DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to amorphous form of asunaprevir and its solid dispersion and processes for preparation thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name asunaprevir, has a chemical name tert-butyl (S)-1-((2R,4R)-4-(7-chloro-4-methoxyisoquinolin-1-yloxy)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate, and is represented by structure of formula I.

Formula I
Asunaprevir is a selective NS3 protease inhibitor and is useful in the treatment of Hepatitis C virus (HCV) infection.
Asunaprevir and its preparation have been previously described in US Patent No. 6,995,174; US Patent No. 7,449,479, and US Patent No. 7,915,291.
PCT application publication WO 2009085658 A1 discloses crystalline Form H-1 and Form TIF-1/2 of asunaprevir and processes for preparation thereof.
There remains a need to provide stable, commercially viable and advantageous amorphous form of asunaprevir.
SUMMARY
In the first embodiment, the present application provides amorphous form of asunaprevir.
In the second embodiment, the present application provides amorphous form of asunaprevir characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figures 1 to 6.
In the third embodiment, the present application provides a process for preparing amorphous form of asunaprevir which comprises;
a) providing a solution of asunaprevir in a solvent or a mixture of two or more solvents;
b) removing solvent from a solution of asunaprevir obtained in step a); and
c) recovering amorphous form of asunaprevir.
In the fourth embodiment, the present application provides a process for preparing amorphous form of asunaprevir which comprises;
a) providing a solution of asunaprevir in a solvent or a mixture of two or more solvents;
b) precipitating asunaprevir by adding an anti-solvent to the solution obtained in step a); and
c) isolating amorphous form of asunaprevir.
In the fifth embodiment, the present application provides a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers.
In the sixth embodiment, the present application provides a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figures 7 to 12.
In the seventh embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution comprising asunaprevir and one or more pharmaceutically acceptable carriers,
b) removing solvent from a solution obtained in step (a), and
c) recovering a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers.
In the eighth embodiment, the present application provides pharmaceutical formulations comprising amorphous asunaprevir or amorphous solid dispersions of asunaprevir together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of asunaprevir prepared according to Example 1.
Figure 2 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of asunaprevir prepared according to Example 2.
Figure 3 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of asunaprevir prepared according to Example 3.
Figure 4 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of asunaprevir prepared according to Example 4.
Figure 5 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of asunaprevir prepared according to Example 5.
Figure 6 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of asunaprevir prepared according to Example 6.
Figure 7 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of asunaprevir and Copovidone (1:1 w/w) prepared according to Example 7.
Figure 8 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of asunaprevir, Copovidone and Syloid NF (1:1:1 w/w/w/) prepared according to Example 7.
Figure 9 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of asunaprevir and PVP-K30 (1:1 w/w) prepared according to Example 8.
Figure 10 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of asunaprevir, PVP-K30 and Syloid NF (1:1:1 w/w) prepared according to Example 8.
Figure 11 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of asunaprevir and hydroxy propyl methyl cellulose (HPMC) (1:1 w/w) prepared according to Example 9.
Figure 12 is powder X-ray power diffraction ("PXRD") pattern of a solid dispersion comprising an amorphous form of asunaprevir, hydroxy propyl methyl cellulose (HPMC) and Syloid NF (1:1: 1 w/w) prepared according to Example 9.

DETAILED DESCRIPTION
Asunaprevir used as the input in the process for preparation of amorphous form of the present application can be prepared by any process known in the art.
In the first embodiment, the present application provides amorphous form of asunaprevir.
In the second embodiment, the present application provides amorphous form of asunaprevir characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figures 1 to 6.
In the third embodiment, the present application provides a process for preparing amorphous form of asunaprevir which comprises;
a) providing a solution of asunaprevir in a solvent or a mixture solvents;
b) removing solvent from a solution of asunaprevir obtained in step a); and
c) recovering amorphous form of asunaprevir.
Providing a solution of asunaprevir in step a) includes direct use of a reaction mixture containing asunaprevir that is obtained in the course of its synthesis; or dissolving asunaprevir in a solvent.
Any physical form of asunaprevir may be utilized for providing the solution of asunaprevir in step a).
Suitable solvents which can be used for dissolving asunaprevir include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene and the like; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from a solution of asunaprevir.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.
Step (c) involves recovering an amorphous form of asunaprevir. The said recovery can be done by using the processes known in the art.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the asunaprevir is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In the fourth embodiment, the present application provides a process for preparing amorphous form of asunaprevir which comprises;
a) providing a solution of asunaprevir in a solvent or a mixture of two or more solvents;
b) precipitating asunaprevir by adding an anti-solvent to the solution obtained in step a); and
c) isolating amorphous form of asunaprevir.
Suitable solvents which can be used for dissolving asunaprevir include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; aromatic hydrocarbons such as toluene and the like; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves precipitating asunaprevir by addition of an anti-solvent to the solution obtained in step-(a), or alternatively the solution obtained in step-(a) is subsequently added to an anti-solvent in which asunaprevir has no solubility or more sparingly soluble such as one in which it is soluble in amounts of not more than 0.1 weight % at room temperature. Examples of anti-solvents are diethyl ether, pentane, heptane, hexane, cyclohexane and methyl cyclohexane.
Step (c) involves isolation of amorphous asunaprevir. After precipitating asunaprevir, by adding an anti-solvent in which asunaprevir has no solubility or asunaprevir is more sparingly soluble, in step-(b) the precipitate is isolated by any of the known methods such as filtration by gravity or filtration by suction. The resulting compound in step (c) may optionally be further dried.
The dried product may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.
In the fifth embodiment, the present application provides a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it required very less external energy to dissolve.
In the sixth embodiment, the present application provides a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figures 7 to 12.
In the seventh embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution of asunaprevir and pharmaceutically acceptable carrier in a solution,
b) removing solvent from a solution obtained in step (a); and
c) recovering a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carrier.
Providing a solution in step a) includes: direct use of a reaction mixture containing asunaprevir that is obtained in the course of its synthesis; or dissolving asunaprevir and pharmaceutically acceptable carrier in a solvent.
Any physical form of asunaprevir may be utilized for providing the solution of asunaprevir in step (a).
Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, 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 or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; 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 of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
An adsorbent may also be necessary when the formulation contains a hygroscopic ingredient, especially when adsorption of moisture produces a cohesive powder that will not feed properly to the tablet press. In such instances use of an adsorbent such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value.
Suitable solvents which can be used for dissolving the asunaprevir include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; and any mixtures of two or more thereof.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from a solution obtained in step (a);
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other technique known in the art.
Step (c) involves recovering a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers. The said recovery can be by using the processes known in the art.
The resulting compound obtained in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as asunaprevir is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
The dried product may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.
In another embodiment, the amorphous form of asunaprevir obtained according to the present application can be used as an intermediate for making any crystalline form of asunaprevir or solid dispersion of asunaprevir along with the other pharmaceutically acceptable excipients.
In another aspect, the present application provides pharmaceutical formulations comprising amorphous form of asunaprevir, together with one or more pharmaceutically acceptable excipients. Amorphous form of asunaprevir together with one or more pharmaceutically acceptable excipients of the present application 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 forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, or modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using 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. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, 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, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Solid states of asunaprevir of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 Å, and were obtained using a PANalytical, Powder X-ray Diffractometer.
Although the exemplified procedures herein illustrate the practice of the present invention in some of its embodiments, the procedures should not be construed as limiting the scope of the invention. Modifications from consideration of the specification and examples within the ambit of current scientific knowledge will be apparent to one skilled in the art.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
“Amorphous form” as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” 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, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “ester” is an organic compound 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 compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” 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 compound 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 compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
An “anti-solvent” is a solvent in which the active ingrediant (solute) is less soluble such as one in which it is soluble in amounts of not more than 0.1 weight % at room temperature.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
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 invention. While particular aspects of the present invention 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 invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example 1: Preparation of amorphous form of asunaprevir.
Asunaprevir (500 mg) was dissolved in 10 mL of methanol and stirred for 10 min at 25°C. The solution was filtered to remove undissolved particles and the filtrate was evaporated under vacuum at 25°C and the solid was dried at 25°C to afford amorphous asunaprevir. PXRD pattern shown in Fig. 1.
Example 2: Preparation of amorphous form of asunaprevir.
500 mg of asunaprevir was dissolved in 15 mL of acetone at 25°C and stirred for 15 min. The solution was filtered to remove un-dissolved particles and the filtrate was evaporated under reduced pressure at 25°C and the solid was dried under vacuum at 25°C to get amorphous asunaprevir. PXRD pattern shown in Fig. 2.
Example 3: Preparation of amorphous form of asunaprevir.
500 mg of asunaprevir was dissolved in 15 mL of ethylacetate at 26°C and stirred for 15 min. The solution was filtered to remove un-dissolved particles and the filtrate was evaporated under reduced pressure at 26°C and the solid obtained was dried under vacuum at 25°C to get amorphous asunaprevir. PXRD pattern is shown in Fig. 3.
Example 4: Preparation of amorphous form of asunaprevir.
Asunaprevir (2.0 g) was dissolved in 75 mL of methanol and stirred for 10 min at 26°C. The solution was filtered to remove un-dissolved particles and the filtrate was evaporated by spray drying, using a Büchi® MINI Spray Dryer B-290 with Büchi® Inert Loop B-295 at 25°C to afford amorphous asunaprevir.PXRD pattern shown in Fig. 4.
Parameters for the spray drier of the above experiment:
Aspirator: 70 %; Feed rate: 6 mL/ minute; Inlet temperature: 70°C; Outlet temperature: 40°C.
Example 5: Preparation of amorphous form of asunaprevir.
500 mg of asunaprevir and 1 mL of ethylacetate were charged at 21°C and stirred for 15 min. The reaction mass was added to precooled (10° C) cyclohexane (15 mL) and stirred for 30 minutes. The precipitated solid obtained was filtered and dried under vacuum at 25°C to get amorphous asunaprevir. PXRD pattern is shown in Fig. 5.
Example 6: Preparation of amorphous form of asunaprevir.
300 mg of asunaprevir and 3 mL of methyl tert.-butyl ether (MTBE) were charged at 21°C and stirred for 15 min. Precooled (10° C) cyclohexane (20 mL) was added and the resultant mixture was stirred for 30 minutes. The precipitated solid obtained was filtered and dried under vacuum at 25°C to get amorphous asunaprevir. PXRD pattern is shown in Fig. 6.
Example 7: Preparation of a solid dispersion of amorphous form of asunaprevir with Copovidone.
Asunaprevir (500 mg) and methanol (20 mL) were charged into a 100 mL round bottom flask, added Copovidone (500 mg) and stirred for 15 minutes at 25°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 25°C. The solid was dried under reduced pressure at 25°C to afford the title compound. PXRD pattern is shown in Fig. 7.
The above amorphous solid dispersion was mixed with Syloid (500 mg) for 30 minutes at 25° C and analyzed PXRD. Amorphous solid dispersion was obtained. PXRD pattern is shown in Fig. 8.
Example 8: Preparation of a solid dispersion of amorphous form of asunaprevir with PVP-K30.
Asunaprevir (500 mg) and methanol (20 mL) were charged into a 100 mL round bottom flask, added PVP K-30 (500 mg) and stirred for 15 minutes at 25°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 25°C. The solid was dried under reduced pressure at 25°C to afford the title compound. PXRD pattern is shown in Fig. 9.
The above amorphous solid dispersion was mixed with Syloid (500 mg) at 25°C for 30 minutes and analyzed PXRD. Amorphous solid dispersion was obtained.
PXRD pattern is shown in Fig. 10.
Example 9: Preparation of a solid dispersion of amorphous form of asunaprevir with HPMC.
Asunaprevir (300 mg) and methanol (20 mL) were charged into a 100 mL round bottom flask, added HPMC (300 mg) and stirred for 15 minutes at 25°C. The resultant clear solution was filtered and the filtrate was taken into a Buchi® flask and completely evaporated under reduced pressure at 25°C. The solid was dried under reduced pressure at 25°C to afford the title compound. PXRD pattern is shown in Fig. 11.
The above amorphous solid dispersion was mixed with Syloid (300 mg) at 21°C for 30 minutes and analyzed PXRD. Amorphous solid dispersion was obtained. PXRD pattern is shown in Fig.12.

,CLAIMS:We Claim:
1. Amorphous form of asunaprevir
2. Amorphous form of asunaprevir characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figures 1 to 6.
3. A process for preparing amorphous form of asunaprevir, comprising;
a) providing a solution of asunaprevir in a solvent or a mixture of solvents;
b) removing solvent from a solution of asunaprevir obtained in step a); and
c) recovering amorphous form of asunaprevir.
4. A process for preparing amorphous form of asunaprevir, comprising;
a) providing a solution of asunaprevir in a solvent or a mixture of solvents;
b) precipitating asunaprevir by adding an anti-solvent to the solution obtained in step a); and
c) isolating amorphous form of asunaprevir.
5. A solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figures 7 to 12.
6. A process for preparing a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers, which comprises;
a) providing a solution comprising asunaprevir and one or more pharmaceutically acceptable carriers,
b) removing solvent from a solution obtained in step (a), and
c) recovering a solid dispersion comprising an amorphous form of asunaprevir and one or more pharmaceutically acceptable carriers.
7. A pharmaceutical composition comprising amorphous asunaprevir or amorphous solid dispersions of asunaprevir together with one or more pharmaceutically acceptable excipients.