Claims:We Claim:

1) Crystalline Afatinib dimaleate designated as Form-SAM characterized by
c) X-ray powder diffraction pattern comprising characteristic 2?° peaks at 4.9, 6.4, 7.3, 8.0, 10.4, 17.1, 19.7, 21.1, 22.5, 23.5, 25.4 ±0.2°2?; and
d) DSC isotherm comprising endothermic peak ranging between175 to 182°C.

2) Crystalline Afatinib dimaleate Form-SAM according to claim 1, further characterized by X-ray powder diffraction pattern comprising characteristic 2?° peaks at 12.9, 13.6, 14.8, 17.6±0.2°2?

3) Crystalline Afatinib dimaleate Form-SAM according to claim 1, wherein X-ray powder diffraction pattern comprising absence of 2?° peaks at 19.4 and 22.9 ±0.2°2?

4) Crystalline Afatinib dimaleate Form-SAM according to claim 1, further characterized by DSC isotherm comprising endothermic peak ranging between 176to 181°C.

5) Crystalline Afatinib dimaleate Form-SAM according to claim 1, further characterized by TGA thermogram comprising weight loss ranging between 0.2-1.5 %.

6) Process for the preparation of crystalline Afatinib dimaleate crystalline Form-SAM, comprising the steps of:
a) dissolving Afatinib dimaleate in a mixture of isopropyl alcohol and Methyl tertiary butyl ether solvent;
b) adding maleic acid solution prepared by combining maleic acid in isopropyl alcohol;
c) stir the contents for the duration ranging between 1 hour to 3 hours at temperature of 25-30°C; and
d) isolatingcrystalline Afatinib dimaleate crystalline Form-SAM.

7) Process for the preparation of crystalline Afatinib dimaleate, wherein Afatinib dimaleate obtained according to the process claimed in claim-6 is having purity of greater than 99.4% by HPLC and having total impurities A to E collectively less than 0.5% by BPLC

8) Afatinib dimaleate having a purity of greater than 99.4 % by HPLC and having total impurities A to E collectively less than 0.6 % by HPLC.

Impurity - A
Impurity - B

Impurity - C
Impurity - D

Impurity - E
9) Afatinib dimaleate having a purity of greater than 99.6 % according to claim 8, wherein Afatinib dimaleate obtained is having moisture content less than 1 % w/w (by KF method)

10) Crystalline Afatinib dimaleate Form-SAMaccording to claim 1, utilized in the preparation of pharmaceutical composition with at least one or more pharmaceutically acceptable excipients.
, Description:FIELD OF THE INVENTION
The present invention relates to novel stable crystalline polymorphic form of Afatinibdimaleate of Formula (I).

(I)
Said crystalline form may be commercially viable and lead to consistently produce as the stable material as per the processes according to the present invention.
This novel crystalline form may be useful in the preparation of dosage forms for the treatment of cancer.

BACKGROUND OF THE INVENTION
Afatinib is chemically known as N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide(I).

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamideor Afatinib is a kinase inhibitor indicated for the First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR). Afatinib as its dimaleate salt is commenrcial available in the trade name as GILOTRIF®. Being selective inhibitors, efficacy of GILOTRIF was not established in patients whose tumors have other EGFR mutations. Afatinib may also be used for the Treatment of patients with metastatic, squamous NSCLC progressing after platinum-based chemotherapy .

Afatinib dimaleate salt is a white to brownish yellow powder and is highly soluble in water. The highest solubility in organic solvents is observed in DMSO then in methanol. For most of the other organic solvents solubility is less than 1 mg/ml. It is highly soluble in aqueous buffer media with a pH of less than 6. The solubility of Afatinib dimaleate is pH-dependent. It was noted that the free base has two ionizable groups due to presence of a dimethylamine and a quinazoline moiety. Afatinib dimaleate is a hygroscopic, with an empirical formula of C32H33ClFN5O11, and a molecular weight of 718.1 g/mol.

Afatinib dimaleate was approved by USFDA in 2013 and is marketed under the brand name GILOTRIF®, and is indicated for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s). Afatinib dimaleate is marketed in a crystalline anhydrous form A.

Afatinib is generically disclosed by Wissner, et al inUS6251912 and specifically disclosed in US RE43431. The process disclosed in these patents for the preparation of Afatinib is delineated below:

This patent has not provided anyinsight about the impurity concern as well as disclosure of any purity of the final product. This patent broadly disclosed the formation of Afatinib dimaleate. In view of this, it was apparentto develop a commercially viable process/or crystallization process resulting in the acceptable product, which is complying with the ICH requirements of quality parameters.

Soyka et al in US 8,426,586disclose a process for the preparation of Afatinib. The process is as disclosed below:

This patent further discloses crystalline Afatinib Dimaleate characterized by peaks at 4.91, 6.42, 7.47, 8.13, 10.37, 17.19, 19.43, 19.91, 21.33, 22.94 and 25.56°2?. This crystalline form was designated as Form-A in further patent applications.

Gidwani et al in US9012464 discloses a crystalline form of Afatinib Dimaleate Form-B, which was prepared by dissolving Afatinib free base in THF solvent and then adding maleic acid.

However, the present inventors repeated the same process and prepared the same crystalline form. As per our study, it was observed that the obtained Afatinib dimaleate crystalline Form-B not meeting the ICH guidelines due to the existence of high quantity of THF solvent as a residual solvent above the ICH Limits.

This patent further discloses crystalline Afatinib Free base Form-A, Form-B, Form-C and Form-D. Further, this patent also discloses crystalline Afatinib dibenzenesulphonate, fumarate, disuphate Form-A, disulphate Form-B, dihydrochloride, dioxalate Form A, dimesylate Form A, dimesylate Form B, Diphosphate Amorphous, diphosphate crystalline Form A, di –L-Malate Amorphous, citrate amorphous, disuccinate Form A, di-l-asparate Form A and difumarate salt.

Bruns in WO 2013052157 discloses Afatinib Dimaleate Form C, which was prepared using THF solvent. Afatinib Dimaleate Form D, which was prepared by using Ethanol solvent and Afatinib Dimaleate Form-E, which was prepared by drying crystalline Form-A.

Tuskar in WO 2015103456 discloses Afatinib Dimaleate Form G, Afatinib Dimaleate Form M, Afatinib Dimaleate Form N, Afatinib Dimaleate Form Alpha and Afatinib Free base Form C.

Rama krishnan in WO2016/027243 discloses Afatinib Dimaleate Form-I, Form-II, Form –III, Form-IV, Form-V, Form-VI, Form-VII, Form-VIII, Form-IX, Form-X, Form-XI, Form-XII, Form-XIII, Form-XIV, Form-XV, Form-XVI, Form-XVII, Form-XVIII, Form-XIX, Form-XX, Form-XXI, Form-XXII, Form-XXIII and amorphous form. This patent further discloses process for the preparation of Afatinib Dimaleate Form-A process

Rao et al in IN 1846/MUM/2014 discloses Afatinib Dimaleate Form-M1, Form-M2, Form-M3, Form-M4, Form-M5, Form-M6, Form-M7, Form-M8, Form-M9. Further, this paten also discloses crystalline Form –M of Afatinib Free base.

In view of the above, it is pertinent to note that there exists an inherent need to develop stable crystalline form of Afatinib dimaleate having further improved physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel process/crystallization process for the preparation of Afatinib dimaleate, which may further improve the characteristics of drug Afatinib dimaleate and in developing the substantially pure stablecrystalline forms of Afatinib dimaleate consistently obtainable and amenable to scale up.

As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.

Exploring new polymorphic form for developing a stable and pure form of Afatinib dimaleate, which are amenable to scale up for pharmaceutically active useful compounds in the preparation of Afatinib dimaleate may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility. Hence, inventors of the present application report a new polymorphic form, which is a stable and substantially pure form of Afatinib dimaleate, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

The present invention provides an improved process for the preparation of substantially pure novel crystalline form of Afatinib dimaleate, wherein substantially pure material having a purity of greater than 99.4% by HPLC and meeting the quality of ICH guidelines. Afatinib dimaleatecrystalline material obtained by the process of the present invention is consistent and chemically stable and has been found with good dissolution characteristics.

In view of the above and to overcome the prior-art problems the present inventors havenow developed a novel process resulting in a new polymorphic forms of Afatinib dimaleate, which aresubstantially pure, stable produced by using industrially friendly solvents, which does not include tedious work up and time lagging steps. Scientist have also confirmed that reproducing the prior disclosed process resulted in serious concerns of impurities formation, lower API purity, unstable API and its polymorphism besides serious handling concerns in the processes.

OBJECTIVE OF THE INVENTION
The main objective of the invention relates to new stable polymorphic forms of Afatinib dimaleate.

Yet another objective of the invention relates to crystalline forms of Afatinib dimaleate, which is a stable and substantially pure form of Afatinib dimaleate, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

Yet another objective of the invention relates a process for the preparation of crystalline forms of Afatinib dimaleate.

Yet another objective of the invention relates a process for the preparation of crystalline form of Afatinib dimaleate, which is free of process related impurities.

SUMMARY OF THE INVENTION
Aspects of the present invention relates to the new stable polymorphic form of Afatinib dimaleate.

In one aspect of present invention relates tocrystalline Afatinib dimaleate Form-SAM characterized by
a) X-ray powder diffraction pattern comprising characteristic 2?° peaks at 4.9, 6.4, 7.3, 8.0, 10.4, 17.1, 19.7, 21.1, 22.5, 23.5, 25.4 ±0.2°2?; and
b) DSC isotherm comprising endothermic peak at 175 to 182°C.

Further aspect of the present invention relates to process for the preparation of crystalline Afatinib dimaleate crystalline Form-SAM, comprising the steps of:
a) dissolving Afatinib dimaleate in a mixture of isopropyl alcohol and Methyl tertiary butyl ether solvent;
b) adding maleic acid solution prepared by combining maleic acid in isopropyl alcohol;
c) stir the contents for the duration ranging between 1 hour to 3 hours at 25-30°C; and
d) isolatingcrystalline Afatinib dimaleate crystalline Form-SAM.

In an another aspect of the present invention relates to Afatinib dimaleate having a purity of greater than 99.4 %, wherein Afatinib dimaleateobtained is having moisture content less than 2 % w/w (by KF method)

In an another aspect of the present invention relates to Afatinib dimaleate having a purity of greater than 99.4 % by HPLC and having total impurities A to E collectively less than 0.6 % by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1is an example of X-ray powder diffraction (“XRPD”) pattern of Afatinib dimaleate crystalline Form-SAM obtained according the present invention.
Fig. 2is an example of slow scan X-ray powder diffraction (“XRPD”) pattern of Afatinib dimaleate crystalline Form-SAM obtained according the present invention.
Fig. 3is an example of DSC endotherm of Afatinib dimaleate crystalline Form-SAM obtained according the present invention.
Fig. 4 is an example of TGA thermogram of Afatinib dimaleate crystalline Form-SAM obtained according the present invention.

DETAILED DESCRIPTION OF THE INVENTION
Although several polymorphs of Afatinib dimaleate have been identified and well known in the literature, each polymorphic form can be distinguished using several different analytical parameters, alone or in combination, such as, but not limited to, powder X-ray diffraction pattern peaks or combinations of two or more peaks. However, the present inventors now developed a new stable crystalline polymorphic form, which aredifferent from the prior-art polymorphic forms disclosed in the literature.

In one embodiment of the present inventionrelates to a novel Afatinib dimaleate crystalline Form-SAM characterized X-ray powder diffraction pattern comprising characteristic 2?° peaks at 4.9, 6.4, 7.3, 8.0, 10.4, 17.1, 19.7, 21.1, 22.5, 23.5, 25.4 ±0.2°2?; and DSC isotherm comprising endothermic peak at 175 to 182°C.

Afatinib dimaleate crystalline Form-SAMis further characterized by X-ray powder diffraction pattern comprising at 2?° peaks selected from 12.9, 13.6, 14.8 and 17.6 ±0.2°2?

Afatinib dimaleate crystalline Form-SAMis further characterized by DSC isotherm comprising endothermic peak ranging between 176to181°C.

The present invention further provides a process for the preparation of Afatinib dimaleate crystalline Form-SAM characterized by X-ray powder diffraction pattern comprising characteristic 2?° peaks at 4.9, 6.4, 7.3, 8.0, 10.4, 17.1, 19.7, 21.1, 22.5, 23.5, 25.4 ±0.2°2? comprising the steps of:
a) dissolving Afatinib dimaleate in a mixture of isopropyl alcohol and Methyl tertiary butyl ether solvent;
b) adding maleic acid solution prepared by combining maleic acid in isopropyl alcohol;
c) stir the contents for the duration ranging between 1 hour to 3 hours at 25-30°C; and
d) isolatingcrystalline Afatinib dimaleate crystalline Form-SAM.

Polymorphism in Afatinib dimaleate has peculiar behavior and shows minor variations with respect to reported forms, e.g., absence of peaks at 19.4 and 22.9, which are known characteristic peaks in the crystalline form, disclosed in Soyka et al in US 8,426,586. The absence of these peaks were analyzed by various methods, but not limited to slow scan XRPD run at the desired 2? values for assessment of any presence.

In one embodiment of the present invention, said Afatinib dimaleate crystalline Form-SAM obtained according to the process was found to possess weight loss ranging between 0.2-1.5 %. (By TGA).

In one embodiment of the present invention, said Afatinib dimaleate crystalline Form-SAM obtained according to the process was found to possess moisture content ranging between 0.2-2 %. (By KF method).

The present inventors analyzed Afatinib dimaleate crystalline Form-SAM for Hygroscopic study. However, the present inventors found that the Non-solvated Afatinib dimaleate crystalline Form-SAM obtained by the present invention is hygroscopic.

The study was performed by exposing Afatinib dimaleate crystalline Form-SAM at 80 ± 2 % relative humidity in desiccator at 25°C containing potassium chloride solution kept in glass petri-dish and placed it into desiccator.Samples were withdrawn and analyzed at different time intervals, the results are as follows:
S.No Time (in Hours) Water content (%)
1 Initial 5.26 %
2 5th hour 10.32 %
3 8th Hour 10.45 %
4 24 hours 10.47 %
5 48 hours 11.73 %
6 72 hours 10.24 %

Further embodimentof the present invention provides crystalline Afatinib dimaleate Form-SAM obtained by the present invention is free of other polymorphic impurities, wherein said crystalline form is present in a solid form greater than 99.4%by weight.

Afatinib dimaleate crystalline Form-SAM is found to be a very stable crystal lattice which is adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics. Afatinib dimaleate crystalline Form-SAM retains its nature even on exposure to uncontrolled environmental conditions. This stable form thus, offers various advantages in terms of storage, shelf life and favorable impurity profile.
Any form of Crude or Pure Afatinib dimaleateobtained by any process may be used for preparing Afatinib dimaleate crystalline Form-SAM. Afatinib dimaleate crystalline Form-SAMof the present invention may have one or more advantageous and desirable properties compared to the known Crystalline Afatinib dimaleate forms, which are not limited to better stability, high solubility and high purity leading to improved storage and distribution.

The process related impurities, including degradation products and other medium dependent impurities like residual solvent, that appear in the impurity profile of the Afatinib dimaleatecan be substantially removed by the process of the present invention resulting in the formation pure Afatinib dimaleate crystalline Form-SAM. A substantially pure product i.e. Afatinib dimaleate crystalline Form-SAM having purity more than 99.4% (by HPLC) can be obtained in high yield by the process of the present invention.

The Afatinib dimaleate crystalline Form-SAMdescribed herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetric (DSC) Analysis and TGA. The samples of Afatinib dimaleate crystalline Form-SAM were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 Å. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative example of analytical data for the Non-solvated Afatinib dimaleate crystalline Form-SAM obtained in the Examples is set forth in the Figures 1-4.

The Afatinib used in the present invention is prepared by comprising the steps of chargingS-(+)-3-hydroxytetrahydrofuranin to reaction flask containing a solvent selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidoneat a temperature ranging from 25-30 °C. The contents are cooled to 0-5 °C andthen added Potassium tert-butoxide. The contents are stirred for 1 hour to 3 hours at 0-5°C. To the reaction mixture N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine was added at 0-5 °C. The reaction mass was allowed to room temperature and stirred for two hours at 25-30 °C. Water was added to the reaction mass at room temperature and cooled to 10-15 °C. pH was adjusted to ~ 6.5-7.5 using hydrochloric acid. The reaction mass was allowed to room temperature and stirred for 1 hour to 3 hours at room temperature. The precipitated solid was filtered and washed with Water and suck dry for 1-2 hours. The product was dried at 60-65 °C under vacuum for 24-30 hours to obtain N-(3-Chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy) quinazoline-4-amine.

The above obtained N-(3-Chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy) quinazoline-4-amine was undergo reduction in presence of a solvent selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohol solvent selected from methanol, ethanol, propanol, isopropanol, butanol at a temperature ranging from 25-30°C for a period of 2 hours to 6 hours in presence of a reducing agent selected from borane complexes; metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel; in the presence of hydrogen or hydrogen source, selected from ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine. The obtained reaction mass was filtered and washed a solvent selected from alcohols selected from methanol, ethanol, propanol, isopropanol, butanol. Waterwas added into reaction mass under stirring at 10-15 °C and stirred for 1 hour to 3 hours. The precipitated solid was filtered and washed with Water and suck dried for 1 hour to 3 hours. The product was dried at 60-65 °C under vacuum for 24-32 hours to obtain 7-((S)-tetrahydrofuran-3-yloxy)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine.

1-Methyl-2-pyrrolidone and trans-4-Dimethylaminocrotonic acid hydrochloride was charged in to reaction flask at 25-30 °C and stirred for 30 minutes. The reaction mass was cooled to 0 to -5 °C. To the obtained reaction mass halogenating agent was added selected from Thionyl chloride, POCl3, PCl3, PCl5was added slowly into reaction mass for a period of 15 minutes to 20 minutes and stirred the contents for 30 minutes at 0-5 °C.

To the above obtained reaction mass 7-((S)-tetrahydrofuran-3-yloxy)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amineadded at 25-30 °C and the reaction mixture was stirred for 2-3 hours at 0 to -5 °C. To the obtained reaction mixture, water was slowly added at 10-15 °C.pH of the aqueous layer was adjusted to ~8.0- 9.0 with aqueous ammonia solution. The reaction mixture was allowed to room temperature and extracted with a solvent selected from Ethyl acetate. The organic layer was washed with sodium chloride solution and distilled out at 40-45 °C under vacuum. To the obtained reaction mass, water was added and stirred for 1 hour to 3 hours at 25-30 °C. The precipitated solid was filtered and washed with Water and n-Heptanes.The product was dried at 38-40 °C under vacuum for 24-32 hours to Afatinib.

The crude Afatinib obtained from the above stage may be purified by treating the compound of the formula (I) or a reaction mixture or a solvated form thereof is treated with an acid selected from methane sulphonic acid, sulphuric acid, trifluoro-methanesulphonic acid, difluoromethanesulphonic acid, dichloroacetic acid, glucornic acid, gluconic acid, Ferulate, glycols and glycol ethers; to form a salt of the compound of the formula (I) which precipitates from the solution containing the solvated compound of the formula (I), the salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the pure form of compound of the formula (I), preferably at a temperature of from 15° C. to 45° C., most preferably from 25° C. to 35° C. If required, repeat again the acidification followed by basification to obtained desired purity, which is greater than 99.5 %.

The Afatinib is dissolved in a solvent selected from solvent selected from alcohol (C1-3) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof. To the obtained solution acid was added at a temperature ranging from -10 to 30°C for 30 min to 2 hrs to yield wet product, which was dried under vacuum at 50-55°C for 2hrs to yield Afatinib acid salt.

The obtained Afatinib acid saltis dissolved in a solvent selected from solvent selected from alcohol (C1-4) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof at a temperature ranging from 25-30°C and stirred for 30min to get clear solution. The obtained solution was treated with an alkaline solution, wherein alkaline solution used is prepared using a base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate; in a solvent selected from organic solvent or water. The reaction mass was stirred for 30 min to 4 hrs depending on the acid used. After completion of the reaction, the reaction mass was cooled to a temperature ranging from 0-10°C and maintained the reaction mass under stirring for 30min to 4 hrs. The precipitated product was filtered, washed with organic solvent or a mixture of organic solvent or mixture of organic solvent and water to get wet cake, which was dried under vacuum at 50-85°C for 3 hrs to 6hrs to yield pure Afatinib.

The obtained pure Afatinib was analyzed, if it is not matching with the desired purity; again repeat the process by treating the Afatinib with acid to prepare the corresponding salt, followed by treating with an alkali solution to obtain substantially pure Afatinib having a purity of greater than 99.5% and meeting the ICH guidelines.

Above obtained pure Afatinib is used as an input for the preparation of Afatinib dimaleate, which parallel yields in the preparation of highly pure Afatinib dimaleate. The obtained pure Afatinibdimaleate was analyzed, if it is not matching with the desired purity.Afatinib dimaleate was purified by dissolving in a solvent andthen heating the contents to the desired temperature followed by isolating/recovering pure Afatinib dimaleate. The obtained substantially pure Afatinibdimaleate having a purity of greater than 99.5%, which meeting the ICH guidelines will be isolated. The process schematic representation is as shown below:

In another embodiment the present invention related to highly pure Afatinib dimaleate having a purity of greater than 99.4 % and total impurities A to E collectively less than 0.6 % by HPLC.

Impurity - A
Impurity - B

Impurity - C
Impurity - D

Impurity - E

Afatinib dimaleate obtained by this process is substantially pure Afatinib dimaleate, wherein substantially pure Afatinib dimaleate contains the process related impurities A, B, C, D and E collectively below 0.6 % and meeting the ICH guidelines.

The use of pure Afatinib dimaleate in the preparation of new polymorphic form parallel results in the formation of substantially pure crystalline forms of Afatinib dimaleate having a purity of greater than 99.5 %, wherein substantially pure Afatinib dimaleate is having an impurity profile meeting the ICH guidelines. The polymorph related impurities formed during the crystallization of crude Afatinib dimaleate has been successfully removed by the present process, which yields in the formation of highly pure crystalline forms of Afatinib dimaleate

Another embodiment of the present invention relates to substantially pure crystalline Afatinib dimaleate having a purity of greater than 99.4 %, wherein substantially pure Afatinib dimaleate contains the process related impurities A, B, C, D and E collectively below 0.6 % area percentage by HPLC and meeting the ICH guidelines.

The process related impurities that appear in the impurity profile of the Afatinib dimaleate (I) may be substantially removed by the process of the present invention resulting in the formation of substantially Afatinib dimaleate (I), which meets the ICH guidelines.

Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic formulation development. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility. The improvement of drug solubility thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. The enhancement in the purity of Afatinib dimaleate and crystalline arrangement of novel polymorphic forms (Afatinib dimaleate Form-SAM) which is free of process related impurities inherently increases the solubility of Afatinib dimaleate, which plays a major role for enhancement of drug dissolution rate in solid oral dosage forms.

The present invention also relates to a process for the preparation of Afatinib dimaleate, which is substantially pure having a purity of greater 99.4 % and meeting the ICH guidelines, by limiting the content of each impurity less than 0.6%. Further, the Afatinib dimaleate obtained as per the present process is found devoid of any other process related impurities and is adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 40-60°C for a time ranging from 5 to 15 hours depending upon the physical attributes of the end product obtained i.e. Pure Afatinib dimaleate, which is obtained according to the present invention is having purity greater than 99.4%.

In another embodiment of the present invention the substantially pure Afatinib dimaleate obtained by the processes of the present application may be taken as such in crystalline form for manufacture of solid dosage forms like tablets, capsules and/or for manufacture of oral liquids.

In another embodiment of the present invention the substantially pure crystalline form of Afatinib dimaleate (Form-SAM) obtained by the processes of the present application may be manufactured as the amorphous form by processing with polymers like hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

In another embodiment, the substantially pure crystalline form of Afatinib dimaleate (Form-SAM) obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with the substantially pure Afatinib dimaleateor its acid addition salt, while retaining the crystalline nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising substantially pure Afatinib or its acid addition saltobtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, di-calcium phosphate, tri-calcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, 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, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from substantially pure Afatinib or its acid addition saltof the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example-1
Preparation of N-(3-Chloro -4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy) quinazoline-4-amine:
S-(+)-3-hydroxytetrahydrofuran(208.0 gm, 2.36 mol) was charged in DMF (2.0 lit) at 25-30 °C and cooled to 0-5 °C and added Potassium tert-butoxide (264.0 gm, 2.36 mol) and stirred for one hours at 0-5 °C. To the reaction mixture N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (200.0 gm, 0.59 mol) was added at 0-5 °C. The reaction mass was allowed to room temperature and stirred for two hours at 25-30 °C. DM Water (2.0 lit) was added to the reaction mass at room temperature and cooled to 10-15 °C. 2N HCl (~800.0 ml) was added at 10-15 °C and pH was adjusted to ~ 6.5-7.5. The reaction mass was allowed to room temperature and stirred for one hour at room temperature. The precipitated solid was filtered and washed with DM Water (500.0 ml) and suck dry for 1-2 hours. The product was dried at 60-65 °C under vacuum for 24-30 hours to obtain title product as yellow color solid.
Yield: 240 g
Chromatographic Purity (By HPLC): 99.52%;
Moisture Content-1.63%

Example-2
Preparation of 7-((S)-tetrahydrofuran-3-yloxy)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine:
Methanol (1.16 lit), DMF (440 ml) and N-(3-Chloro -4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy) quinazoline-4-amine (100.0 gm, 0.25 mol) charged into autoclave at 25-30 °C. Ammonium Chloride (20.0 gm, 0.37 mol) and Raney-Ni (40.0 gm in 500.0 ml methanol) added into autoclave at 25-30 °C and stirred for 4 hours at 25-30 °C. Reaction mass was filtered through celite bed and washed with methanol (200.0 ml). The filtrate was distilled out at 50-55 °C under vacuum and reaction mass was cooled to 10-15 °C. DM water (4.0 lit) was added into reaction mass under stirring at 10-15 °C and stirred for one hour. The precipitated solid was filtered and washed with DM Water (400.0 ml) and suck dried for 1-2 hours. The product was dried at 60-65 °C under vacuum for 24-32 hours to obtain the title product.
Yield: 70 g
Chromatographic Purity (By HPLC): 99.23%;
Moisture Content-1.23%

Example-3
Preparation of N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide (Afatinib):
1-Methyl-2-pyrrolidone (330.0 ml) and trans-4-Dimethylaminocrotonic acid hydrochloride (33.0 gm, 0.20 mol) charged at 25-30 °C in to RBF and stirred for 30 minutes. The reaction mass was cooled to 0 to -5 °C. Thionyl chloride (14.50 ml, 0.20 mol) was added slowly into reaction mass in 15- 20 minutes and stirred for 30 minutes at 0 to -5 °C.7-((S)-tetrahydrofuran-3-yloxy)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (50.0 gm, 0.13 mol) was dissolved in 1-Methyl-2-pyrrolidone (250.0 ml) at 25-30 °C and added into reaction mixture at 0 to -5 °C and stirred for 2-3 hours at 0 to -5 °C. Reaction mixture was slowly added into DM Water (2.25 lit) at 10-15 °C. The pH of the aqueous layer was adjusted to ~8.0- 9.0 with aqueous ammonia solution (~150.0 ml) at 10-15 °C. The reaction mixture was allowed to room temperature and extracted in Ethyl acetate (2 × 1125 ml). The organic layer was washed with sodium chloride solution (NaCl 75.0 gm in 500.0 ml DM Water) and distilled out at 40-45 °C under vacuum. To the residue DM Water (250.0 ml) was added and stirred for one hour at 25-30 °C. The precipitated solid was filtered and washed with DM Water (200.0 ml) and n-Heptanes (100.0 ml). The product was dried at 38-40 °C under vacuum for 24-32 hours to obtain title product.
Yield: 42 g
Chromatographic Purity (By HPLC): 99.49%;

Example-4
Preparation of Afatinib dimaleate:
Afatinib (10.0 gm, 0.021 mol) was charged into mixture of solvents isopropyl alcohol (240.0 ml) and Methyl tert-butyl ether (20.0 ml) andstirred at room temperature to get clear solution. The solution of Maleic Acid (5.0 gm, 0.043 mol) in isopropyl alcohol (140.0 ml) was charged slowly for a period of 1 hour to 2 hours to the reaction mixture at 25-30 °C and stirred for 2 to 3 hours at 25-30 °C. The precipitated solid was filtered and washed with isopropyl alcohol (20.0 ml). The product was dried under vacuum for 12-15 hrs at 40-45 °C to obtain light yellow color solid.
Yield: 12.3 g
Chromatographic Purity (By HPLC): 99.49%;

Example-5
Hygroscopic study of Afatinib dimaleate
By exposing Afatinib dimaleate crystalline Form-SAMat 80 ± 2 % relative humidity in desiccator at 25°C containing saturated potassium chloride solution kept in glass petri-dish and placed it into desiccator.
Samples were withdrawn and analyzed at different time intervals, the results are as follows:
S.No Time (in Hours) Water content (%)
1 Initial 5.26 %
2 5th hour 10.32 %
3 8th Hour 10.45 %
4 24 hours 10.47 %
5 48 hours 11.73 %
6 72 hours 10.24 %

In view of the above it was very clear that Afatinib dimaleate crystalline Form-SAM, obtained as per the present invention is hygroscopic.

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are for illustrative purpose only of the core of the invention and non-limiting in their scope. Furthermore, as many changes maybe made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.