DESC:The following specification describes the invention:

FIELD OF THE INVENTION
The present application relates to novel crystalline 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.
WO 2016/065028A1 discloses crystalline forms A, B, C, D, E, F, G, H, J, K, L and amorphous form of brigatinib.
Isolating a pharmaceutical compound in crystalline form may provide advantages with desirable processing properties, such as ease of handling, ease of processing, storage stability and ease of purification. Such properties may significantly influence the processing, shelf life, and commercial acceptance of a product.
There remains a need to provide crystalline forms of Brigatinib and process for making the same.
SUMMARY OF THE INVENTION
In the first embodiment, the present application provides a crystalline form SP5 of Brigatinib.
In the second embodiment, the present application provides a process for preparing crystalline form SP5 of Brigatinib, comprising the steps of:
a) providing a solution of Brigatinib in a solvent; and
b) isolating crystalline form SP5 of Brigatinib by adding the solution from step a) to an anti-solvent.
In the third embodiment, the present application provides a crystalline form SP5a of Brigatinib.
In the fourth embodiment, the present application provides a process for preparing crystalline form SP5a of Brigatinib comprising drying the crystalline form SP5.
In the fifth embodiment, the present application provides a pharmaceutical composition comprising crystalline form SP5 of Brigatinib and one or more pharmaceutically acceptable excipients.
In the sixth embodiment, the present application provides a pharmaceutical composition comprising crystalline form SP5a of Brigatinib and one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of crystalline form SP5a of Brigatinib according to Example 1.
FIG. 2 is an illustration of powder X-ray diffraction (“PXRD”) pattern of crystalline form SP5 of Brigatinib according to Example 1.
DESCRIPTION OF THE INVENTION
In the first embodiment, the present application provides a crystalline form SP5 of Brigatinib.
In an aspect, the present application provides a crystalline form SP5 of Brigatinib that may be characterized by its PXRD pattern as illustrated by Figure 2.
In an aspect, the present invention provides crystalline Form SP5 of Brigatinib characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 12.30, 21.39 and 28.73± 0.2°.
In an aspect, the crystalline Form SP5 of Brigatinib further characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 4.56, 5.75, 8.72, 13.02, 13.76, 16.02, 16.36, 16.74, 17.58, 18.78, 20.25, 22.37, 22.93 and 27.35± 0.2°.
In the second embodiment, the present application provides a process for preparing crystalline form SP5 of Brigatinib, comprising the steps of:
a) providing a solution of Brigatinib in a solvent; and
b) isolating crystalline form SP5 of Brigatinib, by adding the solution from step a) to an anti-solvent.
Any physical form of Brigatinib may be utilized for providing the solution of Brigatinib in step (a). In an aspect, crystalline Form A of Brigatinib that is reported in WO 2016/065028 A1 may be used as an input for the preparation of crystalline form SP5 of Brigatinib of the present application. The solvent that may be used is selected from alcohols such as methanol, ethanol, isopropanol, butanol, or mixtures thereof; esters such as ethylacetate, isopropylacetate, butyl acetate or 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 crystalline form of Brigatinib, designated as Form SP5 by adding the solution from step a) to an anti-solvent. The anti-solvent that may be used is selected from but not limited to n-pentane, n-hexane, n-heptane, methyl t-butyl ether (MTBE), cyclopropylmethyl ether (CPME), diethyl ether, di-isopropyl ether and petroleum ether or mixtures thereof.
In the third embodiment, the present application provides a crystalline form SP5a of Brigatinib.
In an aspect, the present application provides a crystalline form SP5a of Brigatinib that may be characterized by its PXRD pattern as illustrated by Figure 1.
In the fourth embodiment, the present application provides a process for preparing crystalline form SP5a of Brigatinib, comprising, drying the crystalline form SP5 to give crystalline form SP5a of Brigatinib.
Drying may 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 may 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 may be carried out for any desired times until the required product quality is achieved. Suitable time for drying may vary from few minutes to several hours for example from about 1 minute to about 24 hours or more hours.
In an aspect, crystalline form SP5 may be obtained when the temperature at which form SP5a is formed by drying crystalline form SP5 is reduced to a temperature of less than about 500C or less than about 400C or less than about 300C or less than about 200C or less than about 100C or any other suitable temperature.
In the fifth embodiment, the present application provides a pharmaceutical composition comprising crystalline form SP5 of Brigatinib, and one or more pharmaceutically acceptable excipients.
In the sixth embodiment, the present application provides a pharmaceutical composition comprising crystalline form SP5a of Brigatinib or crystalline form SP5a of Brigatinib, and one or more pharmaceutically acceptable excipients.
Brigatinib together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, 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 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 may further comprise additional 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 may 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 may be carried out using a conventional tableting machine or a rotary compression machine. The tablet cores may vary in shape and may 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 may 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), Thermo gravimetric analysis (TGA) 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 PANalytical X’Pert PRO instrument. 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.
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

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 may 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 may 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.
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.
The “excipient” as used herein interchangeably refer to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.
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 may 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 CRYSTALLINE FORM OF BRIGATINIB, DESIGNATED AS FORM SP5a AND FORM SP5.
n-Pentane (75 ml) was charged in a reactor and stirred for 30 minutes at -5oC. In another reactor Brigatinib (3 gm) was dissolved in methanol (15 ml) at 60oC. The filtered clear solution was added to n-pentane that is at -5oC and stirred for 5 minutes. The reaction mass was stirred over night at 0oC and vacuum filtered. The filtered material was dried in vacuum tray dryer at 50oC for two hours to afford crystalline form SP5a of Brigatinib having powder X-ray diffraction (PXRD) pattern in accordance with Figure 1. The resulting crystalline form SP5a was kept at room temperature (~250C) for 30 minutes to afford crystalline form SP5 of Brigatinib having a powder X-ray diffraction (PXRD) pattern in accordance with Figure 2.

EXAMPLE 2: PREPARATION OF CRYSTALLINE FORM OF BRIGATINIB, DESIGNATED AS FORM SP5a AND FORM SP5.
n-Heptane (75 ml) was charged in a reactor and stirred for 30 minutes at -5oC. In another reactor Brigatinib (3 gm) was dissolved in methanol (12 ml) at 60oC. The filtered clear solution was added to n-heptane that is at -5oC and stirred for 5 minutes. The reaction mass was stirred over night at 0oC and vacuum filtered. The filtered material was dried in vacuum tray dryer at 50oC for 90 minutes to afford crystalline form SP5a of Brigatinib. The resulting crystalline form SP5a was kept at room temperature (~250C) for 30 minutes to afford crystalline form SP5 of Brigatinib.

Claims
Claim 1: A process for preparing crystalline Form SP5 of Brigatinib, comprising the steps of:
a) providing a solution of Brigatinib in a solvent; and
b) isolating crystalline form SP5 of Brigatinib, by adding the solution from step a) to an anti-solvent.
Claim 2: A pharmaceutical composition comprising the crystalline Form SP5 of Brigatinib and pharmaceutically acceptable excipient.
Claim 3: The process of claim 1, wherein the anti-solvent is selected from a group comprising n-pentane, n-hexane, n-heptane, methyl t-butyl ether (MTBE), cyclopropyl methyl ether (CPME), diethyl ether, di-isopropyl ether and petroleum ether or mixtures thereof.
Claim 4: The process of claim 3, wherein the anti-solvent is n-heptane.
Claim 5: A process for preparing crystalline Form SP5a of Brigatinib comprising drying the crystalline form SP5 to give crystalline form SP5a of Brigatinib.
Claim 6: The process of claim 5 wherein the drying is carried out in tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
Claim 7: The process of claim 5, wherein the drying is 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.
,CLAIMS:Claims
Claim 1: A process for preparing crystalline Form SP5 of Brigatinib, comprising the steps of:
a) providing a solution of Brigatinib in a solvent; and
b) isolating crystalline form SP5 of Brigatinib, by adding the solution from step a) to an anti-solvent.
Claim 2: A pharmaceutical composition comprising the crystalline Form SP5 of Brigatinib and pharmaceutically acceptable excipient.
Claim 3: The process of claim 1, wherein the anti-solvent is selected from a group comprising n-pentane, n-hexane, n-heptane, methyl t-butyl ether (MTBE), cyclopropyl methyl ether (CPME), diethyl ether, di-isopropyl ether and petroleum ether or mixtures thereof.
Claim 4: The process of claim 3, wherein the anti-solvent is n-heptane.
Claim 5: A process for preparing crystalline Form SP5a of Brigatinib comprising drying the crystalline form SP5 to give crystalline form SP5a of Brigatinib.
Claim 6: The process of claim 5 wherein the drying is carried out in tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
Claim 7: The process of claim 5, wherein the drying is 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.