DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
AMORPHOUS SOLID DISPERSION OF SOFOSBUVIR AND PROCESSES FOR THE PREPARATION OF AMORPHOUS SOFOSBUVIR

INTRODUCTION
Aspects of the present application relate to process for the preparation of amorphous Sofosbuvir, amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers, process for its preparation and pharmaceutical composition thereof.
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 same patent describes preparation of amorphous Sofosbuvir by isolation of Sofosbuvir from t-butyl methyl ether and heptane & co-evaporation of Sofosbuvir with dichloromethane.
Though, there are processes available in the literature for the preparation of amorphous Sofosbuvir. Still there remains a need for the simple and cost effective process for the preparation of amorphous form of Sofosbuvir.
SUMMARY OF THE INVENTION
In an aspect, the present application provides a process for the preparation of amorphous form of Sofosbuvir, comprising the steps of;
a) providing a solution of Sofosbuvir in a solvent;
b) removing solvent from the solution obtained in step a), and
c) isolating the amorphous form of Sofosbuvir.
In an aspect, the present invention provides a process for the preparation of amorphous Sofosbuvir comprising:
a) providing a solution of Sofosbuvir in a solvent selected from Acetone, Methanol or Ethyl acetate or mixtures thereof;
b) removing solvent from the solution obtained in step a), and
c) isolating amorphous Sofosbuvir.
In an aspect, the present invention also provides pharmaceutical formulations comprising amorphous Sofosbuvir together with one or more pharmaceutically acceptable excipients.
In an aspect, the present application provides an amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers.
In an aspect, the present invention provides a process for preparing an amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers, comprising:
a) providing a solution or suspension of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;
b) removing solvent from the solution obtained in step a), and
c) isolating amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carrier.
In an aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers, comprising:
a) providing a solution of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from Polyvinylpyrrolidone, Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC) in a solvent;
b) removing solvent from the solution obtained in step a), and
c) isolating amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carrier selected from Polyvinylpyrrolidone, Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC).
In an aspect, the present invention also provides pharmaceutical formulations comprising amorphous solid dispersions of Sofosbuvir together with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates an X-ray powder diffraction pattern of amorphous Sofosbuvir, obtained according to the procedure of example 1.
Figure 2 illustrates an X-ray powder diffraction pattern of amorphous Sofosbuvir, obtained according to the procedure of example 3.
Figure 3 illustrates an X-ray powder diffraction pattern of amorphous solid dispersion of Sofosbuvir, obtained according to the procedure of example 5.
DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of amorphous form of Sofosbuvir, comprising the steps of;
a) providing a solution of Sofosbuvir in a solvent;
b) removing solvent from the solution obtained in step a), and
c) isolating the amorphous form of Sofosbuvir.
Providing a solution of Sofosbuvir in step a) includes:
i) direct use of a reaction mixture containing Sofosbuvir that is obtained in the course of its synthesis;
or
ii) dissolving Sofosbuvir in a solvent.
Any physical form of Sofosbuvir may be utilized for providing the solution of Sofosbuvir in step a). Sofosbuvir that may be used as the input for the process of the present invention may be obtained by any process including the processes described in the art.
Suitable solvents that may be used in step a) include, but are not limited to, alcohol solvents; ester solvents; ketone solvents; or mixtures thereof.
The dissolution temperatures may range from about 10°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of Sofosbuvir is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. 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 the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), hot melt extrusion (HME) and the like, or any other suitable technique.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C or any other suitable temperatures.
Step c) involves isolation of an amorphous form of Sofosbuvir from the solution of step b). The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In embodiments of step c), the amorphous obtained from step b) may be optionally dried. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In an aspect, the present invention provides a process for the preparation of amorphous form of Sofosbuvir comprising:
a) providing a solution of Sofosbuvir in a solvent selected from acetone, methanol or ethyl acetate or mixtures thereof;
b) removing solvent from the solution obtained in step a), and
c) isolating the amorphous form of Sofosbuvir.
Providing a solution of Sofosbuvir in step a) includes:
i) direct use of a reaction mixture containing Sofosbuvir that is obtained in the course of its synthesis; or
ii) dissolving Sofosbuvir in a solvent selected from methanol, ethyl acetate, dichloromethane, acetonitrile or mixtures thereof;
Any physical form of Sofosbuvir may be utilized for providing the solution of Sofosbuvir in step a). Sofosbuvir that may be used as the input for the process of the present invention may be obtained by any process including the processes described in the art.
The dissolution temperatures may range from about 10°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of Sofosbuvir is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. 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 the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), hot melt extrusion (HME) and the like, or any other suitable technique.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C or any other suitable temperatures.
Step c) involves isolation of an amorphous form of Sofosbuvir from the solution of step b). The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In embodiments of step c), the amorphous obtained from step b) may be optionally dried. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
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.
Examples of amorphous Sofosbuvir obtained using the above process is characterized by powder X-ray diffraction (“PXRD”) pattern substantially as illustrated by Figs. 1 and 2.
In the embodiment, the amorphous form of Sofosbuvir obtained according to the present invention can be used as an intermediate for making any crystalline form of Sofosbuvir or solid dispersion of Sofosbuvir along with the other pharmaceutically acceptable excipients.
In an aspect, the present application provides pharmaceutical formulations comprising amorphous form of Sofosbuvir, together with one or more pharmaceutically acceptable excipients. Amorphous form of Sofosbuvir 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.
In an aspect, the present invention provides amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers.
In an aspect, the present invention provides a process for preparing an amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers, comprising:
a) providing a solution or suspension of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;
b) removing solvent from the solution obtained in step a), and
c) isolating amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carrier.
Providing the solution in step a) includes:
(i) direct use of a reaction mixture containing Sofosbuvir that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or
(ii) dissolution of Sofosbuvir in a suitable solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.
Any physical form of Sofosbuvir may be utilized for providing a solution in step a).
Pharmaceutically acceptable carriers that may be used for the preparation of amorphous solid dispersions of Sofosbuvir of the present invention include, but are not limited to: pharmaceutical hydrophilic carriers such as polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), gums, cellulose derivatives (including hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxypropyl methylcellulose acetate succinate, microcrystalline celluloses and others), polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives, or the like; water soluble sugar derivatives including any pharmaceutically acceptable water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, or the like; or organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. The preferable pharmaceutically acceptable carriers include but not limited to Polyvinylpyrrolidone (PVP K-30), Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC).
When the solution or suspension of Sofosbuvir is prepared together with a pharmaceutically acceptable carrier, the order of charging different materials to the solution is not critical for obtaining the desired solid dispersion. A specific order may be preferred with respect to the equipment being used and will be easily determined by a person skilled in the art. Sofosbuvir or pharmaceutically acceptable carrier may be completely soluble in the solvent or they may form a suspension.
In embodiments, Sofosbuvir and the pharmaceutically acceptable carrier dissolved either in the same solvent or in different solvents, and then combined to form a mixture.
Suitable solvents that may be used in step a) include, but are not limited to, alcohol solvents; or mixtures thereof.
The dissolution temperatures may range from about 10°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of Sofosbuvir is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. 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 the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), hot melt extrusion (HME) and the like, or any other suitable technique.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C or any other suitable temperatures.
Step c) involves isolation of amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers from the solution of step b).
The compound obtained from step b), may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. The product thus isolated may be optionally further dried to afford an amorphous form of Sofosbuvir together with a pharmaceutically acceptable excipients. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
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.
Examples of amorphous solid dispersion of Sofosbuvir together with a pharmaceutically acceptable carrier obtained using the above process is characterized by powder X-ray diffraction (“PXRD”) pattern substantially as illustrated by Fig. 3.
In an aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carriers, comprising:
a) providing a solution of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from The carriers include but not limited to Polyvinylpyrrolidone, Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC) in a solvent;
b) removing solvent from the solution obtained in step a), and
c) isolating amorphous solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable carrier selected from Polyvinylpyrrolidone, Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC).
In embodiments of step a) the solution of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, copovidone, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate can be obtained by dissolving Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, copovidone, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate in a solvent selected. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, copovidone, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
Step b) involves the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), hot melt extrusion (HME) and the like, or any other suitable technique.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C or any other suitable temperatures.
Step c) involves isolation of amorphous solid dispersion of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, copovidone, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate from the solution of step b).
The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. The product thus isolated may be optionally further dried to afford an amorphous form of Sofosbuvir in combination with one or more pharmaceutically acceptable carriers selected from polyvinylpyrrolidones, copovidone, hydroxypropyl methylcelluloses, hydroxypropyl celluloses or hydroxypropyl methylcellulose acetate succinate. Drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
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 an aspect, the present invention also provides pharmaceutical formulations comprising amorphous solid dispersions of Sofosbuvir together with one or more pharmaceutically acceptable excipients.
In an aspect, the present invention also provides optionally adding of carriers to the amorphous solid dispersion of Sofosbuvir. Addition of carriers to the amorphous solid dispersion of Sofosbuvir may also be necessary when the formulation contains a hygroscopic ingredient, especially when absorption of moisture produces a cohesive powder that will not feed properly to the tablet press. In such instances use of an carrier or absorbent 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.
A solid dispersion of Sofosbuvir together with one or more pharmaceutically acceptable excipients of the present invention may be further 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 forms 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 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, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful in the present invention 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, 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 and 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.
Different solid forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Amorphous form of the application can be further processed to modulate particle size. For example, the amorphous form of the application can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation or formulation.
In an aspect of the application, amorphous Sofosbuvir or amorphous solid dispersions of Sofosbuvir prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC).
Amorphous Sofosbuvir or amorphous solid dispersions of Sofosbuvir produced by the method of present invention can be chemically pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC.
Amorphous solid dispersion of sofosbuvir and amorphous sofosbuvir produced according to the present invention can be used as intermediates in preparation of other polymorphic forms of sofosbuvir.
The pharmaceutical compositions comprising amorphous Sofosbuvir 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.
Amorphous Sofosbuvir or amorphous solid dispersions of Sofosbuvir 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
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
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 following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound 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 and the like.
Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc.
Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” 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, benzyl alcohol, phenol, glycerol, C1-6alcohols, or the like.
An “ester solvent” is an organic solvent containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “Ester solvents” 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, C3-6 esters, or the like.
A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6ketones, 4-methyl-pentane-2-one or the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES
Example 1: Preparation of amorphous Sofosbuvir:
Sofosbuvir (500 mg) and acetone (15 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with acetone (5 ml) at 26°C. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 50°C.
Example 2: Preparation of amorphous Sofosbuvir:
Sofosbuvir (8.5 g) and methanol (170 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with methanol (80 ml) at 26°C. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 57°C. The obtained reaction mass was dried under vacuum 2 hours.
Example 3: Preparation of amorphous Sofosbuvir:
Sofosbuvir (3 g) and methanol (60 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The solution was allowed to evaporate by spray drying at 70°C with a flow rate at 9 ml/min.
Example 4: Preparation of amorphous Sofosbuvir:
Sofosbuvir (500 mg) and ethyl acetate (20 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered at 26°C. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 60°C.
Example 5: Preparation of amorphous solid dispersion of Sofosbuvir with Polyvinylpyrrolidone:
Sofosbuvir (300 mg) and methanol (15 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with methanol (10 ml) at 26°C. Polyvinylpyrrolidone (PVP K-30; 300 mg) added to the reaction mass and the reaction mass was stirred to dissolve PVP K-30 completely. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 60°C. The obtained reaction mass was dried for 30 minutes under vacuum at 60°C.
Sofosbuvir (200 mg) and methanol (5 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with methanol (5 ml) at 26°C. The solution was filtered; and the filtrate was transferred into the reaction mass of Sofosbuvir and polyvinylpyrrolidone obtained in the previous step. Polyvinylpyrrolidone (PVP K-30; 200 mg) added to the reaction mass and the reaction mass was stirred to dissolve PVP K-30 completely. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 60°C. The obtained reaction mass was dried for 30 minutes under vacuum at 60°C.
Syloid (244FP grade; 500 mg) was added to the dry Sofosbuvir with polyvinylpyrrolidone at room temperature and mixed well for the uniform distribution.
Example 6: Preparation of amorphous solid dispersion of Sofosbuvir with Copovidone:
Sofosbuvir (500 mg) and methanol (15 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with methanol (5 ml) at 26°C. Copovidone NF (500 mg) added to the reaction mass and it was stirred to dissolve copovidone NF completely. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 60°C. The obtained reaction mass was dried under vacuum 30 minutes at 60°C. Syloid (244FP grade; 500 mg) was added to the dry Sofosbuvir with copovidone at room temperature and mixed well for the uniform distribution.
Example 7: Preparation of amorphous solid dispersion of Sofosbuvir with Hydroxypropy methyl cellulose:
Sofosbuvir (500 mg) and methanol (15 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with methanol (5 ml) at 26°C. Hydroxypropy methyl cellulose (HPMC SCPS; 500 mg) added to the reaction mass and it was stirred to dissolve HPMC completely. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 60°C. The obtained reaction mass was dried under vacuum 50 minutes at 60°C. Syloid (244FP grade; 500 mg) was added to the dry Sofosbuvir with hydroxypropy methyl cellulose at room temperature and mixed well for the uniform distribution.
Example 8: Preparation of amorphous solid dispersion of Sofosbuvir with Hydroxypropyl cellulose:
Sofosbuvir (500 mg) and methanol (15 ml) were charged into a round bottom flask at 26°C. The contents were stirred to dissolve Sofosbuvir completely. The reaction mass was filtered and washed with methanol (5 ml) at 26°C. Hydroxypropyl cellulose (HPC - Klucel LF; 500 mg) added to the reaction mass and it was stirred to dissolve HPC completely. The resulting solution was evaporated completely in Büchi® Rotavapor® under vacuum at 60°C. The obtained reaction mass was dried under vacuum 90 minutes at 60°C. Syloid (500 mg) was added to the dry amorphous solid dispersion of Sofosbuvir with hydroxypropyl cellulose at room temperature and mixed well for the uniform distribution.
,CLAIMS:We Claim:
1. A process for preparation of amorphous form of sofosbuvir, comprising:
a) providing a solution of sofosbuvir in a solvent;
b) removing solvent from the solution obtained in step a); and
c) isolating the amorphous form of sofosbuvir.
2. A process for preparation of amorphous form of sofosbuvir according to claim 1, wherein the solvent selected from acetone, methanol or ethyl acetate or their combinations.
3. An amorphous solid dispersion of sofosbuvir together with one or more pharmaceutically acceptable carriers.
4. An amorphous solid dispersion of sofosbuvir according to claim 3, wherein the pharmaceutically acceptable carriers are polyvinylpyrrolidones, gums, cellulose derivatives, polymers of carboxymethyl celluloses, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives, water soluble sugar derivatives, aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, or guanidine or its derivatives or .
5. A process for preparation of amorphous solid dispersion of sofosbuvir together with one or more pharmaceutically acceptable carriers according to claim 3, comprising:
a) providing a solution or suspension of sofosbuvir in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;
b) removing solvent from the solution obtained in step a); and
c) isolating amorphous solid dispersion of sofosbuvir together with one or more pharmaceutically acceptable carriers.
6. A process for preparation of amorphous solid dispersion of sofosbuvir together with one or more pharmaceutically acceptable carriers according to claim 5, wherein the pharmaceutically acceptable excipients selected from Polyvinylpyrrolidone, Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC).
7. A process for preparation of amorphous solid dispersion of sofosbuvir according to step a) of claim 4, wherein the solvent or mixture of solvents selected from alcohols solvents or their combinations.
8. A pharmaceutical composition comprising the amorphous sofosbuvir produced according to claim 1 together with one or more pharmaceutically acceptable carriers.
9. A pharmaceutical composition of amorphous solid dispersions of sofosbuvir produced according to claim 3 together with one or more pharmaceutically acceptable excipients.
10. A pharmaceutical composition of sofosbuvir produced according to claim 9 for the treatment of HCV.