DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
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 provides novel solid state forms of Afatinib di-maleate, processes for preparing them, and pharmaceutical compositions containing them.
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 shows an X-ray powder diffractogram of Afatinib di-maleate Form VII prepared according to the process exemplified in example-1.
Figure 2 shows an X-ray powder diffractogram of Afatinib di-maleate Form VIII prepared according to the process exemplified in example-2.
Figure 3 shows an X-ray powder diffractogram of Afatinib di-maleate Form IX prepared according to the process exemplified in example-3.
Figure 4 shows an X-ray powder diffractogram of Afatinib di-maleate Form X prepared according to the process exemplified in example-4.
Figure 5 shows an X-ray powder diffractogram of Afatinib dimaleate Form XI prepared according to the process exemplified in example-5.
Figure 6 shows an X-ray powder diffractogram of Afatinib dimaleate Form XII prepared according to the process exemplified in example-6.
Figure 7 shows an X-ray powder diffractogram of Afatinib di-maleate Form XIII prepared according to the process exemplified in example-7.
Figure 8 shows an X-ray powder diffractogram of Afatinib di-maleate Form XIV prepared according to the process exemplified in example-8.
Figure 9 shows an X-ray powder diffractogram of Afatinib di-maleate Form XV prepared according to the process exemplified in example-9.
Figure 10 shows an X-ray powder diffractogram of Afatinib di-maleate Form XVI prepared according to the process exemplified in example-10.
Figure 11 shows an X-ray powder diffractogram of Afatinib dimaleate Form XVII prepared according to the process exemplified in example-11.
Figure 12 shows an X-ray powder diffractogram of Afatinib dimaleate Form XVIII prepared according to the process exemplified in example-12.
Figure 13 shows an X-ray powder diffractogram of Afatinib di-maleate Form XIX prepared according to the process exemplified in example-13.
Figure 14 shows an X-ray powder diffractogram of Afatinib di-maleate Form XX prepared according to the process exemplified in example-14.
Figure 15 shows an X-ray powder diffractogram of Afatinib di-maleate Form XXI prepared according to the process exemplified in example-15.
Figure 16 shows an X-ray powder diffractogram of Afatinib di-maleate Form XXII prepared according to the process exemplified in example-16.
Figure 17 shows an X-ray powder diffractogram of Afatinib dimaleate Form XXIII prepared according to the process exemplified in example-17.
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 one 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, 11.63, 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, 11.80, 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, 11.60, 14.11, 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, 19.11, 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 5.11, 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, 11.39, 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, 11.06, 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, 11.07, 11.39 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 11.19 ± 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 11.53, 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, 11.82, 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, 19.11, 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, 11.23 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, C1-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.
Sl. No. Solvent Isolated Form
1 Methyl tert-butyl ether and Acetic acid Form VII
2 Methyl tert-butyl ether and Formic acid Form VIII
3 Dimethyl formamide Form IX
4 Formic acid Form X
5 Cyclohexanone Form XI
6 Acetonitrile Form XII
7 1,4-Dioxane Form XIII
8 Nitromethane Form XIV
9 Toluene Form XV
10 Butylacetate Form XVI
11 Xylene Form XVII
12 Dimethyl carbonate Form XVIII
13 Cyclopentyl methyl ether Form XIX
14 Water Form XX

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 XXIII can be prepared using acetone using the procedure mentioned above.
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 “C5-C8 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=O)-O- 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=O)- 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 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 871hours at 30°C. The precipitate was filtered under vacuum.
Powder X-Ray diffractogram is shown in Figure 1.
Example 2: 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 2.
Example 3: 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 3
Example 4: 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 4
Example 5: 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 5
Example 6: 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 6.
Example 7: 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 7.
Example 8: 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 8.
Example 9: 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 9
Example 10: 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 10
Example 11: 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 11
Example 12: 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 12.
Example 13: 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 13.
Example 14: 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 14.
Example 15: 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 15.
Example 16: 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 16.
Example 17: 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 17.
,CLAIMS:WE CLAIM
1. Crystalline Form VII of Afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.13, 9.95, 19.69 and 25.68 ± 0.2 degrees two theta.
2. Crystalline Form IX of Afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.02, 8.99, 9.34, 10.28, 11.80, 19.99, 20.46, 22.75 and 27.78 ± 0.2 degrees two theta.
3. Crystalline Form XI of Afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 9.62, 10.35, 11.60, 14.11, 20.63 and 22.60 ± 0.2 degrees two theta.
4. Crystalline Form XII of Afatinib di-maleate 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.
5. Crystalline Form XIII of Afatinib di-maleate 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.
6. Crystalline Form XIV of afatinib di-maleate 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.
7. Crystalline Form XV of Afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.11, 5.44, 10.26, 10.93, 20.65, and 21.35 ± 0.2 degrees two theta.
8. Crystalline Form XVI of afatinib di-maleate 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.
9. Crystalline Form XVII of Afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.51, 11.06, 16.67 and 19.59 ± 0.2 degrees two theta.
10. Crystalline Form XXIII of afatinib di-maleate characterized by an X-ray powder diffraction having peaks at about 5.72, 19.11, 19.55, 20.30, 21.61, 22.77 and 28.37 ± 0.2 degrees two theta.