WO2016027243A1

WO2016027243A1 - Novel solid state forms of afatinib dimaleate

Info

Publication number: WO2016027243A1
Application number: PCT/IB2015/056315
Authority: WO
Inventors: Srividya Ramakrishnan; Vishweshwar Peddy; Sudarshan MAHAPATRA; Sundara Lakshmi Kanniah; Ramanaiah CHENNURU; Jithin Jose; Yogesh Mohanrao DHAGE; Subba Reddy Peddireddy; Sesha Reddy Yarraguntla; Sherial RAGHUVEER; Srinivasa Rao KOLLA; Shivani ANIL KSHIRSAGAR; Latif JAFAR SHAIKH; Srinivasulu BANDARU
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2014-08-21
Filing date: 2015-08-20
Publication date: 2016-02-25

Abstract

The present application provides novel solid state forms of Afatinib di-maleate, processes for preparing them, and pharmaceutical compositions containing them.

Description

NOVEL SOLID STATE FORMS OF AFATINIB DIMALEATE

INTRODUCTION

The present application relates to novel solid state forms of afatinib dimaleate, methods of their preparation and the use thereof.

The drug compound having the adopted name afatinib dimaleate, has a chemical name N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1 :2), and is represented by structure of formula I

Formula I

Afatinib dimaleate is an anticancer protein kinase inhibitor indicated for treatment of non-small-cell lung cancer. Process for preparation of afatinib, afatinib dimaleate and intermediates useful in preparation of afatinib dimaleate are described in US Patent Nos. 7,019,012; 8,426,586 and 7,960,546.

US Patent No. 8,426,586 discloses crystalline Form A of afatinib dimaleate salt and processes for preparation thereof. US Patent Application Publication No. 20140051713 discloses crystalline Form B of afatinib dimaleate salt and processes for preparation thereof. PCT Application Publication No. 2013052157 discloses crystalline Form C, Form D and Form E of afatinib dimaleate salt and processes for preparation thereof. The PCT publication also discloses crystalline Form A, B, C and Form D of afatinib base.

Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof 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 available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms of Afatinib di-maleate.

SUMMARY

The present application also encompasses the use of novel solid state forms of Afatinib di-maleate provided herein, for the preparation of other afatinib salts, other solid state forms of afatinib dimaleate, and formulations thereof.

The present application also encompasses the use of any one of the novel solid state forms of Afatinib di-maleate disclosed herein for the preparation of a medicament, preferably for the treatment of cancer, particularly for the treatment of cancers mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases. The present invention further provides a pharmaceutical composition comprising any one of the Afatinib di-maleate crystalline forms of the present invention and at least one pharmaceutically acceptable excipient.

The present application also provides a method of treating cancer, comprising administering a therapeutically effective amount of at least one of the Afatinib di- maleate novel solid state forms of the present application, or at least one of the above pharmaceutical compositions to a person suffering from cancer, particularly a person suffering from a cancer mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including but not limited to NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is powder X-ray power diffraction pattern of an amorphous form of afatinib dimaleate prepared according to Example 1 .

Figure 2 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of afatinib dimaleate and hydroxy propyl methyl cellulose (HPMC-AS) prepared according to Example 2.

Figure 3 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of afatinib dimaleate and hydroxy propyl methyl cellulose (HPMC-15 CPS) prepared according to Example 3.

Figure 4 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of afatinib dimaleate and PVP-K30 prepared according to Example 4. Figure 5 is powder X-ray power diffraction pattern of amorphous solid dispersion comprising Afatinib dimaleate and Copovidone (1 :1 w/w) prepared according to Example 6.

Figure 6 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of Afatinib dimaleate, Copovidone and Microcrystalline cellulose (1 :1 :1 w/w/w/) prepared according to Example 6.

Figure 7 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of Afatinib dimaleate, Copovidone and colloidal silicon dioxide (1 :1 :1 w/w/w/) prepared according to Example 6.

Figure 8 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of Afatinib dimaleate, PVP-K30 and Microcrystalline cellulose (1 :1 :1 w/w/w/) prepared according to Example 7. Figure 9 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of Afatinib dimaleate, PVP-K30 and colloidal silicon dioxide (1 :1 :1 w/w/w/) prepared according to Example 7.

Figure 10 is powder X-ray power diffraction pattern of a solid dispersion comprising an amorphous form of Afatinib dimaleate and Eudragit (1 :1 w/w) prepared according to Example 10.

Figure 1 1 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising Afatinib dimaleate and methyl cellulose (1 :1 w/w) prepared according to Example 1 1 .

Figure 12 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising Afatinib dimaleate and methyl cellulose (1 :1 w/w) prepared according to Example 12.

Figure 13 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising Afatinib dimaleate, PVP-K30 and syloid (1 :1 :1 w/w/w) prepared according to Example 13.

Figure 14 is powder X-ray power diffraction pattern of an amorphous solid dispersion comprising Afatinib dimaleate, copovidone and syloid (1 :1 :1 w/w/w) prepared according to Example 14.

Figure 15 shows an X-ray powder diffractogram of Afatinib di-maleate Form I prepared according to the process exemplified in example-15.

Figure 16 shows an X-ray powder diffractogram of Afatinib di-maleate Form II prepared according to the process exemplified in example-16.

Figure 17 shows an X-ray powder diffractogram of Afatinib di-maleate Form III prepared according to the process exemplified in example-17.

Figure 18 shows an X-ray powder diffractogram of Afatinib di-maleate Form IV prepared according to the process exemplified in example-21 .

Figure 19 shows an X-ray powder diffractogram of Afatinib dimaleate Form V prepared according to the process exemplified in example-22.

Figure 20 shows an X-ray powder diffractogram of Afatinib dimaleate Form VI prepared according to the process exemplified in example-24. Figure 21 shows an X-ray powder diffractogram of Afatinib di-maleate Form VII prepared according to the process exemplified in example-25.

Figure 22 shows an X-ray powder diffractogram of Afatinib di-maleate Form VIII prepared according to the process exemplified in example-26.

Figure 23 shows an X-ray powder diffractogram of Afatinib di-maleate Form IX prepared according to the process exemplified in example-27.

Figure 24 shows an X-ray powder diffractogram of Afatinib di-maleate Form X prepared according to the process exemplified in example-28.

Figure 25 shows an X-ray powder diffractogram of Afatinib dimaleate Form XI prepared according to the process exemplified in example-29.

Figure 26 shows an X-ray powder diffractogram of Afatinib dimaleate Form XII prepared according to the process exemplified in example-30.

Figure 27 shows an X-ray powder diffractogram of Afatinib di-maleate Form XIII prepared according to the process exemplified in example-31 .

Figure 28 shows an X-ray powder diffractogram of Afatinib di-maleate Form XIV prepared according to the process exemplified in example-32.

Figure 29 shows an X-ray powder diffractogram of Afatinib di-maleate Form XV prepared according to the process exemplified in example-33.

Figure 30 shows an X-ray powder diffractogram of Afatinib di-maleate Form XVI prepared according to the process exemplified in example-34.

Figure 31 shows an X-ray powder diffractogram of Afatinib dimaleate Form XVII prepared according to the process exemplified in example-35.

Figure 32 shows an X-ray powder diffractogram of Afatinib dimaleate Form XVIII prepared according to the process exemplified in example-36.

Figure 33 shows an X-ray powder diffractogram of Afatinib di-maleate Form XIX prepared according to the process exemplified in example-37.

Figure 34 shows an X-ray powder diffractogram of Afatinib di-maleate Form XX prepared according to the process exemplified in example-38.

Figure 35 shows an X-ray powder diffractogram of Afatinib di-maleate Form XXI prepared according to the process exemplified in example-39. Figure 36 shows an X-ray powder diffractogram of Afatinib di-maleate Form XXII prepared according to the process exemplified in example-40.

Figure 37 shows an X-ray powder diffractogram of Afatinib dimaleate Form XXIII prepared according to the process exemplified in example-41 .

Figure 38 shows an X-ray powder diffractogram of Afatinib di-maleate Form A prepared according to the process exemplified in example-42.

Figure 39 shows an X-ray powder diffractogram of Afatinib base prepared according to the process exemplified in example-46.

DETAILED DESCRIPTION

Afatinib or its dimaleate salt which may be used as the input in the process for preparation of the solid states of the present application can be prepared by any process known in the art.

In the first embodiment, the present application provides amorphous form of afatinib dimaleate.

In the second embodiment, the present application provides amorphous form of afatinib dimaleate characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 1 .

In the third embodiment, the present application provides a process for preparing amorphous form of afatinib dimaleate, comprising

a) providing a solution of afatinib dimaleate in a solvent or a mixture solvents; b) removing solvent from a solution of afatinib dimaleate obtained in step a); and c) recovering amorphous form of afatinib dimaleate.

Providing a solution in step a) includes:

i) direct use of a reaction mixture containing afatinib dimaleate that is obtained in the course of its synthesis; or

ii) direct use of reaction mixture containing afatinib dimaleate that is obtained by treating afatinib with maleic acid; or

iii) dissolving afatinib dimaleate in a solvent.

Any physical form of afatinib dimaleate may be utilized for providing the solution of afatinib dimaleate in step (a). Suitable solvents which can be used for dissolving the dimaleate salt of afatinib include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; and any mixtures of two or more thereof.

After dissolution in step (a), the obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.

Step (b) involves removing solvent from a solution of afatinib dimaleate.

Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art.

Step (c) involves recovering an amorphous form of afatinib dimaleate. The said recovery can be by using the processes known in the art.

The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the afatinib dimaleate is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

In the fourth embodiment, the present application provides a solid dispersion comprising an amorphous form of afatinib dimaleate and one or more pharmaceutically acceptable carriers.

Solid dispersion as used herein refers to the dispersion of one or more active ingredients in an inert excipient or matrix (carrier), where the active ingredients could exist in finely crystalline, solubilized or amorphous state (Sareen et al., 2012 and Kapoor et al., 2012). Solid dispersion consists of two or more than two components, generally a carrier polymer and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it required very less external energy to dissolve.

In the fifth embodiment, the present application provides a solid dispersion comprising an amorphous form of afatinib dimaleate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 2.

In the sixth embodiment, the present application provides a process for preparing a solid dispersion comprising an amorphous form of afatinib dimaleate and one or more pharmaceutically acceptable carriers, comprising;

a) providing a solution of afatinib dimaleate and pharmaceutically acceptable carrier in a solution,

b) removing solvent from a solution obtained in step (a); and

c) recovering a solid dispersion comprising an amorphous form of afatinib dimaleate and one or more pharmaceutically acceptable carrier.

Providing a solution in step a) includes:

i) direct use of a reaction mixture containing afatinib dimaleate that is obtained in the course of its synthesis; or ii) direct use of a reaction mixture containing afatinib dimaleate that is obtained by treating afatinib with maleic acid; or

ii) dissolving afatinib dimaleate and pharmaceutically acceptable carrier in a solvent.

Any physical form of afatinib dimaleate may be utilized for providing the solution of afatinib dimaleate in step (a).

Suitable pharmaceutically acceptable carriers which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

An absorbent may also be necessary when the active ingredient is hygroscopic or formulation contains a hygroscopic ingredient, especially when absorption of moisture produces a cohesive powder that will not feed properly to the tablet press. In such instances use of an absorbent such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value.

Suitable solvents which can be used for dissolving the afatinib dimaleate include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n- propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; and any mixtures of two or more thereof.

After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step (b) involves removing solvent from a solution obtained in step (a);

Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other technique known in the art.

Step (c) involves recovering a solid dispersion comprising an amorphous form of afatinib dimaleate and one or more pharmaceutically acceptable carriers. The said recovery can be by using the processes known in the art.

The resulting compound obtained in step (c) may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the afatinib dimaleate is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours. In one embodiment the present invention provides a crystalline Form of Afatinib di-maleate, designated as Form I. Form I can be characterized by an X-ray powder diffraction pattern having peaks at about 5.23, 10.45, 1 1.53 and 25.70 ± 0.2 degrees two theta.

In another embodiment, crystalline Form I of Afatinib di-maleate can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 15.

In another embodiment, the present invention provides a process for preparation of crystalline Form I of afatinib dimaleate, comprising:

a) providing slurry of afatinib dimaleate in an aromatic hydrocarbon solvent, b) heating the slurry to reflux temperature,

c) cooling the slurry of step (b) to room temperature, and

d) isolating afatinib dimaleate Form I.

Providing slurry in step a) includes:

a) direct use of a reaction mixture containing afatinib dimaleate that is obtained in the course of its synthesis; or

b) any physical form of afatinib dimaleate can be utilized for providing the slurry of afatinib dimaleate.

The aromatic hydrocarbon solvent to be used is selected from toluene, xylene and any mixtures thereof.

Step (b) involves heating the slurry obtained in step (a) to reflux temperature. The slurry may be stirred for about 1 hour to about 10 hours at reflux temperature.

Step (c) involves gradually cooling the slurry obtained in step (b) to room temperature over a period of 1 hour and stirring the slurry at room temperature for about 5 hours.

Step (d) involves isolating afatinib dimaleate crystalline Form I. The Form I can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor. In another embodiment, the present invention provides a crystalline Form of Afatinib di-maleate, designated as Form II. Form II can be characterized an X-ray powder diffraction pattern having peaks at about 4.98, 9.58, 10.53, 14.81 , 15.79, 19.96, 20.60 and 23.48 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form-ll of Afatinib di-maleate can further be characterized by X-ray powder diffraction pattern having peaks at about 14.13, 22.54, 24.61 , and 28.40 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form-ll can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 16.

In another embodiment the present invention provides a process for preparation of crystalline Form II of afatinib dimaleate, comprising:

a) providing a slurry of afatinib dimaleate in ketone solvent,

b) optionally stirring the slurry obtained in step (a) at room temperature, and c) isolating afatinib dimaleate Form II from the slurry.

Providing slurry in step a) includes:

Suitable ketone solvents which can be used for preparing the afatinib dimaleate slurry are selected from acetone, ethyl methyl ketone, methyl isobutyl ketone, cyclohexanone and the like; or any mixtures of two or more thereof.

Step (b) involves stirring the slurry obtained in step (a) for about 10 minutes to about 20 hours.

Step (c) involves isolating afatinib dimaleate crystalline form II. The form II can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids.

The present invention provides a crystalline form of Afatinib di-maleate, designated as Form III. Form III can be characterized by an X-ray powder diffraction pattern having peaks at about 5.37, 5.63, 10.21 , 1 1 .28, 1 1 .76, 1 1 .97, 17.25 and 17.81 ± 0.2 degrees two theta. In another embodiment, the crystalline Form III of Afatinib di-maleate can be characterized by an X-ray powder diffraction pattern having peaks at about 6.53, 21 .68 and 24.87 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form I II can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 17.

In another embodiment the present invention provides a process for preparation of crystalline Form III of afatinib dimaleate, comprising:

a) providing a slurry of afatinib dimaleate in acetonitrile at below 10°C,

b) stirring the slurry of step (a) at below 10°C,

c) isolating afatinib dimaleate Form III from the slurry of step (b).

Step (a) involves providing slurry of afatinib dimaleate in acetonitrile. Afatinib dimaleate is added acetonitrile solvent at about 5°C to provide slurry.

Step (b) involves stirring the slurry of step (a) to about 10°C to about 0°C for about 12 hours.

Step (c) involves isolating afatinib dimaleate crystalline form III. The form III can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids.

Alternatively the crystalline Form III of afatinib dimaleate can be prepared by the process, comprising:

a) adding afatinib dimaleate to acetonitrile to provide a slurry,

b) heating the slurry to obtain a solution,

c) gradually cooling the solution of step (b) to about 40°C, and stirred for about 1 hour at 40°C,

d) further cooling the solution to about 5°C, and

e) isolating afatinib dimaleate Form III.

Step (a) involves providing slurry of afatinib dimaleate in acetonitrile. Afatinib dimaleate is added acetonitrile solvent to provide slurry.

Step (b) involves heating the slurry obtained in step (a) to reflux temperature. The reflux temperature can be maintained up to about 1 hour to get a clear solution.

Step (c) involves cooling the solution obtained in step (b) to 40°C, and stirred the solution at about 40°C for about 3 hours. Step (d) involves further gradually cooling the solution to 5°C over a period of 3 hours and stirring the slurry at 5° C for about 12 hours to get slurry.

Step (e) involves isolating afatinib dimaleate crystalline form III from the slurry of step (d). The form III can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids.

In another embodiment, the present invention provides a crystalline Form of Afatinib di-maleate, designated as Form IV. Form IV can be characterized by an X-ray powder diffraction having peaks at about 5.37, 10.21 , 13.56, 17.20, and 17.73 ± 0.2 degrees two theta.

In another embodiment, the crystalline Afatinib di-maleate Form IV can be characterized by an X-ray powder diffraction having peaks at about 1 1 .98, 21 .74, and 25.36 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form IV can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 18.

In another embodiment, the present invention provides a process for preparation of afatinib dimaleate Form IV, comprising:

a) adding afatinib dimaleate into acetonitrile to provide a slurry,

b) heating the slurry to reflux temperature to obtain a solution,

c) gradually cooling the step (b) solution to about 5°C, and

d) isolating afatinib dimaleate Form IV.

Step (b) involves heating the slurry obtained in step (a) to reflux temperature. The reflux temperature can be maintained up to 1 hour to get a clear solution.

Step (c) involves gradually cooling the solution obtained in step (b) to 5°C over a period of about 10-20 minutes and stirring the slurry at 5° C for about 2 hours.

Step (d) involves isolating afatinib dimaleate crystalline Form IV from the slurry of step (c). The Form IV can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation, the solid can optionally be washed with the solvent used in step a) to wash out residual mother liquor.

Alternatively, the Form IV can be prepared by a process comprising, slurrying afatinib dimaleate hydrate in an organic solvent for about 5 minutes to about 10 hours at room temperature and isolating the precipitation to afford afatinib dimaleate Form IV.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form V. Form V can be characterized by an X-ray powder diffraction having peaks at about 5.57, 1 1 .27, 1 1 .73, 17.21 , and 17.81 ± 0.2 degrees two theta.

In another embodiment, the crystalline form V of Afatinib di-maleate can be characterized by an X-ray powder diffraction pattern having peaks at about 6.63, 21 .64, and 24.83 ± 0.2 degrees two theta.

In another embodiment, the crystalline form V can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 19.

In another embodiment, the present invention provides a process for preparation of crystalline afatinib dimaleate Form V, which comprises:

a) combining afatinib dimaleate with acetonitrile at about 5°C,

b) stirring the slurry for about 20 to about 50 hours at 5°C, and

c) isolating afatinib dimaleate Form V.

The step (a) involves combining afatinib dimaleate with acetonitrile. Afatinib dimaleate is added to acetonitrile to form a slurry.

Step (b) involves stirring the slurry obtained in step (a) for about 20 hours to about 50 hours.

Step (c) involves isolating afatinib dimaleate crystalline form V from the slurry of step (b). The form V can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

In another embodiment, the present invention provides a process for preparation of crystalline afatinib dimaleate Form V, comprising (a) providing a solution of afatinib base in an organic solvent,

(b) adding maleic acid or a solution of maleic acid to the solution of step (a),

(c) stirring the mixture of step (b) at below 5°C, and

(d) isolating crystalline afatinib dimaleate Form V.

Suitable solvents which can be used for preparing the solution of afatinib base include but are not limited to: nitrile solvents such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; and any mixtures of two or more thereof. Optionally the solution may be heated to get complete dissolution and may be filtered through a hyflo bed to remove the undissolved particles.

Step (b) involves adding maleic acid to the solution of afatinib base. The maleic acid may be added by first dissolving in any solvent. The solvent may be same as the solvent used for preparing the solution of afatinib base. The amount of maleic acid to be used is generally within a range of from about 2 to 4 molar ratio relative to afatinib base.

Step (c) involves stirring the slurry obtained in step (b) for about 1 hour to about 20 hours at below 5°C.

Step (d) involves isolating afatinib dimaleate crystalline form V from the slurry of step (c). The form V can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form VI. Form VI can be characterized by an X-ray powder diffraction having peaks at about 5.59, 17.25, 21.39 and 23.77± 0.2 degrees two theta.

In another embodiment, the crystalline Form VI can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 20. In another embodiment, the present application provides a process for preparation of crystalline afatinib dimaleate Form VI comprising heating afatinib dimaleate Form V at about 50°C.

In another embodiment the present invention provides a crystalline Form of Afatinib di-maleate, designated as Form VII. Form VII can be characterized by an X-ray powder diffraction pattern having peaks at about 5.13, 9.95, 19.69 and 25.68 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form VII of Afatinib di-maleate can be further characterized by an X-ray powder diffraction pattern having peaks at about 13.44, 14.82, 17.20, 20.40, 22.71 and 24.10 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form VII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 21 .

In another embodiment, the present invention provides a crystalline Form of Afatinib di-maleate, designated as Form VIII. Form VIII can be characterized an X-ray powder diffraction pattern having peaks at about 5.27, 1 1 .63, 22.59 and 25.78 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form VIII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 22.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form IX. Form IX can be characterized by an X-ray powder diffraction pattern having peaks at about 5.02, 8.99, 9.34, 10.28, 1 1 .80, 19.99, 20.46, 22.75 and 27.78± 0.2 degrees two theta.

In another embodiment, the crystalline Form IX can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 23.

In another embodiment, the present invention provides a crystalline Form of Afatinib di-maleate, designated as Form X. Form X can be characterized by an X-ray powder diffraction having peaks at about 5.02, 9.74, 19.50, 20.28, 21 .49 and 24.55 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form X can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 24. In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XI. Form XI can be characterized by an X-ray powder diffraction having peaks at about 9.62, 10.35, 1 1 .60, 14.1 1 , 20.63 and 22.60 ± 0.2 degrees two theta.

In another embodiment, the crystalline form XI of Afatinib di-maleate can be further characterized by an X-ray powder diffraction pattern having peaks at about 13.27, 13.72, 19.1 1 , 21 .58 and 25.82 ± 0.2 degrees two theta.

In another embodiment, the crystalline form XI can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 25.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XII. Form XII can be characterized by an X-ray powder diffraction having peaks at about 5.14, 13.21 , 20.37, 21 .51 , 22.50 and 25.80 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 26.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XIII. Form XIII can be characterized by an X- ray powder diffraction having peaks at about 4.95, 5.81 13.52, 16.74, 19.55, 20.12, 22.38 and 25.55 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XIII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 27.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XIV. Form XIV can be characterized by an X- ray powder diffraction having peaks at about 4.99, 9.92, 21 .67, 25.45 and 27.94± 0.2 degrees two theta.

In another embodiment, the crystalline Afatinib di-maleate Form XIV can be further characterized by an X-ray powder diffraction having peaks at about 7.46, 14.85, 16.97 and 22.50 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XIV can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 28. In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XV. Form XV can be characterized by an X-ray powder diffraction having peaks at about 5.1 1 , 5.44, 10.26, 10.93, 20.65, and 21 .35 ± 0.2 degrees two theta.

In another embodiment, the crystalline Afatinib di-maleate Form XV can be further characterized by an X-ray powder diffraction having peaks at about 9.48, 1 1 .39, 18.90 and 25.47 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XV can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 29.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XVI. Form XVI can be characterized by an X- ray powder diffraction having peaks at about 3.89, 5.54, 6.21 , 8.77, 9.97 and 12.35 ± 0.2 degrees two theta.

In another embodiment, the crystalline Afatinib di-maleate Form XVI can be further characterized by an X-ray powder diffraction having peaks at about 14.98, 17.83 and 22.33 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XVI can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 30.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XVII. Form XVII can be characterized by an X- ray powder diffraction having peaks at about 5.51 , 1 1 .06, 16.67 and 19.59 ± 0.2 degrees two theta.

In another embodiment, the crystalline Afatinib di-maleate Form XVII can be further characterized by an X-ray powder diffraction having peaks at about 6.10, 8.65, 14.86 and 22.26 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XVII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 31 .

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XVIII. Form XVIII can be characterized by an X-ray powder diffraction having peaks at about 4.93, 5.53, 6.18, 9.97, 1 1 .07, 1 1 .39 and 14.09 ± 0.2 degrees two theta. In another embodiment, the crystalline Afatinib di-maleate Form XVIII can be further characterized by an X-ray powder diffraction having peaks at about 8.73, 12.36,

14.85 and 19.58 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XVIII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 32.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XIX. Form XIX can be characterized by an X- ray powder diffraction having peaks at about 3.94, 5.59, 6.23, 8.84, 10.05 and 1 1 .19 ± 0.2 degrees two theta.

In another embodiment, the crystalline Afatinib di-maleate Form XIX can be further characterized by an X-ray powder diffraction having peaks at about 1 1.53, 12.42 and 15.02 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XIX can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 33.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XX. Form XX can be characterized by an X-ray powder diffraction having peaks at about 5.18, 5.45, 10.36, 10.94, 15.52 and 20.75 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XX can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 34.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XXI. Form XXI can be characterized by an X- ray powder diffraction having peaks at about 5.40, 6.80, 7.94 and 25.46 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XXI can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 35.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XXII. Form XXII can be characterized by an X- ray powder diffraction having peaks at about 5.24, 7.86, 10.52, 1 1 .82, 15.83, 19.78 and

27.86 ± 0.2 degrees two theta. In another embodiment, the crystalline Form XXII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 36.

In another embodiment, the present invention provides a crystalline form of Afatinib di-maleate, designated as Form XXIII. Form XXIII can be characterized by an X-ray powder diffraction having peaks at about 5.72, 19.1 1 , 19.55, 20.30, 21 .61 , 22.77 and 28.37 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XXIII can be further characterized by an X-ray powder diffraction having peaks at about 9.25, 1 1 .23 and 17.36 ± 0.2 degrees two theta.

In another embodiment, the crystalline Form XXIII can be characterized by an X- ray powder diffraction pattern substantially as depicted in Figure 37.

The above crystalline Form VII to Form XX of afatinib dimaleate can be produced by the process comprising:

a) providing slurry of afatinib dimaleate in a solvent or a mixture of solvents, b) stirring the slurry at ambient temperature, and

c) isolating crystalline afatinib dimaleate.

Suitable solvents that can be used for preparing the afatinib dimaleate slurry include but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-Butanol, iso-Butanol, n-Pentanol, benzyl alcohol and the like; ethers such as diethyl ether, methyl ethyl ether, methyl isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1 ,4-Dioxane, cyclopentyl methyl ether and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; hydrocarbons such as n-Hexane cyclohexane, toluene, xylene and the like; ketones such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclohexanone, and the like; esters such methyl carbonate, ethylacetate, isopropyl acetate, butyl acetate and the like; amides such as dimethyl formamide, dimethyl acetamide, C C₄ carbonic acids such as formic acid, acetic acid, propionic acid and the like; nitriles such as, acetonitrile, propionitrile and the like; water, nitromethane and any mixtures of two or more thereof.

Step (b) involves stirring the slurry obtained in step (a) for about 1 hour to about 60 hours at about 0 °C to about reflux temperature of the solvent used. Step (c) involves isolating afatinib dimaleate crystalline Form. The crystalline afatinib dimaleate can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

The crystalline Afatinib di-maleate Form VII to Form XX can be prepared using the solvent given in the below table and using the procedure mentioned above.

The above crystalline Form XXI to Form XXIII of afatinib dimaleate can be produced by the process comprising:

a) providing a slurry or a solution of afatinib base in a solvent or a mixture of solvents,

b) adding maleic acid or a solution of maleic acid to the slurry or solution of step (a), and

c) isolating crystalline afatinib dimaleate. Suitable solvents that can be used for preparing the slurry or solution of afatinib base include but are not limited to: ethers such as diethyl ether, methyl ethyl ether, methyl isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1 ,4-Dioxane, cyclopentyl methyl ether and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; hydrocarbons such as n-Hexane cyclohexane, toluene, xylene and the like; ketones such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclohexanone, and the like; and any mixtures of two or more thereof.

Step (b) involves adding maleic acid or a solution of maleic acid to the solution or slurry of step (a) and stirring the resulted mixture for about 1 hour to about 60 hours at about 0 °C to about reflux temperature of the solvent used.

Step (c) involves isolating afatinib dimaleate crystalline Form. The crystalline afatinib dimaleate can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

The crystalline Afatinib di-maleate Form XXI can be prepared using n-Hexane using the procedure mentioned above.

The crystalline Afatinib di-maleate Form XXII can be prepared using Dichloromethane using the procedure mentioned above.

The crystalline Afatinib di-maleate Form XXI II can be prepared using acetone using the procedure mentioned above.

In another embodiment, the present invention provides a process for preparation of crystalline afatinib dimaleate Form A, comprising

(a) providing a solution of afatinib base in a suitable solvent,

(c) optionally heating the mixture, and

(d) isolating crystalline afatinib dimaleate Form A.

Providing a solution of afatinib base in a suitable solvent in step (a) includes: (i) direct use of a reaction mixture containing afatinib base that is obtained in the course of its synthesis; or

(ii) any physical form of afatinib base can be utilized for providing the solution of afatinib base.

The solvent that can be used for preparing the solution of afatinib base include but are not limited to a ketone solvent such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclohexanone, and the like; a nitrile solvent acetonitrile, propionitrile, and the like; an ester solvent such as methyl carbonate, ethylacetate, isopropyl acetate, butyl acetate and the like. The solution of step (a) may be heated to about 50°C to 100°C.

Step (b) involves adding maleic acid or a solution of maleic acid to the solution obtained in step (a). Optionally maleic acid is added in the form of a solution. The solvent to be used to make the maleic acid solution is same as the solvent used to make afatinib base solution. The amount of maleic acid to be used is generally within a range of from about 2 to 4 molar ratio relative to afatinib base. The resulted mixture is stirred for about 1 hour to about 60 hours and the mixture may be heated to about 50°C to about reflux temperature of the solvent used.

Step (d) involves isolating afatinib dimaleate crystalline Form A. The crystalline afatinib dimaleate Form A can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step (a) to wash out residual mother liquor.

In an aspect, afatinib dimaleate may have a D₉₀ particle size of less than about 200 μιη, or less than about 150 μιη, or less than about 100 μιη, or less than about 90 μιη, or less than about 80 μιη, or less than about 60 μιη, or less than about 50 μιη, or less than about 40 μιη, or less than about 30 μιη, or less than about 20 μιη, or less than about 10 μιη, or less than about 5 μιη, or any other suitable particle sizes.

Particle size distributions of afatinib dimaleate particles may be measured using any techniques known in the art. For example, particle size distributions of afatinib dimaleate particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom.

The crystalline Form A can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 38.

In another embodiment, the present invention provides a crystalline Form I of Afatinib base, designated as Form I. Form I of afatinib base can be characterized by an X-ray powder diffraction having peaks at about 4.82, 6.78, 15.1 1 , 17.86, 21 .00, 22.84, and 25.90 ± 0.2 degrees two theta.

In another embodiment, the crystalline afatinib base Form I can be further characterized by an X-ray powder diffraction having peaks at about 10.70, 18.03, 19.13, and 26.58 ± 0.2 degrees two theta.

In another embodiment, the crystalline afatinib base Form I can be characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 39.

The crystalline afatinib base Form I can be produced by the process comprising:

(a) providing slurry of afatinib base in a solvent or a mixture of solvents,

(b) stirring the slurry at ambient temperature, and

(c) isolating crystalline form I of afatinib base.

Suitable solvents that can be used for preparing the afatinib base slurry include but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n- Butanol, iso-Butanol, n-Pentanol, benzyl alcohol and the like; ethers such as diethyl ether, methyl ethyl ether, methyl isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1 ,4-Dioxane, cyclopentyl methyl ether and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; hydrocarbons such as n-Hexane cyclohexane, toluene, xylene and the like; ketones such as acetone, ethyl methyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclohexanone, and the like; esters such methyl carbonate, ethylacetate, isopropyl acetate, butyl acetate and the like; amides such as dimethyl formamide, dimethyl acetamide, CrC₄ carbonic acids such as formic acid, acetic acid, propionic acid and the like; nitriles such as, acetonitrile, propionitrile and the like; water, nitromethane and any mixtures of two or more thereof. Step (b) involves stirring the slurry obtained in step (a) for about 1 hour to about 60 hours at about 0 °C to about reflux temperature of the solvent used.

Step (c) involves isolating afatinib base crystalline Form I. The crystalline afatinib base Form I can be isolated from the slurry using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

The above solid state forms of Afatinib base and Afatinib di-maleate can be used to prepare 1 ) Afatinib dimaleate and solid state forms thereof; 2) other Afatinib salts and solid state forms thereof; and 3) pharmaceutical formulations.

The present invention further encompasses 1 ) a pharmaceutical composition comprising any one of Afatinib di-maleate crystalline forms, as described above, and at least one pharmaceutically acceptable excipient; and 2) the use of any one or combination of the above-described crystalline forms of Afatinib di-maleate, in the manufacture of a pharmaceutical composition, and 3) a method of treating a solid tumor such as NSCLC, breast, head and neck cancer, and a variety of other cancers, comprising administration of an effective amount of a pharmaceutical composition comprising any one or more of the forms of Afatinib di-maleate described herein.

Solid states of afatinib dimaleate of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1 .541 A, and were obtained using a PanAlytical, Powder X-ray Diffractometer.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .

"Amorphous form" as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "C1 -C6 alcohols" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of "Cs-Cs aliphatic or aromatic hydrocarbons" include, but are not limited to, isopentane, neopentane, isohexane, 3- methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3- ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C₃-C₆ esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms. "C₂-C₆ ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2- ethoxyethanol, anisole, or the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A "ketone" is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C₃-C₆ ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A "nitrile" is an organic compound containing a cyano -(C≡N) bonded to another carbon atom. "C₂-C₆ Nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES

Example 1 : Preparation of amorphous form of afatinib dimaleate.

2.0 g of afatinib dimaleate was dissolved in 80 mL of a mixture of methanol and acetone (3:1 ) at 26°C and stirred for 15 min. The solution was filtered to remove the undissolved particles and the filtrate was distilled under reduced pressure at 50°C. After distillation the solid was dried under vacuum at 45°C to get 1 .29 g of amorphous afatinib dimaleate. PXRD pattern: Fig. 1 .

Example 2: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and hydroxy propyl methyl cellulose (HPMC-15 CPS).

Afatinib dimaleate (1 .0 g) and HPMC-15 CPS (1 .0 g) was dissolved in 70 mL of a mixture of methanol and acetone (3:1 ) and stirred for 10 min at 28°C. The resultant reaction mass solvent was completely evaporated under reduced pressure at 55°C. Separated solid was dried to afford 1 g of title compound. PXRD pattern: Fig. 2.

Example 3: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and hydroxy propyl methyl cellulose (HPMC-AS).

Afatinib dimaleate (1 .0 g) and HPMC-AS (1 .0 g) was dissolved in 70 mL of a mixture of methanol and acetone (3:1 ) and stirred for 10 min at 28°C. The resultant reaction mass solvent was completely evaporated under reduced pressure at 58°C. Separated solid was dried to afford 1 .1 g of the title compound. PXRD pattern: Fig. 3.

Example 4: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and PVP-K30.

Afatinib dimaleate (2.0 g) and PVP-K30 (2.0 g) was dissolved in 144 mL of a mixture of methanol and acetone (3:7) and stirred for 10 min at 28°C. The resultant reaction mass solvent was completely evaporated under reduced pressure at 55°C. Separated solid was dried to afford 3.1 g of the title compound. PXRD pattern: Fig. 4.

Example 5: Preparation of amorphous form of afatinib dimaleate.

Afatinib dimaleate (3.0 g) was dissolved in 240 ml_ of a mixture of methanol and acetone (1 :3) and stirred for 10 min at 26°C. The solution is filtered and the filtrate is evaporated by spray drying, using a Buchi® MINI Spray Dryer B-290 with Buchi® Inert Loop B-295, to afford 1 .8 g of amorphous afatinib dimaleate. PXRD pattern: Fig. 1 .

Parameters for the spray drier of the above experiment:

Aspirator: 65%; Feed rate: 25%; Inlet temperature: 60°C; Outlet temperature: 42°C. Example 6: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and copovidone.

Afatinib dimaleate crystalline Form A (5 g) and copovidone NF (5 g) and methanol (130 ml_) were charged into a round bottom flask and the resulted mixture was heated to 60°C and stirred for 15 min at 60°C. The mass was filtered and the clear solution was completely concentrated under reduced pressure at 55°C. Separated solid was dried to afford 8.2 g of the title compound. PXRD pattern: Fig. 5; Purity: 98.58%.

3 sample taken and exposed to air in fume hood as mentioned in the below table.

Example 7: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and PVP-K30.

Afatinib dimaleate Form A (2.5 g), PVP-K30 (2.5 g) and methanol (70 mL) were charged into a round bottom flask and the mass was heated to 52°C and stirred for 15 minutes. The resultant reaction mass was filtered and the clear solution was concentrated completely under reduced pressure at 58°C. Separated solid was dried to afford 4.1 g of the title compound. PXRD pattern: Fig. 4; Purity: 98.58% by HPLC

3 sample taken and exposed to air in fume hood as mentioned in the below table.

Example 8: Preparation of a solid dispersion of amorphous form of afatinib dimaleate, copovidone and microcrystalline cellulose.

Afatinib dimaleate crystalline (2 g) and copovidone NF (2 g) and methanol (40 mL) were charged into a round bottom flask and the resulted mixture was heated to 55°C and stirred for 1 5. Microcrystalline cellulose (2 g) and methanol (100 mL) were added to the clear solution and stirred for 1 hour at 55°C. The hazy solution was filtered and the clear solution was completely concentrated under reduced pressure at 55°C. Separated solid was dried to afford 8.2 g of the title compound. PXRD pattern: Fig. 5; Purity: 98.58%. 0.5 g of sample taken and exposed to air in fume hood at 23°C for 20 hours. PXRD pattern: Fig. 6. Example 9: Preparation of a solid dispersion of amorphous form of afatinib dimaleate, copovidone and colloidal silicon dioxide.

Afatinib dimaleate crystalline (2 g) and copovidone NF (2 g) and methanol (40 mL) were charged into a round bottom flask and the resulted mixture was heated to 55°C and stirred for 15 minutes. Colloidal silicon dioxide (2 g) and methanol (20 mL) were added to the clear solution and stirred for 1 hour at 55°C. The clear solution was filtered and the clear solution was completely concentrated under reduced pressure at 55°C. Separated solid was dried to afford 8.2 g of the title compound. PXRD pattern: Fig. 5; Purity: 98.29%. 0.5 g of sample taken and exposed to air in fume hood at 23°C for 20 hours. PXRD pattern: Fig. 7; Moisture: 3.6%.

Example 10: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and Eudragit.

Afatinib dimaleate (2 g) and methanol (40 mL) were charged into a round bottom flask and the mass was heated to 54°C and stirred for 15 minutes. Eudragit EPO (2 g) was added to the clear solution and the resultant reaction mass was filtered and the clear solution was concentrated completely under reduced pressure at 60°C. Separated solid was dried to afford 3.23 g of the title compound. PXRD pattern: Fig. 10; Purity: 95.47% by HPLC. 0.5 g of sample taken and exposed to air in fume hood at 23°C for 6 hours. PXRD pattern: Fig. 10; Moisture: 3.85%.

Example 11 : Preparation of a solid dispersion of amorphous form of afatinib dimaleate and methyl cellulose.

Afatinib dimaleate (2 g) and methanol (40 mL) were charged into a round bottom flask and the mass was heated to 55°C and stirred for 15 minutes. Methyl cellulose (2 g) was added to the clear solution and the resultant reaction mass was filtered and the clear solution was concentrated completely under reduced pressure at 62°C. Separated solid was dried to afford 3.31 g of the title compound. PXRD pattern: Fig. 1 1 ; Purity: 98.46% by HPLC. 0.5 g of sample taken and exposed to air in fume hood at 23°C for 6 hours. PXRD pattern: Fig. 1 1 ; Moisture: 4.6%.

Example 12: Preparation of a solid dispersion of amorphous form of afatinib dimaleate and an absorbent Afatinib dimaleate (0.5 g) and an absorbent (0.5 g) were mixed and blended vigorously and exposed to air at 60% RH. The results are tabulated below:

Example 13: Preparation of a solid dispersion of amorphous form of afatinib dimaleate, PVP-K30 and syloid.

Amorphous solid dispersion of afatinib dimaleate and PVP-K30 prepared in example 7 (0.5 g) was blended vigorously with syloid (0.25 g) and exposed to air at 60% RH for 5 hours. PXRD pattern: Fig. 1 3.

Example 14: Preparation of a solid dispersion of amorphous form of afatinib dimaleate, copovidone and syloid.

Amorphous solid dispersion of afatinib dimaleate and copovidone prepared in example 6 (0.5 g) was blended vigorously with syloid (0.25 g) and exposed to air at 60% RH for 5 hours. PXRD pattern: Fig. 14.

Example 15: Preparation of crystalline Form I of afatinib dimaleate.

Xylene (50 mL) and afatinib dimaleate (400 mg) were charged into a 1 00 mL EasyMax reactor. The slurry obtained was heated to 1 20°C and stirred for 1 hour. The slurry was gradually cooled to 25°C over a period of 1 hour and stirred for 30 minutes at 25°C. The precipitate was filtered at 25°C under vacuum.

Powder X-Ray diffractogram is shown in Figure 15.

Example 16: Preparation of crystalline Form II of afatinib dimaleate. Cyclohexanone (10 ml_) and afatinib dimaleate were charged into a 100 mL EasyMax reactor and the obtained slurry was cooled to 15°C. The slurry was stirred for 30 minutes at 15°C. The precipitate was filtered at 25°C under vacuum.

Powder X-ray diffractogram is shown in Figure 16.

Example 17: Preparation of crystalline Form III of afatinib dimaleate.

Acetonitrile (20 mL) was charged in 100 mL EasyMax reactor and cooled to 10°C.

Amorphous afatinib dimaleate (500 mg) was added and stirred for 12 hours at 10°C.

The precipitate was filtered at 25°C under vacuum.

Powder X-ray diffractogram is shown in Figure 17.

Example 18: Preparation of crystalline Form III of afatinib dimaleate.

Acetonitrile (100 mL) was charged in 100 mL EasyMax reactor and afatinib dimaleate

(500 mg) was added and the slurry obtained was heated to 80°C and stirred for 15 minutes. The clear solution obtained was cooled to 40°C and few crystals of afatinib dimaleate Form III (Form III prepared in example 17) was added and the resulted slurry was cooled to 5° C over a period of 3 hours. The precipitate was filtered under vacuum.

Example 19: Preparation of crystalline Form III of afatinib dimaleate.

Acetonitrile (100 mL) was charged in 100 mL EasyMax reactor and cooled to 5°C.

Afatinib dimaleate (1000 mg) was added and stirred for 12 hours at 5°C. The precipitate was filtered at 25°C under vacuum. The solid material was kept in vacuum tray dryer

(VTD) at 30°C for one hour.

Example 20: Preparation of crystalline Form IV of afatinib dimaleate.

Acetonitrile (100 mL) was charged in 100 mL EasyMax reactor and afatinib dimaleate (300 mg) was added and the obtained slurry was heated to 80°C. The solid was dissolved and the clear solution obtained was cooled to 5°C and stirred for about 2 hours. The precipitate was filtered at 25°C under vacuum

Example 21 : Preparation of crystalline Form IV of afatinib dimaleate.

Acetonitrile (100 mL) was charged in 100 mL EasyMax reactor and afatinib dimaleate (1000 mg) was added and the slurry obtained was stirred for 5 hours at 30°C. The slurry was filtered and material was dried under vacuum. The wet material was dried in an air tray dryer (ATD) at 50° C for 2 hours to provide 700 mg of crystalline afatinib dimaleate Form IV. Powder X-ray diffractogram is shown in Figure 18. Example 22: Preparation of crystalline Form V of afatinib dimaleate.

Acetonitrile (50 mL) was charged in 100 mL EasyMax reactor and cooled to 5°C.

Afatinib dimaleate (420 mg) was added and the slurry obtained was stirred for 40 hours at 5°C. The precipitate was filtered and the solid was dried under vacuum.

Powder X-ray diffractogram is shown in Figure 19.

Example 23: Preparation of crystalline Form V of afatinib dimaleate.

Afatinib base (2 g) and acetonitrile (30 mL) were charged into a 100 mL EasyMax reactor at 28°C and heated to 45° C and stirred for 15 minutes. The solution was filtered and the clear filtrate was charged into a 100 mL EasyMax reactor and cooled to 3°C.

Maleic acid solution (1 g of maleic acid was dissolved in 30 mL of acetonitrile) was added slowly over a period of 30 minutes. The precipitation was stirred for 18 hours at

5°C. The precipitation was heated to 28°C and stirred for 3 hours. The suspension was filtered using pressure nutsche filter (PNF) to yield 1 .3 g of afatinib dimaleate crystalline

Form V. Powder X-ray diffractogram is shown in Figure 19.

Example 24: Preparation of crystalline Form VI of afatinib dimaleate.

150 mg of afatinib dimaleate Form V prepared in example 22 was taken in a Petridish and was put in an air tray dryer for about 1 hour. Material was taken out and analyzed the powder X-ray diffraction. Powder X-ray diffractogram is shown in Figure 20.

Example 25: Preparation of crystalline Form VII of afatinib dimaleate.

Methyl tert-butyl ether (19.5 mL), acetic acid (0.5 mL) and afatinib dimaleate (500 mg) were charged into a 100 mL EasyMax reactor. The slurry obtained was stirred for 12

871 hours at 30°C. The precipitate was filtered under vacuum.

Powder X-Ray diffractogram is shown in Figure 21 .

Example 26: Preparation of crystalline Form VIII of afatinib dimaleate.

Methyl tert-butyl ether (19.5 mL), formic acid (0.5 mL) and afatinib dimaleate (500 mg) were charged into a 100 mL EasyMax reactor. The slurry obtained was stirred for 12 hours at 30°C. The precipitate was filtered under vacuum.

Powder X-ray diffractogram is shown in Figure 22.

Example 27: Preparation of crystalline Form IX of afatinib dimaleate. Afatinib dimaleate (500 mg) was slurried in 0.5 mL of dimethyl formamide(DMF) at RT in

HTS platform using 24 well plates for 24 hours. The solvent was evaporated at RT under vacuum for 5 hours. Powder X-ray diffractogram is shown in Figure 23

Example 28: Preparation of crystalline Form X of afatinib dimaleate.

Afatinib dimaleate (500 mg) was slurried in 0.5 mL of formic acid at RT in HTS platform using 24 well plates for 24 hours. The solvent was evaporated at RT under vacuum for

5 hours. Powder X-ray diffractogram is shown in Figure 24

Example 29: Preparation of crystalline Form XI of afatinib dimaleate.

Amorphous Afatinib dimaleate (100 mg) was slurried in 0.5 mL of cyclohexanone at 20°

C in HTS platform using 24 well plates for 72 hours. The solvent was evaporated at RT under vacuum for 5 hours. Powder X-ray diffractogram is shown in Figure 25

Example 30: Preparation of crystalline Form XII of afatinib dimaleate.

Amorphous Afatinib dimaleate (100 mg) was slurried in 0.5 mL of acetonitrile at 20° C in

HTS platform using 24 well plates for 72 hours. The solvent was evaporated at RT under vacuum for 5 hours. Powder X-ray diffractogram is shown in Figure 26.

Example 31 : Preparation of crystalline Form XIII of afatinib dimaleate.

Amorphous Afatinib dimaleate (100 mg) was slurried in 0.5 mL of 1 ,4-dioxane at 20° C in HTS platform using 24 well plates for 72 hours. The solvent was evaporated at RT under vacuum for 5 hours. Powder X-ray diffractogram is shown in Figure 27.

Example 32: Preparation of crystalline Form XIV of afatinib dimaleate.

Amorphous Afatinib dimaleate (100 mg) was slurried in 0.5 mL of nitromethane at 20° C in HTS platform using 24 well plates for 72 hours. The solvent was evaporated at RT under vacuum for 5 hours. Powder X-ray diffractogram is shown in Figure 28.

Example 33: Preparation of crystalline Form XV of afatinib dimaleate.

Afatinib dimaleate Form E (50 mg) was slurried in 0.4 mL of toluene at 50 °C in HTS platform using 24 well plates for 15 hours. The solvent was evaporated at 50 °C under vacuum for 2 hours. Powder X-ray diffractogram is shown in Figure 29

Example 34: Preparation of crystalline Form XVI of afatinib dimaleate.

Afatinib dimaleate Form E (50 mg) was slurried in 0.4 mL of n-Butyl Acetate at 50 °C in

HTS platform using 24 well plates for 15 hours. The solvent was evaporated at 50 °C under vacuum for 2 hours. Powder X-ray diffractogram is shown in Figure 30 Example 35: Preparation of crystalline Form XVII of afatinib dimaleate.

Afatinib dimaleate Form E (50 mg) was slurried in 0.4 mL of xylene at 50 °C in HTS platform using 24 well plates for 15 hours. The solvent was evaporated at 50 °C under vacuum for 2 hours. Powder X-ray diffractogram is shown in Figure 31

Example 36: Preparation of crystalline Form XVIII of afatinib dimaleate.

Afatinib dimaleate Form E (50 mg) was slurried in 0.3 mL of dimethyl carbonate at 50 °C in HTS platform using 24 well plates for 15 hours. The solvent was evaporated at 50 °C under vacuum for 2 hours. Powder X-ray diffractogram is shown in Figure 32.

Example 37: Preparation of crystalline Form XIX of afatinib dimaleate.

Afatinib dimaleate Form E (50 mg) was slurried in 0.4 mL of cyclopentyl methyl ether

(CPME) at 50 °C in HTS platform using 24 well plates for 15 hours. The solvent was evaporated at 50 °C under vacuum. Powder X-ray diffractogram is shown in Figure 33.

Example 38: Preparation of crystalline Form XX of afatinib dimaleate.

Afatinib dimaleate Form E (50 mg) was slurried in 0.4 mL of water. The slurry was cooled to 10 °C and stirred for 15 hours at 10 °C in HTS platform. The solvent was evaporated at 10 °C under vacuum. Powder X-ray diffractogram is shown in Figure 34.

Example 39: Preparation of crystalline Form XXI of afatinib dimaleate.

Afatinib free base (50 mg) was dispensed in to 0.4 mL of n-Hexane at 50 °C in HTS platform. Stock solution (0.2 ml) of methanol containing two molar ratio of maleic acid

(23.9 mg of maleic acid in 0.2 mL of methanol) is dispensed at 50 °C and vortexed for

18 hours. The solvent was evaporated at 50 °C under vacuum. Powder X-ray diffractogram is shown in Figure 35.

Example 40: Preparation of crystalline Form XXII of afatinib dimaleate.

Afatinib free base (50 mg) was dispensed in to 0.4 mL of DCM at 50 °C in HTS platform. Stock solution (0.2 mL) of methanol containing two molar ratio of maleic acid (23.9 mg of maleic acid in 0.2 mL of methanol) is dispensed at 50 °C and vortexed for 18 hours. The solvent was evaporated at 50 °C under vacuum. Powder X-ray diffractogram is shown in Figure 36.

Example 41 : Preparation of crystalline Form XXIII of afatinib dimaleate.

1 g of afatinib base and acetone (15 mL) were charged into a 200 mL round bottom flask at 30 °C and heated to 65° C. Maleic acid (525 mg of maleic acid in 15 mL of acetone) was added to the resulted solution over a period of 10 minutes. The reaction mixture was stirred for 1 hour at 65 °C. The reaction mixture was cooled to 40 °C and stirred for 30 minutes. The resulted suspension was filtered and the wet solid was washed with acetone (5 mL) and suck dried under vacuum. Material was taken out and analyzed the purity and powder X-ray diffraction. Purity: 99.14%

Powder X-ray diffractogram is shown in Figure 37.

Example 42: Preparation of crystalline Form A of afatinib dimaleate.

Afatinib base (10 g) and acetonitrile (150 mL) were charged into a 500 mL round bottom flask at 30 °C and heated to 70° C and stirred for 15 minutes. The solution was filtered and the clear filtrate was charged into a 1000 mL round bottom flask and heated to 70°C. Maleic acid solution (5 g of maleic acid was dissolved in 150 mL of acetonitrile) was added slowly over a period of 30 minutes. The precipitation was cooled to 45°C and stirred for 2 hours. The precipitation was filtered and wet cake was dried in a vacuum tray dryer at 35°C for 20 hours to yield 9.5 g of afatinib dimaleate crystalline Form A. Purity: 96.49%; Moisture: 2.89%; PXRD is shown in Figure 38.

Example 43: Preparation of crystalline Form A of afatinib dimaleate.

Afatinib base (2 g) and methyl ethyl ketone (40 mL) were charged into a 100 mL round bottom flask at 25°C and heated to 40° C and stirred for 15 minutes. The solution was filtered and the clear filtrate was charged into a 100 mL round bottom flask and heated to 40°C. Maleic acid solution (1 g of maleic acid was dissolved in 20 mL of methyl ethyl ketone) was added slowly over a period of 30 minutes. The precipitation was stirred for 2 hours at 40°C. The precipitation was filtered at 28°C and the wet cake was dried under vacuum at 35°C for 4 hours to yield 2 g of afatinib dimaleate crystalline Form A. Purity: 99.31 %; PXRD is shown in Figure 38.

Example 44: Preparation of crystalline Form A of afatinib dimaleate.

Afatinib base (2 g) and acetone (40 mL) were charged into a 100 mL round bottom flask at 25°C and heated to 37° C and stirred for 15 minutes. The solution was filtered and the clear filtrate was charged into a 100 mL round bottom flask and heated to 50°C. Maleic acid solution (1 g of maleic acid was dissolved in 20 mL of acetone) was added slowly over a period of 30 minutes. The precipitation was stirred for 2 hours at 45°C. The precipitation was filtered at 28°C and the wet cake was dried under vacuum at 35°C for 7 hours to yield 2.1 g of afatinib dimaleate crystalline Form A. Purity: 99.68% by HPLC; Moisture: 2.46%; Acetone: 44.3ppm by GC; PXRD is shown in Figure 38.

Example 45: Preparation of crystalline Form A of afatinib dimaleate.

Afatinib base (2 g) and ethylacetate (40 mL) were charged into a 100 mL round bottom flask at 25°C and heated to 41 ° C and stirred for 15 minutes. The solution was filtered and the clear filtrate was charged into a 100 mL round bottom flask and heated to 62°C. Maleic acid solution (1 g of maleic acid was dissolved in 40 mL of ethylacetate) was added slowly over a period of 30 minutes. The precipitation was stirred for 3 hours at 60°C. The precipitation was filtered at 28°C and the wet cake was dried under vacuum at 35°C for 8 hours to yield 2.1 g of afatinib dimaleate crystalline Form A. Purity: 99.65% by HPLC; Moisture: 1 .28%; Ethylacetate: 107.9 ppm by GC; PXRD is shown in Figure 38.

Example 46: Preparation of crystalline Form I of afatinib base.

Afatinib base (94 g) and acetonitrile (940 mL) were charged into a 2000 mL round bottom flask at 30 °C and stirred for 15 minutes. The mixture was heated to 50°C and stirred for 30 minutes. The clear solution was cooled to 0°C and stirred for 30 minutes. The resulted suspension was filtered and the solid was suck dried under vacuum for 30 minutes to yield 78 g of crystalline afatinib base Form I. PXRD is shown in Figure 39. Example 47: Preparation of crystalline Form V of afatinib dimaleate.

Afatinib base (3 g) and acetonitrile (45 mL) were charged into a 100 mL EasyMax reactor at 28°C and heated to 45° C and stirred for 15 minutes. The solution was filtered and the clear filtrate was charged into a 100 mL EasyMax reactor and cooled to -5°C. Maleic acid solution (1 .5 g of maleic acid was dissolved in 45 mL of acetonitrile) was added slowly over a period of 30 minutes. The precipitation was stirred for 3 hours at - 5°C. The precipitation was filtered at 28°C using pressure nutsche filter (PNF) and the solid was washed with acetonitrile (20 mL) and the wet material was dried in a vacuum tray drier to yield 1 .3 g of afatinib dimaleate crystalline Form V. Powder X-ray diffractogram is shown in Figure 19.

Claims

1 . Amorphous form of afatinib dimaleate

2. Amorphous form of afatinib dimaleate characterized by powder X-ray diffraction (PXRD) substantially as illustrated by Figure 1.

3. A process for preparing amorphous form of afatinib dimaleate, comprising:

(a) providing a solution of afatinib dimaleate in a solvent or a mixture of two or more solvents;

(b) removing solvent from a solution of afatinib dimaleate obtained in step a); and

(c) recovering amorphous form of afatinib dimaleate.

4. Amorphous solid dispersion comprising afatinib dimaleate and one or more pharmaceutically acceptable carriers.

5. Amorphous solid dispersion comprising afatinib dimaleate and one or more pharmaceutically acceptable carriers characterized by powder X-ray diffraction (PXRD) substantially as illustrated by any of figure 2 to figure 14.

6. A process for preparing an amorphous solid dispersion comprising afatinib dimaleate and one or more pharmaceutically acceptable carriers, comprising;

(a) providing a solution of afatinib dimaleate and pharmaceutically acceptable carrier in a solvent,

(b) removing solvent from the solution obtained in step (a); and

(c) recovering amorphous solid dispersion comprising afatinib dimaleate and one or more pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising amorphous form of afatinib dimaleate and one or more pharmaceutically acceptable carriers.

8. Crystalline Form IV of Afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.37, 10.21 , 13.56, 17.20, and 17.73 ± 0.2 degrees two theta.

9. The crystalline Afatinib di-maleate Form IV of claim 8 is characterized by an X-ray powder diffraction having peaks at about 1 1.98, 21 .74, and 25.36 ± 0.2 degrees two theta.

10. The crystalline Form IV of claim 8 or claim 9 is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 18.

1 1 . Crystalline Form V of afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.57, 1 1 .27, 1 1 .73, 17.21 , and 17.81 ± 0.2 degrees two theta.

12. The crystalline form V of Afatinib di-maleate of claim 1 1 is further characterized by an X-ray powder diffraction pattern having peaks at about 6.63, 21 .64, and 24.83 ± 0.2 degrees two theta.

13. The crystalline form V of Afatinib di-maleate of claim 1 1 or claim 12 is characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 19.

14. A process for preparation of crystalline Form V of afatinib di-maleate of claims 1 1 to 13, comprising

(a) providing a solution of afatinib base in an organic solvent,

(c) stirring the mixture of step (b) at below 5°C, and

(d) isolating crystalline afatinib dimaleate Form V.

15. A process for preparation of crystalline Form A of afatinib di-maleate, comprising:

(a) providing a solution of afatinib base in a suitable solvent,

(c) optionally heating the mixture, and

(d) isolating crystalline afatinib dimaleate Form A.

16. The suitable solvent used in step (a) of the process of claim 15 is selected from the group comprising of acetonitrile, acetone, methyl ethyl ketone and ethylacetate.

16. A pharmaceutical composition comprising afatinib dimaleate crystalline Form A prepared by the process of claim 15 or claim 16 and one or more pharmaceutically acceptable carriers.

17. A pharmaceutical composition comprising afatinib dimaleate crystalline Form IV as claimed in any of claims 8 to 10 and one or more pharmaceutically acceptable carriers.

18. A pharmaceutical composition comprising afatinib dimaleate crystalline Form V as claimed in any of claims 1 1 to 14 and one or more pharmaceutically acceptable carriers.