FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention – Preparation of Osimertinib Mesylate
2. Applicant(s)
NAME : ALEMBIC PHARMACEUTICALS LIMITED
NATIONALITY: An Indian Company.
ADDRESS: Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

RELATED APPLICATION:
This application claims the benefit of priority of our Indian Provisional Patent Application No. 201721002919 filed on Jan. 25, 2017.
FIELD OF THE INVENTION
The present invention relates to an improved method of producing Osimertinib mesylate and pharmaceutical compositions comprising the same. Further, the present invention provides substantially pure amorphous form of Osimertinib mesylate, solid premix of Osimertinib mesylate with at least one pharmaceutically acceptable excipient and process for preparations thereof.
BACKGROUND OF THE INVENTION
Osimertinib mesylate (TAGRISSO) chemically is N-(2-{2dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2yl]amino}phenyl)prop-2-enamide mesylate salt, represented by the formula (I).

Osimertinib mesylate is an epidermal growth factor receptor (EGFR) inhibitor indicated for the treatment of T790M mutation-positive non-small cell lung cancer (NSCLC).
Patent US8946235B2 discloses Osimertinib base and its mesylate salt and also its preparation method. The patent also discloses crystalline Polymorphs Form A and B of Osimertinib mesylate.
There is always need for a novel preparation process of drugs with inexpensive, feasible reagents, solvents and intermediates and the process that can afford desired products with good yields and to prepare a substantially pure Form thereof, in the present case substantially pure and stable form B as well as amorphous form and premix.

SUMMARY OF THE INVENTION
The main aspect of the invention is to provide an improved process of preparation of Osimertinib mesylate of formula-(I)

5 comprising:
a. condensation of compound of formula (2) and compound of formula (3) to obtain compound of formula (4);


c. reduction of compound of formula (5) to obtain compound of formula (6)
10 b. reacting compound of formula (4) with N-N-N-trimethylethane-1,2-diamine to obtain compound of formula (5);

d. reacting compound of formula (6) with acrylic acid to obtain Osimeratinib;

e. reacting Osimeratinib with methanesulphonic acid to obtain crystalline Osimeratinib mesylate.
Another aspect of the invention provides an improved process for preparation of substantially pure form B using solvents such as alcohol, hydrocarbon or mixtures thereof.
Another aspect of the present invention provides a substantially pure amorphous form of Osimertinib mesylate characterized by X-ray diffraction pattern that exhibits a halo pattern without a distinct peak in X-ray powder diffraction. Present invention further encompasses a process for preparing substantially pure amorphous form of Osimertinib mesylate.
Another aspect of the present invention provides solid premix composition comprising Osimertinib mesylate and at least one pharmaceutically acceptable excipient. Present invention further encompasses a process for preparation of Osimertinib mesylate premix.

Another aspect of the present invention provides a pharmaceutical composition comprising Osimertinib mesylate amorphous form or premix and at least one pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the invention relates to an improved process of preparation of Osimertinib mesylate of formula-(I)

comprising:
a. condensation of compound of formula (2) and compound of formula (3) in presence of an organic or inorganic acid and a suitable solvent to obtain compound of formula (4);

b. reacting compound of formula (4) with N-N-N-trimethylethane-1,2-diamine in presence of an organic or inorganic base and a suitable solvent to obtain compound of formula (5);


c. reduction of compound of formula (5) in presence of metal catalyst and a suitable solvent to obtain compound of formula (6)

d. reacting compound of formula (6) with acrylic acid in presence of base, coupling agent and a suitable solvent to obtain Osimeratinib;

e. reacting Osimeratinib with methane sulphonic acid in presence of a suitable solvent to obtain crystalline Osimeratinib mesylate.
In an embodiment, an acid in step (a) is inorganic or organic acid. An inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. Preferably the acid is p-toluenesulfonic acid monohydrate.
In an embodiment an base in step (b) is selected from an inorganic base or organic base, selected from hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide; bicarbonates of alkali metals or alkaline earth metals such as sodium bicarbonate, potassium bicarbonate and the like; carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, cesium carbonate; sodium hydride, potassium hydride, potassium tert- butoxide,

sodium tert- butoxide,; butyl lithium, methyl lithium, lithium bis trimethylsilyl amide, sodium bis (trimethylsilyl) amide; pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline, butyllithium, and sodium or potassium alcoholates such as sodium methylate, potassium methylate and sodium ethylate; either alone or in mixtures of two or more. Preferably, the base is diisopropyl ethylamine.
In an embodiment, metal catalyst in step (c) is selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel in presence of hydrogen or hydrogen source selected from ammonium formate, sodium dihydrogen phosphate, hydrazine; for example, Fe-NH4Cl, Fe-HCl, Fe-CaCl2, Sn-HCl, NaHS, ZnAcOH, Pd/C-H2, hydrazine hydrate-Raney Ni, NaBH4-NiCl2.6H2O, Ni(OAc)2.4H2O, CoCl2 likes metals, metal halides or metal Salts. Preferably metal catalyst is Pd/C-H2.
In an embodiment, coupling agent in step (d) is selected from HATU, (0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), BOP (Benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate and PFP-TFA pentafluorophenyltrifluoroacetate, DIC (Ν,Ν'- Diisopropylcarbodiimide), EDC l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride, TBTU O- (Benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, DCC (Ν,Ν'- dicyclohexylcarbodiimide), PyBOP (benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, EDC/HOSu (N-hydroxysuccinimide), DCC/HOBT, DCC/HOSu, Isobutyl chloroformate and l-methyl-2-chloropyridinium iodide, propane phosphonic anhydride. Preferably, the coupling agent is EDC l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride.
In an embodiment, base in step (d) is selected from N,N-Diisopropylethylamine, diisopropylamine, 1,8-Diazabicycloundec-7-ene, or DBU, 2,6-Di-tert-butylpyridine Phosphazene bases, such as t-Bu-P4, triethyl amine. Preferably, the base is 1,8-Diazabicycloundec-7-ene, or DBU.

In some embodiments of the invention in any step, wherein the suitable solvent is the solvent that does not affect the course of reaction and selected from water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, benzonitrile, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptanes, cyclohexane, cycloheptane and cyclooctane or mixtures thereof, but non-limited to these.
According to another aspect, there is provided isolated Osimeratinib mesylate impurities. The present inventors have found that the impurities are formed during the synthesis of Osimeratinib mesylate due to chemical instability of the target substance and due to possible side reactions. The novel impurity of Osimeratinib mesylate is isolated, synthesized and characterized, which is mentioned as below.

In an embodiment, crystalline form of Osimeratinib mesylate in step (e) is form B.
Another aspect of the invention relates to an improved process for preparation of substantially pure form B using solvents such as alcohol, hydrocarbon or mixtures thereof; whereas alcohol such as C1-C6 alkanol and hydrocarbon such as toluene or xylene.
In an embodiment, process of preparing form B of Osimeratinib Mesylate involves; 1) providing solution of Osimeratinib in methanol and toluene or mixture thereof;

2) heating the reaction mixture;
3) adding methyl sulfonic acid in reaction mixture;
4) isolating substantially pure form B of Osimeratinib Mesylate
Providing a solution of Osimeratinib in methanol and toluene solvent means the solution of Osimeratinib may be obtained by dissolving Osimeratinib in methanol and toluene solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which Osimeratinib is formed. Providing a solution of Osimeratinib in methanol and toluene optionally involves use of other suitable solvents capable of dissolving Osimeratinib. Then optionally, filtering the solvent solution to remove any extraneous matter; and finally isolating by removing the solvent from the solution to afford form B of Osimeratinib Mesylate. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.
Still another aspect present invention relates to amorphous form of Osimertinib mesylate having X-ray powder diffractogram ("PXRD") pattern as shown in Fig-1. The invention also relates to preparation process of amorphous form of Osimertinib mesylate of Formula-1.
In one embodiment of the invention, a process for preparation of amorphous form of Osimertinib mesylate comprising steps of providing a solution of Osimertinib mesylate in a suitable solvent or a mixture of solvents capable of dissolving Osimertinib mesylate to isolate the amorphous form. In one embodiment of the invention, a process is provided for preparation of amorphous form of Osimertinib mesylate comprising steps of mixing solvent or mixture of solvents with Osimertinib base and slowly adding methanesulphonic acid to isolate the amorphous form.
Yet still another aspect of the invention relates to solid premix comprising Osimertinib mesylate and at least one pharmaceutically acceptable excipient. The invention also relates to stabilized amorphous form of Osimertinib mesylate, prepared by combining a solution of Osimertinib mesylate in a solvent with at least one excipient, and removing the solvent. In an embodiment, the removal of solvent(s) is accomplished by evaporation of the solvent,

concentrating the solution, distillation, distillation under vacuum, evaporation, spray drying, freeze drying, or any other conventional or known technique.
In an embodiment the present invention relates to a pharmaceutical composition comprising Osimertinib mesylate amorphous form or premix and at least one pharmaceutically acceptable excipient.
In few embodiments, the osimertinib mesylate premix according to the present invention is amorphous, substantially amorphous or crystalline or mixture of amorphous and crystalline.
In few embodiments, the Osimertinib mesylate premix can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.
Pharmaceutically acceptable excipients may be utilized as required for conversion of the premixes into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.
In some embodiments, the diluents includes but not limited to microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethylcellulose, fructose, inulin, isomalt, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol.
In some embodiments, the disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL [manufactured by BASF (Germany)], Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA)], and low-substituted hydroxypropylcelluloses.

Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.
In some embodiments, the stabilizers include basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al2(OH)16.CO3.4H2O], aluminum hydroxide-magnesium [2.5MgO.Al2O3.xH2O], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.
In some embodiments, the surface-active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethylenically treated sorbitan esters (TWEEN™), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk.
In some embodiments, the lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate, sodium, sodium or magnesium lauryl

sulfate, sodium stearyl fumarate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof
In some embodiments, the glidants include but are not limited to silicone dioxide, talc and combinations thereof.
In some embodiments of the invention, the excipients or pharmaceutically acceptable excipients used include, but are not limited topolyvinylpyrrolidone (also called povidone), polyvinyl alcohol, polyethylene glycol,polyol (Mannitol), sodium starch glycolate, colloidal silicon dioxide(aerosil), hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, cyclodextrins, gelatins, hypromellose phthalate, sugars, and combinations comprising one or more of the foregoing agents, Preferably selected from Aerosil 200, Microcrystalline cellulose, Sodium steryl fumarate, low-substituted hydroxypropylcellulose, mannitol.
The solvent in the present invention includes but not limited to dimethyl sulfoxide (DMSO) and the like; lower alcohols such as methanol, ethanol, propanol and butanol; polyalcohols such as ethyleneglycol and glycerin, ketones such as acetone, methylethyl ketone, diethyl ketone and cyclohexanone; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol and 1,2-dimethoxyethane; nitriles such as acetonitrile and propionitrile; esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl phthalate; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene and tetrachloroethylene; aromatic compounds such as benzene, toluene, xylene, monochlorbenzene, nitrobenzene, indene, pyridine, quinoline, collidine and phenol; hydrocarbons such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine and petroleum ether, amines such as ethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine and toluidine, amides such as formamide, N-methylpyrrolidone, N,N-dimethylimidazolone, N,N-dimethylacetamide and N,N-dimethylformamide, phosphoric/phosphorous amides such as hexamethylphosphosphoric triamide and hexamethylphosphorous triamide; and

water, as well as other commonly used solvents, either alone or in mixtures of two or more, with no particular restrictions on the solvent ratio.
In some embodiment, the pharmaceutically acceptable excipient may be combined with the solution of Osimertinib mesylate such that the final w/w % of pharmaceutically acceptable excipient to total composition mass is from about 1% w/w to about 90% w/w, which may be about 10% w/w, 15% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 45% w/w, 50% w/w, 60% w/w, 70 w/w or between any of the aforementioned w/w percentages, including the ranges of about 10%-40%, 10%-30%, 10%-20%, 20%-50%, 20%-40%, 20%-30%, 30%-50%, 30%-40%, and 40%-50% w/w, 50%-60% w/w, 60%-70% w/w. The pharmaceutically acceptable excipient can be a mixture of more than one compound.
In an embodiment of the invention, the stable amorphous osimertinib mesylate is prepared by combining solution of osimertinib mesylate with an excipient, wherein the excipient acts as a stabilizer.
As used herein, the term “substantially pure”, when used in reference to amorphous or Form B, refers to amorphous osimertinib mesylate or Form B which is greater than about 90% pure. This means that the amorphous osimertinib mesylate or Form B does not contain more than about 10% of any other compound or solid form osimertinib or its salt(s) thereof and, in particular, does not contain more than about 10% of any other solid form of osimertinib mesylate. More preferably, the term “substantially pure”, when used in reference to amorphous osimertinib mesylate or Form B, refers to amorphous osimertinib mesylate or Form B which is greater than about 95% pure. Even more preferably, the term “substantially pure”, when used in reference to amorphous osimertinib mesylate or Form B, refers to amorphous osimertinib mesylate or Form B which is greater than about 97% pure.
The term "stabilized" is understood that the amorphicity or amorphous form of osimertinib mesylate is preserved when it is subjected to storage at conditions of temperature and humidity for six months. The storage conditions of temperature and humidity according to the invention will be, for example 40°C / 75% RH (relative humidity), 30°C / 65% RH, and 25°C / 60% RH.

Another aspect of the invention relates to pharmaceutical composition comprising Osimertinib mesylate premix for the treatment of cancer, especially T790M mutation-positive non-small cell lung cancer (NSCLC).
In an embodiment, the process for the preparation according to present invention is represented schematically in scheme-I as shown below

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope of the invention.
Example 1: Preparation of N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine
To a solution of 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (100 g) in methyl isobutyl ketone, 4-Fluoro-2-methoxy-5-nitroaniline (77.9 g) and p-toluenesulfonic acid monohydrate were added at room temperature. The resulting reaction mixture was heated to 100-120 °C and stirred till completion of reaction. After completion of the reaction, the product was filtered. The resulting crude product was dissolved in dimethylacetamide (or solvent like DMF, NMP, acetone, etc) and heated to 63-67 °C followed by addition of

water, then reaction mass was stirred, cooled, filtered and dried. (1.20 g, 75% yield). Alternatively the product can be purified using recrystallization using a solvent system.
Example 2: Preparation of N-(2-Dimethylaminoethyl)-2-methoxy-N-methyl-N-[4-(1-methylindol-3-yl) pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine
To a solution of N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) pyrimidin-2-amine (100 g) in N-N dimethylacetamide, N, N’, N’-Trimethylethane-1,2-diamine (38.9 g) and N, N-Diisopropylethylamine were added at room temperature. The resulting reaction mixture was heated to 40-50 °C and stirred at same temperature the till completion of reaction.. After completion of the reaction, the reaction mass cooled to ambient temperature and the product was filtered. The resulting crude product was dissolved in methanol and stirred for 30-60 min, then reaction mass was filtered and dried.
Example 3: N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine
To a solution of N-(2-dimethylaminoethyl)-5-methoxy-N-methyl-N'-[4-(1-methylindol-3-yl) pyrimidin-2-yl]-2-nitrobenzene-1,4-diamine (100 g) in tetrahydrofuran, Pd/C slurry in tetrahydrofuran was added in hydrogenator. The resulting reaction mixture was stirred for 3-5 hrs at 2.0-3.0 Kg/Cm2 pressure of Hydrogen at room temperature. After completion of the reaction, reaction mass was filtered through hyflo bed and concentrated to remove the solvent. The resulting crude product was dissolved in ethyl acetate below 45 °C and stirred,filtered and dried. (0.60 g, 64% yield).
Example 4: Preparation of N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
To a solution of N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (100 g) in dichloromethane, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) was added and stirred for 5-10 minutes under Nitrogen atmosphere at 18±3°C . To the reaction mass Acrylic acid (18.5 g) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl (EDCI HCl) (85.8 g) was added and stirred till completion of reaction at room temperature. After completion of the reaction, reaction mass was extracted with water and organic layer was concentrated to remove the solvent.

The resulting crude product was dissolved in acetonitrile and heated to 45-65 °C and stirred, then reaction mass was cooled, filtered the product and dried. (0.50 g, 45% yield).
Example 5: Preparation of N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl) pyrimidin-2-yl] amino} phenyl) prop-2-enamide methane sulphonate Form B
To a solution of methanol and toluene, N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl) pyrimidin-2-yl]amino}phenyl)prop-2-enamide (100 g) was added and stirred for 25-30 min at 28±3°C followed by addition of activated carbon. Carbon was filtered at 40-50 °C and to filtrate methanesulfonic acid was added and stirred for 4 hrs±10 min at 25±3°C. The product was filtered and obtained product was dried.
Example 6: Preparation of Osimertinib mesylate amorphous Form
Methanol (50 ml) and Osimertinib Mesylate Form B (1.0 g) are charged into a reaction vessel and reaction mixture was heated at 55°C to get a clear solution. Methanol was distilled off under vacuum to obtain Osimertinib Mesylate amorphous form (0.95 g) with PXRD as shown in fig-1.
Example 7: Preparation of Osimertinib mesylate amorphous Form
Methanol (25 ml) and Osimertinib base (1.0 g) are charged into a reaction vessel and reaction mixture was heated at 65°C to get a clear solution. Methanesulphonic acid was slowly added at 65°C. The clear solution was distilled off under vacuum to obtain Osimertinib Mesylate amorphous form (0.90 g) with PXRD as shown in fig-1.
Example 8: Preparation of Osimertinib Mesylate with Aerosil 200
3.0 gm Osimertinib Mesylate was charged in to Methanol (120 ml) and the reaction mixture was heated 65 0C to get clear solution. Then, 1.5 gm Aerosil 200 was added at 65° C and stirred for 30 mins. Methanol was removed by distillation under vacuum below 65°C to afford solid (4.2 gm).
XRD: Fig-2

Example 9: Preparation of Osimertinib Mesylate with Aerosil 200
3.0 gm Osimertinib Mesylate was charged in to Methanol (120 ml) and the reaction mixture was heated 65 °C to get clear solution. Then, 3 gm Aerosil 200 was added at 65° C and stirred for 30 mins. Methanol was removed by distillation under vacuum below 65°C to afford solid (4.2 gm).
XRD: Fig-3
Example 10: Preparation of Osimertinib Mesylate with Microcrystalline cellulose
1.0 gm Osimertinib Mesylate was charged in to Methanol (40 ml) and the reaction mixture was heated 65 °C to get clear solution. Then, 0.5 gm Microcrystalline cellulose was added at 65° C and stirred for 30 mins. Methanol was removed by distillation under vacuum below 65°C to afford solid (4.2 gm).
XRD: Fig-4
Example 11: Preparation of Osimertinib Mesylate with Sodium steryl fumarate
1.0 gm Osimertinib Mesylate was charged in to Methanol (40 ml) and the reaction mixture was heated 65 °C to get clear solution. Then, 0.5 gm Sodium steryl fumarate was added at 65 °C and stirred for 30 mins. Methanol was removed by distillation under vacuum below 65°C to afford solid (1.2 gm).
Example 12: Preparation of Osimertinib Mesylate with Low substituted hydroxy propyl cellulose
1.0 gm Osimertinib Mesylate was charged in to Methanol (40 ml) and the reaction mixture was heated 65 °C to get clear solution. Then, 0.5 gm Low substituted hydroxy propyl cellulose was added at 65°C and stirred for 30 mins. Methanol was removed by distillation under vacuum below 65°C to afford solid (1.2 gm).
XRD: Fig-5
Example 13: Preparation of Osimertinib Mesylate with Mannitol
1.0 gm Osimertinib Mesylate was charged in to Methanol (40 ml) and the reaction mixture was heated 65 °C to get clear solution. Then, 0.5 gm Mannitol was added at 65°C and

stirred for 30 mins. Methanol was removed by distillation under vacuum below 65°C to afford solid (1.2 gm).

We claim:
1. A process for the preparation of substantially pure polymorphic Form B of
Osimertinib mesylate, wherein the process comprises
a. providing solution of Osimertinib mesylate in alcohol, hydrocarbon or
mixture thereof; and
b. isolating substantially pure form B.
2. The process of claim 1, wherein alcohol such as C1-C6 alkanol and hydrocarbon such as toluene or xylene.
3. Substantially pure amorphous form of Osimertinib mesylate.
4. A process for preparing substantially pure amorphous form of Osimertinib mesylate comprising:
a. providing a solution of Osimertinib mesylate in a solvent;
b. removing the solvent from the solution obtained in step a), and
c. isolating amorphous form of Osimertinib mesylate.
5. The process of claim 3, wherein suitable solvent in step a) is selected from alcohols, esters, ketones, hydrocarbons, water, acetic acid or mixtures thereof.
6. The process of claim 3, wherein removal of solvent in step b) is affected by evaporation, freeze drying, spray drying, lyophilization or any combination thereof.
7. A solid premix comprising Osimertinib mesylate and at least one pharmaceutically acceptable excipient.
8. The solid premix of claim 6, wherein the acceptable excipient comprises aerosil 200, microcrystalline cellulose, sodium steryl fumarate, low substituted hydroxy propyl cellulose, Mannitol and the like.
9. A process for preparing a solid premix comprising;
a. providing a solution comprising Osimertinib mesylate and one or more
pharmaceutically acceptable carriers,
b. removing solvent from a solution obtained in step (a) and

c. isolating a solid premix.
10. A pharmaceutical composition comprising amorphous form or solid premix of Osimertinib mesylate.