The following specification describes the invention.

INTRODUCTION

Aspects of the present application relate to process for the preparation of prasugrel hydrobromide and pharmaceutical compositions comprising prasugrel hydrobromide.

The drug compound having the adopted name “prasugrel hydrochloride” can be represented by structural formula (I), and it is a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 adenosine diphosphate (ADP) receptor.
(I)
Prasugrel hydrochloride is the hydrochloride salt of a racemate of prasugrel. A chemical name for prasugrel hydrochloride is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno [3, 2-c] pyridin-2-yl acetate hydrochloride, and it is the active ingredient in Effient® tablets approved for the treatment of acute coronary syndrome. Prasugrel hydrobromide is chemically described as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrobromide and can be represented by the structural formula (II).

(II)

U.S. Patent No. 5,288,726 discloses prasugrel, a tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a method for the treatment or prophylaxis of thrombosis or embolisms comprising administering a mammal an effective amount of the compound(s) thereof. The applicants of US 6,693,115, during the prosecution of the patent, described different pharmaceutically acceptable salts of prasugrel and process for their preparation including the salts such as prasugrel hydrobromide, prasugrel benzene sulfonate, prasugrel methanesulfonate etc. International Application Publication No. WO 2010/111951 A1, International Application Publication No. WO 2011/004392 A1, International Application Publication No. WO 2011/057593 A2, Chinese patent application publication CN 101255169 discloses process for the preparation of prasugrel hydrobromide and their crystalline forms.

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties, such as PXRD patterns, IR absorption spectra, melting points (MP), TGA curves, DSC curves, and solubilities.

Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure. The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, “Tricky Business,” Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form. There remains a need for the development of alternate forms of prasugrel hydrobromide and processes to prepare polymorphic forms in an environmentally-friendly, cost-effective, and industrially applicable manner.

SUMMARY

In an aspect, the application provides process for preparing prasugrel hydrobromide, embodiments comprising:

a) dissolving prasugrel in a solvent;

b) optionally, treating the solution with a decolorizing agent;

c) adding a source of hydrobromic acid to the solution obtained in steps a) or b); and

d) precipitating prasugrel hydrobromide by cooling the solution or by combining the solution with an anti-solvent for prasugrel hydrobromide.

In an aspect, the application provides process for preparing crystalline Form C of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?.

In another aspect, the application provides amorphous prasugrel hydrobromide.

In another aspect, the application provides process for the preparation of amorphous prasugrel hydrobromide.

In an aspect, the application provides crystalline form of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 8.4, 13.9, 17.4, 17.9, 18.6, 18.9, 21.8, 23.7, 24.7, 26.1, 26.6 and 30.7 ± 0.2° 2?.

In an aspect, the application provides process for preparing crystalline form of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 8.4, 13.9, 17.4, 17.9, 18.6, 18.9, 21.8, 23.7, 24.7, 26.1, 26.6 and 30.7 ± 0.2° 2?.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts PXRD pattern of prasugrel hydrobromide crystalline Form C obtained by the procedure of Example 3.

Fig. 2 depicts the PXRD pattern of amorphous prasugrel hydrobromide obtained by the procedure of Example 8.

Fig. 3 depicts PXRD pattern of prasugrel hydrobromide crystalline Form B obtained by the procedure of Example 11.

Fig. 4 depicts PXRD pattern of prasugrel hydrobromide crystalline Form D obtained by the procedure of Example 13.

Fig. 5 depicts PXRD pattern of crystalline form of prasugrel hydrobromide obtained by the procedure of Example 14.

DETAILED DESCRIPTION

In an aspect, the application provides process for preparing prasugrel hydrobromide, embodiments comprising:

a) dissolving prasugrel in a solvent;

b) optionally, treating the solution with a decolorizing agent;

c) adding a source of hydrobromic acid to the solution obtained in steps a) or b); and

d) precipitating prasugrel hydrobromide by cooling the solution or by combining the solution with an anti-solvent for prasugrel hydrobromide.

In embodiments of step a), prasugrel can be dissolved in any suitable inert solvent. Suitable inert solvent can be any solvent which has no adverse effect on the reaction and it can dissolve the starting material to some extent. Examples of such solvents include but are not limited to aliphatic hydrocarbons such as hexane, cyclohexane, heptane, or petroleum ether; aromatic hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; ester solvents such as ethyl acetate, propyl acetate or butyl acetate; alcohol solvents such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or C1-C6 alcohols; carboxylic acid solvents such as acetic acid or propionic acid; or nitrile solvents such as acetonitrile or propionitrile; any mixture of the said solvents; or any mixture of the said solvents with water. Prasugrel solution can also be obtained from the reaction mass of the previous stage.

In embodiments of step a), solution of prasugrel can be prepared at any suitable temperatures, such as from about 0°C to about the reflux temperature of the solvent, or from about 0°C to about 80°C. Stirring may be used to reduce the time required for the dissolution process. Optionally, additional organic solvent may be added to make the solution. Optionally, the solution of prasugrel can be obtained from the reaction mass of the previous stage.

In embodiments of step b) optionally, the solution of prasugrel may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may optionally be treated with a decolorizing agent such as carbon, before the filtration.

In embodiments of step c), prasugrel solution obtained above can be added dropwise in a single lot or in parts to a source of hydrogen bromide. In embodiments of step c), a source of hydrogen bromide can be added or introduced into a prasugrel solution. Alternatively, in embodiments of step c), a source of hydrogen bromide can be added dropwise in a single lot or in parts to prasugrel solution. In embodiments of step c), a source of hydrogen bromide can be hydrobromic acid such as concentrated hydrobromic acid or aqueous diluted hydrobromic acid, hydrogen bromide gas, an organic solvent hydrobromide such as methanol hydrobromide, ethanol hydrobromide, isopropyl alcohol hydrobromide, ethyl acetate hydrobromide, an acid bromide such as acetyl bromide, or a quaternary ammonium salt such as ammonium bromide. In embodiments of step c), an organic solvent hydrobromide can be prepared by introducing hydrobromide gas to the organic solvent or adding hydrobromic acid solution such as aqueous hydrobromic acid to the organic solvent.

In embodiments of step c), the addition of prasugrel solution or a source of hydrogen bromide to the other can be done at any suitable temperatures, such as from about -10°C to about 80°C or from about 0°C to about 60°C. In embodiments of step c), optionally the seed crystal of prasugrel hydrobromide can be added before the initiation of the solid formation to the reaction mass prepared above.

In embodiments of step d), prasugrel hydrobromide can be obtained by cooling the solution obtained in the step c), and maintaining for a time from about 1 hour to about 20 hours, or longer. In embodiments of step d), a solution of prasugrel hydrobromide can be combined with any suitable anti-solvent. In a suitable anti-solvent, prasugrel hydrobromide has lower solubility, compared to the solubility of prasugrel hydrobromide in the solvent. An anti-solvent generally will have less polarity than the polarity of the solvent. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. In embodiments of step d), the reaction mass obtained can be maintained for a time from about 1 hour to about 20 hours, or longer.

In embodiments of step d), prasugrel hydrobromide produced in the reaction can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, evaporation of solvent, or the like, and optionally washing the resulting solid with a solvent. In one embodiment, the washing is with the solvent used in the above reaction. In embodiments of step d), the prasugrel hydrobromide that is isolated can be dried at suitable temperatures, such as from about 40°C to about 100°C, at suitable pressures, and for times from about 1 hour to about 15 hours or longer, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In an aspect, the application provides a process for preparing crystalline Form C of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?.

In an aspect, the application provides process for preparing crystalline Form C of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?, embodiments comprising:

a) dissolving prasugrel in a solvent selected from ketones such as methyl ethyl ketone or methyl isobutyl ketone; esters such as ethyl acetate; or their mixtures;

b) optionally, treating the solution with a decolorizing agent;

c) adding a source of hydrobromic acid to the solution obtained in steps a) or b); and

d) precipitating crystalline Form C of prasugrel hydrobromide by cooling the solution or by combining the solution with an anti-solvent for prasugrel hydrobromide.

In embodiments of step a), prasugrel can be dissolved in solvents such as from ketones such as methyl ethyl ketone or methyl isobutyl ketone; esters such as ethyl acetate; or their mixture. In embodiments of step a), solution of prasugrel can be prepared at any suitable temperatures, such as from about 0°C to about the reflux temperature of the solvent or from about 0°C to about 80°C. Stirring may be used to reduce the time required for the dissolution process. Optionally, additional organic solvent may be added to make the solution. Prasugrel solution can also be obtained from the reaction mass of the previous stage.

In embodiments of step b) optionally, the solution of prasugrel may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may optionally be treated with a decolorizing agent such as carbon, before the filtration.

In embodiments of step c), a source of hydrobromic acid is added to the prasugrel solution obtained in step- a) or step- b). In embodiments of step c), prasugrel solution obtained above can be added dropwise in a single lot or in parts to a source of hydrogen bromide. In embodiments of step c), a source of hydrogen bromide can be added or introduced into a prasugrel solution. Alternatively, in embodiments of step c), a source of hydrogen bromide can be added dropwise in a single lot or in parts to prasugrel solution. In embodiment of step c), a source of hydrogen bromide can be hydrobromic acid such as concentrated hydrobromic acid or aqueous diluted hydrobromic acid, hydrogen bromide gas, an organic solvent hydrobromide such as methanol hydrobromide, ethanol hydrobromide, isopropyl alcohol hydrobromide, ethyl acetate hydrobromide or the like. In embodiments of step c), an organic solvent hydrobromide can be prepared by introducing hydrobromide gas to the organic solvent or adding hydrobromic acid solution such as aqueous hydrobromic acid to the organic solvent.

In embodiments of step c), the addition of a source of hydrogen bromide to prasugrel solution can be done at any suitable temperatures, such as from about -10°C to about 80°C or from about 0°C to about 60°C.

In embodiments of step d), prasugrel hydrobromide can be obtained by cooling the solution obtained in the step c), and maintaining for a time from about 1 hour to about 20 hours, or longer. In embodiments of step d), prasugrel hydrobromide obtained can be isolated by the techniques known in the art or techniques described in the present application. In embodiments of step d), prasugrel hydrobromide obtained can be dried by the techniques known in the art or techniques described in the present application. In embodiments of step d), prasugrel hydrobromide obtained in step d), has PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?. In embodiments of step d), prasugrel hydrobromide obtained characterized by a PXRD pattern has peaks located substantially as shown in Fig. 1.

In an aspect, the application provides process for preparing crystalline Form C of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?, embodiments comprising:

a) dissolving prasugrel hydrobromide in a solvent selected from methyl ethyl ketone, methyl isobutyl ketone; esters such as ethyl acetate or their mixture;

b) optionally, treating the solution with a decolorizing agent; and

c) precipitating prasugrel hydrobromide by cooling the solution or by combining the solution with an anti-solvent for prasugrel hydrobromide.

In embodiments of step a), prasugrel hydrobromide can be dissolved in solvents such as from ketones such as methyl ethyl ketone or methyl isobutyl ketone; esters such as ethyl acetate; or their mixture. In embodiments of step a), solution of prasugrel hydrobromide can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent or from about 0°C to about 80°C. Stirring may be used to reduce the time required for the dissolution process. Optionally, additional organic solvent may be added to make the solution.

In embodiments of step b) optionally, the solution of prasugrel hydrobromide may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may optionally be treated with a decolorizing agent such as carbon, before the filtration.

In embodiments of step c), prasugrel hydrobromide can be obtained by cooling the solution obtained in the step b), or combining with an anti solvent and maintaining for a time from about 1 hour to about 20 hours, or longer. In embodiments of step c), prasugrel hydrobromide obtained can be isolated by the techniques known in the art or techniques described in the present application. In embodiments of step c), prasugrel hydrobromide obtained can be dried the techniques known in the art or techniques described in the present application. In embodiments of step c), the prasugrel hydrobromide obtained in step c) has a PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?. In embodiments of step c), the prasugrel hydrobromide obtained is characterized by a PXRD pattern having peaks located substantially as shown in Fig. 1.

In an aspect, the application provides a process for preparing crystalline Form C of prasugrel hydrobromide having a PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2? comprising slurrying a crystalline form of prasugrel hydrobromide in a solvent. In embodiments, a crystalline form of prasugrel hydrobromide can be slurried in a suitable solvent.

The suitable solvent includes but not limited to ketones such as methyl ethyl ketone or methyl isobutyl ketone, esters such as ethyl acetate, aromatic hydrocarbons such as toluene, or any mixture thereof. In embodiments, a crystalline form of prasugrel hydrobromide can be slurried at any suitable temperatures, such as from about 0°C to about the reflux temperature of the solvent or from about 10°C to about 60°C. In embodiments, prasugrel hydrobromide obtained can be isolated by the techniques known in the art or techniques described in the present application. In embodiments, prasugrel hydrobromide obtained can be dried the techniques known in the art or techniques described in the present application.

In embodiments, the prasugrel hydrobromide obtained above has a PXRD pattern with characteristic peaks located at about 7.9, 13.5, 14.6, 16.9, 21.4, 22.1, 24.4 and 25.0 ± 0.2° 2?. In embodiments, the prasugrel hydrobromide obtained is characterized by a PXRD pattern having peaks located substantially as shown in Fig. 1.

In an aspect, the application provides amorphous prasugrel hydrobromide.

In an aspect, the application provides a process for preparing amorphous prasugrel hydrobromide comprising:

a) providing a solution of prasugrel hydrobromide in a solvent;

b) optionally, treating the solution with a decolorizing agent; and

c) removing the solvent.

Prasugrel hydrobromide can be dissolved in any solvents that are inert to the solutes. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, or butyl acetate; alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or C1-C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane or chloroform; or any mixtures of two or more thereof.

In embodiments, a solution of prasugrel hydrobromide can be prepared at any suitable temperatures, such as from about 0°C to about the reflux temperature of the solvent. Stirring may be used to reduce the time required for the dissolution process. Optionally, the solution of prasugrel hydrobromide can be obtained from the reaction mass of the previous stage. The prasugrel hydrobromide solution can also be obtained by treating the prasugrel solution with a source of hydrogen bromide according to the processes described in this application. In embodiments, solutions comprising prasugrel hydrobromide, may be filtered to make them clear and free of unwanted particles. In embodiments, the solutions may optionally be treated with a decolorizing agent, such as carbon, before filtration. In embodiments, the solvent can be removed by any techniques known in the art such as lyophilization, freeze drying, spray drying, thin film drying, flash drying, evaporation under vacuum etc.

Fig. 2 illustrates the PXRD pattern of amorphous prasugrel hydrobromide, obtained by a process of the present application. The pattern does not have identifiable peaks, but is a “halo” showing the amorphous nature of the material.

In an aspect, the application provides crystalline form of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 8.4, 13.9, 17.4, 17.9, 18.6, 18.9, 21.8, 23.7, 24.7, 26.1, 26.6 and 30.7 ± 0.2° 2?. In an aspect, the application provides a crystalline form of prasugrel hydrobromide, characterized by a PXRD pattern having peaks located substantially as shown in Fig. 5.

In an aspect, the application provides process for preparing crystalline form of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 8.4, 13.9, 17.4, 17.9, 18.6, 18.9, 21.8, 23.7, 24.7, 26.1, 26.6 and 30.7 ± 0.2° 2?, comprising slurrying the crystalline Form A of prasugrel hydrobromide in acetonitrile.

In specific embodiments, the application provides a process for the preparation of crystalline Form B of prasugrel hydrobromide comprising dissolving prasugrel in methyl isobutyl ketone followed by the addition of aqueous solution of hydrobromic acid in ethanol to the prasugrel solution.

In another specific embodiments, the application provides a process for the preparation of crystalline Form D of prasugrel hydrobromide comprising dissolving prasugrel in methyl isobutyl ketone followed by the addition of aqueous solution of hydrobromic acid in acetone to the prasugrel solution.

In embodiments, prasugrel hydrobromide obtained from any of the processes described herein can be purified by any method known in the art such as recrystallization involving single solvent, mixture of solvents or solvent-anti solvent technique; reprecipitation; slurring in a solvent; or chromatography to improve its chemical purity. Any of the solvents described in the present application, can be used for the purification of prasugrel hydrobromide. In embodiments, prasugrel or prasugrel hydrobromide which is used as the starting material can be prepared by any method, including methods known in the art, and optionally can be purified using any method known in the art to enhance its chemical purity.

The X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2o) of 7.9" means "having a diffraction peak at a diffraction angle (2?) of 7.7o to 8.1o. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2.degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not.

Prasugrel hydrobromide obtained according to the process of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce a desired particle size distribution. An aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of prasugrel hydrobromide together with one or more pharmaceutically acceptable excipients.

Prasugrel hydrobromide obtained according to certain processes of the present application has a particle size distribution wherein: d(0.5) is less than about 200 µm, less than about 25 µm, or less than about 10 µm; and d(0.9) is less than about 250 µm, less than about 50 µm, or less than about 25 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.

The pharmaceutical compositions comprising prasugrel hydrobromide of the invention together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to, powders, granules, pellets, tablets, or capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present invention include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, or waxes; or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

DEFINITIONS

The following definitions are used in connection with the compounds of the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like. The term "reacting" is intended to represent bringing the chemical reactants together under condition such to cause the chemical reaction indicated to take place. The term “prasugrel” is intended to represent the free base of prasugrel. The following abbreviations and acronyms are used herein and have the indicated definitions: HPLC is high-pressure liquid chromatography and RT is retention time.

“Alcohols” are organic solvents containing a carbon bound to a hydroxyl group. “C1-C6Alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic or aromatic hydrocarbon” is a liquid hydrocarbon, which may be linear, branched, or cyclic and may be saturated, unsaturated, or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of “C5-C8 aliphatic or aromatic hydrocarbons”, include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof.

An “ester” is an organic solvent containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 Esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An “ether” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “C2-6Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.

A “halogenated hydrocarbon” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbons” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A “ketone” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-6Ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A “nitrile” is an organic solvent containing a cyano -(C=N) bonded to another carbon atom. “C2-6 Nitrile solvents” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application.

EXAMPLES

Example 1: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel (5 g) and methyl isobutyl ketone (75 mL) are charged into a round bottom flask at 27°C. The reaction mass is stirred to obtain a clear solution at 27°C. The reaction mass is cooled to 10°C. An aqueous solution of hydrobromic acid (2.3 g) in methyl isobutyl ketone (20 mL) is added dropwise to the reaction mass at 10°C over 45 minutes. The reaction mass is stirred for 2 hour at 14°C. The solid is collected by filtration and washed with methyl isobutyl ketone (2 X 20 mL). The compound is dried under vacuum at 55°C for 7 hours. Yield: 3.9 g; HPLC Purity: 99.68%. The PXRD pattern is shown in Fig. 1.

Example 2: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel (5 g), methyl isobutyl ketone (50 mL), and ethyl acetate (50 mL) are charged into a round bottom flask at 27°C. The reaction mass is stirred to obtain a clear solution at 27°C. The reaction mass is cooled to 10°C. An aqueous solution of hydrobromic acid (2.3 g) in methyl isobutyl ketone (20 mL) is added dropwise to the reaction mass at 10°C over 1 hour. The reaction mass is stirred for 2 hour at 12°C. The solid is collected by filtration and washed with ethyl acetate (2 X 20 mL). The compound is dried under vacuum at 55°C for 8 hours. Yield: 6.0 g; HPLC Purity: 99.8%. The PXRD pattern is shown in Fig. 1.

Example 3: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel (5 g) and ethyl acetate (75 mL) are charged into a round bottom flask at 27°C. The reaction mass is stirred to obtain a clear solution at 27°C. An aqueous solution of hydrobromic acid (2.2 g) in methyl isobutyl ketone (20 mL) is added dropwise to the reaction mass at 27°C over 1 hour 15 minutes. The reaction mass is stirred for 2 hours 30 minutes at 27°C. The solid is collected by filtration and washed with ethyl acetate (2 X 20 mL). The compound is dried under vacuum at 50°C for 10 hours. Yield: 5.7 g; HPLC Purity: 99.94%. The PXRD pattern is shown in Fig. 1.

Example 4: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel hydrobromide Form A (5 g) and methyl isobutyl ketone (50 mL) are charged into a round bottom flask at 28°C. The obtained suspension is stirred for 1 hour 30 minutes at 28°C. The title compound is obtained by filtration. The obtained compound is dried under vacuum at 50°C for 15 hours. HPLC purity: 99.74%. The PXRD pattern is shown in Fig. 1.

Example 5: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel hydrobromide Form A (5 g) and toluene (50 mL) are charged into a round bottom flask at 28°C. The obtained suspension is stirred for 1 hour 30 minutes at 28°C. The title compound is obtained by filtration. The obtained compound is dried under vacuum at 54°C for 24 hours. HPLC purity: 99.32%. The PXRD pattern is shown in Fig. 1.

Example 6: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel hydrobromide Form A (5 g) and ethyl acetate (50 mL) are charged into a round bottom flask at 27°C. The obtained suspension is stirred for 1 hour 30 minutes at 27°C. The title compound is obtained by filtration. The obtained compound is dried under vacuum at 50°C for 12 hours. HPLC purity: 99.77%. The PXRD pattern is shown in Fig. 1.

Example 7: Preparation of prasugrel hydrobromide crystalline Form C: Prasugrel (5 g) and ethyl acetate (50 mL) are charged into a round bottom flask at 26°C. The reaction mass is stirred to obtain a clear solution at 26°C. Ethyl acetate solution of hydrobromic acid (12.8 mL, 8 %) is added dropwise to the reaction mass at 26°C in 15 minutes. The reaction mass is stirred for 1 hours 30 minutes at 26°C. The solid is collected by filtration and washed with ethyl acetate (10 mL). The compound is dried under vacuum at 68°C for 10 hours. Yield: 4.1 g; HPLC Purity: 99.56%. The PXRD pattern is shown in Fig. 1.

Example 8: Preparation of amorphous prasugrel hydrobromide: Prasugrel hydrobromide (5 g) and methanol (25 mL) are charged into a round bottom flask at 28°C. The reaction mass is stirred to obtain a clear solution. The solvent is evaporated from the reaction mass under vacuum at 45°C to give a solid material which is further dried under vacuum for 12 hours at 50°C to obtain amorphous prasugrel hydrobromide. Yield: 4.5 g. HPLC purity: 99.02%. The PXRD pattern is shown in Fig. 2.

Example 9: Preparation of amorphous prasugrel hydrobromide: Prasugrel hydrobromide (5 g) and dichloromethane (25 mL) are charged into a round bottom flask at 28°C. The reaction mass is stirred to obtain a clear solution. The solvent is evaporated from the reaction mass under vacuum at 45°C to give a solid material which is further dried under vacuum for 12 hours at 50°C to obtain amorphous prasugrel hydrobromide. Yield: 4.9 g. HPLC purity: 98.83%.

Example 10: Preparation of amorphous prasugrel hydrobromide: Prasugrel hydrobromide (5 g) and methanol (25 mL) are charged into a round bottom flask at 28°C. The reaction mass is stirred to obtain a clear solution. The obtained solution is spray dried under nitrogen atmosphere to give amorphous prasugrel hydrobromide. Yield: 1.9 g. HPLC purity: 99.49%.

Example 11: Preparation of prasugrel hydrobromide crystalline Form B: Prasugrel (20 g) and methyl isobutyl ketone (400 mL) are charged into a round bottom flask at 27°C. The reaction mass is stirred to obtain a clear solution at 27°C. The reaction mass is cooled to 12°C. An aqueous solution of hydrobromic acid (8.8 g) in ethanol (80 mL) is added dropwise to the reaction mass at 12°C over 1 hour 40 minutes. The reaction mass is stirred for 2 hour at 12°C. The solid is collected by filtration and washed with methyl isobutyl ketone (80 mL). The compound is dried under vacuum at 51°C for 22 hours. Yield: 17.2 g; HPLC Purity: 99.93%. The PXRD pattern is shown in Fig. 3.

Example 12: Preparation of prasugrel hydrobromide crystalline Form B: Prasugrel hydrobromide Form A (5 g) and methyl ethyl ketone (50 mL) are charged into a round bottom flask at 27°C. The suspension obtained is stirred for 1 hour 30 minutes at 27°C. The title compound is obtained by filtration. The compound obtained is dried under vacuum at 50°C for 9 hours. HPLC purity: 99.82%.

Example 13: Preparation of prasugrel hydrobromide crystalline Form D: Prasugrel (20 g) and methyl isobutyl ketone (300 mL) are charged into a round bottom flask at 28°C. The reaction mass is stirred to obtain a clear solution at 28°C. The reaction mass is cooled to 12°C. An aqueous solution of hydrobromic acid (8.8 g) in acetone (80 mL) is added dropwise to the reaction mass at 12°C over 1 hour 20 minutes. The reaction mass is stirred for 2 hour at 12°C. The solid is collected by filtration and washed with acetone (80 mL). The compound is dried under vacuum at 51°C for 18 hours. Yield: 21.7 g; HPLC Purity: 98.63%. The PXRD pattern is shown in Fig. 4.

Example 14: Preparation of crystalline prasugrel hydrobromide: Prasugrel hydrobromide Form A (3 g) and acetonitrile (30 mL) are charged into a round bottom flask at 28°C. The obtained suspension is stirred for 1 hour 30 minutes at 28°C. The solid compound is obtained by filtration and washed with acetonitrile (12 mL). The obtained compound is dried under vacuum at 50°C for 12 hours. HPLC purity: 99.83%. The PXRD pattern is shown in Fig. 5.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the application. It is therefore intended to cover in the application all such changes and modifications that are within the scope of this application.

CLAIMS:

1. A process for preparaing crystalline Form C of prasugrel hydrobromide comprising;

a) dissolving prasugrel in a solvent selected from ketones such as methylethylketone or methylisobutylketone; esters such as ethyl acetate; or their mixtures;

b) adding a source of hydrobromic acid to the solution obtained in step a); and

c) isolating crystalline Form C of prasugrel hydrobromide.

2. A process according to claim 1, wherein a source of hydrobromic acid used in step b) can be selected from concentrated hydrobromic acid or aqueous diluted hydrobromic acid,

hydrogen bromide gas, aqueous hydrobromic acid dissolved in an organic solvent, an organic solvent hydrobromide such as methanol hydrobromide, isopropyl alcohol hydrobromide,

ethyl acetate hydrobromide methylisobutylketone hydrobromide, ethylmethylketone or the like.

3. A process for preparaing crystalline Form C of prasugrel hydrobromide comprising;

a) dissolving or suspending prasugrel hydrobromide in a solvent; and

b) isolating prasugrel hydrobromide Form C by cooling the solution or suspension obtained in step a).

4. A process according to claim 3, wherein the solvent used in step a) can be selected from ketones such as methylethylketone or methylisobutylketone, esters such as ethyl acetate, aromatic hydrocarbons such as toluene, or any mixture thereof.

5. An amorphous form of Prasugrel hydrobromide.

6. A process for preparing amorphous form of Prasugrel hydrobromide comprising;

a) providing a solution of prasugrel hydrobromide in a solvent; and

b) isolating the amorphous prasugrel hydrobromide by removing the solvent.

7. A crystalline form of prasugrel hydrobromide having PXRD pattern with characteristic peaks located at about 8.4, 13.9, 17.4, 17.9, 18.6, 18.9, 21.8, 23.7, 24.7, 26.1, 26.6 and 30.7 ± 0.2° 29.

8. A crystalline form of prasugrel hydrobromide according to claim 7, characterized in that it provides PXRD pattern substantially in accordance with Fig.5.

9. A process for preparing crystalline form of prasugrel hydrobromide according to claims 7 and 8, comprising;

a) slurrying the crystalline Form A of prasugrel hydrobromide in acetonitrile; and

b) isolating the crystalline form of prasugrel hydrobromide.

10. A pharmaceutical composition comprising the crystalline Form C of prasugrel hydrobromide or amorphous prasugrel hydrobromide or crystalline form of prasugrel hydrobromide according to claims 7, 8 and 9 and one or more pharmaceutical^ acceptable carrier.