DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
INTRODUCTION
The present application relates to amorphous solid dispersion of cobicistat and process for the preparation thereof. Moreover, the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of cobicistat.

Cobicistat is a potent inhibitor of cytochrome P450 monooxygenase, which are responsible for the metabolism of anti-HIV drugs like elvitegravir. By combining an anti-HIV drug and cobicistat, higher concentrations of the anti-HIV drug are achieved in the body with lower dosing. This results in enhancing the pharmacological activity of the drug while diminishing its adverse side-effects.

Cobicistat is approved in USA as a combination with three other anti-HIV drugs, namely elvitegravir, emtricitabine and tenofovir. The combination is marketed as StribildTM in tablet dosage form. Cobicistat is chemically known as thiazol-5-ylmethyl((2R,5S)-5-((S)-2-(3-((2-isopropyl-thiazol-4-yl)methyl)-3-methylureido)-4-morpholinobutanamido)-1,6-diphenylhexan-2-yl)carbamate

US patent No. US8148374B2 covers cobicistat as a product.
PCT publication no. WO2012151165A1 discloses amorphous cobicistat. The application further discloses a process for preparing amorphous cobicistat by adding a toluene solution of cobicistat to heptanes.

PCT publication no. WO2013130766A1 discloses a formulation comprising cobicistat and certain polymers like HPMC-AS, HPMC-E5, HPMC-P, PVP and PVP-VA.

SUMMARY
One aspect of the present application relates to amorphous solid dispersion of cobicistat with a polymer selected form a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose.

Another aspect of the present application relates to amorphous solid dispersion of cobicistat with HPC.

Yet another aspect of the present application relates to amorphous solid dispersion of cobicistat with methacrylic acid.

Still another aspect of the present application relates to amorphous solid dispersion of cobicistat with methyl cellulose.

Another aspect of the present application relates to amorphous solid dispersion of cobicistat with ethyl cellulose.

Yet another aspect of the present application relates to a process for preparing amorphous solid dispersion of cobicistat comprising:
a) dissolving a mixture of cobicistat and a polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose in suitable solvent; and
b) isolating amorphous solid dispersion of cobicistat.

Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of cobicistat comprising:
a) dissolving a mixture of cobicistat and a polymer in suitable solvent;
b) evaporating the solvent in rotary evaporator under vacuum; and
c) isolating amorphous solid dispersion of cobicistat.

Another aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of cobicistat with a polymer, wherein the polymer is selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose and one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with methacrylic acid prepared in example 1.
Figure 2 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with methacrylic acid prepared in example 2.
Figure 3 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with ethyl cellulose prepared in example 3.
Figure 4 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with methyl cellulose prepared in example 4.
Figure 5 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with HPC prepared in example 5.
Figure 6 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with HPMC prepared in example 6.
Figure 7 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with HPMC-AS prepared in example 7.
Figure 8 is an illustration of a PXRD pattern of amorphous solid dispersion of cobicistat with PVP-K-30 prepared in example 8.

DETAILED DESCRIPTION
One aspect of the present application relates to amorphous solid dispersion of cobicistat with a polymer selected form a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose.

Another aspect of the present application relates to amorphous solid dispersion of cobicistat with HPC.

Yet another aspect of the present application relates to amorphous solid dispersion of cobicistat with methacrylic acid.
Still another aspect of the present application relates to amorphous solid dispersion of cobicistat with methyl cellulose.

Another aspect of the present application relates to amorphous solid dispersion of cobicistat with ethyl cellulose.

The amount of cobicistat in amorphous solid dispersion with a polymer selected form a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose may be about 5% w/w to about 95% w/w, or about 10% w/w to about 90% w/w, or about 20% w/w to about 80% w/w, or about 30% w/w to about 70% w/w, or about 40% w/w to about 60% w/w, or about 50% w/w.
One aspect of the present application relates to a process for preparing amorphous solid dispersion of cobicistat comprising:
a) dissolving a mixture of cobicistat and a polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose in suitable solvent; and
b) isolating amorphous solid dispersion of cobicistat.

The suitable solvent for dissolving cobicistat in step a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran; esters such as ethyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform; alcohols such as methanol, ethanol, propanol, isopropanol; water; mixtures thereof. Specifically, the solvent for dissolving cobicistat in step a) include alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as dichloromethane, chloroform; ketones such as acetone; ethers such as tetrahydrofuran; mixtures thereof.
Any physical form of cobicistat may be used for the preparation of solid dispersion of cobicistat of the present application.

The step a) may be performed at a temperature of about 0 °C to about the boiling point of the solvent. Specifically, the solution of cobicistat in a suitable solvent may be prepared at a temperature of about 15 °C to about 40 °C.

In embodiments of step a), the solution of polymer, cobicistat in a suitable solvent is stirred for a sufficient time. Specifically, the solution is stirred for a period of 15 minutes to 15 hours.

In embodiments of step a), polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose may be mixed with cobicistat and the mixture may be dissolved in a suitable solvent. Alternatively, to a solution of cobicistat in a suitable solvent polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose may be added.

The present application encompasses all viscosity grades, molecular weights, commercially available products and the copolymers of HPC, methacrylic acid, methyl cellulose and ethyl cellulose.

In embodiments of step b), isolating amorphous solid dispersion of cobicistat may involve one or more methods including removal of solvent (by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like), cooling, concentrating the reaction mass, adding seed crystals to induce precipitation, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.

Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. Specifically, techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of cobicistat. More specifically, distillation using a rota-vapor device such as a Buchi Rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of cobicistat with a polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose.

The solid obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous solid dispersion of cobicistat.

Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.

The obtained amorphous solid dispersions may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.

It was found that the amorphous solid dispersion of cobicistat with polymers selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose is stable and has excellent physico-chemical properties. The amorphous solid dispersion of the present application may be easily formulated into a pharmaceutical composition comprising cobicistat.
Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of cobicistat comprising:
a) dissolving a mixture of cobicistat and a polymer in suitable solvent;
b) evaporating the solvent in rotary evaporator under vacuum; and
c) isolating amorphous solid dispersion of cobicistat.

The suitable solvent for dissolving cobicistat in step a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran; esters such as ethyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform; alcohols such as methanol, ethanol, propanol, isopropanol; water; mixtures thereof. Specifically, the solvent for dissolving cobicistat in step a) include alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as dichloromethane, chloroform; ketones such as acetone; ethers such as tetrahydrofuran; mixtures thereof.
Any physical form of cobicistat may be used for the preparation of solid dispersion of cobicistat of the present application.
The step a) may be performed at a temperature of about 0 °C to about the boiling point of the solvent. Specifically, the solution of cobicistat in a suitable solvent may be prepared at a temperature of about 15 °C to about 40 °C.

In embodiments of step a), the solution of polymer, cobicistat in a suitable solvent is stirred for a sufficient time. Specifically, the solution is stirred for a period of 15 minutes to 15 hours.

Distillation of the solvent in a rotary evaporator (like Buchi Rotavapor) may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.

The solid obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used. The isolated solid may be optionally further dried to afford amorphous solid dispersion of cobicistat.

Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.

The obtained amorphous solid dispersions may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.

Another aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of cobicistat with a polmyer, wherein the polymer is selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose and one or more pharmaceutically acceptable excipients. The composition may optionally contain other active ingredients, including but not limited to, elvitegravir, emtricitabine and tenofovir. The composition of the present application may be a solid oral dosage form such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage form 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. The composition of the present application may be in the forms of immediate release, delayed release, or modified release.

All PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms “about”, “general” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

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, the terms “comprising” and “comprises” mean 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.

The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

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 disclosure in any manner.

EXAMPLE
Example 1: Preparation of amorphous solid dispersion of cobicistat with methacrylic acid
To a mixture of cobicistat (2.5 g) and methacrylic acid (2.5 g), methanol (60 mL) was added at 26 °C and stirred for 20 minutes. The clear solution obtained thus was spary-dried to afford the title compound.
Yield: 1.5 g

Example 2: Preparation of amorphous solid dispersion of cobicistat with methacrylic acid
A mixture of cobicistat (500 mg), methacrylic acid (500 mg) and methanol (50 mL) was stirred for 10 minutes to provide a clear solution which was distilled under vacuum at 65-75 °C. The solid, obtained thus, was dried under vacuum at 80-90 °C to afford the desired compound.
Yield: 820 mg

Example 3: Preparation of amorphous solid dispersion of cobicistat with ethyl cellulose
A mixture of cobicistat (500 mg), ethyl cellulose (500 mg) and dichloromethane (25 mL) was stirred for 10 minutes and the obtained clear solution was distilled under vacuum at 40-60 °C. The wet solid was dried under vacuum at 65-90 °C to afford the desired compound.
Yield: 760 mg

Example 4: Preparation of amorphous solid dispersion of cobicistat with methyl cellulose
A mixture of cobicistat (500 mg), methyl cellulose (500 mg) and dichloromethane (25 mL) was stirred for 10 minutes to provide a clear solution which was distilled under vacuum at 40-60 °C. The wet solid was dried under vacuum at 60-90 °C for 1 hour to afford the desired compound.
Yield: 800 mg

Example 5: Preparation of amorphous solid dispersion of cobicistat with HPC
A mixture of cobicistat (500 mg), HPC (500 mg) and dichloromethane (25 mL) was stirred for 10 minutes and the obtained clear solution was distilled under vacuum at 40-55 °C. The solid, obtained thus, was dried at 80-90 °C for 1 hour to afford the desired compound.
Yield: 800 mg
Example 6: Preparation of amorphous solid dispersion of cobicistat with HPMC (3 cps)
A mixture of cobicistat (500 mg), HPMC (500 mg) and dichloromethane (25 mL) was stirred for 10 minutes to provide a clear solution which was distilled under vacuum at 40-50 °C. The wet solid was dried under vacuum at 80-90 °C for 1 hour to afford the desired compound.
Yield: 680 mg

Example 7: Preparation of amorphous solid dispersion of cobicistat with HPMC-AS
A mixture of cobicistat (500 mg), HPMC-AS (500 mg) and dichloromethane (50 mL) was stirred for 10 minutes to provide a clear solution which was distilled under vacuum at 40-60 °C. The obtained wet solid was dried at 70-90 °C under vacuum for 1 hour to provide the title compound.
Yield: 650 mg

Example 8: Preparation of amorphous solid dispersion of cobicistat with PVP – K-30
A mixture of cobicistat (500 mg), PVP – K-30 (500 mg) and dichloromethane (25 mL) was stirred for 10 minutes and the obtained clear solution was distilled under vacuum at 40-60 °C. The compound, thus obtained, was dried at 80-90 °C under vacuum for 1 hour to provide the desired compound.
Yield: 600 mg.
,CLAIMS:We claim:
1. Amorphous solid dispersion of cobicistat with a polymer selected form a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose.

2. The amorphous solid dispersion of claim 1, wherein amount of cobicistat in amorphous solid dispersion with a polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose is about 5% w/w to about 95% w/w.

3. A process for preparing amorphous solid dispersion of cobicistat comprising:
a) dissolving a mixture of cobicistat and a polymer selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose in suitable solvent; and
b) isolating amorphous solid dispersion of cobicistat.

4. The process of claim 3, wherein the suitable solvent for dissolving cobicistat in step a) is selected from a group of ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran; esters such as ethyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform; alcohols such as methanol, ethanol, propanol, isopropanol; water; mixtures thereof.

5. The process of claim 4, wherein the suitable solvent for dissolving cobicistat in step a) is methanol; dichloromethane; mixtures thereof.

6. The process of claim 3, wherein isolation in step b) is performed by cooling the reaction mass or concentrating the reaction mass or adding seed crystals to the reaction mass to induce precipitation.

7. A process for preparing amorphous solid dispersion of cobicistat comprising:
a) dissolving a mixture of cobicistat and a polymer in suitable solvent;
b) evaporating the solvent in rotary evaporator under vacuum; and
c) isolating amorphous solid dispersion of cobicistat.

8. The process of claim 7, wherein the suitable solvent for dissolving cobicistat in step a) is selected from a group of ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran; esters such as ethyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform; alcohols such as methanol, ethanol, propanol, isopropanol; water; mixtures thereof.

9. The process of claim 8, wherein the suitable solvent for dissolving cobicistat in step a) is methanol; dichloromethane; mixtures thereof.

10. A pharmaceutical composition comprising amorphous solid dispersion of cobicistat with a polymer, wherein the polymer is selected from a group of HPC, methacrylic acid, methyl cellulose and ethyl cellulose and one or more pharmaceutically acceptable excipients.