*ield oi the Invention: 700159734
The present invention relates to amorphous form of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethy!)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1, represented by the following structural formula:
5 N^
Formuia-1 Back ground of the Invention:
Nilotinib hydrochloride is a kinase inhibitor, approved as Nilotinib hydrochloride
monohydrate, sold using the trade name Tasigna®, in the form of capsule for the treatment of
10 chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous
leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included
imatinib.
International publication No. WO2007/015871 Al describes salts of 4-methyl-N-[3-15 (4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzamide, wherein the salt is a hydrochloride salt, hydrochloride monohydrate, monophosphate salt, diphosphate salt, sulfate salt, methanesulfonate salt, ethanesulfonate salt, benzene sulfonate salt, p-toluene sulfonate salt, citrate salt, furmarate salt, malonate salt, malate salt, tartrate salt, etc., their polymorphic forms and process for the preparation thereof. 20 Further, it also discloses the crystalline forms of Nilotinib hydrochloride designated as Form A and Form 8, process for their preparation and process for the preparation of Nilotinib hydrochloride monohydrate.
International publication No. WO2007/015870 A2 describes substantially pure
25 crystalline forms of Nilotinib hydrochloride designated as Form A, Form A', Form A", Form
B, Form B', Form SB, Form SB', Form C, Form Sc, Form D, Form SE, mixture of Form B and
Form D, and amorphous form of Nilotinib hydrochloride. Further, it also discloses
substantially pure crystalline forms A and B of Nilotinib free base and substantially pure

crystalline forms A and B ofNilotinib sulfate salt.
International publication No. WO2010/054056 A2 describes polymorphic forms of Nilotinib hydrochloride designated as forms 11,12, T3, T4, T5, T6, T7, T8, T9, T10, TIL 5 T12, T13, T14, T15 T16, T17, T18, and T19. Further, it also describes solid dispersion of Nilotinib hydrochloride in combination with a pharmaceutical^ suitable excipient.
International publication No. WO2011/163222 describes polymorphic forms of Nilotinib hydrochloride designated as forms T20, T27, T28 and T29.
10
International publication No. WO2011/086541 Al describes a crystalline form of
Nilotinib hydrochloride monohydrate having an X-ray diffraction pattern comprising peaks at
5.7, 7.5, 9.8, 15.0, 17.3 and 27.6 ± 0.2 degrees 2-theta and process for its preparation.
15 International publication No. WO2012/055351 Al describes a crystalline form of
Nilotinib hydrochloride monohydrate having an X-ray diffraction pattern comprising peaks at 4.9, 8.4, U.3, 14.4, 17.2, 19.2 and 25.5 degrees 2-theta and process for its preparation.
International publication No. WO2012/070062 A2 describes Nilotinib hydrochloride 20 crystalline form HI , characterized by peaks in the powder x-ray diffraction spectrum having 2-theta angle positions at about 8.6, I I .4, 13.2, 14.3, 15.5, 1 7.3, 19.2 and 25.3 ± 0.2 degrees and process for its preparation.
IP.com Journal (2010), 10(3B), I 1 describes the crystalline forms T24, T25, and T26 25 ofNilotinib hydrochloride and process for their preparation.
IP com Jou rnal (2010), 10(I2A), 18 describes the crystalline forms of Nilotinib hydrochloride designated as Forms T19 and T20 and process for their preparation.
30 IP.com Journal (2009), 9(12B), 14 describes the Nilotinib hydrochloride crystalline
forms T2-T6, T9 and Tl 1 -Tl 3 and process for their preparation.
IP.com Journal (2010), 10(5A), 25 describes the Nilotinib hydrochloride crystalline form T5 and process for its preparation.
35
IP.com Journal (2010), 10(7B), 3 describes a method for the preparation of the of 4-
methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-
pyrimidinyl]amino]-benzamide salts in amorphous form.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms 5 where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and 10 to determine the stability, dissolution and flow properties of each polymorphic form.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be 15 administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
20 An amorphous form of some of the drugs exhibit much higher bioavailability than the
crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous
25 forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation. Accordingly, there remains a need to reproducibly obtain amorphous nilotinib free base of similar quality for use in a pharmaceutical preparation.
30 Brief description of the Invention:
The first aspect of the present invention is to provide an amorphous form of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidiny]]amino]-benzamide compound of formula-1.
35 The second aspect of the present invention is to provide a process for the preparation

"of amorphous form of 4-methy]-N-[3-(4-methyl-lH-imidazol-]-y])-5-(trifluoromethyl) phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]aminoJ-benzamide compound of formula-1.
The third aspect of the present invention is to provide a process for the preparation of 5 amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoro methyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 in combination with one or more pharmaceutical acceptable carrier.
Brief description of the Drawings: 10 Figure 1: Illustrates the PXRD pattern of amorphous 4-methyl-N-[3-(4-methyl-lH-imidazol-
l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide.
Figure 2: Illustrates the PXRD pattern of amorphous solid dispersion of 4-methyl-N-[3-(4-
methyl-lH-imidazol-l-yl)-5-(trifiuoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]
amino]-benzamide in combination with HPC. 15 Figure 3: Illustrates the PXRD pattern of amorphous solid dispersion of 4-methyl-N-[3-(4-
methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]
amino]-benzamide in combination with PVP K-30.
Figure 4: Illustrates the PXRD pattern of amorphous solid dispersion of 4-methyl-N-[3-(4-
methyt-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] 20 aminoj-benzamide in combination with HPMC.
Detailed description of the Invention:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene,
25 pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate,
30 ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloro methane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as
35 acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol,

ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifiuoroethanol, ethylene glycol, 2-methoxyethanol, I, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar 5 solvents" such as water or mixtures thereof.
The first aspect of the present invention provides an amorphous form of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1.
10
The amorphous form of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoro
methy])phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1
is further characterized by powder x-ray diffraction pattern as depicted in figure 1.
15 The second aspect of the present invention provides a process for the preparation of
amorphous form of 4-methyl-N-[3-(4-methyl-lH-imidazo1-l-yl)-5-(trifluoromethyt)pheny!]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-l, comprising of the following steps:
a) Adding a suitable solvent to 4-methyl-N-[3-(4-methy!-lH-imidazol-l-yl)-5-
20 (trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide
compound of formula-1,
b) stirring the reaction mixture,
c) optionally, filtering the reaction mixture through hyflow bed,
d) removing the solvent from the filtrate obtained in step-b) or step-c) to provide 25 amorphous form of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoro
methy])phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1.
Wherein, 30 in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ester
solvents, polar aprotic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents and
polar solvent like water or mixture thereof;
in step-d) removal of solvent may be carried out by filtration, solvent dry distillation, spray
drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any 35 other suitable technique or by adding suitable anti-solvent.

The preferred embodiment of the present invention provides a process for the
preparation of amorphous form of 4-methyl-N-[3-(4-methyl-iH-imidazol-l-yl)-5-(trifluoro
methyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-
1, comprising of the following steps:
5 a) Adding a mixture of methanol and dichloromethane to 4-methyl-N-[3-(4-methyl-
lH-imidazo]-l-y!)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridiny!)-2-pyrimidinyl] aminoj-benzamide compound of formula-l,
b) stirring the reaction mixture,
c) filtering the reaction mixture through hyflow bed,
10 d) spray drying the filtrate obtained in step-c) to provide amorphous form of 4-
methy[-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-l.
A preferred method to remove the solvent involves spray-drying, in which a solution
15 of Nilotinib free base is spray dried in spray drier wherein, the flow rate is about 1 to about
30 ml/min, and preferably about 5 to about 20 ml/min. The air inlet temperature to the spray
drier used may range from about 25°C to about 150°C, and preferably from about 60°C to
about 65°C and the outlet air temperature used may range from about 30° C. to about 90°C.
20 The term "spray drying" broadly refers to processes involving breaking up liquid
mixtures into small droplets (atomization) and rapidly removing solvent from the mixture. In a typical spray drying apparatus, there is a strong driving force for evaporation of solvent from the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described in Perry's Chemical Engineer's Handbook, pages. 20-54 to 20-
25 57 (Sixth Edition 1984).
The solid residue obtained after the solvent removal is isolated and, if desired, can be dried further using conventional methods. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use.
30
The substantially pure amorphous Nilotinib free base obtained according to the
present invention may be further dried by utilizing Vacuum Tray Dryer, Rotocon Vacuum
Dryer, Vacuum Paddle Dryer or pilot plant Rotavapor, to further lower residual solvents.
35 By way of non- limiting example only, a typical spray drying apparatus comprises a
drying chamber, atomizing means for atomizing a solvent-containing feed into the drying

'chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber. Examples of such apparatuses include Niro Models PSD-I, PSD-2 and PSD-4 (Niro AJS, Soeborg, Denmark).
5
Typically, the product collection means, collecting the product utilizing a cyclone
connected to the drying apparatus. In the cyclone, the particles produced during spray drying
are separated from the drying gas and evaporated solvent, allowing the particles to be
collected. A filter may also be used to separate and collect the particles produced by spray
10 drying.
Amorphous 4-methyl-N-[3-(4-methyl-l H-imidazol-l-yl)-5-(tri^uoromethyl)phenYl]-
3-[[4-(3-pyridiny!)-2-pyrimidinyl]amino]-benzamide compound of formula-1 obtained
according to the present invention is substantially free of crystalline forms.
15 Amorphous 4-methyl-N-[3-(4-methyl-lH-imida2ol-l-yl)-5-(trifluoromethy!)phenyl]-
3-[[4-(3-pyridinyI)-2-pyrimidinyl]arnino]-benzamide compound of formula-1 obtained according to the present invention is substantially free from residual solvents.
The third aspect of the present invention provides a process for the preparation of 20 amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoro methyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 in combination with one or more pharmaceutical acceptable carrier, comprising of:
a) Dissolving 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyll-
3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide in a suitable solvent,
25 b) optionally, filtering the reaction mixture,
c) adding suitable pharmaceutical acceptable carrier to the filtrate obtained in step-b),
d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-l H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide
30 compound of formula-1.
Wherein,
In step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile 35 solvents and polar solvents like water or mixture thereof;

in step-c) the suitable pharmaceutical acceptable carrier is selected from starches, modified starches, cellulose, methyl cellulose (MC), Microcrystalline cellulose (MCC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS), 5 polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate (PVAc), PVP vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (vinylpyrrolidone -vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, p-cyclodextrins, y-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl
10 propyl-cyclodextrin, sodium carboxymethyl cellulose cross linked polyacrylic acid (carbipol), or a mixture thereof;
in step-e) The isolation can be carried out using a rotational distillation device such as a Buchi Rotavapor, vacuum drying, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying (ATFD) or melt extrusion or freeze drying
15 (lyophilization) or by any other suitable techniques.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazot-l-y!)-5-(trifluoromethyl)phenylJ-3-[[4-(3-pyridinyl)-2-pyrimLdinyl]amino]-benzamide compound of 20 formula-1 in combination with HPC, comprising of:
a) Dissolving 4-methyl-N-[3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyI]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide in a mixture of methanol and dichloromethane,
b) filtering the reaction mixture,
25 c) adding hydroxypropyl cellulose (HPC) to the filtrate obtained in step-b),
d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-l H-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 in combination with HPC.
30
The another preferred embodiment of the present invention provides a process for the
preparation of amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-
(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of
formula-1 in combination with PVP K-30, comprising of:

a) Dissolving 4-methy]-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)pheny!]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide in a mixture of methanol and dichloromethane,
b) filtering the reaction mixture,
5 c) adding PVP K-30 to the filtrate obtained in step-b),
d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-1 H-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amtno]-benEamide compound of formula-1 in combination with PVP K-30.
10
The another preferred embodiment of the present invention provides a process for the
preparation of amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-
(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of
formula-1 in combination with HPMC, comprising of:
15 a) Dissolving 4-methy[-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-
3-[[4-(3-pyridinyl)-2-pyrimidiny]]amino]-benzamide in a mixture of methanol and
dichloromethane,
b) filtering the reaction mixture,
c) adding hydroxypropyl methyl cellulose (HPMC) to the filtrate obtained in step-b). 20 d) stirring the reaction mixture,
e) isolating amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-!H-imidazo!-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 in combination with HPMC.
25 4-Methyl-N-[3-(4-methyl-lH-imidazol-l-y!)-5-(trifluoromethyl)phenyl]-3-[[4-(3-
pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include,
30 but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
Amorphous 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifiuoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 obtained

according to the present invention is having particle size distribution D90 less than 150 u.m. preferably less than 100 u.m, more preferably less than 50 u.m.
Amorphous 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 obtained 5 according to the present invention is stable.
4-Methy!-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-
pyridinyl)-2-pyrimidinyl]amino]-benzamide compound of formula-1 used in the present
invention is prepared according to any of the process known in the art.
10 The invention also encompasses pharmaceutical compositions comprising compound
of formula-1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills. powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
15
P-XRD Method of Analysis: PXRD analysis of compounds produced by the present
invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using
Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.
20 PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not
25 be construed as limitation of the scope of the invention. Examples
Example-1: Preparation of Amorphous 4-methyl-N-[3-(4-rnethyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide: (Formula-1)
30 Methanol (125 ml) and dichloromethane (125 ml) was added to 4-methyl-N-[3-(4-
methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzamide (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. The obtained filtrate was spray dried at below mentioned parameters to obtain amorphous 4-methyl-N-[3-(4-methyl-IH-imidazol-l-
35 yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide.

Operation parameters:
Labultima Instrument.
Aspirator flow rate: 70%
Feed Rate: 10 ml/min 5 Inlet temperature: 55°C to 60°C
Gas flow N2: 2kg/cm2
Yield: 2.5 gms; The P-XRD pattern of the obtained compound was shown in figure-1.
ExampIe-2: Preparation of Amorphous 4-methyI-N-[3-(4-methyl-lH-imidazol-l-yl)-5-
(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide: 10 (Formula-1)
Methanol (380 ml) and dichloromethane (380 ml) was added to 4-methyl-N-[3-(4-
methyl-lH-imidazol-l-yl)-5-(tnfluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]
amino]-benzamide (17.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature.
Filtered the reaction mixture through hyfiow bed. The obtained filtrate was spray dried at 15 below mentioned parameters to obtain amorphous 4-methyl-N-[3-(4-methyl-IH-imidazol-l-
yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide.
Operation parameters:
Labultima Instrument.
Aspirator flow rate: 70% 20 Feed Rate: 10 ml/min
Inlet temperature: 55°C to 60°C
Gas flow N2: 2kg/cm2
Yield: 8.0 gms; Purity by HPLC: 99.97%; Benzoic acid derivative impurity: Not detected;
Aniline derivative impurity: Not detected; Regio isomer impurity: Not detected; HIUI: 25 0.03%; Particle Size Distribution (PSD): D(0.1) is 2.26 UJTI; D(0.5) is 5.58 urn; D(0.9) is 11.0
\im; D[4.3] is 6.20 urn.
The P-XRD pattern of the obtained compound was shown in figure-1.
Example-3: Preparation of Amorphous 4-methyI-N-[3-(4-methyI-lH-imidazol-l-yl)-5-30 (trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide: (Formula-1)
Dichloromethane (50 ml) and 2,2,2-trifluoroethanol (50 ml) was added to 4-methyl-N-[3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] aminol-benzamide (10.0 gms) at 25-30°C and stirred for 15 minutes at the same

temperature. Filtered the reaction mixture through hyflow bed. The obtained filtrate was spray dried at below mentioned parameters to obtain amorphous 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3T[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide. 5 Operation parameters: Labultima Instrument. Aspirator flow rate: 70% Feed Rate: 5 ml/min Inlet temperature: 55°C to 60°C 10 Gas flow N2: 2kg/cm2
Yield: 5.0 gms; The P-XRO pattern of the obtained compound was shown in figure-1.
Example-4: Preparation of Amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenylj-3-[[4-(3-pyridinyl)-2-pyrimidinylJamino]-15 benzamide in combination with HPC: (1:1)
Dichloromethane (22.0) and methanol (22.0) was added to 4-methyl-N-[3-(4-methyl-1H-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide (10.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. The filtrate was added to hydroxypropyl cellulose
20 (10.0 gms) at 25-30°C and stirred for 15 minutes at the same temperature. The obtained
filtrate was spray dried at below mentioned parameters to obtain amorphous solid dispersion
of 4-methyl-N-[3-(4-methyl-IH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-
pyridinyl)-2-pyrimidinyl] amino]-benzamide in combination with HPC. Operation parameters:
25 Labultima Instrument. Aspirator flow rate: 70% Feed Rate: 10 ml/min Inlet temperature: 55°C to 60CC Gas flow N2: 2kg/cm2
30 Yield: 11.2 gms; The P-XRD pattern of the obtained compound was shown in figure-2.
Example-5: Preparation of Amorphous solid dispersion of 4-methyI-N-[3-(4-methyl-IH-imidazoI-l-yl)-5-(trifluoromethyl)phenylJ-3-[l4-(3-pyridinyl)-2-pyrimidinyl)amino]-benzamide in combination with PVPK-30: (1:1)

Dichloromethane (22.0) and methanol (22.0) was added to 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyi)-2-pyrimidinyl]amino]-benzamide (10.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. The filtrate was added to PVP K-30 (10.0 gms) at 5 25-30°C and stirred for 15 minutes at the same temperature. The obtained filtrate was spray dried at below mentioned parameters to obtain amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imida2ol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidiny!] aminoj-benzamide in combination with PVP K-30. Operation parameters:
10 Labultima Instrument. Aspirator flow rate: 70% Feed Rate: 10 ml/min Inlet temperature: 55°C to 60°C Gas flow N2: 2kg/cm2
15 Yield: 11.4 gms.: The P-XRD pattern of the obtained compound was shown in figure-3.
ExampIe-6: Preparation of Amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide in combination with HPMC: (1:1)
20 Dichloromethane (22.0) and methanol (22.0) was added to 4-methyl-N-[3-(4-methyl-
lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide (10.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. The filtrate was added to hydroxypropyl methyl cellulose (10.0 gms) at 25-30°C and stirred for 15 minutes at the same temperature. The
25 obtained filtrate was spray dried at below mentioned parameters to obtain amorphous solid dispersion of 4-methyl-N-[3-(4-methyl-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide in combination with HPMC. Operation parameters: Labultima Instrument.
30 Aspirator flow rate: 70% Feed Rate: 10 ml/min rnlet temperature: 55°C to 60°C Gas flow N2: 2kg/cm3 Yield: 11.0 gms; The P-XRD pattern of the obtained compound was shown in figure-4.