WO2018134843A1

WO2018134843A1 - Polymorphic forms of (e)-n-{4-[3-chloro-4-((pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide, its maleate salt and process for preparation thereof

Info

Publication number: WO2018134843A1
Application number: PCT/IN2018/000006
Authority: WO
Inventors: Srinivasan Thirumalai Rajan; Sajja Eswaraiah; Sagyam RAJESHWAR REDDY; Rangineni Srinivasulu
Original assignee: Msn Laboratories Private Limited, R&D Center
Priority date: 2017-01-23
Filing date: 2018-01-22
Publication date: 2018-07-26

Abstract

The present invention relates to novel polymorphic forms of (E)-N-{ 4-[3-chloro-4-(pyridin-2- yl)methoxy )phenyl )amino)-3 -cyano-7 -ethoxyquinolin-6-yl)-4-( dimethylamino )but-2-enamide, maleate salts and process for the preparation thereof. The chemical structure of said compound is represented by the following formula (I)

Description

fDIMETHYLAMINO)BUT-2-ENAMIDE. ITS MALEATE SALT AND PROCESS FOR

PREPARATION THEREOF

Related Applications:

This application claims the benefit of priority of our Indian patent applications 201741002445 filed on January 23, 2017 and 201741002447 filed on January 23, 2017 which are incorporated herein as reference.

Field of the Invention

The present invention relates to novel polymorphic forms of (E)-N-{4-[3-chloro-4- (pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide. The chemical structure of said compound is represented by the following formula (1)

formula (I)

The present invention also relates to novel polymorphic forms of (E)-N-{4-[3-chloro-4- (pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide maleate salt. The chemical structure of said compound is represented by the following formula (II)

Formula (H) The present invention also provides a process for the preparation of polymorphic forms of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl } -4- (dimethylamino)but-2-enamide of formula (I) and its maleate salt of formula (11).

Background of the invention

The compound name (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (or) (2£)-N-(4-((3-chloro-4-((pyridin-2- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide (or) (2 )-N-(4-((3-chIoro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxy quinolin- 6-yl)-4-(dimethylamino)but-2-enamide of formula (I) is generically known as Neratinib or Neratinib free base. (2£)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)ani)ino}-3:Cyano-7-ethoxy-6- quinolinyl}-4-(dimethylamino)-2-butenamide maleate or (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enami- de maleate of formula (II) is generically known as Neratinib maleate. Neratinib maleate is a kinase inhibitor and it is approved under the brand name of NERLYNX® by US FDA for the treatment of adult patients with early stage human epidermal growth factor receptor 2 (HER2)- overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy to Puma Biotechnology on 17^th July 2017. NERLYNX® available to the public on the dosage strength of EQ 40mg base for oral administration,

US 6288082 Bl (published on September 1 1 , 2001 ) generically discloses the (E)-N-{4- [3-chIoro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl} -4-(dimethylamino) but-2-enamide and its process.

US 7399865 B2 (published on July 15, 2008) specifically discloses the (£)-N- {4-[3- chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl} -4-(dimethylamino) but- 2-enamide and its process.

US 8022216 B2 (published on September 20, 201 1 ) discloses anhydrous crystalline Form-1 and monohydrate crystalline Form-Il of (£)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yI } -4-(dimethylamino)but-2-enamide maleate. WO 2009/052264 A2 (published on April 23, 2009) discloses crystalline forms of Neratinib maleate (an anhydrous form, a monohydrate form, and a mixture of the anhydrous and the monohydrate forms (referred to as a partial hydrate form).

WO 2016/1 10270 (published on July 14, 2016) discloses crystalline Form-A, Form-B and Form-C of Neratinib maleate.

WO 2018/005418 Al (published on January, 04 2018) discloses Neratinib crystalline Form-B 1 , Form-B2, Form-B3, Form-B4 & Form-B6; Neratinib maleate crystalline Form T2.

It is known that crystalline forms (solid state forms (including solvated forms)) of the same active pharmaceutical ingredient (Drug Substance) may have substantial differences in certain pharmaceutically important properties. Different crystalline forms of same active pharmaceutical ingredient exhibit more stability and much higher bioavailability than the known forms, which leads. to the selection of the said stable crystalline form. It broadens the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

Therefore, it is desirable to have alternate crystalline forms of active pharmaceutical ingredients with high purity to meet the needs of regulatory agencies such as USFDA, EMA and TGA and also highly reproducible processes for their preparation.

The polymorphic forms (solid state forms (including solvated forms)) of Neratinib and Neratinib maleate according to the present disclosure may have at least one of advantageous properties like chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density. In view of the above, it is therefore, desirable to provide alternate novel solid state forms (crystalline or amorphous) of Neratinib of formula (I) and Neratinib maleate of formula (II) as well as an efficient, economical and eco-friendly process for their preparation.

The present inventors had developed novel solid state forms of Neratinib formula (I), herein after designated as "Form-S 1 , Form-S2, Form-S3, Form-S4, Form-S5, Form-S6 and Form-S7" which are consistently reproducible and suitable for the pharmaceutical formulations which have advantageous properties over the existing polymorphs.

The present inventors had developed novel solid state forms of Neratinib maleate formula (II), herein after designated as "Form-M, Form-S, Form-N, Form-Ml and Form-M2" which are consistently reproducible and suitable for the pharmaceutical formulations.

The solid state forms of Neratinib formula (I), and Neratinib maleate formula (II), of the present invention is characterized by its Powdered X-Ray Diffraction (PXRD) patterns.

Brief description of the invention

The first aspect of the present invention is to provide novel crystalline form of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl } -4-(dimethylamino) but-2-enamide of formula (I), hereinafter designated as "Form-S 1" and process for its preparation thereof.

The second aspect of the present invention is to provide novel crystalline form of (E)-N- .{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl } -4-(dimethyl amino) but-2-enamide of formula (I), hereinafter designated as "Form-S2" and process for its preparation thereof.

The third aspect of the present invention is to provide novel crystalline form of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino) but-2-enamide of formula (I), hereinafter designated as "Form-S3" and process for its preparation thereof. The fourth aspect of the present invention is to provide novel crystalline form of (E)-N- {4-[3-chloro-4-( yridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinplin-6-yl}-4-(dimethylamin- o)but-2-enamide of formula (1), hereinafter designated as "Form-S4" and process for its preparation thereof.

The fifth aspect of the present invention is to provide novel crystalline form of (E)-N-{4- [3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinoIin-6-yI}-4(dimethyl amino)but-2-enamide of formula (I), hereinafter designated as "Form-S5" and process for its preparation thereof.

The sixth aspect of the present invention is to provide novel crystalline form of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino) but-2-enamide, of formula (I), hereinafter designated as "Form-S6" and process for its preparation thereof.

The seventh aspect of the present invention is to provide novel crystalline form of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylami- no) but-2-enamide, of formula (I), hereinafter designated as "Form-S7" and process for its preparation thereof.

The eighth aspect of the present invention is to provide amorphous form of (E)-N-{4-[3- chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino) but- 2-enamide, of formula (I) and process for its preparation thereof.

The ninth aspect of the present invention is to provide novel crystalline form of (2E)- (E)- N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate of formula (II), hereinafter designated as "Form-M" and process for its preparation thereof. ^'

The tenth aspect of the present invention is to provide novel crystalline form of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate of formula (II), hereinafter designated as "Form-S" and process for its preparation thereof. The eleventh aspect of the present invention is to provide novel crystalline form of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate of formula (II), hereinafter designated as "Form-N" and process for its preparation thereof.

The twelth aspect of the present invention is to provide novel crystalline form of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yi}-4-(dimethyl amino)but-2-enamide maleate of formula (II), hereinafter designated as "Form-Mi" and process for its preparation thereof.

The thirteenth aspect of the present invention is to provide novel crystalline form of (E)- N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate of formula (II), hereinafter designated as "Form-M2" and process for its preparation thereof.

The fourteenth aspect of the present invention is to provide amorphous form of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino) but-2-enamide maleate of formula (II) and process for its preparation thereof.

The fifteenth aspect of the present invention is to provide solid dispersion comprising (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinoliri-6-yl}-4- (dimethylamino)but-2-enamide maleate of formula (II) and at least one pharmaceutically acceptable carrier and process for its preparation thereof.

Brief description of the drawings

Figure- 1 : Illustrates the characteristic Powdered X-Ray Diffraction (PXRD) pattern of crystalline Form- i ofNeratinib.

Figure-2: Illustrates the characteristic PXRD pattern of crystalline Form-S2 of Neratinib.

Figure-3: Illustrates the characteristic PXRD. pattern of crystalline Form-S3 of eratinib.

Figure-4: Illustrates the characteristic PXRD pattern of crystalline Form-S4 of Neratinib.

Figure-5: Illustrates the characteristic PXRD pattern of crystalline Form-S5 of Neratinib.

Figure-6: Illustrates the characteristic PXRD pattern of crystalline Form-S6 ofNeratinib. Figure-7: Illustrates the characteristic PXRD pattern of crystalline Form-S7 of Neratinib.

Figure-8: Illustrates the characteristic PXRD pattern of amorphous Neratinib.

Figure-9: Illustrates the characteristic PXRD pattern of crystalline Form-M of Neratinib maleate.

Figure-10: Illustrates the DSC thermogram of crystalline Form-M of Neratinib maleate.

Figure- 11 : Illustrates the TGA of crystalline Form-M of Neratinib maleate.

Figure-12: Illustrates the characteristic PXRD pattern of crystalline Form-S of Neratinib maleate.

Figure-13: Illustrates the DSC thermogram of crystalline Form-S of Neratinib maleate.

Figure-14: Illustrates the TGA of crystalline Form-S of Neratinib maleate.

Figure-15: Illustrates the characteristic PXRD pattern of crystalline Form-N of Neratinib maleate.

Figure- 16: Illustrates the characteristic PXRD pattern of crystalline Form-M 1 of Neratinib maleate.

Figure-17: Illustrates the characteristic PXRD pattern of crystalline Form-M2 of Neratinib of maleate.

Figure-18: Illustrates the DSC thermogram of crystalline Form-M2 of Neratinib maleate.

Figure-19: Illustrates the TGA of crystalline Form-M2 of Neratinib maleate.

Figure-20: Illustrates the characteristic PXRD pattern of amorphous form of Neratinib maleate. Figure-21 : Illustrates the characteristic PXRD pattern of solid dispersion of amorphous Neratinib maleate with povidone (PVP-K30).

Figure-22: Illustrates the characteristic PXRD pattern of solid dispersion of amorphous Neratinib maleate with hydroxy propyl cellulose (HPC).

Figure-23: Illustrates the characteristic PXRD pattern of solid dispersion of amorphous Neratinib maleate with hydroxy propyl methyl cellulose (HPMC).

Detailed description of the invention

The term "suitable solvent" used in the present invention is selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isopentanol (3 -methyl- 1-butanol), ethylene glycol, propylene glycol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane,. carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; "protic solvent" such as acetic acid; "polar solvent" such as water or mixtures thereof.

The term "suitable base" used herein the present invention refers, but not limited to "inorganic bases" selected from alkali and alkaline earth metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like, ammonia; and organic bases like sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4- dimethylaminopyridine (DMAP), N-methyl morphoiine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiH DS), sodium hexamethyldisilazide NaHMDS), potassium hexamethyldisilazide (KH DS) and/or mixtures.

The term "suitable acid" refers to the acid selected from inorganic acids like HC1, HBr, HI, H₂S0₄; organic acids like AcOH, MsOH, -TsOH, TFA.

A solid state form or crystalline form or polymorphic form used herein may be referred to herein as polymorphically pure or substantially free of any other solid state (or polymorphic) forms.

The term "pharmaceutical acceptable carrier" is preferably a polymeric carrier, and more preferably at least one from the group consisting of starches, modified starches, cellulose, methyl cellulose (MC), microcrystaliine cellulose (MCC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP -30, polyvinyl acetate (PVAc), PVP vinylacetate-copolymer (PVP- VA), PVP-cross polymer, Kollidon VA 64 (vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, β- cyclodextrins, γ-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol) or a mixture thereof.

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 "amorphous solid dispersion" as used herein, refers to solid dispersion which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%, is in amorphous form as determined by powder x-ray diffraction pattern.

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 acetone from the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described, for example, in Perry's Chemical Engineer's Handbook, pages. 20-54 to 20-57 (Sixth Edition 1984).

The first aspect of the present invention provides crystalline Form-Si of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide. The crystalline Form-S i of the present invention is characterized by its Powder X- Ray Diffraction (PXRD) pattern having characteristic peaks at about 4.0, 5.8, 8.1 , 12.0, 19.7 ± 0.2 degrees of 2-theta. The crystalline Form-Si of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at about 1 1.0, 16.2, 16.6, 17.7, 23.4, 25.8, 28.6 ± 0.2 degrees of 2-theta. The crystalline Form-Si is further characterized by the PXRD pattern as illustrated in figure- 1.

The another aspect of the present invention provides a process for the preparation of crystalline Form-Si of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising: a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) isolating crystalline Form-Si of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide. wherein, in step-a), the suitable solvent is selected from chioro solvents such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; the suitable temperature in step-a) and step-c) is between 25°C to 30°C; the suitable temperature in step-b) is ranging between 30°C to the reflux temperature of the solvent used; in step-d) the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-Si of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) adding (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I) to methylene chloride at 25-30°C;

b) heating the reaction mixture to 60-65°C;

c) cooling the reaction mixture to 25-30°C;

d) filtering the precipitated solid and drying to provide crystalline Form-S i of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4- (dimethylamino)but-2-enamide.

The second aspect of the present invention provides crystalline Form-S2 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide. The crystalline Form-S2 of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 3.9, 5.4, 8.1 , 1 1.9, 16.7, 21.9, 23.9 and 29.2 ± 0.2 degrees of 2-theta. The crystalline Form-S2 of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at 7.7, 10.6, 1 1.5, 16.4, 17.3, 20.0, 22.4, 23.1 , 24.9 and 26.7 ± 0.2 degrees of 2-theta. The crystalline Form-S2 is further characterized by the PXRD pattern as illustrated in figure-2.

The another aspect of the present invention provides a process for the preparation of crystalline Form-S2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)aniIino]-3-cyano-7- ethoxyquinolin-6-yl} -4-(dimethylamino)but-2-enamide, which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) filtering the precipitated solid and drying to provide crystalline Form-S2 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide. wherein, in step-a) the suitable solvent is selected from polar aprotic solvents such as dimethyl formamide, dimethylsulfoxide, dimethyiacetamide, N-methyl pyrrolidine (NMP) or mixtures thereof. The suitable temperature in step-a) and step-c) is 25-30°C. The suitable temperature in step-b) is ranging between 30°C to the reflux temperature of the solvent used.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in DMF at 25-30°C; b) heating the reaction mixture to 60-65°C;

c) cooling the reaction mixture to 25-30°C;

d) filtering the precipitated solid and drying to provide crystalline Form-S2 of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4- (dimethyl amino)but-2-enamide. The third aspect of the present invention provides crystalline Form-S3 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yI } -4-(dimethylamino)but- 2-enamide. The crystalline Form-S3 of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 4.9, 9.0, 1 1.1 , 12.3, 15.1 , 16.2, 18.3, 20.6, 22.8, 23.8, 26.0 and 26.6 ± 0.2 degrees of 2-theta. The crystalline Form-S3 of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at 10.0, 1 1.5, 19.0, 19.9, 21.7, 24.3, 24.8, 31.4, 32.4, 33.8 ± 0.2 degrees of 2-theta. The crystalline Form- S3 is further characterized by the PXRD pattern as illustrated in figure-3.

The another aspect of the present invention provides a process for the preparation of crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) isolating crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide. wherein, in step-a) the suitable solvent is selected from ketone solvents such as acetone, methyl isobutyl ketone, methyl butyl ketone, butanone, pentanone or mixtures. The suitable temperature in step-a) and step-c) is 25-30°C. The suitable temperature in step-b) is ranging between 30°C to the reflux temperature of the solvent used; in step-d) the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl} -4-(dimethylamino)but-2-enamide, which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in methyl isobutyl ketone at 25-30°C; b) heating the reaction mixture to 60-65°C; c) cooling the reaction mixture to 25-30°C;

d) filtering the precipitated solid and drying to provide crystalline Form-S3 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide.

The fourth aspect of the present invention provides crystalline Form-S4 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide. The crystalline Form-S4 of the present invention is characterized by its powder X-ray diffraction pattern having peaks at about 5.2, 9.0, 10.3, 12.0, 14.2, 17.4 and 20.5 ± 0.2 degrees of 2-theta. The crystalline Form-S4 of the present invention is further characterized by its X- ay powder diffraction pattern having additional peaks at 5.7, 7.1 , 15.4, 16.6, 22.2, 24.3, 25.3 ± 0.2 degrees of 2-theta. The crystalline Form-S4 is further characterized by the PXRD pattern as illustrated in figure-4.^'

The another aspect of the present invention provides a process for the preparation, of crystalline Form-S4 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a mixture of suitable solvents at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) removing the solvent from the reaction mixture and drying to provide crystalline Form- S4 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6- yl } -4-(dimethylamino)but-2-enamide. wherein, in step-a), the suitable solvent is selected from alcohol solvents having C 1 -C5 atoms such as methanol, ethanol, propanol, isopropanol, butanol, pentanol, ethylene glycol and halo hydrocarbon solvents such as dichloromethane, trichloromethane and chloroform thereof. The suitable temperature in step-a) is 25-30°C. The suitable temperature in step-b) is from 30°C to the reflux temperature of the solvent used. The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S4 of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy .quinolin-6-yl}-4-(dimethylamino)but-2-enamide in dichloromethane and methanol at 25- 30°C;

b) _. heating the reaction mixture to 50-55°C;

c) distilling off the solvent from the reaction mixture and drying to provide crystalline Form-S4 of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

The fifth aspect of the present invention provides crystalline Form-S5 of (E)-N- {4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl } -4-(dimethylamino)but- 2-enamide. The crystalline Form-S5 of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 22.5, 23.3, 24.1 , 26.0, 29.0 ± 0.2 degrees of 2- theta. The crystalline Form-S5 of the present invention is further characterized by its X- ay powder diffraction pattern having additional peaks at 1 5.0, 18.5, 19.3, 19.9, 22.9 and 24.7 ± 0.2 degrees of 2-theta. The crystalline FornvSS is further characterized by the PXRD pattern as illustrated in figure-5.

The other aspect of the present invention provides a process for the preparation of crystalline Form-S5 of (E)-N- {4-[3-chloro-4-(pyridin-2-yl methoxy)anilind]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) isolating crystalline Form-S5 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide. wherein, in step-a), the suitable solvent is selected from ether solvents such as 1 , 4-dioxane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether and the like. The suitable temperature in step-a) and step-c). is between 25-30°C. The suitable temperature in step-b) is ranging between 30°C to the reflux temperature of the solvent used; in step-d) the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S5 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinplin-6-yl}-4-(dimethylamino)but-2-enamide in 1 , 4-dioxane at 25-30°C;

b) heating the reaction mixture to 50-55°C;

c) cooling the reaction mixture to 25-30°C;

d) filtering the precipitated solid and drying to provide crystalline Form-S5 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide.

The sixth aspect of the present invention provides crystalline Form-S6 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide. The crystalline Form-S6 of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 4.0, 5.9, 8.4, 10.8, 1 1.9, 17.0 and 17.8 ± 0.2 degrees of 2-theta. The crystalline Form-S6 of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at 5.7, 7.8, 8.9, 1 1.1 , 12.2, 16.4, 22.3, 24.3, 26.3 and 30.0 ± 0.2 degrees of 2-theta. The crystalline Form-S6 is further characterized by the PXRD pattern as illustrated in figure-6.

The another aspect of the present invention provides a process for the preparation of crystalline Form-S6 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl ^' methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in acetone at 50-55°C;

b) distilling off the solvent completely from the reaction mixture; c) drying the material to provide crystalline Form-S6 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

The seventh aspect of the present invention provides crystalline Form-S7 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyIamino)but- 2-enamide. The crystalline Form-S7 of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 5.0, 9.1 , 20.7 ± 0.2° of 2-theta. The crystalline Form-S7 of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at 8.5, 10.3, 1 1.2, 12.4, 13.8, 14.3, 14.7, 15.1 , 16.4, 17.9, 18.5, 19.4, 23.0, 24.5, 26.1, 26.7, 28.0 ± 0.2° of 2-theta. The crystalline Form-S7 is further characterized by the PXRD pattern as illustrated in figure-7.

The another aspect of the present invention provides a process for the preparation of crystalline Form-S7 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent;

b) heating the reaction mixture to a suitable. temperature;

c) cooling the reaction mixture obtained in step-b) to a suitable temperature;

d) isolating crystalline Form-S7 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide. wherein, the suitable solvent in step-a) is selected from hydrocarbon solvents such as cyclohexane, toluene, o-xylene, n-heptane, n-hexane and the like; the suitable temperature in step-a) is 25-30°C; the suitable temperature in step-b) is ranging between 30°C to the reflux temperature of the solvent used and in step-c) the suitable temperature is 0-10°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S7 of (E)- -{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in cyclohexane or toluene or o-xylene; b) heating the reaction mixture to 60-65°C;

c) cooling the reaction mixture obtained in step-b) to 0-5°C;

d) filtering the precipitated solid and drying to provide crystalline Form-S7 of (E)-N-{4-[3- chloro-4-(pyridin-2-yl , methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide.

The eighth aspect of the present invention provides amorphous form of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide. The amorphous form of the present invention is characterized by its powder X-ray diffraction pattern as illustrated in figure-8.

The another aspect of the present invention provides a process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-e-yli^-tdimethylaminojbut^-enamide, comprising following steps:

b) stirring the reaction mixture;

c) heating the reaction mixture to a suitable temperature;

d) optionally, filtering the reaction mixture;

e) removing the solvent to get amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide. wherein, the suitable temperature in step-a) is 25-30°C; the suitable temperature in step-c) is from 30°C to the reflux temperature of the solvent used.

The suitable solvent in step-a) is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvent and ether solvents or mixture; preferably alcohol solvents.

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, comprising following steps: a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in methanol;

b) filtering the solution for making particle free ;

c) spray drying the solution to get amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

The ninth aspect of the present invention provides crystalline Form-M of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyIamino)but- 2-enamide maleate of formula (II). The crystalline FornvM of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 6.2, 7.1, 8.5 and 16.8 ± 0.2° of 2-theta. The crystalline Form-M of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at about 4.0, 4.6, 10.4, 10.9, 12.4, 13.4, 14.6, 15.0, 15.7, 18.3, 20.5, 23.1, 25.3 and 27.6 ± 0.2° of 2-theta. The crystalline Form-M is further characterized by the PXRD pattern as illustrated in figure-9.

Further, crystalline Form-M of formula (II) is characterized by its differential scanning calorimetric (DSC) thermogram which is showing first endotherm at about 123±5°C, and the second endotherm at about 140±5°C and the same has been illustrated in figure- 10.

The crystalline Form-M of formula (II) is further characterized by its thermo gravimetric analysis (TGA) thermogram which is showing weight loss of 5.5% and same has been illustrated in figure- 1 1.

The another aspect of the present invention provides a process for the preparation of crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) adding (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide to suitable alcohol solvent;

b) heating the reaction mixture to suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c); e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate. wherein, in step-a) the suitable temperature is 25-30°C; in step-b), the suitable temperature is 30°C to the reflux temperature of the solvent used, in step-e) the suitable temperature is 0-5°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) adding (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(diifnethylamino)but-2-enamide to isopentanol at 25-30°C;

b) heating the reaction mixture to 40-45°C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) and Filtering to provide crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethyIamino)but-2-enamide maleate.

The tenth aspect of the present invention provides crystalline Form-S of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide maleate of formula (II). The crystalline Form-S of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 5.7, 6.2, 13.1 and 24.5 ± 0.2° of 2-theta. The crystalline Form-S of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at about 6.8, 8.5, 10.7, 10.9, 1 1.7,13.1, 14.4, 15.7, 17.3, 19.0, 19.4, 19.6, 20.5, 21.8, 23.5 and 25.5 ± 0.2° of 2-theta. The crystalline Form-S is further characterized by the PXRD pattern as illustrated in figure-12.

Further, crystalline Form-S of formula (II) is characterized by its differential scanning calorimetric (DSC) thermogram which is showing endotherm at about 167±5°C and the same has been illustrated in figure- 13. The crystalline Form-S of formula (II) is further characterized by its thermo gravimetric analysis (TGA) thermogram which is showing weight loss of 3.0% and same has been illustrated in figure- 14.

The another aspect of the present invention provides a process for the preparation of crystalline Form-S of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent; b) heating the reaction mixture to a suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form-S of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate. wherein, in step-a), the suitable solvent is selected from ester solvents such as ethyl acetate, methyl acetate, isobutyl acetate, isopropyl acetate, ether solvents such as tetrahydrofuran, 1 ,4- dioxane, methyl tert-butyl ether, diethyl ether, chloro solvents such as methylene chloride and the like, ketone solvents like acetone, methyl isobutyl ketone and the like; the suitable temperature is 25-30°C. In step-b), the suitable temperature is from 30°C to the reflux temperature of solvent used. In step-e), the suitable temperature is 0-5°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-S of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in isopropyl acetate; b) heating the reaction mixture to 70-75°C;

c) adding maleic acid to the reaction mixture obtained in step-b); d) cooling the reaction mixture to 0-5°C

e) filtering the precipitate solid to provide crystalline Form-S of (E)-N-{4-[3-chloro-4- (pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino) but-2-enamide maleate.

The eleventh aspect of the present invention provides crystalline Form-N of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yI}-4-(dimethylamino)but- 2-enamide maleate of formula (II). The crystalline Form-N of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 5.0, 10.2, 1 1.2, 16.9, 18.9 and 21.4 ± 0.2° of 2-theta. The crystalline Form-N of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at about 5.9, 6.7, 7.5, 9.4, 12.8, 13.4, 13.9, 15.0, 18.0, 20.1, 22.4, 23.1 , 25.5, 28.4 and 29.4 db 0.2° of 2-theta. The crystalline Form-N is further characterized by the PXRD pattern as illustrated in figure-] 5.

The another aspect of the present invention provides a process for the preparation of crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-' ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent;

b) heating the reaction mixture to a suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) isolating crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide maleate. wherein, in step-a), the suitable solvent is selected from alcohol solvents having C 1 -C5 carbon atoms such as methanol, ethanol, n-propanol, i-propanol, 1-butanol and 2-butanol or mixtures. In step-b), the suitable temperature is from 30°C to the reflux temperature of the solvent used. The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide in 2-butanol;

b) heating the reaction mixture to 80-85°C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) filtering the precipitated solid to provide crystalline Form-N of (E)-N-{4-[3-chloro- 4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate.

The twelth aspect of the present invention provides crystalline Form-Ml of (E)-N-{4-[3- chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyqu^'inolin-6-yl}-4-(dimethylamino)but- 2-enamide maleate of formula (II). The crystalline Form-Ml of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 4.9, 6.7, 12.9, 22.2 ± 0.2° of 2-theta. The crystalline Form-Ml of the present invention is further characterized by its X-ray powder diffraction pattern having additional peaks at about 9.9, 1 1.3, 13.4, 15.0, 15.8, 16.8, 18.0, 24.7, 25.6, 26.5, 27.3, 28.4 and 31.6 ± 0.2° of 2-theta. The crystalline Form-Ml is further characterized by the PXRD pattern as illustrated in figure- 16.

The another aspect of the present invention- provides a process for the preparation of crystalline Form-Ml of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

b) heating the reaction mixture to a suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c); e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form- Mi of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6- yl}-4-(dimethylamino)but-2-enamide maleate. wherein, in step-a), the suitable solvent is selected from aqueous alcohol solvents such as aqueous methanol, aqueous ethanol, aqueous n-propanol, aqueous isopropanol or mixtures thereof, in step-b), the suitable temperature is from 30°C to the reflux temperature of the solvent used.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-Mi of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in aqueous n-propanol;

b) heating the reaction mixture to 70T75°C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture to 0-5°C

f) filtering the precipitated solid to provide crystalline Form-Mi of (E)-N-{4-[3-chloro-4- (pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but- 2-enamide maleate.

The thirteenth aspect of the present invention provides crystalline Form-M2 of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino) but-2-enamide maleate of formula (II). The crystalline Form-M2 of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 5.7, 6.6, 8.0, 1 1.2, 16.6 and 17.8 ± 0.2° of 2-theta. The crystalline Form-M2 is further characterized by the PXRD pattern as illustrated in figure- 17. Further, crystalline Form- 2 of formula (II) is characterized by its differential scanning calorimetric (DSC) thermogram which is showing first endotherm at about 123±5°C and the second endotherm at 181±5°C and the same has been illustrated in figure-18.

The crystalline Form-M2 of formula (II) is further characterized by its thermo gravimetric analysis (TGA) thermogram which is showing weight loss of 0.8% and same has been illustrated in figure- 19.

The another aspect of the present invention provides a process for the preparation of crystalline Form-M2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yI methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent; b) heating the reaction. mixture to a suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form-M2 of (2E)-N-(4-((3-chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3- cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide maleate salt wherein, in step-a), the suitable solvent is selected from keto solvents such as acetone, methyl isobutyl ketone, methyl butyl ketone, methyl ethyl ketone, butanone, pentanone or mixtures thereof, the suitable temperature is ranging between 25-30°C. In step-b), the suitable temperature is from 30°C to the reflux temperature of the solvent used.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-M2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in methyl ethyl ketone; b) heating the reaction mixture to 60-65°C; c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture to 0-5°C

f) filtering the precipitated solid to provide crystalline Form-M2 of (2E)-N-(4-((3- chloro-4-((pyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4- (dimethylarnino)but-2-enarnide maleate salt

The fourteenth aspect of the present invention provides an amorphous form of (E)-N-{4- [3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino) but-2-enamide maleate of formula (II) which is characterized by its PXRD pattern substantially in accordance with figure-20.

The another aspect of the present invention provides a process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps of:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate in a suitable solvent;

b) stirring the reaction mixture obtained in step-a);

c) removing the solvent from the reaction mixture obtained in step-b) to provide amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate. wherein, in step-a) the suitable solvent is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,3-dioxane and the like; in step-b), the stirring is carried out at temperature starting from 25°C to the reflux temperature of the solvent used. In step-c), the removing of the solvent is carried out by distillation at boiling temperature of the solvent which is used under reduced pressure. The preferred embodiment of the present invention provides a process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps of:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate in methanol;

b) optionally, filtering the solution for making it particle free;

c) spray drying or distilling off the solvent from the solution to provide amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6- yl}-4-(dimethyl amino)but-2-enamide maleate.

The another aspect of the present invention provides the use of Neratinib crystalline Form SI , S2, S3, S4, S5, S6 and S7 in the preparation of Neratinib maleate. ^■

The another aspect of the present invention provides the use of Neratinib crystalline Form SI, S2, S3, S4, S5, S6 and S7 and Neratinib maleate crystalline Form M , S, N, Ml and M2 in the preparation of pharmaceutical compositions.

The fifteenth aspect of the present invention provides amorphous solid dispersion of (E)- N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate of formula (II) in combination with one or more pharmaceutical acceptable carrier.

As used herein, the term "solid dispersion" means any solid composition having at least two components, in certain embodiments, a solid dispersion as disclosed herein includes an active ingredient (compound of formula-II) dispersed among at least one other component, for example an excipient.

In general, the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP; PVP of different grades like -15, K-30, K-60, -90 and -120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (cros- povidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthatate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxy methylethyl cellulose (CMEC), ethyl . cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethy I cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or com starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, α-, β-, γ-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

Prefarebly pharmaceutical acceptable carrier is selected from polyvinylpyrrolidone (PVP), PVP-30, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl methyl cellulose-acetyl succinate (HPMC-AS).

The another aspect of the present invention provides a process for the preparation of solid dispersion comprising amorphous (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano- 7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II) and pharmaceutically acceptable carrier, comprising the following steps:

b) adding pharmaceutically acceptable carrier in a suitable solvent; c) removing the solvent from the reaction mixture obtained in step-b) to provide, the solid dispersion of formula (II). wherein, in step-a) and step-b), the suitable solvent is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1 ,3-dioxane and the like.

After dissolving the compound of formula (II) in the said solvent system, the solution may optionally be treated with charcoal to remove color and/or to clarify the solution and the solution may optionally be filtered to make it particle free. in step-c), the suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to spray drying, evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, agitated thin film drying (ATFD), melt extrusion, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.

A preferred method to remove the solvent involves spray-drying, in which a solution of Neratinib eratinib maleate is sprayed with spray drier at the flow rate ranging from 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.

Of course, specific conditions will vary somewhat for spray drying using different equipment configurations. 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.

The preferred embodiment of the present invention provides a process for the preparation of solid dispersion comprising amorphous (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]- 3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II) and pharmaceutically acceptable carrier, comprising the following steps:

b) adding pharmaceutically acceptable carrier in methanol to the reaction mixture;

c) distilling off the solvent from the reaction mixture to provide the solid dispersion of formula (II).

The substantially pure amorphous Neratinib and Neratinib maleate were obtained according to the present invention may be further dried in, for example, Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor, to further lower residual solvents.

Drying techniques includes spray drying, vacuum drying, freeze drying or agitated thin film drying.

Pharmaceutical compositions of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Another aspect of the present invention provides crystalline Form-M, S, N, Ml and M2 of compound of formula (II) having particle size distribution of D90 less than 300 μπι. Prefarebly less than 50 μπι. More prefarebly less than 15 μηι.

Neratinib of formula (I) which is used as a starting material in the present invention was prepared according to the method described in US 7126025 or any other known methods in art.

Neratinib maleate of formula (II) which is used as a starting material in the present invention was prepared according to the methods described in US 2006/0270668 and US 2006/0270669 (or) it can be prepared according to present invention. PXRD analysis of the crystalline and amorphous forms of Neratinib and Neratinib maleate were carried out using BRUKER-AXS D8 Advance X-Ray diffractometer using Cu-Ka radiation of wavelength 1.5406 A⁰ and at continuous scan speed of 0.03°/min,

TGA analysis of the crystalline and amorphous forms of Neratinib and Neratinib maleate were carried out using Q series explorer software and TA Universal integrator (Q-500) and at RAMP from 10.0°C/min to 350°C.

DSC analysis of the crystalline forms of Neratinib and Neratinib maleate were carried out using Q series explorer software and TA Universal integrator (Q-2000) and at 10.0°C/min, scan range: 40-350°C.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of crystalline Form-Si of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino|-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylaniino)but-2-enamide.

Dichloromethane (2ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 60- 65°C. Cooled the reaction mixture to 25-30°C and filtered the obtained precipitated solid and then dried to get the title compound. Yield: 370 mg.

The P-XRD pattern of the obtained crystalline Form-Si was illustrated in figure- 1.

ExampIe-2: Preparation of crystalline Form-S2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinoIin-6-yl}-4-(dimethylamino)but-2-enamide.

Dimethylformamide (30ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 60- 65°C. Cooled the reaction mixture to 25-30°C and filtered the precipitated solid to get the title compound. Yield: 390 mg. The P-XRD pattern of the obtained crystalline Form-S2 was illustrated in figure-2. Example-3: Preparation of crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yI}-4-(dimethylamino)but-2-enamide.

Methyl isobutyl ketone (100 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 60- 65°C and cooled to 25-30°C and filtered the precipitated solid to get the title compound. Yield: 350 mg.

The P-XRD pattern of the obtained crystalline Form-S3 was illustrated in figure-3.

Example-4: Preparation of crystalline Form-S4 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

Dichloromethane (10 ml) and methanol (50 ml) were added to (E)-N-{4-[3-chloro-4- (pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enami- de (1 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 50-55°C and stirred for 15 min at same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried to get the title compound. (Yield: 820 mg)

The P-XRD pattern of the obtained crystalline Form-S4 was illustrated in figure-4.

ExampIe-5: Preparation of crystalline Form-S5 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethyIamino)but-2-enamide.

1 ,4-Dioxane (10 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]- 3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 50-55°C and stirred for 15 min at same temperature. Cooled the reaction mixture to 25-30°C. Filtered the precipitated solid, washed with 1,4-dioxane and then dried to get the title compound. Yield: 360 mg.

The P-XRD pattern of the obtained crystalline Form-S5 was illustrated in figure-5. Example-6: Preparation of crystalline Form-S6 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

Acetone (40 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)aniIino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 50-5 °C and stirred for 30 min at same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure at below 50°C and then dried to get title compound. Yield: 420 mg.

The P-XRD pattern of the obtained crystalline Form-S6 was illustrated in figure-6.

Example-7: Preparation of crystalline Form-S7 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

Cyclohexane (20 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]- 3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 2 hours at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours. Filtered the precipitated solid, washed with cyclohexane and then dried the material to get the title compound. (Yield: 390 mg).

The P-XRD pattern of the obtained crystalline Form-S7 was illustrated in figure-7.

Example-8: Preparation of crystalline Form-S7 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinoIin-6-yl}-4-(dimethylamino)but-2-enamide.

Toluene (40 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (1 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 65-70°C and stirred for 10 min at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 30 min. Filtered the precipitated solid, washed with toluene and then dried the material to get the title compound. (Yield: 910 mg). ExampIe-9: Preparation of crystalline Form-S7 of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(diniethyIaniino)but-2-enamide. o-Xylene (30 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yI methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (0.5 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 65-70°C and stirred for 2 hours at same temperature. Cooled the reaction mixture to -30±5°C and stirred for 35 min. filtered the precipitated solid, washed with o-xylene and then dried to get the title compound. (Yield: 420 mg).

Example-10: Preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

Methanol (200 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)aniUno]-3- cyano-7-ethoxyquinoIin-6-yl}-4-(dimethylamino)but-2-enamide (5.0 gm) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 45 min at same temperature. Filtered the reaction mixture and the obtained filtrate was spray dried at below mentioned parameters to obtain amorphous (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

Operation parameters:

Labultima Instrument.

Aspirator: 65%

Feed Rate: 10 ml/min

Inlet temperature: 50°C to 55°C.

Gas flow N₂: 5.0 kg cm2.

Yield: 2.0 gms.

The P-XRD pattern of the obtained compound was illustrated in figure-8.

Example-lit Preparation of crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquino in-6-yl}-4-(dimethylamino)but-2-enamide malcate. 3-Methyl-l-butanol (isopentanol) (40 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2- yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (1 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 40- 45°C and added maleic acid (500 mg) and stirred for 10 min at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 40 min at same temperature. Filtered the precipitated solid and then dried to get title compound. (Yield: 810 mg).

The P-XRD pattern of the obtained crystalline Form-M was illustrated in figure-9.

Example-12: Preparation of crystalline Form-S of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)aniIino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate.

Isopropyl acetate (40 ml) was added to (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (1 gm) at 25-30°C. Heated the reaction mixture to 70-75°C and added maleic acid (500 mg) and stirred the obtained reaction mixture for 10 min at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 30 min at same temperature. Filtered the precipitated solid and then dried to get the title compound. (Yield: 850 mg).

The P-XRD pattern of the obtained crystalline Form-S was illustrated in figure- 12.

Example-13: Preparation of crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yI}-4-(dimethyIamino)but-2-enamide maleate.

2-Butanol (20 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (500 mg) at 25-30°C. Heated the reaction mixture to 80-85°C and added maleic acid (200 mg) and stirred the obtained reaction mixture for 10 min at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at same temperature. Filtered the precipitated solid and then dried to get title compound. (Yield: 400 mg).

The P-XRD pattern of the obtained crystalline Form-N was illustrated in figure- 15. ExampIe-14: Preparation of crystalline Form-Ml of (E)-N-{4-[3-chloro-4-(pyridin-2-yI methoxy)anilino]-3-cyano-7-ethoxyquinoIin-6-yl}-4-(dimethytamino)but-2-enamide tnaleate.

Aqueous n-propanol (20 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (1 gm) at 25-30°C. Heated the reaction mixture to 70-75°C and added maleic acid (500 mg) and stirred the obtained reaction mixture for 10 min at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at same temperature. Filtered the precipitated solid and dried under reduced pressure at 40°C to get title compound. (Yield: 840 mg).

The P-XRD pattern of the obtained crystalline Form-Ml was illustrated in figure- 16.

Example-15: Preparation of crystalline form-M2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate.

Methyl ethyl ketone (20 ml) was added to (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide (500 mg) at 25-30°C. Heated the reaction mixture to 60-65°C and added maleic acid (200 mg) and stirred the obtained reaction mixture for 10 min at same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at same temperature. Filtered the precipitated solid and then dried under reduced pressure at 50°C to get the title compound. (Yield: 450 mg).

The P-XRD pattern of the obtained crystalline Form-M2 was illustrated in figure- 17.

Example-16: Preparation of amorphous form of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)aniIino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate.

Methanol (100 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate (1 gm) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 50-55°C and stirred for 25 min. at same temperature. Filtered the solution for particle free and distilled off the solvent completely from the reaction mixture under reduced pressure. Dried the obtained material to get title compound. (Yield: 0.8 gms).

The P-XRD pattern of the obtained compound was illustrated in figure-20.

Example-17: Preparation of amorphous form of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate.

Methanol (200 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate (5 gms) at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 60 min. at same temperature. Filtered the solution and spray dried at below mentioned parameters to obtain amorphous (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)aniIino]-3-cyano- 7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate.

Operation parameters:

Labultima Instrument.

Aspirator: 65%

Feed Rate: 10 ml/min

Inlet temperature: 55°C to 60°C.

Gas flow N₂: 5.0 kg cm2.

Yield: 2.0 gms.

The P-XRD pattern of the obtained compound was similar to the PXRD pattern illustrated in figure-20.

Example-18: Preparation of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)aniIino]-3-cyano-7- cthoxyquinolin-6-yI}-4-(dimethylarnino)but-2-cnamide maleate with Povidone - K30 ^'(PVP- K30) (l:l)

Methanol (100 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate (1.0 gm) at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 50-55°C. Slowly added PVP-K30 solution (1.0 gm of PVP-K30 in 10 ml of methanol) to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide the title compound. (Yield: 1.88 gms)

The P-XRD pattern of the obtained compound was illustrated in figure-21.

ExampIe-19: Preparation of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate with HPC (1:1).

Methanol (100 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate (1.0 gm) at 25-30°C and stirred for 15 minutes at the same temperature. The reaction mixture was heated to 50-55°C. Slowly added HPC solution (1.0 gm of HPC in 20 ml of methanol) to the reaction mixture at 25- 30°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide the title compound.

(Yield: 1.50 gms)

The P-XRD pattern of the obtained compound was illustrated in figure-22.

Example-20: Preparation of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate with HPMC (1:1).

Methanol (80 ml) was added to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate (1.0 gm) at 25-30°C and stirred for 15 minutes at the same temperature. The reaction mixture was heated to 50-55°C. Slowly added HPMC solution (1.0 gm of HPMC dissolved in 20 ml of methanol) to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to provide the title compound. Yield: 1.80 gms.

The P-XRD pattern of the obtained compound was illustrated in figure-23.

Claims

We Claim:

1. Crystalline Form-Sl of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide characterized by Powder X-Ray Diffraction (PXRD) having peaks at about 4.0, 5.8, 8.1, 12.0, 19.7 ± 0.2 degrees of 2-theta.

2. The crystalline Form-Sl of claim 1 is further characterized by its PXRD having additional peaks at about 11.0, 16.2, 16.6, 17.7, 23.4, 25.8, 28.6 ± 0.2 degrees of 2-theta.

3. The crystalline Form-S l of claim 1 and 2, is further characterized by its PXRD pattern as illustrated in figure-1.

4. A process for the preparation of crystalline Form-Sl of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) dissolving (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) isolating crystalline Form-Sl of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino] -3 -cyano-7 -ethoxyquinolin-6-y 1 } -4-(dimethylamino)but-2 -enamide. wherein, in step-a), the suitable solvent is selected from chloro solvents such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; the suitable temperature in step-a) and step-c) is between 25°C to 30°C; the suitable temperature in step- b) is from 30°C to the reflux temperature of the solvent used.

5. A process for the preparation of crystalline Form-Sl of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising: a) adding (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I) to dichloromethane at 25-30°C;

b) heating the reaction mixture to 60-65°C;

c) cooling the reaction mixture to 25-30°C;

d) isolating crystalline Form-Si of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.

6. Crystalline Form-S2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide characterized by its PXRD having peaks at about 3.9, 5.4, 8.1 , 1 1.9, 16.7, 21.9, 23.9 and 29.2 ± 0.2 degrees of 2-theta.

7. The crystalline Form-S2 of claim 6 is further characterized by its PXRD having additional peaks at about 7.7, 10.6, 1 1.5, 16.4, 17.3, 20.0, 22.4, 23.1 , 24.9 and 26.7 ± 0.2 degrees of 2- theta.

8. The crystalline Form-S2 of claim 6 is further characterized by its PXRD pattern as shown in figure-2.

9. A process for the preparation of crystalline Form-S2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) filtering the precipitated solid to provide crystalline Form-S2 of (E)-N-{4-[3-chloro- 4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino) but-2-enamide.

wherein, in step-a) the suitable solvent is selected from polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl pyrrolidine (NMP) or mixtures; the suitable temperature in step-a) and step-c) is 25-30°C; the suitable temperature in step-b) is from 30°C to the reflux temperature of the solvent used.

10. A process for the preparation of crystalline Form-S2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in D F at 25-30°C;

b) heating the reaction mixture to 60-65°C;

c) cooling the reaction mixture to 25-30°C;

d) filtering the precipitated solid to provide crystalline Form-S2 of formula (I).

11. Crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide characterized by PXRD having peaks at about 4.9, 9.0, 1 1.1 , 12.3, 15.1 , 16.2, 18.3, 20.6, 22.8, 23.8, 26.0 and 26.6 ± 0.2 degrees of 2-theta.

12. The crystalline Form-S3 of claim 1 1 is further characterized by PXRD having additional peaks at 10.0, 1.5, 19.0, 19.9, 21.7, 24.3, 24.8, 31.4, 32.4, 33.8 ± 0.2 degrees of 2-theta.

13. The crystalline Form-S3 of claim 1 1 is further characterized by its PXRD pattern as shown in figure-3.

14. A process for the preparation of crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yI}-4-(dimethylamino)but-2-enamide in a suitable solvent at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature; d) isolating crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide. wherein, in step-a) the suitable solvent is selected from ketone solvents such as acetone, methyl isobutyl ketone, methyl butyl ketone, butanone, pentanone or mixtures; the suitable temperature in step-a) and step-c) is 25-30°C; the suitable temperature in step-b) is from 30°C to the reflux temperature of the solvent used.

15. A process for the preparation of crystalline Form-S3 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in methyl isobutyl ketone at 25- 30°C;

b) heating the reaction mixture to 60-65°C;

c) cooling the reaction mixture to 25-30°C;

d) isolating crystalline Form-S3 of formula (I).

16. Crystalline Form-S4 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide characterized by its PXRD having peaks at about 5.2, 9.0, 10.3, 12.0, 14.2, 17.4 and 20.5 ± 0.2 degrees of 2-theta.

17. The crystalline Form-S4 of claim 16 is further characterized by its PXRD having additional peaks at 5.7, 7.1 , 15.4, 16.6, 22.2, 24.3, 25.3 ± 0.2 degrees of 2-theta.

18. The crystalline Form-S4 of claim 16 is further characterized by its PXRD pattern as shown in figure-4.

19. A process for the preparation of crystalline Form-S4 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising: a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethyIamino)but-2-enamide in a mixture of suitable solvents at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) removing the solvent from the reaction mixture;

d) drying the material to provide crystalline Form-S4 of (E)-N-{4-[3-chloro-4-(pyridin- 2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide.^' wherein, in step-a), the suitable solvent is selected from alcohol solvents having C 1 -C5 atoms such as methanol, ethanol, propanol, isopropanol, butanol, pentanol, ethylene glycol and halo hydrocarbon solvents such as dichloromethane, trichloromethane and chloroform thereof; the suitable temperature in step-a) is 25-30°C; the suitable temperature in step-b) is from 30°C to the reflux temperature of the solvent used.

20. A process for the preparation of crystalline Form-S4 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in dichloromethane and methanol at 25-30°C;

b) heating the reaction mixture to 50-55°C;

c) distilling off the solvent from the reaction mixture;

d) drying the material to provide crystalline Form-S4 of formula (I).

21. Crystalline Form-S5 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide characterized by its PXRD having peaks at about 22.5, 23.3, 24.1 , 26.0, 29.0 ± 0.2 degrees of 2-theta.

22. The crystalline Form-S5 of claim 21 , is further characterized by its PXRD having additional peaks at 15.0, 18.5, 19.3, 19.9, 22.9 and 24.7 ± 0.2 degrees of 2-theta.

23. The crystalline Form-S5 of claim 21, is further characterized by its PXRD pattern as shown in figure-5.

24. A process for the preparation of crystalline Form-S5 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising:

a) providing (£)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent at a suitable temperature;

b) heating the reaction mixture to a suitable temperature;

c) cooling the reaction mixture to a suitable temperature;

d) isolating crystalline Form-S5 of formula (I). wherein, in step-a), the suitable solvent is selected from ether solvents such as 1, 4-dioxane, tetrahydrofuran, methyl tert-butyl ether, diethyl ether and the like; the suitable temperature in step-a) and step-c) is between 25-30°C; the suitable temperature in step-b) is starting from 30°C to the reflux temperature of the solvent used.

25. A process for the preparation of crystalline Form-S5 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide, which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in 1 , 4-dioxane at 25-30°C;

b) heating the reaction mixture to 50-55°C;

c) cooling the reaction mixture to 25-30°C;

d) filtering and drying the precipitated solid to provide crystalline Form-S5 of formula (I).

26. Crystalline Form-S6 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide characterized by its PXRD having peaks at about 4.0, 5.9, 8.4, 10.8, 11.9, 17.0 and 17.8 ± 0.2 degrees of 2-theta.

27. The crystalline Form-S6 of claim 26, further characterized by its PXRD having additional peaks at 5.7, 7.8, 8.9, 1 1.1 , 12.2, 16.4, 22.3, 24.3, 26.3 and 30.0 ± 0.2 degrees of 2-theta.

28. The crystalline Form-S6 of claim 26, further characterized by its PXRD pattern as shown in figure-6.

29. A process for the preparation of crystalline Form-S6 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in acetone at 50-55°C; b) distilling off the solvent completely from the reaction mixture;

c) drying the material to provide crystalline Form-S6 of (E)-N-{4-[3-chloro-4-(pyridin- 2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide.

30. Crystalline Form-S7 of (E)-N-{4-[3-chloro-4- pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinoIin-6-yl}-4-(dimethyIamino)but-2-enamide characterized by its PXRD having peaks at about 5.0, 9.1 , 20.7 ± 0.2° of 2-theta.

31. The crystalline Form-S7 of claim 30, is further characterized by its PXRD having additional peaks at 8.5, 10.3, 1 1.2, 12.4, 13.8, 14.3, 14.7, 15.1 , 16.4, 17.9, 18.5, 19.4, 23.0, 24.5, 26.1 , 26.7, 28.0 ± 0.2° of 2-theta.

32. The crystalline Form-S7 of claim 30, is further characterized by its PXRD pattern as shown in figure-7.

33. A process for the preparation of crystalline Form-S7 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent; b) heating the reaction mixture to a suitable temperature; c) cooling the reaction mixture obtained in step-b) to a suitable temperature; d) isolating crystalline Form-S7 of formula (I). wherein, the suitable solvent in step-a) is selected from hydrocarbon solvents such as cyclohexane, toluene, o-xylene, n-heptane, n-hexane and the like; the suitable temperature in step-a) is 25-30°C; the suitable temperature in step-b) is ranging between 30°C to the reflux temperature of the solvent used.

34. A process for the preparation of crystalline Form-S7 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anil ino] -3 -cyano-7-ethoxyquinol ίη-6-y 1 } -4-(dimethylamino)but-2-enamide, comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in cyclohexane or toluene or o- xylene;

b) heating the reaction mixture to 60-70°C;

c) cooling the reaction mixture obtained in step-b) to 0-5°C;

d) filtering the precipitated solid and drying to provide crystalline Form-S7 of formula (I).

35. Amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl } -4-(dimethylamino)but-2-enamide.

36. The amorphous form of claim 35, characterized by its powder X-ray diffraction pattern as shown in figure-8.

37. A process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl memoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (1), which comprising:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent; b) stirring the reaction mixture;

c) heating the reaction mixture to a suitable temperature; d) optionally, filtering the reaction mixture;

e) removing the solvent to get amorphous form of formula (I). wherein, the suitable temperature in step-a) is 25-30°C; the suitable temperature in step-c) is from 30°C to the reflux temperature of the solvent used; the suitable solvent in step-a) is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, hydrocarbon solvents and ether solvents or mixture thereof; preferably alcohol solvents.

38. A process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide of formula (I), which comprising following steps:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in methanol;

b) optionally filtering the reaction mixture;

c) spray drying the solution to get amorphous form of (E)-N-{4-[3-chloro-4-(pyridin- 2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide.

39. Crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II) characterized by its powder X-Ray diffraction having characteristic peaks at about 6.2, 7.1, 8.5 and 16.8 ± 0.2° of 2-theta.

40. The crystalline Form-M of claim 39, is further characterized by its PXRD pattern as shown in figure-9.

41. A process for the preparation of crystalline Form-M of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) adding (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide to a suitable solvent; b) heating the reaction mixture to suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) to provide crystalline Form-M of formula (II). wherein, in step-a) the suitable solvent is selected from alcohol solvents such as methanol, ethanol, isopropanol, isobutanol, isopentanol; the suitable temperature is 25- 30°C; in step-b), the suitable temperature is 30°C to the reflux temperature of the solvent used; in step-e) the suitable temperature is 0-5°C.

42. Crystalline Form-S of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II) characterized by its PXRD having characteristic peaks at about 5.7, 6.2, 13.1 and 24.5 ± 0.2" of 2-theta.

43. The crystalline Form-S of claim 42, is further characterized by its PXRD having additional peaks at about 6.8, 8.5, 10.7, 10.9, 1 1.7,13.1, 14.4, 15.7, 17.3, 19.0, 19.4, 19.6, 20.5, 21.8, 23.5 and 25.5 ± 0.2° of 2-thefa.

44. The crystalline Form-S of claim 42, further characterized by its PXRD pattern as shown in figure- 12.

45. A process for the preparation of crystalline Form-S of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form-S of formula (II). wherein, in step-a), the suitable solvent is selected from ester solvents such as ethyl acetate, methyl acetate, isobutyl acetate, isopropyl acetate, ether solvents such as tetrahydrofuran, 1 ,4-dioxane, methyl tert-butyl ether, diethyl ether, chloro solvents such as dichloromethane and the like, ketone solvents like acetone, methyl isobutyl ketone and the like; the suitable temperature is 25-30°C; in step-b), the suitable temperature is from 30°C to the reflux temperature of solvent used; in step-e), the suitable temperature is 0-5°C

46. A process for the preparation of crystalline Form-S of (E)-N-{4-[3-chIoro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinoIin-6-yl}-4-(dimethylamino)but-2-enamide in isopropyl acetate;

b) heating the reaction mixture to 70-75 C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) cooling the reaction mixture to 0-5°C

e) filtering the precipitated solid to provide crystalline Form-S of formula (II).

47. Crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinoiin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II) characterized by its PXRD having characteristic peaks at about 5.0, 10.2, 11.2, 16.9, 18.9 and 21.4 ± 0.2° of2-theta.

48. The crystalline Form-N of claim 47, is further characterized by its PXRD having additional peaks at about 5.9, 6.7, 7.5, 9.4, 12.8, 13.4, 13.9, 15.0, 18.0, 20.1, 22.4, 23.1, 25.5, 28.4 and 29.4 ± 0.2° of2-theta. .

49. The crystalline Form-N of claim 47 is further characterized by its PXRD pattern as shown in figure- 15.

50. A process for the preparation of crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the. following steps: a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent;

b) heating the reaction mixture to a suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) isolating crystalline Form-N of formula (II). wherein, in step-a), the suitable solvent is selected from alcohol solvents having C]-C₅ carbon atoms such as methanol, ethanol, n-propanol, isopropanol, 1-butanol and 2-butanol or mixtures; in step-b), the suitable temperature is from 30°C to the reflux temperature of the solvent used.

51. A process for the preparation of crystalline Form-N of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enarnide in 2-butanol;

b) heating the reaction mixture to 80-85°C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) filtering the precipitated solid to provide crystalline Form-N of formula (II).

52. Crystalline Form-Ml of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II) characterized by its PXRD having characteristic peaks at about 4.9, 6.7, 12.9, 22.2 ± 0.2° of 2-theta.

53. The crystalline Form-Ml of claim 52, having additional peaks at about 9.9, 1 1.3, 13.4, 15.0, 15.8, 16.8, 18.0, 24.7, 25.6, 26.5, 27.3, 28.4 and 31.6 ± 0:2° of 2-theta.

54. The crystalline Form-Ml of claim 52 is further characterized by its PXRD pattern as shown in figure- 16.

55. A process for the preparation of crystalline Form-Ml of (E)-N-{4-[3-chloro-4-(pyridin-2-yI methoxy)anilinoJ-3-cyano-7-ethoxyquinolin-6-yI}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyanp-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in a suitable solvent; b) heating the reaction mixture to a suitable temperature;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form-Ml of formula (II). wherein, in step-a), the suitable solvent is selected from alcohol solvents such as methanol, ethanol, n-propanol, i-propanol and aqueous mixtures; in step-b), the suitable temperature is from 30°C to the reflux temperature of the solvent used.

56. A process for the preparation of crystalline Form-Ml of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) providing (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in aqueous n-propanol; b) heating the reaction mixture to 70-75°C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture to 0-5°C

f) filtering the precipitated solid to provide crystalline Form-Ml of formula (II).

57. Crystalline Form-M2 of (E)- -{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino) but-2-enamide maleate of formula (II) characterized by its PXRD having characteristic peaks at about 5.7, 6.6, 8.0, 1 1.2, 16.6 and 17.8 ± 0.2° of 2-theta.

58. The crystalline Form-M2 of claim 57, is further characterized by its PXRD pattern as shown in figure- 18.

59. A process for the preparation of crystalline Form-M2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide mateate of formula (II), comprising the following steps:

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture obtained in step-d) and filtering to provide crystalline Form-M2 of formula (II). wherein, in step-a), the suitable solvent is selected from keto solvents such as acetone, methyl isobutyl ketone, methyl butyl ketone, methyl ethyl ketone, butanone, pentanone or mixtures thereof, the suitable temperature is ranging between 25-30°C; in step-b), the suitable temperature is selected from 30°C to the reflux temperature of the solvent used.

60. A process for the preparation of crystalline Form-M2 of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide in methyl ethyl ketone; b) heating the reaction mixture to 60-65°C;

c) adding maleic acid to the reaction mixture obtained in step-b);

d) stirring the reaction mixture obtained in step-c);

e) cooling the reaction mixture to 0-5°C

f) filtering the precipitated solid to provide crystalline Form-M2 of formula (II).

61. Amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7- ethoxyquinolin-6-yl}-4-(dimethylamino) but-2-enamide maleate of formula (II).

62. Amorphous form of formula (II) of claim 61 , is further characterized by its PXRJP pattern as shown in figure-20.

63. A process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps of:

b) stirring the reaction mixture obtained in step-a);

c) removing the solvent from the reaction mixture obtained in step-b) to provide amorphous form of formula (II). wherein, in step-a) the suitable solvent is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1 ,3-dioxane and the like.

64. A process for the preparation of amorphous form of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yI}-4-(dimethylamino)but-2-enamide maleate of formula (II), comprising the following steps of:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate in methanol; b) optionally, filtering the solution for making it particle free;

c) spray drying or distilling off the solvent from the solution to provide amorphous form of formula (II).

65. Amorphous solid dispersion of (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3- cyano-7-ethoxyquinolin-6-yl}-4-(dimethyl amino)but-2-enamide maleate of formula (II) in combination with one or more pharmaceutical acceptable carrier.

66. A process for the preparation of solid dispersion comprising amorphous (E)-N-{4-[3-chloro- 4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2- enamide maleate of formula (II) and pharmaceutically acceptable carrier, comprising the following steps:

a) dissolving (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxy quinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate in suitable solvent; b) adding pharmaceutically acceptable carrier in suitable solvent;

c) removing the solvent^' from the reaction mixture to provide the corresponding solid dispersion of formula (II).

67. The process according to claim 66, wherein, in step-a) and step-b), the suitable solvent is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol and the like; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1 ,3-dioxane.

68. The process according to claim 66, the pharmaceutically acceptable carrier is selected from polyvinylpyrrolidone (PVP), PVP-30, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl methyl cellulose-acetyl succinate (HP C-AS).

69. Use of Neratinib crystalline Form SI , S2, S3, S4, S5, S6 and S7 in the preparation of Neratinib maleate.

70. Use of Neratinib crystalline Form SI, S2, S3, S4, S5, S6 and S7 and Neratinib maleate crystalline Form M , S, N, Ml and M2 in the preparation of pharmaceutical compositions.