Field of the invention:
The present invention relates to novel polymorphs of N-[4-[(3Tchloro-4-fluorophenyI) amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the below structural formula-1 and process for their preparation.
Background of the invention:
N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide is commonly known as Afatinib. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyI]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) is commonly known as Afatinib dimleate.
Afatinib is investigational orally administered irreversible inhibitor of both the epidemial growth factor receptor (EGFR) and human epidemial receptor 2 (HER2) tyrosine kinases. Afatinib is marketed as Afatinib dimaleate under the trade ñames Gilotrif in the US, Giotrif inEurope.
The patents US6251912 Bl & USRE43431 El described Afatinib, its salts and process for preparation thereof.
US8426586 B2, WO2013052157 Al and IPCOM000240150D 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 intermedíate 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 or polymorphs of compound of formula-1.
Brief description of the invention:
The present invention provides amorphous 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) and its solid dispersions.
The first aspect of the present invention is to provide puré amorphous 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) compound of formula-1 and its process for the preparation.

The second aspect of the present invention is to provide amorphous solid dispersión comprising N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenarnide (2Z)-2-butenedioate (1:2) compound of formula-1 and at least one pharmaceutically acceptable excipient.
The third aspect of the present invention is to provide a process for the preparation of amorphous solid dispersión comprising 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) compound of formula-1 and at least one pharmaceutically acceptable excipient.
The fourth aspect of the present invention relates to a novel crystalline form of 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) compound of formula-1, hereinafter designated as crystalline Form-M.
The fifth aspect of the present invention present invention is to provide a process for the preparation of crystalline form-M of 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) compound of formula-1.
The sixth aspeci of the present invention relates to another novel crystalline form of 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) compound of formula-1, hereinafter designated as crystalline form-S.
The seventh aspect of the present invention is to provide a process for the preparation of crystalline form-S of 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) compound of formula-1.

Brief description of the drawings:
Figure-1: Illustrates the powder X-ray diffraction pattem of puré amorphous form of compound of formula-1 prepared in accordance with example-1.
Figure-2: Illustrates the powder X-ray diffraction pattem of amorphous solid dispersión comprising compound of formula-1 and PVP K-30.
Figure-3: Illustrates the powder X-ray diffraction pattem of amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl cellulose (HPC).
Figure-4: Illustrates the powder X-ray diffraction pattem of amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl methylcellulose (HPMC).
Figure-5: Illustrates the powder X-ray diffraction pattem of amorphous solid dispersión comprising compound of formula-1 and Eudragit L 100-55.
Figure-6: Illustrates the powder X-ray diffraction pattem of amorphous solid dispersión
comprising compound of formula-1 and hydroxypropyl methylcellulose acétate succinate
(HPMCAS).
Figure-7: Illustrates the powder X-ray diffraction pattem of crystalline form-M of
compound of formula-1.
Figure-8: Illustrates the powder X-ray diffraction pattem of crystalline form-S of compound
of formula-1.
Detailed description of the invention:
The "suitable solvent" used in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acétate, ethyl acétate, n-propyl acétate, isopropyl acétate, n-butyl acétate, isobutyl acétate, tert-butyl acétate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro

solvents" such as dichloromethane, dichloroethane, chloroform, carbón tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, ethane-l,2-diol, propane-1,2-diol, alkyl ethers of ethylene glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether , diethylene glycol mono n-butyl ether and the like; "polar solvents" such as water; formic acid, acetic acid or mixtures thereof.
The term "puré amorphous" refers to a solid without long-range crystalline order. The amorphous form of the present invention preferably contain 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 term "solid dispersión" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. In the present invention, one component of solid dispersión is active pharmaceutical ingredient such as 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) and other component is a pharmaceutically acceptable excipient. -^
The first aspect of the present invention provides puré 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) compound of formula-1 which is characterized by its powder X-ray diffarction pattern as shown in figure-1.
Further, the first aspect of the present invention also providés a process for the preparation of puré amorphous compound of formula-1, which comprises of:

a) Dissolving the compound of formula-1 in a suitable solvent or mixture of solvents,
b) removing the solvent(s) from the reaction mixture and drying the material to get puré amorphous compound of formula-1.
Wherein, the suitable solvent used in step-(a) can be selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid, alkyl ethers of ethylene glycol or propylene glycol or their mixtures; the compound of formula-1 may be dissolved in a suitable solvent by heating the reaction mixture to a suitable temperature ranges from 0°C to 150°C;
After dissolving the compound of formula-1 in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution;
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The solution may be filtered by passing through paper, glass fíber or other membrane material or a bed of a clarifying agent such as Celite® or hyflow. 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.
In step-b) suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusión, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooiing the clear solution to lower temperatures to precipítate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.
In a preferred embodiment of the present invention provides a process for the preparation of puré amorphous compound of formula-1, which comprising of:

a) Dissolving the compound of formula-1 in methanol,
b) distilling off the solvent from the réaction mixture under reduced pressure and drying to get puré amorphous compound of formula-1.
The second aspect of the present invention provides amorphous solid dispersión comprising of 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) compound of formula-1 and at least one pharmaceutically acceptable excipient.
In general, the pharmaceutically acceptable excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acétate, propylene glycol, cellulose, cellulose acétate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulosé, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acétate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acétate succinate (HPMCAS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acétate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acétate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, tale, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium stárch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, 0-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid,

succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acétate phthalates and the like.
In the present invention, the ratio of the amount by weight of compound pf formula-1 within the solid dispersión to the amount by weight of the excipient therein ranges from but not limited to about 1:0.05 to about 1:5.
The third aspect of the present invention provides a process for the preparation of amorphous solid dispersión comprising of 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) compound of formula-1 and at least one pharmaceutically acceptable excipient, which comprising of:
a) Dissolving a mixture of compound of formula-1 and at least one pharmaceutically acceptable excipient in a suitable solvent or mixture of solvents,
b) removing the solvent(s) from the reaction mixture and drying the material to provide its corresponding amorphous solid dispersión.
Wherein,
in step-a) the suitable excipient is same as defined above in the second aspect;
the suitable solvent can be selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid, alkyl ethers of ethylene glycol or propylene glycol or their mixtures; a mixture of compound of formula-1 and pharmaceutically acceptable excipient was dissolved in a suitable solvent by heating the mixture to a suitable temperature ranges from 0°C to 150°C;
After dissolving the mixture of compound of formula-1 and excipient in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution;
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The solution may be filtered by passing through paper, glass fiber or other membrane material or a bed of a clarifying agent such as Celite® or hyflow. 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.
In step-b) suitahíe techniques which may be used for the removal of solvent from the reaction mixture is same as defined above.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersión comprising 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) compound of formula-1 and at least one pharmaceutically acceptable excipient selected from PVP of different grades, HPC, HPMC, Eudragit L 100-55 and HPMCAS, which comprising of;
a) Dissolving a mixture of compound of formula-1 and at least one pharmaceutically acceptable excipient selected from PVP of different grades, HPC, HPMC, Eudragit L 100-55 and HPMCAS in methanol,
b) distilling off the solvent from the reaction mixture under reduced pressure and drying the material to provide its corresponding amorphous solid dispersión.
The fourth aspect of the present invention provides a novel crystalline form of 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), hereinafter designated as crystalline form-M. Further, the crystalline form-M is characterized by
a) its powder X-ray diffraction pattern having peaks at 5.0, 9.4, 9.7, 10.7, 15.1, 16.0, 18.4, 18.8, 19.3,20.2, 20.9, 21.6, 22.9, 23.9, 25.0, 25.7, 25.9, 28.7 and 29.0 ± 0.2 degrees of 2-theta; and
b) its powder X-ray diffraction pattern as illustrated in figure-7.
The fifth aspect of the present invention present invention provides a process for the preparation of crystalline form-M of 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) compound of formula-1, comprising of:

a) Dissolving compound of formula-1 in dimethylformamide,
b) adding ethylacetate to the solution obtained in step-(a),
c) filtering the precipitated solid, washed with ethyl acétate and then dried to get crystalline form-M of compound of formula-1.
The sixth aspect of the present invention provides another novel crystalline form of 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), hereinafter designated as crystalline form-S. Further, the crystalline form-S is characterized by:
a) its powder X-ray diffraction pattern having peaks at 5.0, 8.9, 9.3, 9.7,10.6, 15.0, 17.7, 18.4, 18.8, 19.3, 19.9, 20.4, 20.8, 21.2, 21.6, 23.8, 24.4, 24.9, 25.6, 27.7 and 28.6 ± 0.2 degrees of 2-theta; and
b) its powder X-ray diffraction pattern as illustrated in figure-8.
The seventh aspect of the present invention present invention provides a process for the preparation of crystalline form-S of 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) compound of formula-1, comprising of:
a) Dissolving compound of formula-1 in dimethylformamide,
b) adding methyl tert-butyl ether to the solution obtained in step-(a),
c) filtering the precipitated solid, washed with methyl tert-butyl ether and then dried to get crystalline form-S of compound of formula-1.
The compound of formula-1 used herein the present invention can be prepared by the methods known in the art such as US8426586 B2, WO2013052157 Al and IPCOM000240150D.
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous sean speed of 0.03°/min.

The novel polymorphs produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniqües 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 polymorphs produced by the present invention can be utilized in the preparation of pharmaceutical composition as a medicament.
The best mode of carrying out 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 to the scope of the invention.
Examples:
Example-1: Preparation of puré amorphous N-[4-[(3-chloro-4-fluorophenyl) amino]-7^
[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyIamino)-(2E)-2-butenamide
(2Z)-2-butenedioate (1:2) (Formula-l)
A mixture of compound of formula-l (3.0 gms) and methanol (150 mi) was heated to 45-50°C and stirred for 40 mins to get clear solution. Filtered the reaction mixture. Distilled off the solvent completely from the fíltrate under reduced pressure and then dried the obtained compound to get tilte compound. Yield: 2.0 gms.
The powder X-ray diffraction pattern of the obtained compound is shown in figure-1.
Example-2: Preparation of amorphous solid dispersión comprising compound of formula-l and povidone k-30 (PVP K-30)
A mixture of compound of formula-l (500 mg), PVP K-30 (500 mg) and methanol (20 mi) was heated to 45-50°C and stirred for 35 mins to get clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained material to get the title compound. Yield: 700.0 mg.
The powder X-ray diffraction pattern of the obtained compound is shown in figure-2.

Exmaple-3: Preparation of amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl cellulose (HPC)
A mixture of compound of formula-1 (500 mg), hydroxypropyl cellulose (500 mg) and methanol (25 mi) was heated to 45-50°C and stirred for 25 mins to get clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained material to get the title compound. Yield: 450.0 mg.
The powder X-ray diffraction pattern of obtained compound is shown in figure-3.
Example-4: Preparation of amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl methylcellulose (HPMC)
A mixture of compound of formula-1 (500 mg), hydroxypropyl methylcellulose (500 mg) and methanol (30 mi) was heated to 45-50C and stirred for 25 mins to get clear solution. Distilled off the solvent completely from the the reaction mxiture under reduced pressure and then dried the obtained material to get the title compound. Yield: 700.0 mg.
The powder X-ray diffraction pattern of the obtained compound is shown in figure-4.
Example-5: Preparation of amorphous solid dispersión comprising compound of formula-1 and Eudragit L 100-55
A mixture of compound of formula-1 (500 mg), Eudragit L 100-55 (500 mg) and methanol (40 mi) was heated to 45-50°C and stirred for 30 mins to get clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained material to get the title compound. Yield: 600.0 mg.
The powder X-ray diffraction pattern of obtained compound is shown in figure-5.
Example-6: Preparation of amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl methylcellulose acétate succinate (HPMCAS)
A mixture of compound of formula-1 (500 mg), HPMCAS (500 mg) and methanol (40 mi) was heated to 45-50°C and stirred for 25 mins to get clear solution. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the obtained material to get the title compound; Yield: 550.0 mg.
The powder X-ray diffraction pattern of obtained compound is shown in figure-6.

Example-7: Preparation of crystalline form-M of compound of formula-1.
A mixture of compound of formula-1 (2 gms) and dimethylformamide (12 mi) was stirred for 15 min at 25-30°C to get clear solution. Ethyl acétate (30 mi) was added to the above solution at 25-30°C and stirred for 1 hr 30 mins. Filtered the precipitated solid, washed with ethyl acétate and then dried to get title compound. Yield: 1.2 gms.
The powder X-ray diffraction pattern of the obtained compound is shown in figure-7.
Example-8: Preparation of crystalline form-S of compound of formula-1.
A mixture of compound of formula-1 (2 gms) and dimethylformamide (12 mi) was stirred fpr. 15 min at 25-30°C to get clear solution. Methyl tert-butyl ether. (30 mi) was added to the above solution at 25-30°C and stirred for 1 hr 50 mins. Filtered the precipitated solid, washed with methyl tert-butyl ether and then dried to get title compound. Yield: 1.8 gms.
The powder X-ray diffraction pattern of the obtained compound is shown in figure-8.

We claim:
1. A Puré 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).
2. The 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) of claim-1 is characterized by its powder X-ray diffraction pattern as shown in figure-1.
3. Novel crystalline forms of 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) compound of formula-1, wherein,
i. Crystalline form-M is characterized by:
a) its powder X-ray diffraction pattern having peaks at 5.0, 9.4, 9.7, 107, 15.1, 16.0,
18.4, 18.8, 19.3,20.2, 20.9, 21.6, 22.9, 23.9, 25.0, 25.7, 25,9, 28.7 and 29.0 ± 0.2
degrees of 2-theta; and
b) its powder X-ray diffraction pattern as illustrated in figure-7;
ii. Crystalline form-S. is characterized by:
a) its powder X-ray diffraction pattern having peaks at 5.0, 8.9, 9.3, 9.7,10.6, 15.0, 17.7, 18.4, 18.8, 19.3, 19.9, 20.4, 20.8, 21.2, 21.6, 23.8, 24.4, 24.9, 25.6, 27.7 and 28.6 ± 0.2 degrees of 2-theta; and
b) its powder X-ray diffraction pattern as illustrated in figure-8.
4. Amorphous solid dispersión comprising N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-
tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(diméthylamino)-(2E)-2-butenamide (2Z)-2-
butenedioate (1:2) compound of formula-1 and at least one pharmaceutically acceptable
excipient, wherein pharmaceutically acceptable excipient is selected from
polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl
methylcellulose (HPMC), Eudragit L 100-55 and hydroxypropyl methylcellulose acétate
succinate (HPMCAS).

5. The amorphous solid dispersión of claim-4, wherein,
a) amorphous solid dispersión comprising compound of formula-1 and PVP K-30 is characterized by powder X-ray diffraction pattern as shown in figure-2,
b) amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl cellulose (HPC) is characterized by powder X-ray diffraction pattern as shown in figure-3,
c) amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl methylcellulose (HPMC) is characterized by powder X-ray diffraction pattern as shown in figure-4,
d) amorphous solid dispersión comprising compound of formula-1 and Eudragit L 100-55 is characterized by powder X-ray diffraction pattern as shown in figure-5,
e) amorphous solid dispersión comprising compound of formula-1 and hydroxypropyl methylcellulose acétate succinate (HPMCAS) is characterized by powder X-ray diffraction pattern as shown in figure-6,
6. A process for the preparation of puré amorphous N-[4-[(3-chloro-4-fluorophenyi) amino]-
7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-(2E)-2-butenamide
(2Z)-2-butenedioate (1:2) compound of formula-1, comprising of:
a) Dissolving the 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) compound of formula-1 in a suitable solvent or mixture of solvents,
b) removing the solvent from the reaction mixture and drying the material to provide puré amorphous compound of formula-1.
7. A process for the preparation of amorphous solid dispersión comprising N-[4-[(3-chloro-
4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyÍ]-4-(dimethyl
amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) compound of formula-1 and at least
one pharmaceutically acceptable excipient selected from PVP, HPC, HPMC, Eudragit L
100-55 and HPMCAS, comprising of:

a) Dissolving a mixture of 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) compound of formula-1 and pharmaceutically acceptable excipient selected from PVP, HPC, HPMC, Eudragit l 100-55 and HPMCAS in a suitable solvent or mixture of solvents,
b) removing the solvent from the reaction mixture and drying the material to get its corresponding amorphous solid dispersión.
8. The process according to claim 6 & 7, wherein,
in step-(a) the suitable solvent used is selected from hydrocarbon solvents, ether solvents,
ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid, alkyl ethers of ethylene glycol and propylene glycol;
In step-(b) removal of solvent can be carried by suitable techniques includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusión, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture foliowed by filtration of the precipitated solid and cooling the clear solution to lower temperatures to precipítate the solid followed by filtration of the reaction.
9. A process for the preparation of puré amorphous 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) compound of formula-1, comprising of:
a) Dissolving the 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) compound of formula-1 in methanol,
b) distilling off the solvent from the reaction mixture under reduced pressure and drying the material to provide puré amorphous compound of formula-1.

10. A process for the preparation of amorphous solid dispersión comprising N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) compound of formula-1 and a pharmaceutically acceptable excipient selected from PVP, HPC, HPMC, Eudragit L 100-55 and HPMC AS, comprising of:
a) Pissolving the 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) compound of formula-1 and pharmaceutically acceptable excipient selected from PVP, HPC, HPMC, Eudragit L J00-55 and HPMCAS in methanol,
b) distilling off the solvent from the reaction mixture under reduced jpressure and drying the material to provide its corresponding amorphous solid dispersión.