DESC:The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

Process for Preparing Amorphous Solid Dispersion of Cabozantinib (S)-malate

INTRODUCTION
The present application relates to amorphous solid dispersion of cabozantinib (S)-malate and process for the preparation thereof. Moreover, the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of cabozantinib (S)-malate.

Cabozantinib (S)-malate is used for treating medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma.
Cabozantinib is chemically known as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and approved as (S)-malate salt.

US patent No. US 7579473 discloses cabozantinib as a product for the first time.
PCT publication no. WO2010083414 first time discloses (S)-malate salt of Cabozantinib. The application further discloses amorphous form of Cabozantinib (S)-malate.

SUMMARY
One aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient.

Another aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient selected from a group of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), polyvinylpyrrolidone (PVP) and co-povidone.

Yet another aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with PVP.

Still another aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with copovidone.

Yet another aspect of the present application relates to a process for preparing amorphous solid dispersion of cabozantinib (S)-malate comprising:
a) dissolving a mixture of cabozantinib (S)-malate and a suitable pharmaceutically acceptable excipient in a suitable solvent and
b) isolating amorphous solid dispersion of cabozantinib (S)-malate.

Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of cabozantinib (S)-malate comprising:
a) dissolving a mixture of cabozantinib (S)-malate and a suitable pharmaceutically acceptable excipient in a suitable solvent;
b) evaporating the solvent in rotary evaporator under vacuum; and
c) isolating amorphous solid dispersion of cabozantinib (S)-malate.

Another aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of amorphous solid dispersion of cabozantinib (S)-malate with PVP prepared in example 1.
Figure 2 is an illustration of a PXRD pattern of amorphous solid dispersion of cabozantinib (S)-malate with copovidone prepared in example 2.

DETAILED DESCRIPTION
One aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient.

Another aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient selected from a group of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), polyvinylpyrrolidone (PVP) and copovidone.

Yet another aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with PVP.

Still another aspect of the present application relates to amorphous solid dispersion of cabozantinib (S)-malate with copovidone.

The amount of cabozantinib (S)-malate in amorphous solid dispersion with a suitable pharmaceutically acceptable excipient 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.

The pharmaceutically acceptable carrier may be any suitable carrier reported in the literature. Specifically, the pharmaceutically acceptable carrier includes, but not restricted to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinyl alcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, PVP, copovidone, methacrylic acid, polymethacrylate, mixtures of two or more thereof, copolymers thereof and derivatives thereof. More specifically, the pharmaceutically acceptable carrier may be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, copovidone, PVP, Eudragit, and mixtures thereof.
In one embodiment, the pharmaceutically acceptable carrier may include a surfactant. The surfactant may include but not limited to alkyl sulfates (e.g. sodium lauryl sulfate), alkylcarboxylates, alkylbenzole sulfates, secondary alkane sulfonates, polyoxyethylene glycerides (including polyoxyethylene castor oil derivatives), polysorbates and mixture thereof.
In another embodiment, the pharmaceutically acceptable carrier may include a glidant. The glidant may include but not limited to colloidal silicon dioxide or fumed silica (e.g. Aerosil).

Yet another aspect of the present application relates to a process for preparing amorphous solid dispersion of cabozantinib (S)-malate comprising:
a) dissolving a mixture of cabozantinib (S)-malate and a suitable pharmaceutically acceptable excipient in a suitable solvent and
b) isolating amorphous solid dispersion of cabozantinib (S)-malate.

The suitable solvent for dissolving cabozantinib (S)-malate 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 cabozantinib (S)-malate in step a) include alcohols such as methanol, ethanol, propanol, isopropanol. Any physical form of cabozantinib (S)-malate may be used for the preparation of solid dispersion of cabozantinib (S)-malate 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. In embodiments of step a), the solution comprising a suitable pharmaceutically acceptable excipient and cabozantinib (S)-malate 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), a suitable pharmaceutically acceptable excipient may be mixed with cabozantinib (S)-malate and the mixture may be dissolved in a suitable solvent. Alternatively, to a solution of cabozantinib (S)-malate in a suitable solvent, a suitable pharmaceutically acceptable excipient may be added.

In embodiments of step b), isolating amorphous solid dispersion of cabozantinib (S)-malate 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 cabozantinib (S)-malate. 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 cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient.

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 cabozantinib (S)-malate.

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 cabozantinib (S)-malate cobicistat with pharmaceutically acceptable excipient selected from a group of PVP and copovidone 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 cabozantinib (S)-malate.

Still another aspect of the present application relates to a process for preparing amorphous solid dispersion of cabozantinib (S)-malate comprising:
a) dissolving a mixture of cabozantinib (S)-malate and a suitable pharmaceutically acceptable excipient in a suitable solvent;
b) evaporating the solvent in rotary evaporator under vacuum; and
c) isolating amorphous solid dispersion of cabozantinib (S)-malate.

The suitable solvent for dissolving cabozantinib (S)-malate 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 cabozantinib (S)-malate in step a) include alcohols such as methanol, ethanol, propanol, isopropanol.
Any physical form of cabozantinib (S)-malate may be used for the preparation of solid dispersion of cabozantinib (S)-malate 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. In embodiments of step a), the solution of pharmaceutically acceptable excipient and cabozantinib (S)-malate in a suitable solvent may be 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 cabozantinib (S)-malate.

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 cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient. 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 cabozantinib (S)-malate with PVP
To a mixture of cabozantinib (S)-malate (300 mg) and PVP-K30 (200 mg), methanol (100 mL) was added at 30 °C and then heated to 75 °C and stirred for 10 minutes. The solvent was evaporated under vacuum at the same temperature to provide the title compound.

Example 2: Preparation of amorphous solid dispersion of cabozantinib (S)-malate with copovidone
To a mixture of cabozantinib (S)-malate (300 mg) and povidone (200 mg), methanol (100 mL) was added at 30 °C and then heated to 75 °C and stirred for 10 minutes. The solvent was evaporated under vacuum at the same temperature to afford the title compound.
,CLAIMS:WE CLAIM:
1. Amorphous solid dispersion of cabozantinib (S)-malate with a suitable pharmaceutically acceptable excipient.
2. The Amorphous solid dispersion as claimed in claim 1, wherein the suitable pharmaceutically acceptable excipient is selected from a group of hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl methyl cellulose – acetate succinate (HPMC-AS), polyvinylpyrrolidone (PVP) and copovidone.
3. The Amorphous solid dispersion as claimed in claim 2, wherein the suitable pharmaceutically acceptable excipient is PVP.
4. The Amorphous solid dispersion as claimed in claim 2, wherein the suitable pharmaceutically acceptable excipient is copovidone.
5. A process for preparing amorphous solid dispersion of cabozantinib (S)-malate comprising:
a) dissolving a mixture of cabozantinib (S)-malate and a suitable pharmaceutically acceptable excipient in a suitable solvent and
b) isolating amorphous solid dispersion of cabozantinib (S)-malate.
6. The process as claimed in claim 5, wherein the suitable solvent is methanol.