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WO2018189695A1 - Formes cristallines de nératinib et leur procédé de préparation - Google Patents

Formes cristallines de nératinib et leur procédé de préparation Download PDF

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Publication number
WO2018189695A1
WO2018189695A1 PCT/IB2018/052535 IB2018052535W WO2018189695A1 WO 2018189695 A1 WO2018189695 A1 WO 2018189695A1 IB 2018052535 W IB2018052535 W IB 2018052535W WO 2018189695 A1 WO2018189695 A1 WO 2018189695A1
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Prior art keywords
neratinib
solvate
crystalline
depicted
ray powder
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Ceased
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English (en)
Inventor
Palash Sanphui
Vikas Ashokrao SADAPHAL
Radhakrishna SHIVDAVKAR
Rohidas Shivaji SULAKE
Rajinder Singh Siyan
Nandu Baban Bhise
Girij Pal Singh
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Lupin Ltd
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Lupin Ltd
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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

  • Neratinib is a tyrosine kinase inhibitor formula (I), having the chemical name (2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl) methoxy] phenyl] amino]-3-cyano-7- ethoxyqui nol i n-6-yl] -4-( di methyl ami no) but-2-enami de.
  • formula (I) having the chemical name (2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl) methoxy] phenyl] amino]-3-cyano-7- ethoxyqui nol i n-6-yl] -4-( di methyl ami no) but-2-enami de.
  • Neratinib is a tyrosine kinase inhibitor. Tyrosine kinase inhibitors are known to be useful in the treatment of cancers, including non-small cell lung cancer (NSCLC), breast cancer, polycystic kidney disease, colonic polyps, and stroke in mammals. Neratinib has the following chemical structure:
  • PCT application WO 2010/048477 discloses process for preparation of Neratinib; the Neratinib is obtained as a crude product For pharmaceutical development of a compound, , the compound in its pure form is required so as to achieve desired pharmaceutical effects.
  • Polymorphism the occurrence of different crystalline forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of i3 ⁇ 4 polymorphs having distinct crystal structures and physical properties like melting ⁇ thermal behaviors (e.g. measured by thermogravi metric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fi ngerprint and solid state ( 13 C) NMR spectrum.
  • TGA thermogravi metric analysis -
  • DSC differential scanning calorimetry -
  • Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving
  • T hese variations in the properties of different salts and solid state forms may also off er i mprovements to the final dosage form, for instance, if they serve to improve bioavailability.
  • Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystal line forms, which may in turn provide additional
  • Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handli ng, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal , forms that facilitate conversion to other polymorphic forms.
  • New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product It enlarges the repertoire of materials that a formulation scientist has avai lable for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit i3 ⁇ 4 higher crystal I inity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or i mproved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional crystal I i ne forms ( i ncl udi ng solvated forms) of N erati ni b.
  • Figure 1 Illustrates X-ray powder diffraction (XRPD) pattern of crystalline dichloromethane solvate of Neratinib
  • FIG. 2 Illustrates differential scanning calorimetry (DSC) plot of crystalline 3 ⁇ 4 di chl oromethane solvate of N erati ni b
  • FIG. 3 Illustrates thermogravi metric analysis (TGA) plot of crystalline dichloromethane solvate of Neratinib
  • Figure4 Illustrates X-ray powder diffraction (X RPD) pattern of crystalline ethyl acetate solvate of Neratinib
  • FIG. 6 Illustrates thermogravi metric analysis (TGA) plot of crystalline ethyl acetate solvate of Neratinib
  • Figure 7 Illustrates X-ray powder diffraction (XRPD) pattern of crystalline methanol 3 ⁇ 4 solvate of Nerati ni b
  • Figure 8 Illustrates differential scanning calorimetry (DSC) plot of crystalline methanol solvate of Neratinib
  • FIG. 9 Illustrates thermogravi metric analysis (TGA) plot of crystalline methanol solvate of Neratinib
  • Figure 10 Illustrates X-ray powder diffraction (XRPD) pattern of crystalline acetone solvate of Neratinib
  • Figure 11 Illustrates differential scanning calorimetry (DSC) plot of crystalline acetone solvate of Neratinib
  • FIG. 12 Illustrates thermogravi metric analysis (TGA) plot of crystalline acetone 3 ⁇ 4 solvate of Nerati ni b
  • Figure 13 Illustrates X-ray powder diffraction (XRPD) pattern of crystalline ethanol solvate of Neratinib
  • F igure 14 Illustrates differential scanning calorimetry (DSC) plot of crystalline ethanol solvate of Neratinib
  • F igure 15 Illustrates thermogravi metric analysis (TGA) plot of crystalline ethanol solvate of Neratinib
  • F igure 17 Illustrates differential scanning calorimetry (DSC) plot of crystalline acetonitrile solvate of Neratinib
  • F igure 18 Illustrates thermogravi metric analysis (TGA) plot of crystalline acetonitrile 3a solvate of Nerati ni b
  • F igure 19 Illustrates X -ray powder diffraction (X R PD) pattern of crystalline anhydrate of Neratinib
  • F igure 20 Illustrates differential scanning calorimetry (DSC) plot of crystalline anhydrate of Neratinib
  • the present invention provides novel solvates of Neratinib.
  • the present invention provides crystalline dichloromethane solvate of Neratinib, crystalline ethylacetate solvate of Neratinib, crystall ine methanol solvate of Neratinib, crystal line acetone solvate of Neratinib, crystalline ethanol solvate of Neratinib and crystal I i ne acetonitri I e solvate of N erati ni b.
  • the present invention provides process for the preparation of the novel 3 ⁇ 4 crystalline solvates of Neratinib.
  • the present invention provides a crystalline anhydrate of Neratinib and process for preparation thereof.
  • the invention provides a pharmaceutical composition comprising said solvated and anhydrates of Neratini b and at least one pharmaceutically acceptable excipient or carrier.
  • the present invention provides novel solvated forms of Neratinib having enhanced flow property, stability, dissolution properties that can be easily formulated i nto pharmaceutical compositions.
  • solvate means an aggregate or a substance that consists of a solute ion or molecule with one or more solvent molecules.
  • Solvates are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated withi n the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates.
  • Neratinib of the present invention are dichloromethane solvate; ethylacetate solvate; methanol solvate; acetone solvate; ethanol solvate and acetonitri I e solvate.
  • Neratinib used herein is prepared as per methods known in the literature and it can be in crystal I i ne or amorphous form
  • the present invention provides a process for preparation of Nerati nib solvates comprising the steps of:
  • substantially removing the solvent refers to at least 80%, specifically greater ⁇ 3a than about 85%, more specifically greater than about 90%, still more specifically greater than about 99%, and most specifically essentially complete (100%) removal of the solvent from the reaction mixture.
  • the solvent employed in step (i) is selected from dichloromethane, methanol, ethanol, 3 ⁇ 4 acetone, ethyl acetate and acetonitrile.
  • step (i) is carried out at a temperature of about 20eC to about 100eC, preferably at about 50eC to about 90eC and more preferably at a temperature of about 25eC to about 80eC.
  • Removal of solvent i n step (iii) is accomplished, for example, by filtration, substantially removing solvent by evaporation, concentrating the solution or distillation of solvent to obtain the Neratinib solvate.
  • the evaporation process can be achieved by Rotavapor, a Rotary V acuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg, by flash evaporation techniques, by using an agitated thin film dryer (AT FD), or evaporated by spray drying to obtai n a dry crystal I i ne powder.
  • the distillation process can be performed at atmospheric pressure or reduced pressure. Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specif ical ly from about 30 to about 80 mm Hg.
  • i3 ⁇ 4 Another suitable method for solvent removal is vertical agitated thin-film drying (or evaporation).
  • Agitated thin film evaporation technology involves separating the volati le component using indirect heat transfer coupled with mechanical agitation of the flowing fil m under controlled conditions.
  • vertical agitated thin-film drying (or evaporation) AT FD-V
  • the starting solution is fed from the top into a cylindrical space between a t3 ⁇ 4a centered rotary agitator and an outside heating jacket
  • the rotor rotation agitates the downsi de-fl owi ng sol uti on whi I e the heati ng j acket heats it.
  • DC M crystalline dichloromethane
  • the crystalline DCM solvate of Neratinib is characterized by an X-ray powder diffraction 3 ⁇ 4 pattern substantially as depicted in Figure 1.
  • the crystalline DCM solvate of Neratinib is further characterized by an X -ray powder diffraction pattern comprising of characteristic peaks at 6.30, 8.37 and 18.97 e 0.2 degrees two theta.
  • the crystalline DC M solvate of Neratinib is further characterized by differential scanning calorimetry (DSC), having a DSC pattern substantial ly as depicted in Figure 2 and having an endothermic peak at 132eC e 5eC occurring during thermal analysis at a heating rate of 10eC/min.
  • DSC differential scanning calorimetry
  • the crystalline DC M solvate of Neratinib further characterized by thermogravi metric analysis (TGA), having a TGA pattern substantially as depicted in Figure 3.
  • TGA thermogravi metric analysis
  • Process for preparation of the crystalline DCM solvate of Neratinib comprises of , dissolving Neratinib in dichloromethane at ambient temperature and isolating the crystalline DCM solvate of Neratinib by slow evaporation of dichloromethane at ambient temperature.
  • the present invention provides a crystalline ethyl acetate solvate 3 ⁇ 4 of Neratinib.
  • the crystalline ethyl acetate solvate of Neratinib is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 4. t3 ⁇ 4a
  • the crystalli ne ethyl acetate solvate of Neratinib is further characterized by an X -ray powder diffraction pattern comprising of characteristic peaks at 5.69, 5.92, 8.40, 12.13, 16.83, 17.13, 22.24 and 24.28 e 0.2 degrees two theta.
  • the crystalline ethyl acetate solvate of Neratinib is further characterized by differential scanning calorimetry (DSC), having a DSC pattern substantially as depicted in Figure 5 and having an endothermic peak at 133eC e 5eC occurring during thermal analysis at a 3 ⁇ 4 heati ng rate of 1 C C /mi n.
  • DSC differential scanning calorimetry
  • TGA thermogravi metric analysis
  • Process for preparation of the crystalline ethylacetate solvate of Neratinib comprises of dissolving Neratinib in ethylacetate at 70"3 ⁇ 4 ⁇ to 75"3 ⁇ 4 ⁇ and isolating the crystalline ethylacetate solvate of Neratinib by slow evaporation of ethylacetate at ambient temperature.
  • the present invention provides a crystalline methanol solvate of Nerati nib.
  • the crystalline methanol solvate of Neratinib is characterized by an X -ray powder , diffraction pattern substantially as depicted in Figure 7.
  • the crystalline methanol solvate of Neratinib is further characterized by an X -ray powder diffraction pattern comprising of characteristic peaks at 4.87, 5.11, 5.46, 5.66, 7.07, 8.06, 8.51, 8.98, 10.22, 11.50, 12.08, 14.19 and 17.56 e 0.2 degrees two theta.
  • the crystalline methanol solvate of Neratinib is further characterized by differential scanning calorimetry (DSC), having a DSC pattern substantially as depicted in Figure 8 and having an endothermic peak at 107eC e 5eC occurring during thermal analysis at a heating rate of 10eC /min.
  • DSC differential scanning calorimetry
  • TGA thermogravi metric analysis
  • Process for preparation of the crystalline methanol solvate of Neratinib comprises of dissolving Neratinib in ethylacetate at 60eC to 65eC and isolating the crystalline methanol solvate of Neratinib by slow evaporation of methanol at ambient temperature.
  • the present invention provides a crystalline acetone solvate of 3a Neratinib.
  • the crystalline acetone solvate is characterised by an X -ray powder diffraction pattern substantially as depicted in Figure 10.
  • the crystalline acetone solvate of Neratinib is further characterized by an X -ray powder diffraction pattern comprising of characteristic peaks at 5.73, 5.97, 8.46, 11.92, 12.21 and 16.95 e 0.2 degrees two theta.
  • the crystall ine acetone solvate of Neratinib is further characterized by differential , scanning calorimetry (DSC), having a DSC pattern substantially as depicted in Figure 11 and having an endothermic peak at 122eC e 5eC occurring during thermal analysis at a heating rate of 10eC /min.
  • DSC differential , scanning calorimetry
  • TGA thermogravi metric i3 ⁇ 4 analysis
  • Process for preparation of the crystalline acetone solvate of Nerati nib comprises of dissolving Neratinib in acetone at 70eC to 75eC and isolating the crystalline acetone solvate of Neratinib by slow evaporation of acetone at ambient temperature.
  • the present invention provides a crystal line ethanol solvate of Nerati nib.
  • the crystalline ethanol solvate of Neratinib is characterized by an X -ray powder diffraction pattern substantially as depicted in Figure 13.
  • the crystalline ethanol solvate of Neratinib is further characterized by an X -ray powder diffraction pattern comprising of characteristic peaks at 5.99, 8.18, 11.87 and 17.13 e 0.2 degrees two theta.
  • the crystalline ethanol solvate of Neratinib is further characterized by differential 3a scanning calorimetry (DSC), having a DSC pattern substantially as depicted in Figure 14 and having two characteristic broad endotherms.
  • DSC differential 3a scanning calorimetry
  • Process for preparation of the crystalline ethanol solvate of Neratinib comprises of stirring slurry of Neratinib in ethanol at ambient temperature for about 24hrs and isolating , the crystal I i ne ethanol solvate of Nerati ni b.
  • the present invention provides a crystalline acetonitrile solvate of Neratinib. i3 ⁇ 4
  • the crystalline acetonitrile solvate of Nerati nib is characterized by an X -ray powder diffraction pattern substantially as depicted in Figure 16.
  • the crystalline acetonitrile solvate of Neratinib is further characterized by an X -ray powder diffraction pattern comprising of characteristic peaks at 5.82, 6.61, 7.19, 9.76 and til 19.8 e 0.2 degrees two theta.
  • the crystalli ne acetonitrile solvate of Neratinib is further characterized by differential scanning calorimetry (DSC), having a DSC pattern substantially as depicted in Figure 17 and having a characteristic broad endotherm between 70eC to 120eC occurring during thermal analysis at a heating rate of 10eC /min.
  • DSC differential scanning calorimetry
  • TGA thermogravi metric analysis
  • Process for preparation of the crystalline acetonitrile solvate of Neratinib comprises of stirring sl urry of Neratinib in ethanol at ambient temperature for about 24 hrs and isolating the crystalline acetonitrile solvate of Neratinib.
  • the present invention provides a crystall ine anhydrate of 3 ⁇ 4 Neratinib.
  • the crystalline anhydrate of Neratini b is characterized by X -ray powder diffraction pattern substantially as depicted in Figure 19. , The crystalline anhydrate of Neratinib is further characterized by X -ray powder diffraction comprising of characteristic peaks at 5.12, 8.67, 10.41, 11.40, 17.15, 18.04 19.67; 20.82 & 24.62 e 0.2 degrees two theta.
  • the crystalline anhydrate of Neratinib is further characterized by differential scanning i3 ⁇ 4 calorimetry (DSC), having a DSC pattern substantially as depicted in Figure 20 and having two characteristic endotherms; the first endothermic signal at 172eC e 5eC and the second relatively sharp signal at 178eC e 5eC occurring during thermal analysis at a heating rate of 10eC /min.
  • DSC differential scanning i3 ⁇ 4 calorimetry
  • the crystalline anhydrate of Neratinib is further characterized by thermogravi metric analysis (TGA), having a TGA pattern substantially as depicted in Figure 21.
  • TGA thermogravi metric analysis
  • the invention provides a process for preparation of crystalline anhydrate of Neratinib, comprising the steps of:
  • the solvent employed in step (i) is selected from halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and 3a t-butyl alcohol; ketones such as acetone, ethyl methyl ketone, diethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n- butyl acetate and t-butyl acetate; ethers such as anisole, diethyl ether, dimethyl ether, di isopropyl ether, methyl t- butyl ether and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; water
  • the preferred solvent of step (i) is anisole
  • step (i) is carried out at a temperature of about 20eC to about 100eC, preferably at about 50eC to about 90eC and more preferably at a temperature of about tft 25eC to about 80eC.
  • Isolation of crystalline anhydrate of Neratinib in step (iii) is accomplished, for example, by filtration, substantially removing the solvent by evaporation at ambient temperature, concentrating the solution or distillation of solvent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising novel solvated and anhydrates of Neratinib and at least one pharmaceutically acceptabl e exci pi ent or carri er.
  • exci pi ent or " pharmaceutically acceptable exci pient_ means a component of a pharmaceutical product that is not an active i ngredient and includes but not limited to fil ler, diluent disintegrants, glidants, stabilizers, surface active agents etc.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.
  • the crystalline Neratinib solvates and the crystalli ne anhydrate of the present invention 3 ⁇ 4 can be formulated into various pharmaceutical compositions l ike powder, granules, capsules, tablets, pellets etc. for the treatment of cancers, including non-smal l cell lung cancer (NSC LC), breast cancer, polycystic kidney disease, colonic polyps, and stroke in mammals.
  • NSC LC non-smal l cell lung cancer
  • breast cancer breast cancer
  • polycystic kidney disease colonic polyps
  • stroke in mammals including stroke in mammals.
  • composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like.
  • the composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art.
  • compositions may be utilized as required for conversion of the Neratinib solvates into the final pharmaceutical dosage forms and include, for example, any one or more of dil uents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical , dosage form preparati ons.
  • X R PD X -ray powder diffraction spectrum
  • Thermogravi metric analysis was performed using a Pyris 1 TGA PE RKIN E L M E R measurement unit 2-5 nrg samples were placed in open Platinum pans and heated from ⁇ 3a 25 eC to 300 eC i n a dry nitrogen atmosphere at a heati ng rate of 10 eC/mi n. 3) Differential Scanning Calorimetry
  • Neratinib (0.5 mg) was dissolved in DCM (1 ml; 2v) at ambient temperature and kept for si ow evaporati on for three days at ambi ent temperature. T hereafter the wet cake was dri ed under vacuum at 25eC to afford 0.3g of crystalline DCM solvate of Neratinib.
  • the obtained solid was Characterized by X R PD (figurel); DSC (figure 2); TGA (figure 3).
  • Neratinib (0.5g) was dissolved in ethyl acetate (15ml; 30v) at 75eC and kept for slow evaporation for three days at ambient temperature. Thereafter the wet cake was dried under vacuum at 25eC to afford 0.3g of crystalline ethyl acetate solvate of Neratinib.
  • the obtained solid was Characterized by X R PD (figure 4); DSC (figure 5); TGA (figure 6). , E xample 3
  • Neratinib (0.5g) was dissolved in methanol (7.5ml; 15v) at 60eC. T hereafter the solution was kept for slow evaporation for three days at ambient temperature. Thereafter the wet cake was dried under vacuum at 25eC to afford 0.4 g of crystalline methanol solvate of i3 ⁇ 4 Neratinib.
  • the obtained sol id was Characterized by X RPD (figure 7); DSC (figure 8);
  • Neratinib (1 gm) was sl urried in acetone (20ml; 20v) for two days at ambient 3 ⁇ 4 temperature. Thereafter the reaction mixture was filtered and dried at 25eC under vacuum to afford 0.6 g of crystalline acetone solvate of Neratinib.
  • the obtained solid was characterized by X R PD (figure 10); DSC (figure 11); TGA (figure 12).
  • Neratinib (1gm) was dissolved in anisole (6ml; 6v) at 70eC and the solution was kept for si ow evaporati on for four days at ambi ent temperature. T hereafter the wet cake was dri ed at 25eC under vacuum to afford 0.8 gm of crystalli ne anhydrate of Neratinib.
  • the i3 ⁇ 4 obtained solid was characterized by X R PD (figure 19); DSC (figure 20); TGA (figure 21).

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Abstract

La présente invention concerne de nouvelles formes cristallines de nératinib et des procédés de préparation correspondants. Le nératinib, selon l'invention, est un inhibiteur de tyrosine kinase de formule (I), portant le nom chimique (2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl)méthoxy]phényl]amino]-3-cyano-7-éthoxyquinolin-6-yl]-4-(diméthylamino)but-2-énamide.
PCT/IB2018/052535 2017-04-11 2018-04-11 Formes cristallines de nératinib et leur procédé de préparation Ceased WO2018189695A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2702930A1 (fr) * 2007-10-17 2009-04-23 Wyeth Llc Sels maleates de (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide 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
CA2702930A1 (fr) * 2007-10-17 2009-04-23 Wyeth Llc Sels maleates de (e)-n-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide 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

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