentrated solution into an anti-solvent and/or by co-precipitation so as to obtain a precipitate with the appropriate particle size distribution. Further, prasugrel hydrochloride of defined particle size may be produced by known methods of particle size reduction starting with crystals, powder aggregates and course powder of either crystalline or amorphous prasugrel hydrochloride. The principal operations of conventional size reduction are milling of a feedstock material and sorting of the milled material by size. A fluid energy mill, or micronizer, is an especially preferred type of mill for its ability to produce particles of small size in a narrow size distribution. The feedstock should be provided in an average particle size range of about 150 μm to about 850μm which may be achieved using a conventional ball, roller or hammer mill if necessary. It is conventional knowledge for those of ordinary skill in the art that fluid energy mills use the kinetic energy of collision between particles suspended in a rapidly moving fluid (typically air) stream to cleave particles. The suspended particles are injected under pressure into a recirculating gas stream. Smaller particles are carried aloft inside the mill and swept into a vent and are collected. The vent may be connected to a particle size classifier such as a cyclone. Fluid energy mills are designed so that particles are classified by mass. Only particles with a momentum in a certain range will enter the vent and be collected. Centrifugal forces serve to classify the particles in a fluid energy mill.

When milled in another type of mill, a powder composition according to this invention can be produced using cyclonic or centrifugation separation techniques. As prasugrel hydrochloride is both pH dependent and poorly soluble in aqueous medium, it is essential to attain a prasugrel hydrochloride that has reduced particle size distribution and larger surface area, which subsequently leads to better solubility and bioavailability in aqueous medium. In view of the foregoing, there is a need in the medical arts for prasugrel hydrochloride with defined particle size distribution and surface area which are interlinked and has effect on the solubility and bioavailability. The present invention provides prasugrel and its hydrochloride salt having desirable particle size distribution and specific surface area suitable for enhanced bioavailability and solubility in aqueous medium.

The present invention provides crystal particles of prasugrel obtained by the processes herein described, having a surface area of about 0.1 rrr/g to about 1 m²/g, as measured by B. E. T. (Brunauer-

Emmett-Teller), preferably from about 0.5 rrr/g to about 1nrr/gm and with a mean particle size of about 50μm to about 100 μm, preferably of about 75μm to about 90μm.

The present invention provides crystal particles of prasugrel hydrochloride obtained by the processes herein described, having a surface area of about 1 m²/g to about 15 m^z/g, as measured by B. E. T. (Brunauer-Emmett-Teller), preferably from about 5 m²/g to about 10 m²/gm, with a mean particle size of about 5μm to about 50μm, preferably of about 10 μm to about 20 μm. The present invention provides crystal particles of prasugrel obtained by the processes herein described having the following characteristics:

Specific surface area of about 0.98 m²/g, as measured by B.E.T. (Brunauer-Emmett-Teller) Sulfated ash of about 0.03% w/w. Loss on drying of about 0.23% w/w. Moisture content of about 0.22% w/w by TGA (Thermogravimetric Analysis).

Crystal particles are flake shape as observed by SEM (Scanning electron microscope), which is substantially as depicted in Fig. 8. Mean particle size distribution d (0.5) of about 86.471 μm.

The present invention provides crystal particles of prasugrel hydrochloride obtained by the processes herein described having the following characteristics:

Specific surface area of about 3.88 m²/gm, as measured by B. E.T. (Brunauer-Emmett-Teller) 5 Sulfated ash of about 0.02% w/w. Loss on drying of about 0.23% w/w. Moisture content of about 0.45% w/w by TGA.

Crystal particles are condensation floe shape, as observed by SEM (Scanning electron microscope), which is substantially as depicted in Fig.9. 10 Mean particle size distribution d (0.5) of about 6.208μm.

As used herein, the term "μm" refers to "micrometer" which is 1x10~⁶ meter. As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates.

As used herein "Particle Size Distribution (P.S.D.)" means the cumulative volume size distribution 15 of equivalent spherical diameters as determined by laser diffraction at 1 bar dispersive pressure in a SympatecHelos equipment.

"Mean particle size distribution, i.e., d (0.5)" correspondingly, means the median of said particle size distribution.

Specific surface area is defined in units of square meters per gram (m²/g). It is usually measured by 10 nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the B. ET. formula.

BET Surface Area Analyser Model SAA-2000, specifically designed for BET Surface Area Analysis. The Specific Surface Area is expressed in meters square per gram of a sample. It is a measure of area '.5 covered by Nitrogen gas adsorbed in a mono-layer form.

Crystal particle shapes of prasugrel and prasugrel hydrochloride are analysed by powder sample is spread on the stub and coated with gold ions and observed under scanning electron microscope.

In another preferred embodiment of the present invention provides a pharmaceutical composition comprising prasugrel or its pharmaceutically acceptable salt/s obtained by the process of present invention

SO and suitable pharmaceutical carriers. The pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The pharmaceutical compositions

S 5 comprising prasugrel or its pharmaceutically acceptable salts, obtained by the process disclosed herein, and suitable pharmaceutical carriers also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, where the most preferred route of administration is oral. A pharmaceutical formulation according to the present invention can be presented in forms such as tablets, capsules, granules, spheroids, beads, pellets, mini-tablets, multilayered tablets, powders, sachets, gels, dispersions, solutions or suspensions.

Capsule dosages will contain the prasugrel or its pharmaceutically acceptable salts which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate.carboxymethylethyl-cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin. Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

In further embodiments the invention includes methods of treating patients suffering from thrombotic disorders using pharmaceutical formulations of the present invention. Thrombotic disorders can be due to the formation or presence of a blood clot within a blood vessel due to prior and acute myocardial infarction, unstable and stable angina, acute reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis, thrombotic stroke, prior transient ischemic attack (TIA) and reversible ischemic neurological deficit (RIND). '

Pharmaceutical formulations of the present invention can optionally be administered together with one, or more than one, other therapeutic agents in the treatment of thrombotic disorders including, but not limited to, salicylates such as aspirin, angiotensin 11 receptor antagonists such as candesartan, valsartan, eprosartan, losartan, irbesartan, saprisartan, zola^'sartan, saralasin, telmisartan, and tasosartan, isoteoline, HMG CoA reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitvastatin, fluindostatin, mevastatin, velostatin and dalvastatin, and any pharmaceutically acceptable salts, solvates, hydrates, enantiomers thereof. The useful therapeutic agents are well known to those skilled in the art, and the use of any of them falls within the scope of the invention. The pharmaceutical dosage forms of the present invention are intended for oral administration to a patient in need thereof. The process for'the preparation of prasugrel or its pharmaceutically acceptable salt of the present invention is simple, eco-friendly and easily scaleable.

Certain specific aspects and embodiments of the invention will be explained in more detail with reference to the following examples, being provided only for purposes of illustration, and it is to be understood that the present invention should not be deemed to be limited thereto.

PRASUGREL EXPERIMENTAL PROTOCOL:

EXAMPLE 1: PREPARATION OF COMPOUND OF FORMULA VII

Charge 10 g of thienopyridinone tosylate (IX) and 100 ml of acetonitrile in a clean and dry round bottom flask. Add diisopropyl ethyl amine (10.5 g) and stir for about 30 min. Add 14 g of trityl chloride (VIII) and stir at about at 30⁰C for about 14 hrs. Check the reaction progress by TLC monitoring. Distill off the solvent under vacuum to obtain oil mass. Add 50 ml of dichloromethane and wash with 3X50 ml of water. Separate the organic layer and distill off solvent under vacuum completely at below 50°C. Isolate the compound by adding diisopropyl ether (50 ml). The isolated compound is impure, so purify the material by subjecting to column chromatography using eluent, hexane: ethyl acetate(9:1). Distill off the solvents under vacuum completely to give light yellow powder material. Dry wt: 6.2 g.

EXAMPLE 2: PREPARATION OF COMPOUND OF FORMULA V

Charge 10 gm of compound of formula VII , 8.0 gm of 2-fluoro benzyl bromide (Vl), 100 ml of acetonitrile and 17.5 gms potassium carbonate in a clean and dry round bottom flask. Heat the reaction mixture to about 45°C and stir for about 9 hrs and monitor the reaction progress by TLC. Cool the reaction mass to about 25°C. Filter the separated salt and wash with 10 ml of acetonitrile. Distill off the solvent completely at below 50⁰C and add 50 ml of n-hexane and stir for about 30 min, decant hexane from oily mass. Add 20 ml of ethyl acetate and 50 ml of diethyl ether and stir for about 5hrs. Filter the compound and wash with 10 ml of diethyl ether. Dry the compound at about 50-60⁰C. Wt: 4.8 gm

EXAMPLE 3: PREPARATION OF COMPOUND OF FORMULA IV

Charge the compound obtained in example 2 (10.0 g) and 100ml of dichloromethane in a clean and dry round bottom flask and stir for dissolution. Add N-Bromo succinamide (7.8 g) and 0.1 g AIBN and heat to reflux for about 6-10 hrs. After completion of reaction wash the organic layer with 50 ml of water and 5% sodium Meta bisulphate (2X50 ml) solution followed by 50 ml of water. Distill off solvent under vacuum completely to give oily mass Wt: 8.O g

EXAMPLE 4: PREPARATION OF COMPOUND OF FORMULA Il

Charge 10.2 g of magnesium powder and 100 ml of Tetrahydrofuran and stir under nitrogen atmosphere. Add 0.1 g of iodine (for activation) and heat to about 40-50°C. Add a solution of 10 g of compound obtain in example 3 in 50 ml tetrahydrofuran slowly in about 2 hrs. Stir the reaction mixture for about 4 hrs. Add 5.6 ml of cyclopropane carbonitrile (III) in 50 ml tetrahydrofuran drop wise at about 40- 50⁰C over a period of 60 min. Stir the resultant reaction mixture for about 3 hrs. After completion of the reaction, cool the reaction mass to about 25-30⁰C. Add 10% ammonium chloride solution 100 ml at about 25-30⁰C and extract with dichloromethane (4X100 ml). Distill off the solvent completely under vacuum. Wt. of oily mass: 6.7 g

EXAMPLE 5: PREPARATION OF PRASUGREL

Charge 50 ml of dichloromethane and the compound obtain in example 4 (10.0 g) in a clean and dry round bottom flask. Add triethyl amine and stir for about 15 min. Add 20 ml acetic anhydride drop wise at about 25~30°C. Stir for about 60-120 min at about 25-3O⁰C. Quench the reaction with 5% sodium bicarbonate solution (100 ml). Separate the organic and aqueous layers and wash the organic layer with 2X100 ml 5% sodium bicarbonate solution. Distill off solvent under vacuum completely and strip out traces of solvent with isopropyl ether (25 ml). Isolate the compound from 50 ml of isopropyl ether and dry the compound under vacuum. Dry wt: 3.0 g

EXAMPLE 6: PREPARATION OF PRASUGREL HYDROCHLORIDE USING ACETONITRILE

Charge 150 ml of acetonitrile and 10 g of prasugrel in a clean and dry round bottom flask and stir for about 5- 10 minutes. Add 2.5 ml of concentrated hydrochloric acid (30-35% v/v) and stir for about 4-5 hrs at about 25-30⁰C. Filter the separated solid and slurry the wet cake slurry with acetonitrile (20 ml) and dry the solid at about 50-55°C under vacuum for about 10 hrs. Wt: 5.5 g

EXAMPLE 7: PREPARATION OF PRASUGREL HYDROCHLORIDE USING TOLUENE

Charge 150ml of toluene and 10 g of prasugrel in a clean and dry round bottom flask and stir for about 5- 10 minutes. Add 3.0 ml of concentrated hydrochloric acid (30-35%v/v) and stir for about 4-5 hrs at about 25-3O⁰C. Filter the separated solid and wash the solid with toluene (20 ml) and dry the solid at about 70-75⁰C under vacuum for about 10 hrs. Wt: 5.O g EXAMPLE 8: PREPARATION OF PRASUGREL HYDROCHLORIDE USING THF

Charge 150ml of tetrahydrofuran and 10 g of prasugrel in a clean and dry round bottom flask and stir for about 5- 10 minutes. Add 2.5 ml of concentrated hydrochloric acid (30-35%v/v) and stir for about 4-5 hrs at about 25-30°C. Filter the separated solid and wash the solid with 10 ml of tetrahydrofuran and dry the solid at about 50-55⁰C under vacuum for about 10 hrs. Wt: 6.0 g

EXAMPLE 9: PREPARATION OF PRASUGREL HYDROCHLORIDE USING CYCLOHEXANE

Charge 50ml of cyclohexane and 10 g of prasugrel in a clean and dry round bottom flask and stir for about 5- 10 minutes. Add 2.5 ml of concentrated hydrochloric acid (30-35%v/v) and stir for about 4-5 hrs at about 25-3O⁰C. Filter the separated solid and wash the solid with 5 ml of cyclohexane and dry the solid at about 70-75⁰C under vacuum for about 10 hrs. Wt: 5.0 g

EXAMPLE 10: PREPARATION OF PRASUGREL HCI CRYSTALLINE FORM G1

To a solution of prasugrel hydrochloride (5g) in dichloromethane (200 ml) was added drop wise addition of cyclohexane (830 ml) over 10 min with stirring at 25-3O⁰C. Then mixture was stirred for 20-24 hrs at room temperature (25°C).The resulting crystals were separated by filtration and the crystals were washed with a small amount of cyclohexane and then dried at 50°C under reduced pressure for 12 hrs to give 4.0 g rams of the title compound as white crystals.

The powder X-ray diffraction pattern of the solid obtained is substantially in accordance with Fig.2 and the DSC thermogram curve at about 145.7°C, which is substantially in accordance with the Fig. 3.

EXAMPLE 11 : PREPARATION OF PRASUGREL HCI CRYSTALLINE FORM G2 To a solution of prasugrel hydrochloride (5g) in lsopropyl alcohol (375 ml) was added drop wise addition of hexane (375 ml) over 10 min with stirring at reflux temperature. Then allowed the mixture to reach room temperature (ca. 25⁰C) and stirred for about 20hours to about 24 hours. The resulting crystals were separated by filtration and the crystals were washed with a small amount of hexane and then dried at 50°C under reduced pressure for 12 hrs to give 4.1 g of the title compound as white crystals. The powder X-ray diffraction of the solid obtained is substantially in accordance with Fig.4 and the

DSC thermogram curve at 166.O⁰C, which is substantially in accordance with Fig. 5.

EXAMPLE 12: PREPARATION OF AMORPHOUS PRASUGREL HCI

To a solution of prasugrel hydrochloride (5g) in dichloromethane (250 ml) was subjected to spray drying at 65° and obtained solid was dried at 50°C for 20 hrs under reduced pressure to give 4.6 g of the title compound as white crystals. The powder X-ray diffraction pattern of the solid is substantially in accordance with Fig.6 and thermogram is substantially in accordance with Fig.7.

Claims

CLAIMS:

1. A process for preparing prasugrel of formula Ia or a pharmaceutically acceptable salt thereof

Ia comprising : reacting a compound 2-(triphenylmethyl)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula Il

Il with an acetylating agent in the presence of a base and an organic solvent. 2. The process of claim 1, where in the compound of formula Il is prepared by the process comprising: reacting a compound 2-(triphenylmethyl)-5-(α-bromo-2-fluorobenzyl)-4,5, 6,7-tetrahydrothieno[3,

2-c]pyridine-2(3H)one of formula IV

IV with a cyclopropane carbonitrile of formula III

in the presence of magnesium and an organic solvent.

3. The process of claim 2, wherein the compound of formula IV is prepared by the process comprising: a) reacting a compound 5,6,7,7a-tetrahydro-4 H-thieno-[3,2-c]pyridin-2-one or a salt thereof of formula IX

IX with a compound trityl halide of formula VIII

where X = F, Cl, Br or I , in the presence of a base and an organic solvent to afford the compound 4,5,6,7- tetrahydthieno-5-(triphenylmethyl)[3,2-c]pyridine-2(3H)-one of formula VII

VII b) reacting a compound of formula VII with a compound 1-(bromomethyl)-2- fluorobenzene of formula Vl

^•0 vi in the presence of a base and an organic solvent to afford the compound 2- (triphenylmethyl)-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula V

v c) reacting a compound of formula V with bromine or its derivative in the presence of an organic solvent to afford the compound of formula IV.

IV

4. The process of claim 3, wherein the reaction step b) of a compound of formula Vl and a compound of formula VIl is carried out in the presence of an ammonium salt and/or an alkali metal halide.

5. A compound, 4,5,6,7-Tetrahydthieno-5-(triphenylmethyl)[3,2-c]pyridine-2(3H)- one of formula VII or a salt thereof.

VIl

6. A compound, 2-(triphenylmethyl)-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2- c] pyridine-2(3H)one of formula V or a salt thereof.

V

7. A compound, 2-(triphenylmethyl)-5-(α-bromo-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula IV or a salt thereof.

IV

8. A compound, 2-(triphenylmethyl)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno [3,2-c]pyridine-2(3H)one of formula Il or a salt thereof.

9. The preparation of prasugrel or a pharmaceutically acceptable salt thereof using a compound of any of the formulae II, IV, V and VII

10. A process for preparing prasugrel HCI comprising: a) providing a solution of prasugrel or a salt thereof in a solvent or mixture of solvents or aqueous mixture thereof; b) reacting the solution with hydrochloric acid; and c) precipitating the solid by cooling or by adding anti solvent; and d) isolating the solid to obtain the substantially pure prasugrel HCI.

11. The process of Claim 10, wherein the solvent is selected from acetonitrile, toluene, tetrahydrofuran, 1 ,4-dioxane, cyclohexane, methyl t-butyl ether, methyl isobutyl ketone, and mixtures thereof, and mixtures of said organic solvents and water.

12. The prasugrel hydrochloride obtained by the process of claim 11 having a purity of at least

98 area % as measured by high performance liquid chromatography (HPLC).

13. The prasugrel hydrochloride of claim 12, having a purity of about 99 area % or more as measured by HPLC.

14. The prasugrel hydrochloride of claim 13, having less than about 0.15 area % of any individual impurity and not more than about 0.5 area % of total impurities as measured by HPLC.

15. A crystalline form G1 of prasugrel HCI.

16. Crystalline form G1 of claim 15, having an X- ray powder diffraction pattern with characteristic peaks at about 6.4, 8.1, 8.4, 12.0, 12.6, 12. 8, 13.3, 15.2, 15.6, 18.6, 20.5, 23.6, 24.4, 25.5, 26.9, 27.4, and 28.5 ± 0.2 degrees two-theta.

17. The crystalline form of claim15 , having an PXRD spectrum, which is substantially in accordance with Figure 2.

18. A process for preparing the crystalline form G1 of prasugrel HCI comprising: providing a solution of prasugrel hydrochloride in a solvent or mixture of solvents 5 or aqueous mixtures thereof and precipitating the solid by adding an antisolvent to obtain the substantially pure prasugrel HCI crystalline form G1.

19. The process of claim 18, wherein the solvent is selected from water, C_1-4 alcohols, C₅.₈ cyclic, branched, halogenated hydrocarbons, C _3-7 esters, C ₃.₇ nitriles, C ₂-e ethers and mixtures thereof. 0

20. The process of claim 19, wherein the solvent is selected from methanol, dichloromethane, ethyl acetate, isobutyl acetate, acetonitrile, THF, 1 ,4-Dioxane and mixtures thereof.

21. The process of claim 20, wherein the solvent is dichloromethane.

22. The process of claim 18, wherein the solution is prepared at temperature from about L 5 25⁰C to about reflux temperature of the solvent or mixture of solvents used.

23 The process of claim 18, wherein the anti solvent is selected from Ci_-4 aliphatic, aromatic hydrocarbons, C ₂.₈ ethers and mixtures thereof.

24. The process of claim 23, wherein the antisolvent is n-hexane, n-heptane, cyclohexane, toluene and mixtures thereof. iO

25. The process of claim 24, wherein the anti solvent is cyclohexane.

26. A crystalline form G2 of prasugrel HCI.

27. Crystalline form G2 of claim 26, having an X- ray powder diffraction pattern with characteristic peaks at about 8.3, 11.9, 12.5, 12.8, 13.2, 15.5, 18.5, 20.3, 20.7, 23.4, 24.4, 25.2, 26.6, 27.2 and 28.3 ± 0.2 degrees two-theta.

Ϊ5 28. The crystalline form of claim 27, is depicted by PXRD spectrum which is substantially as in Figure 4.

29. A process for preparing crystalline form G2 of prasugrel HCI comprising: providing a solution of prasugrel hydrochloride in a solvent or mixture of solvents or aqueous mixtures thereof and precipitating the solid by adding an antisolvent to SO obtain the substantially pure prasugrel HCI crystalline form G2.

30. The process of claim 29, wherein the solvent is selected from water, C_1-4 alcohols, C₅.₈ cyclic, branched, halogenated hydrocarbons, C _3-7 esters, C _3-7 nitriles, C 2.₈ ethers and mixtures thereof.

31. The process of claim 30, wherein the solvent is selected from methanol, ethanol,

!5 isopropanol, dichloromethane, ethyl acetate, isobutyl acetate, acetonitrile, THF, 1 ,4- dioxane and mixtures thereof.

32. The process of claim 31 , wherein the solvent used is isopropyl alcohol.

33. The process of claim 29, wherein the solution is prepared at temperature from about 25⁰C to about reflux temperature of the solvent or mixture of solvents used.

34. The process of claim 33, wherein the antisolvent is selected from C-u aliphatic, aromatic hydrocarbons, C _2-8 ethers and mixtures thereof.

35. The process of claim 34, wherein the antisolvent is n-hexane, n-heptane, cyclohexane, toluene and mixtures thereof.

36. The process of claim 35, wherein the anti solvent is n-hexane.

37. Prasugrel having a mean particle size less than about 90 μm.

38. Prasugrel crystal particles having a specific surface area from about 0.1 m²/g to about 1m²/g, as measured by B. E. T.

39. Prasugrel crystal particles having flake shape as observed by SEM, which is substantially in accordance with Fig.8

40. Prasugrel hydrochloride having a mean particle size less than about 10μm.

41. Prasugrel hydrochloride crystal particles having a specific surface area from about 1 m²/g to about 5 m²/g, as measured by B.E.T.

42. Prasugrel hydrochloride crystal particles having a condensation floe shape as observed by SEM , which is substantially in accordance with Fig. 9.

43. A pharmaceutical composition comprising prasugrel or a pharmaceutically acceptable salts thereof of formula Ia obtained by the process described above and at least one pharmaceutically acceptable carrier.

Ia

10

Fig.1

15