Field of the invention:
The present invention relates to an amorphous N-[4-[(3-chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula and its process for preparation.
Background of the invention:
N- [4-[(3 -chloro-4-fluorophenyl)amino]-7- [ [(3 S)-tetrahydro-3 -furanyl] oxy] -6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide, is commonly known as Afatinib.
N- [4- [(3 -chloro-4-fluorophenyl)amino] -7- [ [(3 S)-tetrahydro-3 -furanyl]oxy] -6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) is commonly known as Afatinib dimaleate.
Afatinib is investigational orally administered irreversible inhibitor of both the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases.
Afatinib is marketed as Afatinib dimaleate under the trade ñames Gilotrif in the US, Giotrif inEurope.
US6251912 Bl & USRE43431 El are described Afatinib, its salts and process for preparation thereof.
US8426586 B2 & WO2013052157 Al are described various crystalline forms of Afatinib dimaleate.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having same molecular formula and distinct physical properties like melting point, solubility profiles, thermal behaviors (e.g. measured by thermo gravimetric 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. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry and differential scanning calorimetry. Solvent médium and mode of crystallization play very important role in obtaining a polymorphic form over the other.
Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilítate conversión 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.
Brief description of the invention:
The fírst aspect of the present invention is to provide an amorphous Afatinib dimaleáte.
The second aspect of the present invention is to provide a process for the preparation of amorphous Afatinib dimaleáte.
The third aspect of the present invention is to provide a process for the preparation of amorphous Afatinib dimaleáte.

Brief description of the drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of amorphous Afatinib dimaleate.
Detailéd description of the invention:
The term "suitable solvent" used in the present invention includes, but not limited to "ester solvents" such as ethyl acétate, methyl acétate, isopropyl acétate, n-butyl acétate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbón tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "polar solvent" such as water or mixtures thereof.
"Lyophilization" is also called freeze-drying. Lyophilization is a process which converts water from a frozen state to a gaseous state without going through a liquid state. This process removes moisture from the cells of specimens while the specimens remain frozen.
The term "amorphous" refers to a solid without long-range crystalline order. The amorphous form of the present invention preferably contains less than about 10% crystalline forms, more preferably less than 5% crystalline forms, and still more preferably less than 1% or is essentially free of crystalline forms. "Essentially free of crystalline forms" means that no crystalline polymorph forms can be detected within the limits of an X-ray Powder Diffractometer.
The first aspect of the present invention provides an amorphous Afatinib dimaleate. Further, the amorphous Afatinib dimaleate is characterized by its powder X-ray diffraction pattern as shown in figure-1.

The second aspect of the present invention provides a process for the preparation of amorphous Afatinib dimaleate, comprising of:
a) Dissolving Afatinib dimaleate in a suitable solvent,
b) isolating the amorphous Afatinib dimaleate from the solution of step-(a). Wherein,
in step-a) the suitable solvent is selected from ester solvents, ether solvents, nitrile solvents, alcoholic solvents, hydrocarbon solvents, polar aprotic solvent, chloro solvents, ketone solvents and polar solvents,
in step-b) the isolation of amorphous Afatinib dimaleate involves removal of solvent by the techniques such as lyophilization, spray drying, recrystalhzation, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, antisolvent addition, slurry recrystallization, crystallization from the melt and desqlvation etc.
In a preferred embodiment of the present invention provides a process for the preparation of amorphous Afatinib dimaleate, comprising of:
a) Dissolving the Afatinib dimaleate in water,
b) lyophilizing the amorphous Afatinib dimaleate from the solution of step-(a).
Afatinib dimaleate used here in the present invention is obtained by the process reported in the prior art such as US8426586 B2.
The third aspect of the present invention is to provide a process for the preparation of amorphous Afatinib dimaleate, comprising of:
a) Adding maleic acid to a mixture of Afatinib and a suitable solvent,
b) stirring the reaction mixture to obtain a clear solution,
c) isolating the amorphous Afatinib dimaleate from the solution of step-(b). wherein,
in step-a) the suitable solvent is selected from ester solvents, ether solvents, nitrile solvents, alcoholic solvents, hydrocarbon solvents, polar aprotic solvent, chloro solvents, ketone solvents and polar solvents;

in step-c) the isolation of amorphous Afatinib dimaleate involves removal of solvent by the
techniques such as lyophilization, spray drying, recrystallization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, anti-solvent addition, slurry recrystallization, crystallization from the melt and desolvation etc.
Apreferred embodiment of the present invention provides a process for the preparation of amorphous Afatinib dimaleate, comprising of:
a) Adding maleic acid to a mixture of Afatinib and water,
b) stirring the reaction mixture to get clear solution,
c) lyophilizing the amorphous Afatinib dimaleate from the solution of step-(b).
Afatinib used herein the present invention is obtained by the process disclosed in prior art such as US6251912 Bl and US RE43431 E.
Afatinib dimaleate obtained according to the present invention is substantially in amorphous form.
PXRD analysis of the amorphous form of Afatinib dimaleate of the present invention was carried out by using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and at continuous sean speed of 0.03°/min.
The amorphous form of Afatinib dimaleate of the present invention can be further micronized or milled by using conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer milis, and jet milis. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The amorphous form of Afatinib dimaleate produced by the present invention can be utilized in the preparation of pharmaceutical composition.

The best mode of carrying óut the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and henee should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of amorphous Afatinib dimaleate
1 gm of Afatinib dimaleate was dissolved in 10 mi of water. The resulting clear solution was filtered through hyflow bed and frozen. The frozen mixture is lyophilized for 24 hrs to get amorphous Afatinib dimaleate.
Yield: 0.8 g.
The PXRD diffraction pattern of the obtained compound is shown in figure-1.
ExampIe-2: Preparation of amorphous Afatinib dimaleate
Maleic acid (4.77 gms) was added to a mixture of Afatinib (10 gms) and water (100 mi) at 30-35°C and stirred for 15 mins at 30-35°C. Filtered the reaction mixture through the hyflow bed and washed with water. The fíltrate was frozen and lyophilized for 24 hrs to get the amorphous Afatinib dimaleate. Yield: 8.5 gms The powder X-ray diffraction pattern of the obtained compound is shown in figure-1.

We claim:
1. Amorphous Afatinib dimaleate.
2. The Afatinib dimaleate according to claim-1, is substantially in amorphous form.
3. The Amorphous Afatinib dimaleate of claim 1 or 2, substantially as depicted in Figure-1.
4. A process for the preparation of amorphous Afatinib dimaleate, comprising of:

a) Dissolving Afatinib dimaleate in a suitable solvent,
b) isolating the amorphous Afatinib dimaleate from the solution of step-(a).
5. The process according to claim-4, wherein
in step-a) the suitable solvent is selected from ester solvents, ether solvents, nitrile
solvents, alcoholic solvents, hydrocarbon solvents, polar aprotic solvent, chloro solvents, ketone solvents and polar solvents; and
in step-b) the isolation of amorphous Afatinib dimaleate involves removal of solvent by the techniques such as lyophilization, spray drying , recrystallization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation and the like.
6. A process for the preparation of amorphous Afatinib dimaleate, comprising of;
a) Dissolving the Afatinib dimaleate in water,
b) lyophilizing the amorphous Afatinib dimaleate from the solution of step-(a).
7. A process for the preparation of amorphous Afatinib dimaleate, comprising of:
a) Adding maleic acid to a mixture of Afatinib and a suitable solvent,
b) stirring the reaction mixture to obtain a clear solution,
c) isolating the amorphous Afatinib dimaleate from the solution of step-(b).
8. The process according to claim-7, wherein
in step-a) the suitable solvent is selected from ester solvents, ether solvents, nitrile

solvents, alcoholic solvents, hydrocarbon solvents, polar aprotic solvent, chloro solvents, ketone solvents and polar solvents; and in step-c) the isolation of amorphous Afatinib dimaleate involves removal of solvent by the techniques such as lyophilization, spray drying , recrystallization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, anti-solvent addition, slurry recrystallization, crystallization from the melt, desolvation and the like.
9. The process for the preparation of amorphous' Afatinib dimaleate, comprising of:
a) Adding maleic acid to a mixture of Afatinib and water,
b) stirring the reaction mixture to obtain a clear solution,
c) isolating the amorphous Afatinib dimaleate from the solution of step-(b).
10. Amorphous Afatinib dimaleate obtained according to any of the preceding claims
useful for the preparation of pharmaceutical composition.