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 Capmatinib Dihydrochloride

INTRODUCTION
The present application relates to amorphous solid dispersion of capmatinib dihydrochloride and process for the preparation thereof. Moreover, the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of capmatinib dihydrochloride.

Capmatinib dihydrochloride is used for treating medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma.
Capmatinib is chemically known as 2-Fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2b][1,2,4]triazin-2-yl]benzamide and approved as dihydrochloride monohydrate.

US patent No. 7767675 discloses capmatinib as a product for the first time.
PCT publication no. WO 2009143211 first time discloses dihydrochloride salt of capmatinib. The application further discloses monohydrate form of Capmatinib dihydrochloride.

SUMMARY
First aspect of the present application relates to amorphous form of capmatinib dihydrochloride.

Second aspect of the present application relates to a process for preparation of amorphous capmatinib dihydrochloride comprising the steps of:
a) Dissolving capmatinib dihydrochloride in a suitable solvent; and
b) isolating amorphous form of capmatinib dihydrochloride.

Third aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of capmatinib dihydrochloride with a suitable pharmaceutically acceptable excipient.

Fourth aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride with a suitable pharmaceutically acceptable excipient.

Fifth aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride 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.

Sixth aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride with PVP.

Seventh aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride with HPMC-AS.

Eighth aspect of the present application relates to a process for preparing amorphous solid dispersion of capmatinib dihydrochloride comprising:
a) dissolving a mixture of capmatinib dihydrochloride and a suitable pharmaceutically acceptable excipient in a suitable solvent and
b) isolating amorphous solid dispersion of capmatinib dihydrochloride.

Ninth aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of capmatinib dihydrochloride with a suitable pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of a PXRD pattern of amorphous form of capmatinib dihydrochloride as prepared in example 1.
Figure 2 is an illustration of a PXRD pattern of amorphous solid dispersion of capmatinib dihydrochloride with PVP K-30 as prepared in example 2.
Figure 3 is an illustration of a PXRD pattern of amorphous solid dispersion of capmatinib dihydrochloride with HPMC AS LG as prepared in example 3.

DETAILED DESCRIPTION
First aspect of the present application relates to amorphous form of capmatinib dihydrochloride.

One of the embodiments of the present application relates to amorphous form of capmatinib dihydrochloride characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 1.

Second aspect of the present application relates to a process for preparation of amorphous capmatinib dihydrochloride comprising the steps of:
a) Dissolving capmatinib dihydrochloride in a suitable solvent; and
b) isolating amorphous form of capmatinib dihydrochloride.

Any crystalline form of capmatinib dihydrochloride or mixture thereof may be used as starting material for preparing amorphous form of capmatinib dihydrochloride. Specifically, capmatinib dihyrochloride monohydrate may be used for the preparation of solid dispersion of capmatinib dihydrochloride of the present application.
In embodiments of step (a), suitable solvents include, but are not limited to ketone solvent such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like; alcohol solvent such as methanol, ethanol, propanol, isopropanol and the like; and mixtures thereof. Specifically, the solvent may be selected from a group of alcohol solvent such as methanol, ethanol, isopropanol and the like. Specifically, the solvent may be methanol.
In one embodiment of step (a), capmatinib dihydrochloride may be dissolved in a suitable solvent at a temperature of about 5 °C to about boiling point of the solvent. In a specific embodiment, capmatinib dihydrochloride may be dissolved in a suitable solvent at a temperature of about 40 °C to about 80 °C. In another specific embodiment, capmatinib dihydrochloride may be dissolved at about boiling point of the solvent. In yet another specific embodiment, capmatinib dihydrochloride may be dissolved at about boiling point of methanol.
In another embodiment of step (a), the solution of capmatinib dihydrochloride may be filtered to remove any un-dissolved particles or extraneous matter.
In one embodiment of step (b), suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), Rotary cone vacuum dryer (RVPD), melt crystallization and the like, optionally under reduced pressure. One specific embodiment of the present application relates to spray-drying or freeze-drying technique, to provide amorphous form of capmatinib dihydrochloride. Another specific embodiment of the present application relates to using Buchi Rotavapor to provide amorphous form of capmatinib dihydrochloride. Alternatively, an anti-solvent may be added to the solution of capmatinib dihydrochloride of step (a) to precipitate amorphous form of capmatinib dihydrochloride and the precipitated solid may be isolated by any methods known in the art, such as filtration. The suitable anti-solvent may be any organic solvent known in the art in which capmatinib dihydrochloride is insoluble or slightly soluble. Specifically, the anti-solvent may include but not limited to ether solvent such as diethyl ether, diisopropyl ether and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; aliphatic hydrocarbon hydrocarbon solvent such as heptane, hexane and the like.
The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The isolated solid may optionally be further dried to afford amorphous form of capmatinib dihydrochloride. 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, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
The dried product 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 product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
It was found that the amorphous capmatinib dihydrochloride is stable and has excellent physico-chemical properties. The amorphous form of capmatinib dihydrochloride of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
Third aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of capmatinib dihydrochloride with a suitable pharmaceutically acceptable excipient.

Pharmaceutical composition comprising amorphous form of capmatinib dihydrochloride of the present application 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. Pharmaceutical composition 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 any one or more of techniques such as direct blending, dry granulation, wet granulation, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

Fourth aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride with a suitable pharmaceutically acceptable excipient.

Fifth aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride 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.

Sixth aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride with PVP.

Seventh aspect of the present application relates to amorphous solid dispersion of capmatinib dihydrochloride with HPMC-AS.

The amount of capmatinib dihydrochloride 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).

Eighth aspect of the present application relates to a process for preparing amorphous solid dispersion of capmatinib dihydrochloride comprising:
a) dissolving a mixture of capmatinib dihydrochloride and a suitable pharmaceutically acceptable excipient in a suitable solvent and
b) isolating amorphous solid dispersion of capmatinib dihydrochloride.

Any physical form of capmatinib dihydrochloride may be used for the preparation of solid dispersion of capmatinib dihydrochloride of the present application. Specifically, capmatinib dihyrochloride monohydrate may be used for the preparation of solid dispersion of capmatinib dihydrochloride of the present application.

The suitable solvent for dissolving capmatinib dihydrochloride 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. In one embodiment, the solvent for dissolving capmatinib dihydrochloride in step a) include alcohols such as methanol, ethanol, propanol, isopropanol. In another embodiment, the solvent for dissolving capmatinib dihydrochloride may be a mixture of al alcohol solvent and a halogenated hydrocarbon solvent. In yet another embodiment, the solvent for dissolving capmatinib dihydrochloride may be a mixture of methanol and dichloromethane.

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 capmatinib dihydrochloride in a suitable solvent is stirred for a sufficient time.

In embodiments of step a), a suitable pharmaceutically acceptable excipient may be mixed with capmatinib dihydrochloride and the mixture may be dissolved in a suitable solvent. Alternatively, to a solution of capmatinib dihydrochloride in a suitable solvent, a suitable pharmaceutically acceptable excipient may be added.

In embodiments of step b), isolating amorphous solid dispersion of capmatinib dihydrochloride 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 capmatinib dihydrochloride. 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 capmatinib dihydrochloride 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 capmatinib dihydrochloride.

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 capmatinib dihydrochloride with pharmaceutically acceptable excipient selected from a group of PVP and HPMC-AS 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 capmatinib dihydrochloride.

Ninth aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of capmatinib dihydrochloride 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 capmatinib dihydrochloride
Capmatinib dihydrochloride monohydrate (0.5 g) was dissolved in methanol (25 mL) at reflux condition. The solvent was evaporated under vacuum. The resulting glassy material was recovered to provide the title compound.
Yield: 0.35 g

Example 2: Preparation of amorphous solid dispersion of capmatinib dihydrochloride with PVP K-30
Capmatinib dihydrochloride monohydrate (0.5 g) and PVP K-30 (0.5 g) was dissolved in methanol (25 mL) at reflux condition. The solvent was evaporated under vacuum. The resulting glassy material was recovered to provide the title compound.
Yield: 0.78 g

Example 3: Preparation of amorphous solid dispersion of capmatinib dihydrochloride with HPMC AS LG
Capmatinib dihydrochloride monohydrate (0.5 g) and HPMC AS LG (0.5 g) was dissolved in a mixture of methanol (25 mL) and dichloromethane (10 mL) at 65 °C. The solvent was evaporated under vacuum. The resulting glassy material was recovered to provide the title compound.
Yield: 0.74 g
,CLAIMS:We Claim:
1. Amorphous form of capmatinib dihydrochloride, characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 1.
2. A process for preparation of amorphous form of capmatinib dihydrochloride comprising the steps of:
a) dissolving capmatinib dihydrochloride in a suitable solvent; and
b) isolating amorphous form of capmatinib dihydrochloride.
3. The process of claim 2, wherein the suitable solvent is methanol.
4. Amorphous solid dispersion of capmatinib dihydrochloride with a suitable pharmaceutically acceptable excipient.
5. The amorphous solid dispersion of capmatinib dihydrochloride of claim 4, 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 co-povidone.
6. The amorphous solid dispersion of capmatinib dihydrochloride of claim 5, wherein the suitable pharmaceutically acceptable excipient is selected from a group of PVP and HPMC-AS.
7. A process for preparing amorphous solid dispersion of capmatinib dihydrochloride comprising:
a) dissolving a mixture of capmatinib dihydrochloride and a suitable pharmaceutically acceptable excipient in a suitable solvent and
b) isolating amorphous solid dispersion of capmatinib dihydrochloride.
8. The process of claim 7, wherein the suitable solvent is methanol.