DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
CRYSTALLINE POLYMORPH, COCRYSTAL OF SOFOSBUVIR AND PROCESSES FOR THEIR PREPARATION

INTRODUCTION
Aspects of the present application relate to crystalline form of sofosbuvir, cocrystal of sofosbuvir and processes for their preparation. Further aspects relate to pharmaceutical compositions comprising the crystalline polymorph and cocrystal of sofosbuvir.
Sofosbuvir is one of the nucleoside phosphoramidate prodrugs which chemically described as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy) (phenoxy) phosphorylamino) propanoate. It has the structure of Formula A.

Formula A
Sofosbuvir is an orally administrable, direct-acting antiviral agent against the hepatitis C virus which is approved in USA for the treatment of subjects with HCV genotype 1, 2, 3 or 4 infections. U.S. Patent No. 7,964,580 B2 discloses sofosbuvir and process for its preparation.
U.S. Patent No. 8,618,076 B2 describes six polymorphic forms of sofosbuvir. This patent describes Form 1, Form 2, Form 3, Form 4, Form 5, Form 6 and amorphous form and their processes for preparation by using different solvents.
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.
Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same molecular 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.
The active pharmaceutical ingredients (APIs) containing an acidic or basic functional group this principle can be exploited by the preparation of various crystalline salts of the active pharmaceutical ingredient to modulate and optimize the physicochemical properties of the obtained crystalline solid for a specific application. The changes in the physicochemical properties resulting from the inclusion of a counter ion in the crystal structure are a consequence of both the molecular structure and properties of the active pharmaceutical molecule and counter ion and the intermolecular interactions between the molecules in the crystal structure. It is therefore possible to change the physicochemical properties of the crystalline solid through the inclusion of different counter ions, giving crystalline salts with different physicochemical properties.
A major limitation of salt formation is that it is inapplicable to neutral APIs. Furthermore, the range of possible counter ions for weakly acidic or weakly basic APIs can be limited by the ionization constant of the acid or base groups on the molecule.
On the other hand, the formation of pharmaceutically acceptable cocrystals of active pharmaceutical ingredients provides an alternative approach to the generation of new solid forms of the active substance. In this context a cocrystal, or alternatively co-crystal, is understood to be a binary molecular crystal containing the molecules of the API together with another molecular species in a defined stoichiometric ratio where both components are in their neutral state. In this case the terms "cocrystal" and "co-crystal" are generally understood to be synonymous terms referring to such a system. The second component in the cocrystal (the component other than the active pharmaceutical ingredient) is commonly referred to as a "cocrystal former". Pharmaceutically acceptable cocrystal formers include any molecule considered acceptable as a counter ion for a pharmaceutical salt or known as a pharmaceutical excipient.
A widely accepted definition of a pharmaceutical cocrystal is a crystalline system containing an active pharmaceutical molecule and a cocrystal former that is a solid at ambient temperature and pressure in a defined stoichiometric ratio, although a cocrystal is not limited to containing only two components. The components of the cocrystal are linked by hydrogen bonding and other non-covalent and non-ionic interactions. This definition differentiates cocrystals from crystalline solvates, in which case one of the components is a liquid at ambient temperature and pressure.
There remains a need for additional polymorphic form, cocrystal of sofosbuvir and for processes to prepare polymorphic and cocrystal forms in an environmentally-friendly, cost-effective, and industrially applicable manner.
SUMMARY
In an aspect, the application provides a crystalline Form A of sofosbuvir, characterized by a PXRD pattern comprising peaks at about 4.55, 8.53, 9.10, 12.78 and 13.68 ±0.2° 2?. Crystalline Form A of sofosbuvir further characterized by PXRD pattern having peaks selected from the following: about 4.91, 7.15, 15.91, 17.91 and 25.04 ±0.2°2?.
In another aspect, the application provides a process for preparation of Form A comprising peaks at about 4.55, 8.53, 9.10, 12.78 and 13.68 ±0.2° 2?; comprising:
a) contacting sofosbuvir and a solvent or a mixture of solvents wherein the solubility of sofosbuvir is low;
b) mixing the slurry obtained in step (a);
c) isolating crystalline Form A of sofosbuvir.
In an aspect, the application provides a cocrystal of sofosbuvir with caffeine, characterized by a PXRD pattern comprising peaks at about 3.70, 4.42, 5.32, 14.82, 16.36, 17.21 and 21.04 ± 0.2° 2?. Cocrystal of sofosbuvir with caffeine, further characterized by PXRD pattern having peaks selected from the following: about 7.41, 10.03 and 19.36 ± 0.2° 2?.
In another aspect, the application provides a process for preparation of cocrystal of sofosbuvir with caffeine comprising peaks at about 3.70, 4.42, 5.32, 14.82, 16.36, 17.21 and 21.04 ± 0.2° 2?; comprising:
a) contacting sofosbuvir and caffeine to a solvent or a mixture of solvents wherein the solubility of sofosbuvir and caffeine is low;
b) contacting slurry obtained in step (a) with a solvent or a mixture of solvents;
c) mixing the slurry obtained in step (b);
d) isolating the cocrystal of sofosbuvir with caffeine.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts a PXRD pattern of sofosbuvir Form A, obtained by the procedure of Example 2.
Fig. 2 depicts a PXRD pattern of a cocrystal of sofosbuvir with caffeine, obtained by the procedure of Example 4, after vacuum filtration.
Fig. 3 depicts a PXRD pattern of a cocrystal of sofosbuvir with caffeine, obtained by the procedure of Example 4, after vacuum filtration followed by drying at 40°C in Air tray dryer for about 1 hour.
DETAILED DESCRIPTION
In an aspect, the application provides a crystalline Form A of sofosbuvir, characterized by a PXRD pattern comprising peaks at about 4.55, 8.53, 9.10, 12.78 and 13.68 ±0.2° 2?. Crystalline Form A sofosbuvir further characterized by PXRD pattern comprising peaks at about 4.91, 7.15, 15.91, 17.91 and 25.04 ±0.2° 2?.
In another aspect, the application provides a process for preparation of Form A comprising peaks at about 4.55, 8.53, 9.10, 12.78 and 13.68 ±0.2° 2?; embodiments comprising:
a) contacting sofosbuvir with a solvent or a mixture of solvents wherein the solubility of sofosbuvir is low;
b) mixing the slurry obtained in step (a);
c) isolating crystalline Form A of sofosbuvir.
In embodiment, the application provides a process for preparation of Form A of sofosbuvir, wherein step a) involves contacting sofosbuvir to a solvent or a mixture of solvents wherein the solubility of sofosbuvir is low. In embodiments, sofosbuvir added into a solvent or a mixture of such solvents wherein sofosbuvir has low solubility. In embodiments, a solvent a mixture of solvents which would least dissolve sofosbuvir is added to sofosbuvir. In embodiments, the ratio of sofosbuvir to a solvent or a mixture of such solvents, wherein sofosbuvir has low solubility, used is about 1: 20 to about 20: 1.
In embodiment, the solvents or a mixture of solvents used are those wherein the sofosbuvir has low solubility. In embodiment, the solvents or mixture of solvents used are anti-solvents or mixture of anti-solvents. In embodiments, slurry of sofosbuvir is prepared by contacting sofosbuvir to anti-solvent or mixture of anti-solvents or vice versa. The anti-solvents used in the process can be alkanes or cycloalkanes or aromatic hydrocarbons or ethers and their mixtures comprising but not limited to n-heptane, n-hexane, cyclohexane, n-pentane, xylenes, toluene, MTBE, DIPE and their combinations. In embodiments, the ratio of sofosbuvir to anti-solvent or mixture of anti-solvents used is about 1: 20 to about 20: 1.
In embodiment, the application provides a process for preparation of Form A of sofosbuvir, wherein step b) involves, mixing the slurry obtained in step (a). In embodiments, sofosbuvir and anti-solvent or mixture of anti-solvents is allowed to physical mixing. In embodiments, sofosbuvir and anti-solvent or mixture of anti-solvents is allowed to mechanical stirring. In embodiments, sofosbuvir and anti-solvent or mixture of anti-solvents is allowed to slurrying. Mixing may be used to reduce the time required for the making slurry.
In embodiments, slurry of sofosbuvir can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature based on the anti-solvent or mixture of anti-solvents selected. In embodiment, the slurrying comprises suspending sofosbuvir. The slurry of sofosbuvir can be maintained at any suitable temperatures, such as from about -5°C to 80°C. Optionally, the slurry of sofosbuvir and anti-solvent or mixture of anti-solvents is heated once after formation of slurry. Slurrying at above room temperature may reduce the required time for the formation Form A of sofosbuvir.
In embodiment, optionally solvents wherein sofosbuvir is soluble can be added to the slurry of sofosbuvir and anti-solvents or mixture of anti-solvents. The solvent or mixture of solvents can be added at any suitable temperatures, such as from about room temperature to about the reflux temperature based on the solvent or mixture of solvents added to the slurry. The solvents can be used this process preferably comprising but not limited to alcohols such as propanol, ethanol and methanol or their combination.
In embodiment, the temperature at which the slurry is maintained plays a role with respect to time for which the desired formation of Form A of sofosbuvir.
In embodiments, optionally slurry of sofosbuvir and anti-solvent or mixture of anti-solvents is cooled. In embodiments, optionally slurry of sofosbuvir, anti-solvent or mixture of anti-solvents and solvent or mixture of solvents can be cooled. Slurry of sofosbuvir can be cooled to a temperature ranging from 28°C to -5°C or lower.
In embodiment, in general, yields of the crystalline product will be improved by maintaining the reaction mass at lower temperatures that are above the freezing point of the solvent or anti-solvent, and/or by increasing the solute content of the solution.
In embodiment, the application provides a process for preparation of Form A of sofosbuvir, wherein step c) involves, isolating crystalline Form A of sofosbuvir. In embodiments, crystalline Form A of sofosbuvir can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, crystalline Form A of sofosbuvir can be isolated by filtration and optionally washing the wet cake with the same solvent.
In embodiments, crystalline Form A of sofosbuvir that is isolated can be dried at suitable temperatures such as room temperature to about 50°C reduced pressures, for about 10 minutes to about 10 hours, or longer, using any types of drying equipment, 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 cocrystal of sofosbuvir with caffeine, characterized by a PXRD pattern comprising peaks at about 3.70, 4.42, 5.32, 14.82, 16.36, 17.21 and 21.04 ± 0.2° 2?. Cocrystal of sofosbuvir with caffeine, further characterized by PXRD pattern having peaks selected from the following: about 7.41, 10.03 and 19.36 ± 0.2° 2?.
The cocrystal of sofosbuvir with caffeine described herein in the present application is consistently reproducible and cocrystal of sofosbuvir with caffeine which may be used in the preparation of pharmaceutical formulations for the treatment of HCV genotype 1, 2, 3 or 4 infections.
In another aspect, the application provides a process for preparation of cocrystal of sofosbuvir with caffeine comprising peaks at about 3.70, 4.42, 5.32, 14.82, 16.36, 17.21 and 21.04 ± 0.2° 2?; comprising:
a) contacting sofosbuvir and caffeine to a solvent or a mixture of solvents wherein the solubility of sofosbuvir and caffeine is low;
b) contacting slurry obtained in step (a) with a solvent or a mixture of solvents;
c) mixing the slurry obtained in step (b);
d) isolating the cocrystal of sofosbuvir with caffeine.
In embodiment, the application provides a process for preparation of cocrystal of sofosbuvir with caffeine, wherein step a) involves contacting sofosbuvir and caffeine to a solvent or a mixture of solvents wherein the solubility of sofosbuvir and caffeine is low. In embodiments, sofosbuvir added into a solvent or a mixture of such solvents wherein sofosbuvir caffeine have low solubility. In embodiments, a solvent a mixture of solvents which would least dissolve sofosbuvir and caffeine is added to sofosbuvir and caffeine. In embodiments, the ratio of sofosbuvir and caffeine mixture to a solvent or a mixture of such solvents, wherein sofosbuvir and caffeine have low solubility, used is about 1: 20 to about 20: 1.
In embodiment, the molar ratio of sofosbuvir and caffeine can be used in the range of about 5:1 to about 1:5. Caffeine can be initially added to sofosbuvir before contacting sofosbuvir with the solvent or a mixture of solvents (or) after contacting it with the solvent or mixture of solvents. Caffeine can be contacted with sofosbuvir or a solution of sofosbuvir in one lot or many lots.
In embodiment, the solvents or a mixture of solvents used are those wherein the sofosbuvir and caffeine have low solubility. In embodiment, the solvents or mixture of solvents used are anti-solvents or mixture of anti-solvents. In embodiments, slurry of sofosbuvir is prepared by contacting sofosbuvir to anti-solvent or mixture of anti-solvents or vice versa. The anti-solvents used in the process can be alkanes or cycloalkanes comprising but not limited to n-heptane, n-hexane, cyclohexane, n-pentane and their combinations. In embodiments, the ratio of sofosbuvir to anti-solvent or mixture of anti-solvents used is about 1: 20 to about 20: 1.
In embodiments, slurry of cocrystal of sofosbuvir with caffeine can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature based on the anti-solvent or mixture of anti-solvents selected. In embodiment, the slurrying comprises suspending sofosbuvir and caffeine. The slurry of sofosbuvir and caffeine can be maintained at any suitable temperatures, such as from about -5°C to 80°C. Optionally, the slurry of sofosbuvir and caffeine & anti-solvent or mixture of anti-solvents can be heated once after formation of slurry. Slurrying at above room temperature may reduce the required time for the formation cocrystal of sofosbuvir with caffeine. In embodiment, sofosbuvir, caffeine, solvents or a mixture of solvents used are those wherein the sofosbuvir and caffeine have low solubility can be added into a reactor in any order at a temperature ranging from about 10 to about 50°C, or longer.
In embodiment, the application provides a cocrystal of sofosbuvir with caffeine, wherein step b) involves contacting slurry obtained in step a) with a solvent or a mixture of solvents. The solvents or mixture of solvents are those wherein sofosbuvir and caffeine are soluble. The solvent or mixture of solvents can be added at any suitable temperatures, such as from about room temperature to about the reflux temperature based on the solvent or mixture of solvents added to the slurry. The solvents can be used this step preferably comprising but not limited to alcohols such as propanol, ethanol and methanol or their combination.
In embodiment, the application provides a process for preparation of cocrystal of sofosbuvir with caffeine, wherein step c) involves mixing the slurry obtained in step b). In embodiments, the slurry obtained in step b) is allowed to physical mixing. In embodiments, the slurry obtained in step b) is allowed to mechanical stirring. In embodiments, the slurry obtained in step b) is allowed to slurrying. Mixing may be used to reduce the time required for the making slurry.
In embodiments, optionally the slurry obtained in step c) is cooled. In embodiments, optionally slurry of sofosbuvir, caffeine, anti-solvent or mixture of anti-solvents and solvent or mixture of solvents can be cooled. Slurry of sofosbuvir and caffeine can be cooled to a temperature ranging from 28°C to -5°C or lower.
In embodiment, in general, yields of the cocrystalline product will be improved by maintaining the reaction mass at lower temperatures that are above the freezing point of the solvent or anti-solvent, and/or by increasing the solute content of the solution.
In embodiment, the application provides a process for preparation of cocrystal of sofosbuvir with caffeine, wherein step d) involves, isolating cocrystal of sofosbuvir with caffeine. In embodiments, cocrystal of sofosbuvir with caffeine can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, such as the solvent used for the crystallization to reduce the amount of entrained impurities in the product. In embodiments, cocrystal of sofosbuvir with caffeine can be isolated by filtration and optionally washing the wet cake with the same solvent.
In embodiments, cocrystal of sofosbuvir with caffeine that is isolated can be dried at suitable temperatures such as room temperature to about 50°C under atmospheric or reduced pressures, for about 10 minutes to about 10 hours, or longer, using any types of drying equipment, 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 embodiment, sofosbuvir which is used as the starting material may be prepared by any method, including methods known in art. Optionally, sofosbuvir which is used as the starting material may be purified by using any methods known in art to enhance chemical purity.
In embodiment, the staring material, i.e.: sofosbuvir used for the preparation of Form A and caffeine cocrystal may be any crystalline form or amorphous form, preferably Form 1 of sofosbuvir.
In embodiments, isolated crystalline Form A or cocrystal of sofosbuvir with caffeine according to the present invention can have a degree of crystallinity of at least about 80%, about 90%, about 95%, about 98%, about 99%, or above.
In embodiments, isolated crystalline Form A or cocrystal of sofosbuvir with caffeine according to the present invention can have isomeric purity of sofosbuvir at least about 90% of ‘S’ configuration at phosphorous position, about 98%, about 99%, or about 100%.
In embodiments, crystalline Form A or cocrystal of sofosbuvir with caffeine according to the present application can be substantially pure having a chemical purity greater than about 98% purity or greater than 99% purity, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using High Performance Liquid Chromatography (HPLC). Crystalline forms of sofosbuvir according to the present application can be chemically pure having purity greater than about 99% and containing no single known impurity in amounts greater than about 0.15%, by HPLC. In embodiment, crystalline forms of sofosbuvir according to the present application can be chemically pure having purity greater than about 99% and containing no single unknown impurity in amounts greater than about 0.1%, by HPLC.
Form A of sofosbuvir and cocrystal of sofosbuvir with caffeine according to the present invention can be used as intermediates in preparation of other polymorphic forms of sofosbuvir.
The pharmaceutical compositions comprising crystalline Form A or cocrystal of sofosbuvir with caffeine 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, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and 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, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.
The pharmaceutical compositions comprising crystalline Form A or cocrystal of sofosbuvir with caffeine of the invention together with one or more other active pharmaceutically ingredients, such as pan-genotypic NS5B/NS5A inhibitors, NS3 protease inhibitors, non-nucleoside NS5B site 2 polymerase inhibitors, pan-genotypic NS3 protease inhibitors, nucleotide reverse transcriptase inhibitors, Tarmogen T cell immunity stimulators, TLR-7 agonists, monoclonal antibodies etc., and 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, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and 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, and 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 application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and 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, and the like.
The polymorphic forms and cocrystal disclosed in instant application may exhibit advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, morphology or crystal habit, specific surface and pycnometric density, bulk/tap density, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents. These powder characteristics can greatly affect the efficiency, productivity and quality of formulation processes.
DEFINITIONS
As used throughout herein, the term room temperature refers to a temperature of from about 18°C to about 28°C., preferably about 20°C to about 25°C.
The anti-solvent is a solvent in which sofosbuvir, caffeine and a mixture of sofosbuvir and caffeine have a low solubility.
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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES
Example 1: Preparation of sofosbuvir Form A:
Sofosbuvir (500 mg) and n-heptane (30 ml) were charged into an easy max reactor at 28°C. The obtained mixture was heated to 50°C and stirred for 30 minutes. Ethanol (200 µL) was added slowly into the mixture to give slurry. The slurry was stirred for at 50°C for 5 hours. Ethanol (300 µL) was added to the slurry at 50°C and the slurry was cooled to 25°C and kept the material at 25°C overnight. It was filtered and dried at 30°C in air tray dryer for 1 hour.
Example 2: Preparation of sofosbuvir Form A:
Sofosbuvir (500 mg), n-heptane (30 mL) and ethanol (200 µL) were charged in easy max reactor and the mixture was heated to 50°C. The mixture was stirred for 8 hours at the same temperature. It was cooled to 25°C filtered and dried at 30°C in vacuum tray dryer for 1 hour.
Example 3: Preparation of sofosbuvir Form A:
Sofosbuvir (500 mg) and n-heptane (30 ml) were charged into an easy max reactor at 28°C. The obtained suspension was stirred and heated to 50°C for 2 hours. The hot mixture was filtered and dried at 30°C in vacuum tray dryer for 1 hour.
Example 4: Preparation of sofosbuvir Form A:
Sofosbuvir (500 mg) and n-heptane (30 ml) were charged into an easy max reactor at 0°C. The mixture was stirred at the same temperature for 6 hours 30 minutes. It was filtered at 0°C and dried at 30°C in vacuum tray dryer for 1 hour.
Example 5: Preparation of cocrystal of sofosbuvir with caffeine:
Sofosbuvir (500 mg), Caffeine (90 mg) and n-heptane (30 ml) were charged into an easy max reactor at 30°C. The obtained suspension was stirred for 5 minutes. Ethanol (2 mL) was charged slowly into the suspension. The obtained slurry was stirred at the same temperature for 2 hours and kept the material at 25°C overnight. It was filtered at 25°C and dried at 40°C air tray dryer for 1 hour.
,CLAIMS:We Claim:
1. A crystalline Form A of sofosbuvir, characterized by a PXRD pattern comprising peaks at about 4.55, 8.53, 9.10, 12.78 and 13.68 ±0.2° 2?.
2. A crystalline Form A of sofosbuvir according to claim 1, further characterized by a PXRD pattern comprising peaks at about 4.91, 7.15, 15.91, 17.91 and 25.04 ±0.2°2?.
3. A process for preparation of crystalline Form A of sofosbuvir, characterized by a PXRD pattern comprising peaks at about 4.55, 8.53, 9.10, 12.78 and 13.68 ±0.2° 2?, comprising:
a) contacting sofosbuvir and a solvent or a mixture of solvents wherein the solubility of sofosbuvir is low;
b) mixing the slurry obtained in step (a); and
c) isolating crystalline Form A of sofosbuvir.
4. A process for preparation of crystalline Form A of sofosbuvir according to claim 3, wherein step a) the solvent selected from n-heptane, n-hexane, cyclohexane, n-pentane, xylenes, toluene, MTBE, DIPE and their combinations.
5. A process for preparation of crystalline Form A of sofosbuvir according to claim 3, wherein step c) crystalline Form A of sofosbuvir is isolated by adding solvent selected from propanol, ethanol and methanol or their combination.
6. A cocrystal of sofosbuvir with caffeine, characterized by a PXRD pattern comprising peaks at about 3.70, 4.42, 5.32, 14.82, 16.36, 17.21 and 21.04 ± 0.2° 2?.
7. A cocrystal of sofosbuvir with caffeine according to claim 6, further characterized by PXRD pattern comprising peaks at about 7.41, 10.03 and 19.36 ± 0.2° 2?.
8. A process for preparation of cocrystal of sofosbuvir with caffeine comprising peaks at about 3.70, 4.42, 5.32, 14.82, 16.36, 17.21 and 21.04 ± 0.2° 2?; comprising:
a) contacting sofosbuvir and caffeine to a solvent or a mixture of solvents wherein the solubility of sofosbuvir and caffeine is low;
b) contacting slurry obtained in step (a) with a solvent or a mixture of solvents;
c) mixing the slurry obtained in step (b); and
d) isolating the cocrystal of sofosbuvir with caffeine.

9. A pharmaceutical composition comprising the crystalline Form A of sofosbuvir, cocrystal of sofosbuvir with caffeine produced according to any of the preceding claims together with one or more pharmaceutically acceptable carriers.

10. A pharmaceutical composition of sofosbuvir produced according to claim 9 for the treatment of HCV.