WO2018134843A1 - Formes polymorphes de (e)-n-{4-[3-chloro-4-((pyridin-2-yl-méthoxy)-anilino]-3-cyano-7-éthoxyquinolin-6-yl)-4-(diméthylamino)-but-2-énamide, son sel de maléate et un procédé de préparation correspondant - Google Patents

Formes polymorphes de (e)-n-{4-[3-chloro-4-((pyridin-2-yl-méthoxy)-anilino]-3-cyano-7-éthoxyquinolin-6-yl)-4-(diméthylamino)-but-2-énamide, son sel de maléate et un procédé de préparation correspondant Download PDF

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WO2018134843A1
WO2018134843A1 PCT/IN2018/000006 IN2018000006W WO2018134843A1 WO 2018134843 A1 WO2018134843 A1 WO 2018134843A1 IN 2018000006 W IN2018000006 W IN 2018000006W WO 2018134843 A1 WO2018134843 A1 WO 2018134843A1
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pyridin
chloro
cyano
methoxy
anilino
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PCT/IN2018/000006
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English (en)
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Sagyam RAJESHWAR REDDY
Rangineni Srinivasulu
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2018134843A1 publication Critical patent/WO2018134843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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)
  • 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).
  • 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 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 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 discloses crystalline Form-A, Form-B and Form-C of Neratinib maleate.
  • WO 2018/005418 Al discloses Neratinib crystalline Form-B 1 , Form-B2, Form-B3, Form-B4 & Form-B6; Neratinib maleate crystalline Form T2.
  • 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.
  • 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.
  • 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.
  • Neratinib formula (I), and Neratinib maleate formula (II), of the present invention is characterized by its Powdered X-Ray Diffraction (PXRD) patterns.
  • 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.
  • Form-M formula (II)
  • 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.
  • 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).
  • 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
  • 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.
  • suitable base 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,
  • suitable acid refers to the acid selected from inorganic acids like HC1, HBr, HI, H 2 S0 4 ; 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.
  • 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, malt
  • 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.
  • amorphous solid dispersion 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.
  • spray drying broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture.
  • 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;
  • 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.
  • 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
  • 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:
  • 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:
  • 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:
  • 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:
  • step-a) 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.
  • 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:
  • 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:
  • step-a) 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.
  • 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:
  • 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:
  • step-a) 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.
  • 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:
  • 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:
  • 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:
  • step-b) cooling the reaction mixture obtained in step-b) to a suitable temperature
  • 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:
  • step-b) cooling the reaction mixture obtained in step-b) to 0-5°C;
  • 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:
  • 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;
  • 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.
  • 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.
  • DSC differential scanning calorimetric
  • 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.
  • TGA thermo gravimetric analysis
  • 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:
  • step-a) 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.
  • 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:
  • 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.
  • 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.
  • DSC differential scanning calorimetric
  • TGA thermo gravimetric analysis
  • 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:
  • 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.
  • ester solvents such as ethyl acetate, methyl acetate, isobutyl acetate, isopropyl acetate
  • ether solvents such as tetrahydrofuran, 1 ,4- dioxane, methyl tert-butyl ether,
  • 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:
  • step-b c) adding maleic acid to the reaction mixture obtained in step-b); d) cooling the reaction mixture to 0-5°C
  • 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:
  • step-a) 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.
  • 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.
  • 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:
  • 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:
  • 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:
  • 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.
  • 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.
  • DSC differential scanning calorimetric
  • 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.
  • TGA thermo gravimetric analysis
  • 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:
  • step-a) 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
  • 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.
  • 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:
  • 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:
  • step-b) 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.
  • 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.
  • 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
  • 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:
  • 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.
  • 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.
  • 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 .
  • polyvinylpyrrolidone povidone or PVP; PVP of different grades like -15, K-30, K-60, -90 and -120 may be used
  • polyvinylpolypyrrolidone polysorbate
  • 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, x
  • 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).
  • PVP polyvinylpyrrolidone
  • HPMC hydroxy propyl methyl cellulose
  • HPMC-AS hydroxy propyl methyl cellulose-acetyl succinate
  • 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:
  • 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.
  • 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
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • 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 ⁇ . Prefarebly less than 50 ⁇ . More prefarebly less than 15 ⁇ .
  • 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 A 0 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.
  • Example-1 Preparation of crystalline Form-Si of (E)-N- ⁇ 4-[3-chloro-4-(pyridin-2-yl methoxy)anilino
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Inlet temperature 50°C to 55°C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Inlet temperature 55°C to 60°C.
  • 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)
  • 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).

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Abstract

La présente invention concerne de nouvelles formes polymorphes de (E)-N-{4-[3-chloro-4-((pyridin-2-yl)-méthoxy)phényle)amino)-3-cyano-7-éthoxyquinolin-6-yl)-4-(diméthylamino)-but-2-énamide, les sels de maléate et un procédé de préparation correspondants. La structure chimique dudit composé est représentée par la formule (I) suivante.
PCT/IN2018/000006 2017-01-23 2018-01-22 Formes polymorphes de (e)-n-{4-[3-chloro-4-((pyridin-2-yl-méthoxy)-anilino]-3-cyano-7-éthoxyquinolin-6-yl)-4-(diméthylamino)-but-2-énamide, son sel de maléate et un procédé de préparation correspondant WO2018134843A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112679473A (zh) * 2019-10-18 2021-04-20 四川科伦药物研究院有限公司 来那替尼中间体晶体、制备方法及其用途
CN116473923A (zh) * 2023-05-29 2023-07-25 杭州剂泰医药科技有限责任公司 一种奈拉替尼固体分散体组合物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009052264A2 (fr) * 2007-10-17 2009-04-23 Wyeth Sels maléates de (e)-n-{4-[3-chloro-4-(2-pyridinylméthoxy)anilino]-3-cyano-7-éthoxy-6-quinolinyl}-4-(diméthylamino)-2-buténamide et leurs formes cristallines
CA2973853A1 (fr) * 2015-01-09 2016-07-14 Crystal Pharmatech Co., Ltd. Nouvelle forme cristalline de maleate de neratinib et methode de preparation de cette derniere

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009052264A2 (fr) * 2007-10-17 2009-04-23 Wyeth Sels maléates de (e)-n-{4-[3-chloro-4-(2-pyridinylméthoxy)anilino]-3-cyano-7-éthoxy-6-quinolinyl}-4-(diméthylamino)-2-buténamide et leurs formes cristallines
CA2973853A1 (fr) * 2015-01-09 2016-07-14 Crystal Pharmatech Co., Ltd. Nouvelle forme cristalline de maleate de neratinib et methode de preparation de cette derniere

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112679473A (zh) * 2019-10-18 2021-04-20 四川科伦药物研究院有限公司 来那替尼中间体晶体、制备方法及其用途
CN112679473B (zh) * 2019-10-18 2024-03-05 四川科伦药物研究院有限公司 来那替尼中间体晶体、制备方法及其用途
CN116473923A (zh) * 2023-05-29 2023-07-25 杭州剂泰医药科技有限责任公司 一种奈拉替尼固体分散体组合物及其制备方法和应用
CN116473923B (zh) * 2023-05-29 2024-05-14 杭州剂泰医药科技有限责任公司 一种奈拉替尼固体分散体组合物及其制备方法和应用

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