WO2015170345A1 - Pharmaceutical cocrystals of gefitinib - Google Patents

Abstract

The present invention discloses pharmaceutical co-crystals of gefitinib with co-crystal former selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids which exhibit better solubility, dissolution rate hence enhanced bioavailability compared to the parent drug.

Description

PHARMACEUTICAL COCRYSTALS OF GEFITINIB

FIELD OF THE INVENTION

[0001] The present invention relates to pharmaceutical co-crystals of gefitinib with co-crystal former selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids which exhibit better solubility, dissolution rate hence enhanced bioavailability as compared to the pure drug. Particularly, present invention relates to a process for the preparation of pharmaceutical co-crystals of gefitinib. More particularly, the present invention relates to pharmaceutical composition of gefitinib and at least one pharmaceutically acceptable carrier.

BACKGROUND AND PRIOR ART OF THE INVENTION

[0002] Gefitinib is an anilinoquinazoline (N-(3-chloro-4-fluoro-phenyl)-7-methoxy- 6-(3-morpho!in-4-ylpropoxy) quinazolin-4-amine) with the chemical name 4- Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-mo holin) propoxy]. It has the molecular formula C₂₂H24C1FN403, a relative molecular mass of 446.9 and is a white-colored powder. Gefitinib is a free base. The molecule has pKa's of 5.4 and 7.2 and therefore ionizes progressively in solution as the pH falls. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility dropping sharply between pH 4 and pH 6. In non-aqueous solvents, Gefitinib is freely soluble in glacial acetic acid and dimethylsulphoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and Acetonitrile.

N-(3-ch!oro-4-(luoro-phenyl)-7-methox -

Chemical structure of gefitinib [0003] Gefitinib is an anticancer drug commonly used for the treatment of non- small-cell lung and breast cancer. Gefitinib acts as an inhibitor of mutated or overactive epidermal growth factor receptor (EGFR) by binding to the ATP binding site. Because epidermal growth factors are responsible for controlling cell growth and proliferation, a mutated form would likely facilitate cancer growth and development. In May 2003, the orally administered EGFR inhibitor gefitinib was approved by Food and Drug Administration as third-line therapy for non-small-cell lung cancer. In phase I studies, gefitinib was active against non-small-cell lung cancer across a broad range of doses, and in randomized phase II trials, response rate of 9% to 19% were reported with the use of doses of 250 or 500 mg per day. Gefitinib is sparingly soluble in aqueous solution (0.027 mg/mL). Gefitinib is a selective epidermal growth factor receptor (EGFR)-tyrosin kinase inhibitor. Many titles in the literature refer to Gefitinib as a "specific" or "selective" inhibitor of EGFR. Gefitinib binds at the ATP site of the T (tyrosine Kinase) region, a region that is highly conserved across the various transmembrane TKs.

[0004] Pharmaceutical co-crystals have attracted phenomenal interest in recent years for their potential for improving the physicochemical properties of drug substances. Apart from offering potential improvements in solubility, dissolution rate, bioavailability and physical stability, pharmaceutical co-crystals can enhance other essential properties of the APIs such as flowability, chemical stability, compressability and hygroscopicity. Co-crystals are homogeneous solid phases containing two or more neutral molecular components in a crystal lattice with defined stoichiometry, which are solids at room temperature and are held together by weak interactions, mainly hydrogen bonding. In co-crystals at least one component is molecular and a solid at room temperature i.e. co former and forms a supramolecular synthon with a molecular or ionic API. The first co-crystal synthesized was quinhydrone which is a 1 : 1 co-crystal between benzoquinone and hydroquinone.

[0005] API in pharmaceutical compositions can exist in variety of distinct solid forms and each form exhibit unique physiochemical properties such as morphology, hygroscopicity and more significantly the solubility. However, the desirable molecular pharmacological properties of some of the potentially useful drug compound could not be utilized to its maximum potential because the physical properties of the bulk compound show unfavorable bioavailability, unwanted processing characteristics, and unacceptable shelf life. Therefore, the active pharmaceutical ingredients (API) in pharmaceutical compositions can be prepared in a variety of different chemical forms to address these issues. The current methods of altering the solid state properties of API include exploitation of polymorphs, salts, hydrates, and solvates. For example the crystalline polymorphs typically have different solubility from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical co-crystals can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.

[0006] New forms of APIs having improved properties such as increased aqueous solubility and stability in oral formulations is always preferred. It is also advantageous to improve the processability and crystallization of formulation so as to avoid obtaining the needle shaped crystals which causes aggregation and thus affects the compression properties and poses difficulties in tablet making. It is also desirable to increase the dissolution rate of API- in aqueous solution which eventually increases its bioavailability and thus provide a more rapid onset to therapeutic effect. The new co- crystalline forms of APIs can be obtained as free acid, free base, zwitterions, salts, etc. which improve the properties of APIs as compared to such APIs in a non-co-crystalline state.

[0007] The utility co-crystals as a means to improve the solubility and dissolution rates of solid forms of drugs are reported in the published literature (N. Blagden, M. de Matas, P.T. Gavan and P. Cork, Advanced Drug Delivery Rev., 2007, 59, 617-630). [0008] The literature study reveals that one anhydrous (WO 96/33980), trihydrate and two solvates with methanol and DMSO (WO 03/072108) and monohydrate (WO2006/090413 Al) of this life saving drugs is reported in the patents.

[0009] PCT Publication no. 2003072108 discloses certain crystalline solvates and hydrates of gefitinib. The invention discloses a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD 1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD 1839 trihydrate.

[0010] US patent application no. 20050209229 concerns a first solvate that occurs in the presence of methanol which is designated as Form 2 ZD 1839 MeOH solvate, a second solvate that occurs in the presence of dimethyl sulphoxide which is designated as Form 3 ZD 1839 DMSO solvate and a trihydrate that occurs in the presence of water which is designated Form 5 ZD 1839 trihydrate.

[0011] PCT Publication no. 2006090413 discloses a stable novel crystalline form of Gefitinib designated as Form-6, and a process for the preparation of the same. The invention further discloses a pharmaceutical composition useful for anti-cancer activity comprising the novel stable crystalline Form-6 of Gefitinib and a pharmaceutically acceptable carrier.

[0012] US patent application no. 2010031 1701 discloses a co-crystal of an API and a co-crystal former; wherein the API has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, imine, thiocyanate, cyanamide, oxime, nitrile diazo, organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring, pyrrole, O-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, pyridine and the co-crystal former has at least one functional group selected from amine, amide, pyridine, imidazole, indole, pyrrolidine, carbonyl, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methyl thio, such that the API and co-crystal former are capable of co-crystallizing from a solution phase under crystallization conditions.

[0013] PCT Publication no. 2014016848 discloses solid forms of tyrosine kinase inhibitors, in particular combinations of tyrosine kinase inhibitors with anti-oxidative acids, wherein the kinase inhibitor is imatinib, gefitinib, erlotinib, sorafenib, nilotinib, dasatinib, lapatinib, or sunitinib and the antioxidative acid is a benzoic acid derivative selected from p-hydroxy benzoic acid, vanillic acid, syringic acid, or 3,4-dihydroxy benzoic acid and cinnamic acid derivative is selected from p-coumaric acid, ferulic acid, sinapic acid, or caffeic acid. The invention also particularly describes a solid form comprising gefitinib and caffeic acid, or gefitinib and p-coumaric acid, or gefitinib and ferulic acid, wherein the solid form is a salt, a co-crystal, or a polymorph of a salt or of a co-crystal.

[0014] Therefore, there is a need in the art to provide improved solid forms of gefitinib having better solubility, dissolution rate and hence enhanced bioavailability. Accordingly, the present inventors provide co-crystals of gefitinib which exhibit better solubility, dissolution rate hence enhanced bioavailability as compared to parent drug. OBJECTIVE OF INVENTION

[0015] The main objective of the present invention is to provide pharmaceutical co- crystals of gefitinib which exhibit better solubility, dissolution rate hence enhanced bioavailability and processes for their preparation.

[0016] Another objective of present invention is to provide co-crystals of gefitinib with co-crystals coformers selected from aliphatic dicarboxylic acid and aromatic di and tri carboxylic acid to enhance the aqueous solubility of the API so as to increase the dissolution and hence affecting its bioavailability so that it is easily absorbed as a medication in the systemic circulation.

[0017] Yet another objective of present invention is to provide a pharmaceutical composition comprising pharmaceutical co-crystals of gefitinib and at least one pharmaceutically acceptable carrier.

SUMMARY OF THE INVENTION [0018] Accordingly, present invention provides a pharmaceutical co- crystals of gefitinib comprising gefitinib and co-crystal formers selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids in stoichiometric ratio in the ratio ranging between 1 :0.5 to 1 :3, characterized in that solubility and dissolution of co- crystals is enhanced.

[0019] In an embodiment of the present invention, aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids are selected from oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives such as /?-amino benzoic acid and 7-chloro benzoic acid and the like.

[0020] In another embodiment of the present invention, said cocrystals are useful in the treatment of cancer.

[0021] The pharmaceutical co-crystal of gefitinib as claimed in claim 1, wherein the co-crystal of gefitinib may prepared by various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding.

[0022] In yet another embodiment of the present invention, the solution crystallization and liquid-assisted grinding are done by the solvent selected from polar organic solvent either alone or in aqueous mixture thereof, preferably the polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, dichloromethane, dimethylformamide and the like.

In yet another embodiment, present invention provides a pharmaceutical composition comprising pharmaceutical co-crystals of gefitinib as claimed in claim 1 with one or more pharmaceutically acceptable carriers.

[0023] In yet another embodiment of the present invention, said composition is useful in the treatment of cancer.

[0024] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and oxalic acid having characteristic peaks in X-ray powder diffraction pattern at 5.2, 8.0, 9.9, 18.25 and 26.4. [0025] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and malonic acid having characteristic peaks in X-ray powder diffraction pattern at 8.6, 16.4, 20.2, 25.5, 37.0 and 42.2.

[0026] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and succinic acid having characteristic peaks in X-ray powder diffraction pattern for G-SAl at 6.4, 9.4, 20.0, 22.2, 26.0, 27.4, 28.5 and for G-SA2 at 5.7, 8.8, 12.3, 15.0, 17.7, 21.3, 22.6, 26.3, 28.4.

[0027] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and glutaric acid having characteristic peaks in X-ray powder diffraction pattern at 5.3, 1 1.6, 21.8, 26.6.

[0028] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and adipic acid having characteristic peaks in X-ray powder diffraction pattern for G-AA1 at 5.7, 10.3, 12.2, 20.0, 23.5, 26.3, for G-AA2 at 5.7, 10.4, 17.8, 20.2, 23.4, 26.1 and for G-AA3 at 4.8, 5.9, 1 1.1, 15.7, 17.8, 20.6, 23.8, 25.6, 26.3.

[0029] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and fumaric acid having characteristic peaks in X-ray powder diffraction pattern at 4.0, 7.2, 16.1, 19.5, 23.0, 24.4, 26.8 and 29.0.

[0030] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and citric acid having characteristic peaks in X-ray powder diffraction pattern at 5.4, 9.4, 10.7, 13.8, 20.2, 23.9, 27.2

[0031] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and terephthalic acid having characteristic peaks in X-ray powder diffraction pattern for TA1 at 5.7, 17.4, 20.6, 23.1, 26.3, 29.0, 30.6.

[0032] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and benzoic acid which exhibits characteristic DSC endothermic peak at l54.13°C. [0033] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and p-amino benzoic acid having characteristic peaks in X-ray powder diffraction pattern at 4.8, 21.6, 22.5, 23.5, 26.4 and 30.8.

[0034] In yet another embodiment of the present invention, said co-crystal is composed of gefitinib and p-chloro benzoic acid having characteristic peaks in X-ray powder diffraction pattern at 4.66, 15.58, 16.72, 20.5, 25.94.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1: The ORTEPs of cocrystals (a) pure gefitinib anhydrous Form I crystals, (b) gefitinib- oxalic acid cocrystals (1 : 1), with two molecules of water (solvent system: isopropanol-water mixture, 1 :1 , v/v), (c) gefitinib-malonic acid cocrystals (1 : 1) (solvent system: n-Butanol), (d) gefitinib-succinic acid cocrystals (1 : 1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib- succinic acid cocrystals (1 :2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (g) gefitinib-adipic acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water mixture (1 :1, v/v), (h) gefitinib-adipic acid cocrystals (1:1 ) with one molecule of water (solvent system: n-butanol), (i) gefitinib-adipic acid cocrystals (1 :2) with one molecule of water (solvent system: nitrobenzene), (j) gefitinib-fu marie acid cocrystals (1 :1.5) with one molecule of water (solvent system: ethanol-water (1 :1, v/v), (k) gefitinib-citric acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (1) gefitinib-terephthalic acid cocrystal (1 : 1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (m) gefitinib-terephthalic acid cocrystal (1 :0.5) with two water molecule (solvent system:ethyl acetate), (n) gefitinib-benzoic acid cocrystal (1 :2) (solvent system: acet one- CCU_, 1 : 1, v/v), (o) gefitinib - /7-amino benzoic acid cocrystal (1 :1) with one molecule of water (solvent system: acetone-CCU. 1 : 1, v/v). (p) gefitinib - 7-chloro benzoic acid cocrystal (1 : 1) with one molecule (solvent system: ethanol-water (1 :1 , v/v).

[0036] Figure 2: The collected DSC thermogram of (a) pure gefitinib anhydrous Form I crystals, (b) gefitinib-oxalic acid cocrystals (1 :1), with two molecules of water (solvent system: isopropanol-water mixture, 1 :1 , v/v), (c) gefitinib-malonic acid cocrystals (1 :1) (solvent system: n-Butanol), (d) gefitinib-succinic acid cocrystals (1 :1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib-succinic acid cocrystals (1 :2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (g) gefitinib-adipic acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water mixture (1 :1 , v/v), (h) gefitinib-adipic acid cocrystals (1 : 1) with one molecule of water (solvent system: n-butanol), (i) gefitinib-adipic acid cocrystals (1 :2) with one molecule of water (solvent system: nitrobenzene), (j) gefitinib-fumaric acid cocrystals (1 :1.5) with one molecule of water (solvent system: ethanol-water (1 :1, v/v), (k) gefitinib-citric acid cocrystals (1: 1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (1) gefitinib-terephthalic acid cocrystal (1 : 1) with two molecules of water (solvent system: ethanol-water (1 :1, v/v), (m) gefitinib-benzoic acid cocrystal (1 :2) (solvent system: acetone- CC1_4, 1 :1, v/v), (n) gefitinib- p-amino benzoic acid cocrystal (1 :1) with one molecule of water (solvent system: acetone-CCU. 1 :1, v/v).

[0037] Figure 3: The collected thermogravemetric analysis of (a) pure gefitinib anhydrous Form I crystals, (b) gefitinib-oxalic acid cocrystals(l: l), with two molecules of water (solvent system: isopropanol-water mixture, 1 :1, v/v), (c) gefitinib-malonic acid cocrystals (1:1) (solvent system: n-Butanol), (d) gefitinib-succinic acid cocrystals (1 : 1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib-succinic acid cocrystals (1 :2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1 : 1) with two molecules of water (solvent system: ethanol-water, 1 :1, v/v), (g) gefitinib-adipic acid cocrystals (1 :1) with two molecules of water (solvent system: ethanol-water mixture, 1 :1, v/v),(h) gefitinib-adipic acid cocrystals (1 :1) with one molecule of water (solvent system: n-butanol), (i) gefitinib-adipic acid cocrystals (1:2) with one molecule of water (solvent system: nitrobenzene), (j) gefitinib-fumaric acid cocrystals (1 : 1.5) with one molecule of water (solvent system: ethanol-water, 1 : 1, v/v), (k) gefitinib-j3-amino benzoic acid cocrystal (1:1) with one molecule of water (solvent system: acetone-CCl₄.1:1, v/v).

[0038] Figure 4: The collected PXRD patterns of gefitinib and cocrystals of gefitinib, (a) pure gefitinib anhydrous Form I crystals (b) gefitinib- oxalic acid cocrystals (1:1), with two molecules of water (solvent system: isopropanol-water mixture, 1:1, v/v), (c) gefitinib-malonic acid cocrystals (1:1) (solvent system: n- Butanol), (d) gefitinib-succinic acid cocrystals (1:1) with two molecules of water (solvent system: acetonitrile), (e) gefitinib- succinic acid cocrystals (1:2) (solvent system: nitromethane), (f) gefitinib-glutaric acid cocrystals (1:1) with two molecules of water (solvent system: ethanol-water, 1:1, v/v), (g) gefitinib-adipic acid cocrystals (1:1) with two molecules of water (solvent system: ethanol-water mixture, 1:1, v/v), (h) gefitinib-adipic acid cocrystals (1:1) with one molecule of water (solvent system: n- butanol), (i) gefitinib-adipic acid cocrystals (1:2) with one molecule of water (solvent system: nitrobenzene), (j) gefitinib-fumaric acid cocrystals (1:1.5) with one molecule of water (solvent system: ethanol-water, 1:1, v/v), (k) gefitinib-citric acid cocrystals (1:1) with two molecules of water (solvent system: ethanol-water (1:1, v/v), (1) gefitinib- terephthalic acid cocrystal (1:1) with two molecules of water (solvent system: ethanol- water, 1:1, v/v), (m) gefitinib - -amino benzoic acid cocrystal (1:1) with one molecule of water (solvent system: acetone-CCl₄. 1:1, v/v), (n) gefitinib- -Cl benzoic acid cocrystal (1:1) with one molecule of water (solvent system: ethanol-water.1:1, v/v).

[0039] Figure 5: The dissolution study of gefitinib (black) and cocrystals of gefitinib with various cocrystals former such as G-OA, G-MA G-SA], G-SA_2j G-FA, G-GA, GAALGAAZ.GAAJ.G-CA, G-TAI, G-J3ABA.

DETAILED DESCRIPTION OF THE INVENTION

[0040] Present invention provides pharmaceutical co-crystals of gefitinib which exhibit better solubility, dissolution rate hence enhanced bioavailability as compared to parent drug. [0041] In an aspect, the present invention provides pharmaceutical co-crystals of gefitinib with co-crystals coformers selected from aliphatic dicarboxylic acid and aromatic di and tri carboxylic acid in various compositions.

[0042] In another aspect, co-crystals coformers are selected from oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives such as 7-amino benzoic acid and p- chloro benzoic acid and the like.

[0043] The pharmaceutical co-crystal of gefitinib may be prepared by various co- crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding and solvent for solution crystallization and liquid assisted grinding is selected from polar organic solvent either alone or in aqueous mixture thereof, preferably the polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, DCM, DMF and the like.

[0044] In still another aspect, the present invention provides a pharmaceutical composition comprising co-crystals of gefitinib and at least one pharmaceutically acceptable carrier.

[0045] The invention further discloses use of the "composition of the invention" in preparing the medicament intended to treat cancer.

[0046] The ratio of gefitinib to coformers may be stoichiometric or non- stoichiometric according to the present invention.

[0047] The ratio of gefitinib to co-crystal formers is in the range of 1 :0.5 to 1 :3.

More preferably the ratio is in the range of 1 :0.5 to 1 :2, Most preferably the ratio is 1 : 1.

The present invention provides a controlled process for the synthesis of gefitinib cocrystals with various coformers selected from aliphatic and aromatic dicarboxylic and tricarboxylic acid in various compositions.

[0048] The processes for preparation include various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding.

Accordingly, the process for preparation comprises: i. providing a grinded mixture of amorphous gefitinib and a coformer in stoichiometric ratio in suitable solvent until complete dissolution and;

ii. crystallizing the co-crystals from the mixture or solution.

[0049] The solvent for solution crystallization and liquid assisted grinding is selected from polar organic solvent either alone or in aqueous mixture thereof. The polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, DCM, DMF and the like.

[0050] The novel co-crystals of gefitinib prepared by the process of instant invention are characterized by single crystal X-ray crystallography which is summarized below in Table 1 ; melting point, DSC analysis and TGA .

[0051] The value of the characteristic peaks in the X-ray powder diffraction pattern are described in 2-theta scale. The pharmaceutical co-crystal of gefitinib and oxalic acid showing characteristic peaks in X-ray powder diffraction pattern at 5.2, 8.0, 9.9, 18.25 and 26.4. The pharmaceutical co-crystal of gefitinib malonic acid showing characteristic peaks in X-ray powder diffraction pattern at 8.6, 16.4, 20.2, 25.5, 37.0 and 42.2. The pharmaceutical co-crystal of gefitinib and succinic acid showing characteristic peaks in X-ray powder diffraction pattern for G-SA1 at 6.4, 9.4, 20.0, 22.2, 26.0, 27.4, 28.5 and for G-SA2 at 5.7, 8.8, 12.3, 15.0, 17.7, 21.3, 22.6, 26.3, 28.4. The pharmaceutical co-crystal of gefitinib glutaric acid showing characteristic peaks in X-ray powder diffraction pattern at 5.3, 1 1.6, 21.8, 26.6. The pharmaceutical co-crystal of gefitinib and adipic acid showing characteristic peaks in X-ray powder diffraction pattern for G-AAl at 5.7, 10.3, 12.2, 20.0, 23.5, 26.3, for G-AA2 at 5.7, 10.4, 17.8, 20.2, 23.4, 26.1 and for G-AA3 at 4.8, 5.9, 1 1.1 , 15.7, 17.8, 20.6, 23.8, 25.6, 26.3. The pharmaceutical co-crystal of gefitinib and fumaric acid showing characteristic peaks in X-ray powder diffraction pattern at 4.0, 7.2, 16.1 , 19.5, 23.0, 24.4, 26.8 and 29.0. The pharmaceutical co-crystal of gefitinib and citric acid showing characteristic peaks in X- ray powder diffraction pattern at 5.4, 9.4, 10.7, 13.8, 20.2, 23.9, 27.2. The pharmaceutical co-crystal of gefitinib and terephthalic acid showing characteristic peaks in X-ray powder diffraction pattern for TA1 at 5.7, 17.4, 20.6, 23.1 , 26.3, 29.0, 30.6. The pharmaceutical co-crystal of gefitinib and p-amino benzoic acid showing characteristic peaks in X-ray powder diffraction pattern at 4.8, 21.6, 22.5, 23.5, 26.4 and 30.8. The pharmaceutical co-crystal of gefitinib and p-chloro benzoic acid having characteristic peaks in X-ray powder diffraction pattern at 4.66, 15.58, 16.72, 20.5, 25.94

The present invention provides a pharmaceutical composition comprising therapeutically effective amount of co crystals of gefitinib prepared by the processes of the present invention.

[0052] The pharmaceutical composition comprising a therapeutically effective amount of gefitinib with any one of the co-crystal former as mentioned above along with one or more suitable pharmaceutically acceptable carriers/excipients. Further, the pharmaceutical composition of the invention may be any pharmaceutical form which contains the co-crystals of the invention. The pharmaceutical composition may be solid form such as tablets, powders, capsule, liquid suspension or an injectable composition along with any suitable carrier well known in the prior art. The dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. Suitable excipients and the amounts to use may be radially determined by the standard procedures and reference works in the field, e.g. the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents, disintegrants, etc.

[0053] The invention relates to administering 'an effective amount' of the 'composition of invention' to the subject suffering from cancer. Accordingly, gefitinib co-crystals and the pharmaceutical composition containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for the treatment of cancer.

[0054] The present invention provides comparative solubility and dissolution studies of gefitinib (Form I) and pharmaceutical co-crystals of gefitinib.

[0055] The solubility and dissolution properties of gefitinib (Form I) and novel co- crystals of gefitinib with various co-crystal former is studied in HC1 solution of pH-3 using USP-certified Electrolab TDL-08 Tablet dissolution Tester at 37°C with a constant stirring speed of 50 rpm. Aliquots (1 ml) are withdrawn at specific intervals of time and replenished with an equal amount of fresh pH solution so as to maintain the constant volume. These aliquots were analyzed by UV spectrophotometer (UV-1601 PC, Shimadzu Scientific Instrument) at wavelength 253 nm and compared with standard calibration curve. The results are shown in the figure 5 and table 1.

Table: 1

[0056] These comparative solubility and dissolution studies of gefitinib (Form I) and novel co-crystal of gefitinib indicates improved solubility and dissolution rate of co- crystal at 3 pH solution. The dissolution profile reveals that the solubility of co-crystal of gefitinib prepared from malonic acid (MA), succinic acid (SA), fumaric acid (FA), glutaric acid (GA), adipic acid (AA), terphthalic acid (TA) and and />-amino benzoic acid (PABA) was found to be more than that of parent drug whereas the co-crystals obtained from oxalic acid (OA) and citric acid (CA) revealed less solubility. The less solubility of co-crystals G-OA and G-CA with respect to the solubility of parent drug could be attributed to the strong hydrogen bonding between the molecules of oxalic acid, citric acid with gefitinib.

[0057] The invention further discloses use of the "composition of the invention" in preparing the medicament intended to treat cancer. EXPERIMENTAL

A. CRYSTAL STRUCTURE INVESTIGATION

[0058] Single Crystal structure X-ray analysis of co-crystals of gefitinib with all the co-crystals formers were carried out at room temperature using a Bruker SMART APEX II single crystal X-ray CCD diffractometer, with graphite-monochromatised (Μο-Κα = 0.71073 A) radiation at room temperature. The X-ray generator was operated at 50 kV and 30 mA. Diffraction data were collected with a ω scan width of 0.5° and at different settings of φ and 2Θ. The sample-to-detector distance was fixed at 5.00 cm. The X-ray data acquisition was monitored by APEX2 program package. All the data were corrected for Lorentz-polarization and absorption effects using SAINT and SADABS programs integrated in APEX2 package. The structures were solved by direct methods and refined by full matrix least squares, based on F², using SHELX-97. Molecular diagrams were generated using ORTEP-32 and Mercury programs. Geometrical calculations were performed using SHELXTL and PLATON.

[0059] The preliminary investigation revealed that gefitinib co-crystals with oxalic acid (G-OA), malonic acid (G-MA), succinic acid (G-SA-1, G-SA-2), glutaric acid (G- GA), adipic acid (G-AA-1, G-AA-2, G-AA-3), fumaric acid(G-FA), citric acid (G-CA), terephthalic acid (G-TA-1, G-TA-2), benzoic acid (G-BA), p-amino benzoic acid (G- pABA) and p-chloro benzoic acid (G-pCBA) crystals have different unit cell parameters and thus may have exhibit different pharmaceutical compositions. The crystallography data of all the samples is summarized in Table 2.

Table 2. Crystallography data of cocrystals of gefitinib.

Δρ max,Ap_min/eA^* 0.568, -0.344 1.187, -0.455 0.471,-0.459 0.581,-0.412

Δρ max_jApmin e A^" 0.828, -0.497 0.383, -0.259 0.397,-0.358 0.514,-0.385

B. DSC ANALYSIS

[0060] The thermal behavior of gefitinib (form I known anhydrous form) and co- crystals of gefitinib with oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives was investigated by measuring the enthalpy change o a Mettler Toledo Differential Scanning Calorimeter instrument. Crystals (~ 3-5 nig) were placed in a sealed aluminium pan with crimped pan closure and were analyzed from room temperature 2S-2S0°C using an empty pan as the reference. The heating rate was T0°C min^'1 and nitrogen gas was used for purging. The DSC curve for form I crystals (known anhydrous form) of gefitinib showed onl a single sharp endothermic peak centered at 1.94.2°C corresponding to its melting point (Fig. 2a). The DSC thermo gram of all the co-crystals of gefitinib with oxalic acid, malonie acid, succinic acid, glutaric acid, adipic acid, fumarle acid, citric acid, .terepH^'thalic acid, benzoic acid and its derivatives revealed small phase transition endothermic peak followed by sharp endothemiic peak attributed to its melting. The DSC thermo gram of gefitinib oxalic acid co-crystal (G- QA, Fig. 2b) shows the phase transition peaks at 172.77, 186. 12, 227.55°C followed by a sharp melting endotherm at 248.68⁰C corresponding to its melting. In gefitftub- malonic acid co-crystals (G- A, Fig. 2c) the DSC thermogram shows the phase transition peak at j 17.54°C and sharp melting endotherm was observed at 17S,73°C. The DSC thermogram of gefitinib-succinic acid co-crystal (G-SA-1, Fig. 2d) revealed shar endothermic phase transition peak at. 137.55°C followed by a broad endothern at l73.6i°C corresponding to the melting point of the co-ery stal. The DSC thermogram of gefitinib-succinic acid co-crystal (G-SA-2, Fig, 2e) showed only one sharp endotherm at 168,63"C attributed to the melting point of co-crystal. The DSC thermogram of gefittnib-glutaric acid co-erysta s (G-GA, Fig. 21) shows the sharp endothermic. phase transition peak at 1 13.36°C followed by broad endotherm at I47:.45°C: corresponding to the melting point of the co-crystal. The DSC thermogram of gefitinib-adipic acid co- crystal (G-AA-1, Fig. 2 g) reveals the phase transition peak centred at. 130.87°C followed fey endotherm at 185.88°C corresponding to the melting point of the gefitinib- adipic acid co-crystal. The DS.C thermogram of gefitinib-adipic acid co-crystal (G-AA-. 2, Fig. 2h) reveals the phase transition peak centred at 1.37. °C followed endotherm at I 57.32°C, corresponding to the melting point of the gefitinib-adipic acid co-crystal. The DSC thermogram of gefitinib-adipic acid co-crystal (G-AA-3, Fig, 2i) reveals the phase transition peaks centred at 104.75, 123.25°C respectively followed a endotherm at 207.61°C corresponding to the it's melting. The DSC thermogram of gefitinib-fumaric acid co-crystal (G-FA, Fig. 2j) reveals the phase transition peaks centred at 126.17,195.73°C respectively followed a endotherm at 237.95°C corresponding to the melting point of the gefitinib-fumaric acid co-crystal. The DSC thermogram of gefitinib citric acid co-crystal (G-CA, Fig. 2k) reveals the phase transition peaks centered at 144.34°C followed a small endotherm at 193.84°C corresponding to the melting point of the gefitinib citric acid co-crystal. The DSC thermogram of gefitinib-terephthalic acid co-crystal (G-TA-l,Fig. 21) reveals the phase transition peaks centered at 136.18°C and 170.43°C respectively followed by a endotherm at 230.13°C corresponding to its melting point. The DSC thermogram of gefitinib-benzoic acid co-crystals (G-BA, Fig. 2in) reveals sharp endothermic peak centred at 154.13°C which corresponds to the melting point of anhydrous gefitinib benzoic acid co-crystal. The DSC thermogram of gefitinib /?-amino benzoic acid (G- >ABA, Fig. 2n) co-crystal reveals sharp endothermic peak at 134.47°C followed by broad endothermic peak at 157.37°C which corresponds to the melting point of gefitinib- -amino benzoic acid co-crystal.

C. MELTING POINT MEASUREMENTS

[0061] The melting point of gefitinib and all the co-crystals of gefitinib was determined on a Buchi melting point apparatus. The melting point of gefitinib form I (Known anhydrous form) was found to be 193-195°C and co-crystals of gefitinib with oxalic acid (G-OA) was found to be 247-250°C, while the melting point of co-crystal of gefitinib-malonic acid (G-MA), was found to be 173-176°C. The melting point of co- crystal of gefitinib-succinic acid crystallized from Acetonitrile (G-SA-1) and Nitromethane (G-SA-2) were found to be 172-174°C and 168-170°C respectively. The co-crystal of gefitinib-glutaric acid (G-GA-2) was found to be 1 6-148^°C. The co- crystal of gefitinib-adipic acid co-crystal crystallized from Ethanol water mixture (G- AA-1), n-ButanoI (G-SA-2) and Nitrobenzene (G-SA-3) were found to be 184-186°C, 156-158°C and 206-208°C respectively, and the co-crystal of gefitinib-Fumaric acid (G- FA) were found to be 237-238°C. The melting point of gefitinib citric acid co-crystals (G-CA) was found to be 190-194°C. The melting point of gefitinib-terephthalic acid (G-TA-1) co-crystals ranges in between 230-232°C. The melting point of gefitinib- benzoic acid (G-BA) co-crystal was found to bel 54-155°C.The melting point of p- Amino benzoic acid (G-pABA) co-crystal was found to bel 57-158°C.

[0062] The melting point behavior of gefitinib anticancer drug and various cocrystals of gefitinib with dicarboxylic acid were found to be the totally different. The gefitinib oxalic acid and fumaric acid cocrystals shows the melting point more than the pure gefitinib drug which indicate that these are thermally more stable cocrystals. While the gefitinib malonic acid, succinic acid, glutaric acid and adipic acid cocrystals shows low melting point than the normal gefitinib drugs which indicate these were found to be the thermally low stable cocrystals. The thermal stability of cocrystal which affects on the bioavailability and dissolution profile and much more physicochemical properties.

D. TGA ANALYSIS

[0063] The thermogravimetric analysis of gefitinib and all the cocrystals of gefitinib with malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid were carried out at TA Q10 apparatus.

E. PXRD STUDIES

[0064] The experimental Powder X-ray diffraction patterns were recorded on Rigaku Micromax-007HF instrument (High intensity microfocous rotating anode X-ray Generator) with R-axis detector IV++ at a continuous scanning rate of 2° 20/min using Cu K radiation (40 kV, 30 mA) with the intensity of the diffracted X-ray being collected at intervals of 0.1 ° 20. A nickel filter was used to remove Cu Κ_β radiation. The powder X-ray diffraction pattern of the gefitinib (Known Form I) and cocrystals of gefitinib with various dicarboxylic acid samples is displayed in the Fig.4. Notably the overlay does not indicate a perfect match revealing in homogeneity in the samples of gefitinib and gefitinib cocrystals.

F. DISSOLUTION AND SOLUBILITY MEASUREMENT

[0065] The solubility and dissolution properties of gefitinib (Form I) and novel cocrystals of gefitinib with various cocrystal former was studied in HC1 solution of pH- 3 using USP-certified Electrolab TDL-08 Tablet dissolution Tester at 37 °C with a constant stirring speed of 50 rpm. Aliquots (1 ml) were withdrawn at specific intervals of time and replenished with an equal amount of fresh pH solution so as to maintain the constant volume. These aliquots were analyzed by UV spectrophotometer (UV-1601 PC, Shimadzu Scientific Instrument) at wavelength 253 nm and compared with standard calibration curve. The results are shown in the table 3.

Table: 3

[0066] Comparative solubility and dissolution studies of gefitinib (Form I) and novel cocrystal of gefitinib indicates improved solubility and dissolution rate of cocrystal at 3 pH solution. The dissolution profile reveals that the solubility of cocrystal of gefitinib prepared from malonic acid (MA), succinic acid (SA), fumaric acid (FA), glutaric acid (GA), adipic acid (AA), terephthalic acid (TA) and /j-amino benzoic acid (PABA) was found to be more than that of parent drug whereas the cocrystals obtained from oxalic acid (OA) and citric acid (CA) revealed less solubility. The less solubility of cocrystals G-OA and G-CA with respect to the solubility of parent drug could be attributed to the strong hydrogen bonding between the molecules of oxalic acid, citric acid with gefitinib.

EXAMPLES [0067] The following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

PREPARATION OF THE SAMPLE

[0068] The novel crystalline co-crystals of gefitinib are obtained with various cocrystal former such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives by various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding (solvent drop grinding using few drops of ethanol). Both polar organic solvents as well as mixture of solvent comprising aqueous solution with organic solvents were used for the cocrystal synthesis.

EXAMPLE 1: CO-CRYSTALS WITH OXALIC ACID (G-OA)

[0069] 100 mg of amorphous gefitinib and oxalic acid (28.20 mg) was taken in 1 : 1 stoichiometric molar ratio, and both components were grinded with the help of mortar and pestle. Both dry grinding and liquid-assisted grinding (with few drops of absolute ethanol, also known as solvent drop grinding, SDG) was employed for the cocrystal synthesis. The grinded material was then transferred to round bottom flask and dissolved in 10-15 mL of isopropanol and water mixture (1 : 1, v/v). The resulting mixture was stirred at 50-60°C for 30 min to dissolve the solute. To ensure the complete dissolution of grinded material 4-5 mL of excess isopropanol-water solution was added to the crystallization assembly. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate is kept for crystallization for 24h. The yielded block type crystals were characterized by single crystal X-ray diffraction, PXRD, DSC, TGA techniques. These cocrystals were also obtained when crystallization is attempted from ethanol- water mixture (1 :1, v/v).

EXAMPLE 2: CO-CRYSTALS WITH MALONIC ACID (G-MA)

[0070] 100 mg of amorphous gefitinib and malonic acid (23.28 mg) was taken in 1 :1 stoichiometric molar ratio, and both components were grinded with the help of mortar and pestle. Dry grinding and liquid-assisted grinding (using few drops of absolute ethanol) was employed for the cocrystal synthesis. The grinded material was then transferred to round bottom flask and dissolved in 5-10 mL of n-butanol. The resulting mixture was stirred at 70-80°C for 30min to dissolve the compound. To ensure the complete dissolution of material, 4-5 mL excess n-Butanol was added to the crystallization chamber. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate is kept for crystallization for 24h. Needle types crystals were produced which were characterized by single crystal X-ray diffraction, PXRD, DSC, TGA techniques.

EXAMPLE 3: CO-CRYSTALS WITH SUCCINIC ACID

[0071] In case of gefitinib-succinic acid cocrystallization experiment, two different types of cocrystals were obtained having different pharmaceutical compositions. Crystallization from acetonitrile yielded cocrystals having composition of API and succinic acid in the ratio 1 :1 along with two water molecule, whereas crystallization from nitromethane exclusively produced anhydrous cocrystal with 1 :2 ratio of gefitinib and succinic acid.

a) Crystallization from Acetonitrile(G-SA-l)

[0072) 100 mg of amorphous gefitinib and succinic acid (26.42 mg) was taken in 1 :1 stoichiometric molar ratio and both components grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 20 mL of acetonitrile. The resulting mixture was stirred at 60-70°C for 30 min to dissolve the compound. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Needle type crystals were obtained which were characterized by single crystal X-ray diffraction, powder X-ray diffraction, DSC and TGA techniques. These cocrystals were also produced from acetone as well as from n-propanol.

b) Crystallization from Nitromethane(G-SA-2)

[0073] 100 mg of amorphous gefitinib and succinic acid (26.42 mg) was taken in 1 : 1 stoichiometric molar ratio and both components grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 20 mL of nitromethane. The resulting mixture was stirred at 60-70°C for 30 min to dissolve the compound. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24 h. Block type crystals were produced during crystallization which were further characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, DSC, and TGA. Interestingly, both these cocrystal forms (block and needle) were also obtained concomitantly when crystallization was achieved from nitrobenzene.

Example 4: Co-crystals with Glutaric Acid (G-GA)

[0074] 100 mg of amorphous gefitinib and 29.56 mg of glutaric acid were taken in 1 :1 stoichiometric molar ratio, and both components were grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 15 mL of ethanol-water mixture (1 :1, v/v). The resulting mixture was stirred at 50-60°C for 30min to dissolve the compound. To ensure the complete dissolution of material, 4-5 mL excess of ethanol-water mixture was added. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate is kept for crystallization for 24h. Block type crystals were observed in the crystallization flask which was characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, DSC and TGA techniques. These cocrystals were also produced from n-butanol, water, ethyl acetate and nitromethane solvents.

Example 5: Co-crystals with Adipic Acid

[0075] Cocrystal lization of gefitinib with adipic acid produced four different cocrystals having different pharmaceutical compositions depending on the solvent of crystallization. Ethanol-water mixture (1 :1 v/v) gave needle (1 :1, gefitinib: adipic acid with two molecules of water), and block (l :l ,gefitinib:adipic acid with ten water molecules and one molecule of ethanol) shaped cocrystals. While crystallization from n- butanol produced block types crystals (1 :1, gefitinib: adipic acid with one water molecule). Additionally, another cocrystals of gefitinib and adipic acid were obtained when crystallization was attempted with nitrobenzene solvent having needle type appearance comprising 1 :2 ratio of gefitinib and adipic acid with one water molecule, a) Crystallization from Ethanol water mixture (G-AA-1) [0076] 100 mg of amorphous gefitinib and adipic acid (32.70 mg) was taken in 1 :1 stoichiometric molar ratio and both the components were grinded with the help of mortar and pestle. The grinded material was then transferred to crystallization flask and suspended in 25 mL of ethanol-water mixture (1: 1, v/v). The resulting mixture was stirred at 60-70°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material 4-5 mL excess of ethanol-water mixture was added to the reaction chamber. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Both needle and block shaped crystals were obtained concomitantly during crystallization. In needle type crystals the ratio of gefitinib and adipic was found to be 1 :1 with two water molecules in the crystal structure, while the block type crystals with ratio 1 : 1 also contained ten molecules of water as well as one molecule of ethanol in the asymmetric unit. The needle shaped crystals were characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, DSC and TGA methods.

b) Crystallization from n-Butanol (G-AA-2)

[0077] 100 mg of amorphous gefitinib and 32.70 mg of adipic acids was taken in 1 : 1 stoichiometric molar ratio and both components were grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 15 mL of n-butanol (or nitromethane). The resulting mixture was stirred at 70-80°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material 3-4 mL excess of n-Butanol was added to the crystallization container. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. The yielded block type crystals were characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, differential scanning calorimetric and thermo gravimetric analysis,

c) Crystallization from Nitrobenzene (G-AA-3)

[0078] 100 mg of amorphous gefitinib and adipic acid (32.70 mg) was taken in 1 :1 stoichiometric molar ratio, and both components were grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 15 mL of nitrobenzene. The resulting mixture was stirred at 80-90°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material 2-3 mL excess of nitrobenzene was added to the crystallization chamber. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate is kept for crystallization for 24h.Needle and block shape crystals obtained were characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, differential scanning calorimetric and thermo gravimetric analysis (TGA). Example 6: Co-crystals with Fumaric Acid (G-FA)

[0079] 100 mg of amorphous gefitinib and fumaric acid (25.97 mg) was taken in 1 : 1 stoichiometric molar ratio, and both components were grinded with the help of mortar and pestle either by dry grinding or by liquid-assisted grinding (in absolute ethanol) method.The grinded material was then transferred to the crystallization flask and suspended in 10-15 mL of ethanol-water mixture (1 :1, v/v). The resulting mixture was stirred at 60-70°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material 4-5 mL excess of ethanol-water mixture was added to the same flask. The resulting mixture was then filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24hrs. Plate type crystals were obtained which were characterized by single crystal X-ray diffraction, melting point, powder X-ray diffraction, differential scanning calorimetric and thermo gravimetric analysis (TGA). These cocrystals were also produced from ethanol, water, n-butanol, methanol, 1 , 4-dioxan and isopropanol solvents

Example 7: Co-crystals with Citric Acid (G-CA)

[0080] 100 mg of amorphous gefitinib and tricarboxylic, citric acid (43.0 mg) were taken in 1 : 1 stoichiometric molar ratio, and both components were grind with the help of mortar and pestle. The grind material was then transferred to the crystallization vessel and suspended in 10-15 mL of ethanol-water mixture (1 : 1, v/v). The resulting mixture was stirred at 60-70°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material a 4-5 mL excess of ethanol- water mixture was added to the vessel. The resulting mixture was then filtered off to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Plate type crystals obtained were characterized by single crystal X-ray diffraction, melting Point, Powder X-ray diffraction, differential scanning calorimetric.

EXAMPLE 8: CO-CRYSTALS WITH TEREPHTHALIC ACID

[0081] Cocrystallization of gefitinib and terephthalic acid yielded two different cocrystal compositions depending on the solvent of crystallization. Cocrystallization form ethanol-water mixture (1 :1, v/v) gave plate type crystals with 1 :1 ratio of gefitinib and terephthalic acid along with two molecules of water molecule, while crystallization from ethyl acetate produced again plate type crystals however with l :0.5ratio of gefitinib and terephthalic acid which also includes two water molecules.

a) Crystallization from Ethanol- Water mixture. (G-TA-1)

[0082] 100 mg of amorphous gefitinib and terephthalic acid (37.21 mg) were taken in 1 : 1 stoichiometric molar ratio and both the components were grinded with the help of mortar and pestle. The grinded material was then transferred to the crystallization vessel and suspended in 10-15 mL of ethanol -water mixture (1 : 1, v/v). The resulting mixture was stirred at 60-70°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material a 4-5 mL excess of ethanol- water mixture was added to the crystallization flask. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h.Plate type crystals produced were characterized by single crystal X-ray diffraction, melting Point, Powder X-ray diffraction, differential scanning calorimetric. These cocrystals were also obtained from ethanol, isopropanol and w-propanol solvents.

b) Crystallization from Ethyl Acetate (G-TA-2)

[0083] 100 mg of amorphous gefitinib and terephthalic acid (37.21 mg) were taken in 1 : 1 stoichiometric molar ratio and both the components were grinded with the help of mortar and pestle.The grinded material was then transferred to the flask and suspended in 10-15 mL of ethyl acetate. The resulting mixture was stirred at 60-70°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material 4-5 mL excess of ethyl acetate was added to the flask. The resulting mixture was filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Plate shape crystals obtained were characterized by single crystal X-ray diffraction.

EXAMPLE 9: CO-CRYSTALS WITH BENZOIC ACID (G-BA)

[0084] 100 mg of amorphous gefitinib and benzoic acid (27.35 mg) were taken in 1 : 1 stoichiometric molar ratio and both the components were grinded with the help of mortar and pestle. The grinded material was then transferred to the flask and suspended in 10-15 mL of acetone-CC14 mixture (1 : 1, v/v). The resulting mixture was stirred at 50-60°C for 30min to dissolve the compound. To ensure the complete dissolution of grinded material 4-5 mL excess of ethanol-water mixture was added to the flask. The resulting mixture was then filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Plate type crystals recovered were characterized by single crystal X-ray diffraction, melting point, differential scanning calorimetric.

EXAMPLE 10: CO-CRYSTALS WITH P-AMINO BENZOIC ACID (G-PABA)

[0085] 100 mg of amorphous gefitinib and p-amino benzoic acid (30.7 lmg) were taken in 1 : 1 stoichiometric molar ratio and both the components were grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and suspended in 10-15 mL of acetone-CCl₄ mixture (1 :1, v/v). The resulting mixture was stirred at 50-60°C for 30min to dissolve the compound. To ensure the complete dissolution of material 4-5 mL excess of acetone-CCU mixture was added. The resulting mixture was then filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h.Plate type crystals collected were characterized by single crystal X-ray diffraction, melting Point, differential scanning calorimetric.

EXAMPLE 11: CO-CRYSTALS WITH P-CHLORO BENZOIC ACID (G-PCBA)

[0086] 100 mg of amorphous gefitinib and p-chlorobenzoic Acid (34.97 mg) were taken in 1 : 1 stoichiometric molar ratio and both components grinded with the help of mortar and pestle. The grinded material was then transferred to round bottom flask and dissolved in 10-15 mL of ethanol-water mixture (1 :1, v/v). The resulting mixture was stirred at 60-70°C for 30min to dissolve the compound. To ensure the complete dissolution of material 4-5 mL excess of ethanol-water mixture was added to the crystallization flask. The resulting mixture was then filtered to remove the traces of undissolved compound and filtrate was kept for crystallization for 24h. Plate type crystals obtained were characterized by single crystal X-ray diffraction technique.

[0087] ADVANTAGES OF INVENTION

1. Novel co-crystals of gefitinib have better solubility compared to the other known forms.

2. Novel co-crystals of gefitinib have improved dissolution compared to the other known forms.

3. Novel co-crystals of gefitinib have improved bioavailability compared to the other known forms.

Claims

WE CLAIM

1. Pharmaceutical co- crystals of gefitinib comprising gefitinib and co-crystal formers selected from aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids in stoichiometric ratio in the ratio ranging between 1 :0.5 to 1 :3, characterized in that solubility and dissolution of co- crystals is enhanced.

2. The pharmaceutical co-crystal of gefitinib as claimed in claim 1, wherein aliphatic dicarboxylic acid and aromatic di and tricarboxylic acids are selected from oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, citric acid, terephthalic acid, benzoic acid and its derivatives such as p- amino benzoic acid and 7-chloro benzoic acid and the like.

3. The pharmaceutical co-crystal of gefitinib as claimed in claim 1 , wherein said cocrystals are useful in the treatment of cancer.

4. The pharmaceutical co-crystal of gefitinib as claimed in claim 1 , wherein the co- crystal of gefitinib may prepared by various co-crystallization techniques like solution crystallization, dry grinding, and liquid-assisted grinding.

5. The pharmaceutical co-crystal of gefitinib as claimed in claim 1 , wherein the solution crystallization and liquid-assisted grinding are done by the solvent selected from polar organic solvent either alone or in aqueous mixture thereof, preferably the polar protic or aprotic solvents include lower alcohols, nitromethane, acetone, acetonitrile, ethyl acetate, dichloromethane, dimethylformamide and the like.

6. The pharmaceutical composition comprising pharmaceutical co-crystals of gefitinib as claimed in claim 1 with one or more pharmaceutically acceptable carriers.

7. The pharmaceutical composition as claimed in claim 6, wherein said composition is useful in the treatment of cancer.