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

AMORPHOUS FORM AND SOLID DISPERSIONS OF BRIGATINIB

FIELD OF THE INVENTION
The present application relates to solid state forms of Brigatinib and processes for preparation thereof.
The drug compound having the adopted name “Brigatinib”, chemically designated as 5-chloro-N4-[2-(dimethylphosphinyl)phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-pyrimidinediamine and is represented by structure of Formula I.

Formula I
Brigatinib is a potent anaplastic lymphoma kinase (ALK) inhibitor, that also inhibits EGFR and c-ros oncogene 1 (ROS1), for the potential oral treatment of ALK-positive non-small-cell lung cancer (NSCLC).
U.S. Patent No. 9,012,462 discloses Brigatinib and process for its preparation.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. For some therapeutic indications, one bioavailability pattern may be favored over another. Therefore, it is desirable to have stable and pure amorphous forms of drugs to meet the regulatory requirements for a pharmaceutical product and also highly reproducible processes for their preparation.
In view of the above, it is therefore, desirable to prepare a stable amorphous form of Brigatinib. The amorphous form provided herein is a free flowing powder.
Solid dispersions comprising amorphous forms of drugs are generally known to improve the stability and solubility of drug products. The present invention, further provides stable solid dispersions comprising amorphous forms of Brigatinib which may be reproduced easily on plant scale and are amenable for processing into a dosage form.

SUMMARY OF THE INVENTION
In the first embodiment, the present application provides Brigatinib in amorphous form.
In the second embodiment, the present application provides amorphous Brigatinib that can be characterized by its PXRD pattern as illustrated by Figure 1.
In the third embodiment, the present application provides a process for preparing an amorphous form of Brigatinib, comprising the steps of:
a) providing a solution of Brigatinib in a solvent; and
b) isolating amorphous form of Brigatinib.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
In the fifth embodiment, the present application provides a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
In the sixth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients comprising the steps of:
a) providing a mixture of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients in a solvent; and
b) isolating solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
In the seventh embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients comprising the steps of:
a) physically blending Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients; and
b) isolating solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Brigatinib prepared according to example 1.
FIG. 2 is an illustration of powder X-ray diffraction (“PXRD”) pattern of amorphous Brigatinib prepared according to example 2.
FIG. 3 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Brigatinib amorphous solid dispersion Brigatinib prepared according to example 3.
FIG. 4 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Brigatinib amorphous solid dispersion Brigatinib prepared according to example 4.
FIG. 5 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Brigatinib amorphous solid dispersion Brigatinib prepared according to example 5.
FIG. 6 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Brigatinib amorphous solid dispersion Brigatinib prepared according to example 6.
FIG. 7 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Brigatinib amorphous solid dispersion Brigatinib prepared according to example 7.
FIG. 8 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Brigatinib amorphous solid dispersion Brigatinib prepared according to example 8.
DESCRIPTION OF THE INVENTION
In the first embodiment, the present application provides Brigatinib in amorphous form.
In the second embodiment, the present application provides amorphous form of Brigatinib that can be characterized by its PXRD pattern as illustrated by Figure 1.
In an aspect, the present application provides amorphous Brigatinib that can be characterized by its PXRD pattern as illustrated by any one of the Figures 1 to 2.
In the third embodiment, the present application provides a process for preparing an amorphous form of Brigatinib, comprising the steps of:
a) providing a solution of Brigatinib in a solvent; and
b) isolating amorphous form of Brigatinib.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Brigatinib that is obtained in the course of its synthesis; or
ii) dissolving Brigatinib in a solvent.
Any physical form of Brigatinib may be utilized for providing the solution of Brigatinib in step (a).
Suitable solvents which can be used in step (a) include but are not limited to: water, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated solvents such as chloroform, dichloromethane and the like; polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and the like; Nitrile solvents such as acetonitrile, propionitrile and the like; Organic acids such as Formic acid, Acetic acid and the like and any mixtures thereof.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 150°C, less than about 130°C, less than about 100°C, less than about 70°C, less than about 40°C, less than about 20°C, less than about 0°C, or any other suitable temperatures, as long as a clear solution of Brigatinib is obtained without affecting its quality.
The solution obtained in step (a) may be optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. 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 under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth 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 precipitation of solid.
Step (b) involves isolating the amorphous form of Brigatinib.
In one aspect present application involves isolation of amorphous Brigatinib by removing solvent from a solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art.
The solvent can be removed, optionally under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C or any other suitable temperatures.
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 be optionally further dried to afford an amorphous form of Brigatinib. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Brigatinib is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In an aspect, thee present application provides amorphous form of Brigatinib by ball milling any physical form or mixture of one or more physical form of Brigatinib.
In the fourth embodiment, the present application provides a pharmaceutical composition comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients;.
In an aspect, the said amorphous form of Brigatinib 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 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, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
In the fifth embodiment, the present application provides a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more components, generally a polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer or carrier or excipient in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve.
A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a carrier or polymer or excipient. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the carrier dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles.
In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers. Further the term "solid dispersion" as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers with or without adsorbent/absorbent. By "amorphous drug substance," it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
The solid dispersion of Brigatinib of the present invention can be made by any of the numerous methods that result in a solid dispersion comprising amorphous form of Brigatinib. Several approaches can be used for the preparation of solid dispersion which includes spray drying, fusion method, solvent evaporation, hot-melt extrusion, ball milling, particle size reduction, supercritical fluid (SCF) processes, kneading, inclusion complexes, electrostatic spinning method, melt crystallization and surface-active carriers.
Brigatinib can be incorporated in the dispersion in amorphous state.
The dispersing agent is typically composed of a pharmaceutically acceptable substance that does not substantially interfere with the pharmaceutical action of Brigatinib. The phrase "pharmaceutically acceptable" is employed herein to refer to those substances which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, the carrier is a solid at room temperature (e.g., about 22oC).
Non-limiting examples of suitable carriers or polymers or excipients are celluloses (e.g., carboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses); polysaccharides, heteropolysaccharides (pectins); poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid; mixtures of two or more thereof, copolymers thereof, derivatives thereof, and the like. Further examples of carriers include copolymer systems such as polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxybutyric acid (PEG-PHB), polyvinylpyrrolidone-polyvinylalcohol (PVP-PVA), and derivatized copolymers such as copolymers of N-vinyl purine (or pyrimidine) derivatives and N-vinylpyrrolidone.
An enteric coating polymer can also be used according to the present invention. Specific examples of the enteric coating polymers include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate and hydroxypropylmethyl trimellitate.
In an aspect of the invention, the polymer or carrier is polyvinylpyrrolidone (PVP) or a derivative thereof. PVP is a polyamide that forms complexes with a wide variety of substances and is considered to be chemically and physiologically inert. Examples of suitable PVPs include polyvinylpyrrolidones having an average molecular weight from about 10,000 to about 50,000. In some embodiments, the polyvinylpyrrolidone has an average molecular weight of about 10,000 to about 20,000. In further embodiments, the polyvinylpyrrolidone has a molecular weight of about 15,000 to about 20,000.
In the sixth embodiment, the present application provides a method for preparing a solid dispersion comprising amorphous Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients comprising the steps of:
a) providing a mixture of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients in a solvent; and
b) isolating solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
Step (a) involves providing a mixture of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients in a solvent;
Any physical form of Brigatinib may be utilized for providing the mixture of Brigatinib in step (a).
Suitable pharmaceutically acceptable carriers or polymers or excipients that are dispersing agents which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide (Syloid, Aerosil, Cab-o-sil etc.) and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Suitable solvent which can be used for preparing the solid dispersion of Brigatinib are the same as described in step (a) of third embodiment.
Any undissolved particles in the solution obtained in step (a) may be removed by suitable method as described herein above or any other technique known in the art.
Step (b) involves isolation of solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
Isolation of solid dispersion in step (b) may be carried out by removing solvent from a solution or suspension or mixture obtained in step (a). Suitable techniques which can be used for the removal of solvent are the same as described in step (b) of third embodiment or any other technique known in the art.
Although the solid dispersions of the present invention are preferably prepared using conventional spray drying techniques, it will be understood that suitable solid dispersions may be formed utilizing other conventional techniques known to those skilled in the art, such as vacuum drying, fluid-bed drying, freeze-drying, rotary evaporation, rotary vacuum paddle dryer, drum drying, or other solvent removal process.
Another aspect of the invention involves preparation of solid dispersions of Brigatinib by melt processing, wherein the compound and a carrier or polymer or excipient are heated to a temperature above the melting point of both the carrier or polymer or excipient and compound, which results in the formation of a fine colloidal (as opposed to molecular) dispersion of compound particles, with some solubilization of the compound in the carrier matrix. Processing of such a molten mixture often includes rapid cooling, which results in the formation of a congealed mass which must be subsequently milled to produce a powder which can be filled into capsules or made into tablets.
Recovery of solid dispersion comprising an amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients may be carried out by methods as described in step (b) of third embodiment or any other technique known in the art.
The resulting solid dispersion comprising an amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients may be optionally further dried. Drying can be can be carried out by methods as described in step (b) of third embodiment herein above or any other technique known in the art.
In the seventh embodiment, present application provides a method for preparing a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients comprising the steps of:
a) physically blending of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients; and
b) isolating solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
Step (a) involves physically blending of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.
Brigatinib substantially in amorphous form may be utilized for physical blending of Brigatinib in step (a).
Suitable pharmaceutically acceptable polymers or carriers that are dispersing agents which can be used in step (a) are the same as dispersing agents defined in step (a) of sixth embodiment.
Physical blending as used in step a) involves dry blending in motor pistol, flask or any other suitable container or any other technique known in the art.
Step (b) involves isolation of solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients which can be carried out by any other technique known in the art.
The amount of Brigatinib in the solid dispersions of the present invention ranges from about 0.1% to about 90% by weight of the solid dispersion; or from about 10% to about 70% by weight of the solid dispersion; or from about 20% to about 60% by weight of the solid dispersion; or from about 20% to about 40% by weight of the solid dispersion; or about 30% by weight of the solid dispersion. In some aspects, the weight ratio of Brigatinib to polymer or carrier is about 1:99 to about 99:1. In some aspects, the weight ratio of Brigatinib to polymer or carrier is about 1:99 to about 75:25 or about 1:99 to about 60:40. In further aspects, the weight ratio of Brigatinib to polymer or carrier is about 1:99 to about 15:85; about 1:99 to about 10:90; or about 1:99 to about 5:95. In further aspects, the weight ratio of Brigatinib to polymer or carrier is about 25:75 to about 75:25, about 40:60 to about 60:40 or about 1:1 or about 2:1.
Amorphous form or the solid dispersions of Brigatinib of the present application can be optionally subjected to a particle size reduction procedures before or after the completion of drying of the product to produce desired particle sizes and distributions. Milling or micronization can be performed to achieve the desired particle sizes or distributions. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
In another general aspect, there is provided amorphous form of Brigatinib or solid dispersion comprising amorphous form of Brigatinib having particle size distributions wherein D90 is less than about 500 microns or less than about 200 microns or less than about 100 microns or less than about 50 microns or less than about 40 microns or less than about 30 microns or less than about 20 microns or less than about 10 microns or any other suitable particle sizes.
In an aspect, the present application provides pharmaceutical formulations comprising an amorphous form of Brigatinib or solid dispersion comprising amorphous form of Brigatinib, together with one or more pharmaceutically acceptable carriers or polymers or excipients. Brigatinib together with one or more pharmaceutically acceptable carriers or polymers or excipients 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. 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 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, and modified release coated.
Pharmaceutically acceptable carriers or polymers or 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, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
The pharmaceutical dosage form according to the present invention may be coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
The pharmaceutical dosage form according to the present invention can further comprise additional carriers or polymers or excipients and adjuvants, which are pharmaceutically acceptable and general coating materials, which are preferably applied as a coating to the pharmaceutical dosage form of the present invention. Such further excipients and adjuvants are known to the person skilled in the art.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tableting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
Brigatinib which may be used as the input in the process for preparation of the solid states of the present application can be prepared by any process known in the art.
The solid form of Brigatinib of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.
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. PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1.5406 Å and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer and PANalytical X’Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
The D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Methods for determining D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.
DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The abbreviation “MC” mean moisture content. Moisture content can be conveniently measured, for example, by the Karl Fischer method.
“Amorphous form” as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," or 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.
Where this document refers to a material, such as in this instance, Brigatinib and its solid state forms thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid state form, within any associated and recited margin of error, for purposes of identification.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
As used herein, the term "room temperature" refers to a temperature of from about 20oC to about 35oC, from about 25oC to about 35oC, from about 25oC to about 30oC, or for example, about 25oC.
As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
The "polymer" or “carrier” or “excipient” as used herein interchangeably refer to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.
The term “dispersed” means random distribution of a therapeutically active substance throughout the carrier.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
EXAMPLE 1: PREPARATION OF AMORPHOUS FORM OF BRIGATINIB
Brigatinib (1 gm) was dissolved in dichloromethane (25 mL) in a round bottom flask and filtered the solution. The solution was taken in a flask and heated to 45oC under vacuum for 10 minutes to completely evaporate dichloromethane. The resultant product was dried at 30oC for 10 minutes to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib obtained in above example is in accordance with Figure 1.

EXAMPLE 2: PREPARATION OF AMORPHOUS FORM OF BRIGATINIB
Brigatinib (2 gm) was charged into a ball milling chamber and milled for 3 and half hours (Speed:400 RPM, Interval:10 min) to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib obtained in above example is in accordance with Figure 2.

EXAMPLE 3: PREPARATION OF BRIGATINIB SOLID DISPERSION WITH SYLOID (1:1 w/w)
Brigatinib (250 mg) and Syloid (250 mg) were ground into mortar-pestle for about 5 minutes to afford the title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib solid dispersion obtained in above example is in accordance with Figure 3.

EXAMPLE 4: PREPARATION OF BRIGATINIB SOLID DISPERSION WITH PVPK-30 (1:1 w/w)
Brigatinib (500 mg) and PVPK-30 (500 mg) were dissolved in dichloromethane (25 mL) in a round bottom flask. The reaction mass was filtered and the filtrate was taken into a flask and was subjected to solvent evaporation by rotavapor under vacuum at 45°C to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib solid dispersion obtained in above example is in accordance with Figure 4.

EXAMPLE 5: PREPARATION OF BRIGATINIB SOLID DISPERSION WITH COPOVIDONE (1:1 w/w)
Brigatinib (500 mg) and Copovidone (500 mg) were dissolved in dichloromethane (25 mL) in a round bottom flask. The reaction mass was filtered and the filtrate was taken into a round bottom flask and was subjected to solvent evaporation by rotavapor under vacuum at 45°C to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib solid dispersion obtained in above example is in accordance with Figure 5.

EXAMPLE 6: PREPARATION OF BRIGATINIB SOLID DISPERSION WITH HPMC-AS (1:1 w/w)
Brigatinib (500 mg) and HPMC-AS (500 mg) were dissolved in dichloromethane (35 mL) in a round bottom flask. The reaction mass was filtered and the filtrate was taken into a round bottom flask and was subjected to solvent evaporation by rotavapor under vacuum at 45°C to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib solid dispersion obtained in above example is in accordance with Figure 6.

EXAMPLE 7: PREPARATION OF BRIGATINIB SOLID DISPERSION WITH HYDROXYPROPYLCELLULOSE (HPC)-L (1:1 w/w)
Brigatinib (500 mg) and HPC-L (500 mg) were dissolved in dichloromethane (35 mL) in a round bottom flask. The reaction mass was filtered and the filtrate was taken into a round bottom flask and was subjected to solvent evaporation by rotavapor under vacuum at 45°C to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib solid dispersion obtained in above example is in accordance with Figure 7.

EXAMPLE 8: PREPARATION OF AMORPHOUS BRIGATINIB SOLID DISPERSION WITH HPMC-AS AND SYLOID (1:1:1 w/w/w)
Brigatinib and HPMC-AS amorphous solid suspension premix (200 gm) and Syloid (100 mg) were ground in a mortar-pestle for about 10 minutes to afford the title compound.
The Powder X-ray diffraction (PXRD) pattern of Brigatinib solid dispersion obtained in above example is in accordance with Figure 8.
,CLAIMS:1) A method of preparing a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients, comprising the steps of:
a) providing a mixture of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients in a solvent; and
b) isolating solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.

2) A method of preparing a solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients, comprising the steps of:
a) physically blending Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients; and
b) isolating solid dispersion comprising amorphous form of Brigatinib and one or more pharmaceutically acceptable carriers or polymers or excipients.