DESC:Related Applications:
This application is Complete Cognate Application of the Provisional Patent Application No. 201721043590 filed on 5th December, 2017 and Provisional Patent Application No. 201821019075 filed on 22nd May, 2018.

TECHNICAL FILED:
The present invention relates to novel crystalline polymorphic forms of 4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, methods of preparation, pharmaceutical compositions and methods of therapeutic treatment involving polymorphic forms thereof.

BACKGROUND OF THE INVENTION:
4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, compound of formula I

is an oral molecule that inhibits multiple tyrosine kinase receptors such as VEGF-R-1-3, FGF-R-1-4, RET, c-KIT and PDGF-R-ß. It blocks VEGFR2 activation by VEGF, resulting in inhibition of the VEGF receptor signal transduction pathway, decreased vascular endothelial cell migration and proliferation, and vascular endothelial cell apoptosis.

The angiogenesis inhibitor and antitumor agent, 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide, salts or hydrates and methods for making the same are illustrated in US 7,253,286 B2 which is hereby incorporated by reference in their entirety.

US 7550483 B2, incorporated herein by reference, discloses amorphous forms of 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and esylate salts and a process of preparation thereof.

US 7612208 B2, incorporated herein by reference, discloses crystalline forms A, B, C, F (hydrate) and I (acetic acid solvate), DMSO solvate of 4-(3-chloro-4-(cyclopropylamino carbonyl) amino phenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and crystalline forms a, ß and DMSO solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinoline carboxamide esylate and a process of preparation thereof .

US 9334239 B2, incorporated herein by reference, discloses amorphous form of 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide and a process of preparation thereof.

WO 2016/184436 A1 incorporated herein by reference, discloses crystalline form M of 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and a process of preparation thereof.

The discovery of a new crystalline form of a pharmaceutically useful compound provides an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. It is clearly advantageous when this repertoire is enlarged by the discovery of new crystalline forms of a useful compound. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G.M. Wall, Pharm Manuf 3, 33 (1986); J.K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J.K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

The solid state physical properties of crystalline forms of a pharmaceutically useful salt can be influenced by controlling the conditions under which the salt is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid-state form of a compound may also affect its behaviour on compaction and its storage stability.

Regulatory agencies worldwide require a reasonable effort to identify the polymorphs of the drug substance and check for polymorph interconversions. Due to the often-unpredictable behaviour of polymorphs and their respective differences in physicochemical properties, consistency in manufacturing between batches of the same product must be demonstrated. Proper understanding of the polymorph landscape and nature of the polymorphs of a pharmaceutical will contribute to manufacturing consistency.

Consequently, it would be a significant contribution to the art to provide new forms of 4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinolinecarboxamide mesylate; having increased solubility, and methods of preparation, pharmaceutical formulations, and methods of use thereof.

SUMMARY OF THE INVENTION:
The present invention discloses novel crystalline polymorphic forms of the angiogenesis inhibitor and antitumor agent 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate of Formula I.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarbox- amide mesylate may be in anhydrous form or a pseudopolymorphic form. Accordingly, pseudopolymorphs provided include hydrates and/or solvates, more particularly, C1-C4 alcohol solvates, a benzyl alcohol solvate, a ketone solvates, a glycol solvate, a nitrile solvate, a DMSO ( dimethylsulfoxide) solvate, a THF (tetrahydrofuran) solvate and/or hydrated solvates thereof.

Particularly preferred polymorphic forms of the present invention are those compounds designated herein as “Form C2 ( hydrated form)”, “Form C3 (Benzyl alcohol solvate)”, “Form C4 (3-Methyl 2-Butanol solvate)”, “Form C5 (1,3-Propane diol solvates)”, “Form C6 (4-Methyl pentane 2-one solvate)”, “Form C7 (Propylene glycol solvate)”, “Form C8 (Acetonitrile)”, “Form C9 (Acetonitrile)”, “Form C10 (DMSO/water solvate)”, “Form C11” and “Form C12 ( hydrated form)” . The novel polymorphic forms of the present invention are characterized by unique XRD patterns.

The novel polymorphic forms of the present invention possess certain physical and chemical properties which render them particularly suitable for pharmaceutical development, such as good solubility, permeability and bioavailability. In addition, they are suitable for bulk handling and formulation.

In another aspect, the present invention relates to process for preparing novel polymorphic forms of the angiogenesis inhibitor and antitumor agent 4-(3-chloro-4-(cyclopropylamino carbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate.

The present invention also relates to pharmaceutical compositions containing novel polymorphic forms of the angiogenesis inhibitor and antitumor agent 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, optionally comprising one or more pharmaceutically acceptable excipients.

The invention also provides methods of treatment of tumor wherein 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate is useful.

In a further aspect of the present invention, there is provided method for the prevention or treatment of tumor which method comprises administering novel polymorphic forms of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate to a patient in need thereof.

In a further aspect of the present invention, there is provided novel polymorphic forms of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate for use in the prevention or treatment of tumors.

BRIEF DESCRIPTION OF THE DRAWINGS :
FIG.1 is an X-ray powder diffraction pattern of crystal Form C2 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG. 2 is an X-ray powder diffraction pattern of crystal Form C3 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG. 3 is an X-ray powder diffraction pattern of crystal Form C4 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.4 is an X-ray powder diffraction pattern of crystal Form C5 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.5 is an X-ray powder diffraction pattern of crystal Form C6 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.6 is an X-ray powder diffraction pattern of crystal Form C7 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.7 is an X-ray powder diffraction pattern of crystal Form C8 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.8 is an X-ray powder diffraction pattern of crystal Form C9 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG. 9 is an X-ray powder diffraction pattern of crystal Form C10 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.10 is an X-ray powder diffraction pattern of crystal Form C11 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

FIG.11 is an X-ray powder diffraction pattern of crystal Form C12 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate compound of formula I.

DETAILED DESCRIPTION:
As used herein, the term "solvated" is understood to mean formation of a complex of variable stoichiometry comprising 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate of Formula (I) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Typically, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include C1-C4 alcohol solvents, benzyl alcohol, 4-methyl pentane 2-one, propylene glycol, acetonitrile and dimethylsulfoxide (DMSO), and solvates of more than 1%.

The solvate can be isolated either as an amorphous form or in a crystalline form, preferably in crystalline form.

The solvate can be further isolated either in anhydrous form or hydrated form.

As used herein, the term "hydrate" is understood as a substance that is formed by adding water molecules. The skilled person will appreciate that the water molecules are absorbed, adsorbed or contained within a crystal lattice of the solid compounds, usually in defined stoichiometric ratio. The notation for a hydrated compound may be .nH2O, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on.

In comparison to the restricted stoichiometric hydrates, non-stoichiometric hydrates can vary in water content without major change in their crystal structure. The amount of water in the crystal lattice only depends on the partial pressure of water in the surrounding atmosphere.

Structurally, non-stoichiometric hydrates normally show channels or networks, through which the water molecules can diffuse. Depending on how the water is arranged inside the crystals, they are classified as isolated hydrates, channel hydrates and ion associated hydrates.

As used herein, the term "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2? values within ± 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.

In one aspect the present invention provides novel polymorphic forms of the angiogenesis inhibitor and antitumor agent 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate. The mesylate may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.
Accordingly, pseudo polymorphs provided include solvates, more in particular, C1-C4 alcohol solvates, a benzyl alcohol solvate, a 4-methyl pentane 2-one solvate, a propylene glycol solvate, a acetonitrile solvate and a dimethyl sulfoxide (DMSO) solvate, optionally in hydrated form.

As polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, the polymorphs of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2? values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper-K-a radiation source.

The invention further provides processes for the preparation of polymorphs.

Thus, in first aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate hydrate, wherein the said hydrate is referred to as “Form C2”.

The crystalline Form C2 is relatively stable towards moisture and humidity, thereby representing a crystalline form of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C2 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C2 may be characterized by having an XRPD diffractogram comprising peaks at 4.82, 9.82, 10.82 and 25.63 ± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 1.

Those skilled in the art would recognize that Form C2 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C2, the process comprising, a) combining 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA) and a mixture of acetone and water to form a mixture b) heating the mixture at a temperature and for a sufficient period to obtain dissolution, preferably at about 40° C to about 100° C, more preferably at 50° C to about 80° C; c) removing the solvent under reduced pressure to obtain a residue; d) stirring the residue in a mixture of solvent selected from the group consisting of diethylether and n-heptane or n-hexane; d) stirring for at about 20 hours to about 50 hours and e) isolating the precipitated crystalline Form C2 and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

The 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarbox- amide mesylate, may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C2 prepared by a process according to the process described above. The process produces crystalline Form C2 in high yield and purity.

According to second aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide mesylate benzyl alcohol solvate, wherein the said solvate is referred to as “Form C3”.

The crystalline Form C3 is relatively stable towards moisture and humidity, thereby representing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C3 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C3 may be characterized by having an XRPD diffractogram comprising peaks at 4.59, 9.0, 18.74, 21.6 and 24.84 ± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 12.3, 18.0, 12.50 and 23.51± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 2.

Those skilled in the art would recognize that Form C3 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C3, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and benzyl alcohol; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) heating the mixture at a temperature and for a sufficient period to effect complete dissolution, preferably at about 40°C to about 100°C, more preferably at 50° C to about 80°C; d) adding the clear solution into MTBE solution; e) cooling the reaction mass to a temperature ranging from around 0°C to around 30°C; preferably ranging from around 0°C to around 10°C; f) stirring for at least 2hours ; g) isolating the precipitated crystalline Form C3 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C3 prepared by a process according to the process described above. The process produces crystalline Form C3 in high yield and purity.

According to third aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate 3-methyl 2-butanol solvate, wherein the said solvate is referred to as “Form C4”.

The crystalline Form C4 is relatively stable towards moisture and humidity, thereby representing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C4 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C4 may be characterized by having an XRPD diffractogram comprising peaks at 7.260, 9.34, 18.10 and 21.80± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 12.04, 22.62 and 23.24 ± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 3.
Those skilled in the art would recognize that Form C4 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C4, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and 3-methyl 2-butanol; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 12hours ; g) isolating the precipitated crystalline Form C4 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C4 prepared by a process according to the process described above. The process produces crystalline Form C4 in high yield and purity.

According to fourth aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate 1,3-propane diol solvate, wherein the said solvate is referred to as “Form C5”.

The crystalline Form C5 is relatively stable towards moisture and humidity, thereby representing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C5 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C5 may be characterized by having an XRPD diffractogram comprising peaks at 4.73, 9.30, 12.82,15.68, 23.02 and 26.09 ± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 10.26, 11.14, 18.57, 19.40 and 27.26 ± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 4.

Those skilled in the art would recognize that Form C5 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C5, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and 1,3- propane diol in a solvent selected from the group consisting of DMF to form a mixture; b) cooling the reaction mass to a temperature ranging from around 0°C to around 30°C; preferably ranging from around 0°C to around 10°C; c) adding methane sulfonic acid at a temperature ranging from 0°C to 10°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; d) stirring the reaction mass at a temperature ranging from 0°C to 10°C, for at least 2 hours ; e) isolating the precipitated crystalline Form C5 and f) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C5 prepared by a process according to the process described above. The process produces crystalline Form C5 in high yield and purity.

According to fifth aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate 4-methyl pentane 2-one solvate, wherein the said solvate is referred to as “Form C6”.

The crystalline Form C6 is relatively stable towards moisture and humidity, thereby representing a stable crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C6 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C6 may be characterized by having an XRPD diffractogram comprising peaks at 8.08, 14.19, 14.98, 15.70, 19.64 and 24.90± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 11.46, 20.69, 21.88 and 26.24 ± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 5.

Those skilled in the art would recognize that Form C6 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C6, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and 4-methyl pentane 2-one; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 8 hours ; g) isolating the precipitated crystalline Form C6 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C6 prepared by a process according to the process described above. The process produces crystalline Form C6 in high yield and purity.

According to sixth aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate 1,3- propylene glycol solvate, wherein the said solvate is referred to as “Form C7”.

The crystalline Form C7 is relatively stable towards moisture and humidity, thereby representing a stable crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C7 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C7 may be characterized by having an XRPD diffractogram comprising peaks at 7.02, 9.04, 13.38, 17.91, 19.60 and 21.75 ± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 16.74, 22.44 and 24.30± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 6.

Those skilled in the art would recognize that Form C7 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C7, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and propylene glycol ; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) adding the clear solution into MTBE solution; d) f) stirring for at least 2 hours ; g) isolating the precipitated crystalline Form C7 and h) drying under reduced pressure at 30-80°C, preferably at 30-60°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C7 prepared by a process according to the process described above. The process produces crystalline Form C7 in high yield and purity.

According to seventh aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate
acetonitrile solvate, wherein the said solvate is referred to as “Form C8”.

The crystalline Form C8 is relatively stable towards moisture and humidity, thereby representing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C8 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C8 may be characterized by having an XRPD diffractogram comprising peaks at 7.53, 9.82, 11.40, 14.93, 17.59, 19.60 and 26.72± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 13.02, 20.56 and 28.60± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 7.

Those skilled in the art would recognize that Form C8 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C8, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base and acetonitrile to form a mixture; b) cooling the reaction mass to a temperature ranging from around -15°C to around 0°C; preferably ranging from around - 10°C to around -5°C; c) adding methane sulfonic acid at a temperature ranging from -10°C to -5°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; d) stirring the reaction mass at a temperature ranging from -10°C to -5°C, for at least 30 minutes to around 2 hours; e) allowing the reaction mass to stand at a temperature ranging from 25°C to 30°C, for at least 30 minutes to around 4 days , preferably from around 60 minutes to around 3.5 days, more preferably for a time of around 1 days to 3 days; e) isolating the precipitated crystalline Form C8 and f) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C8 prepared by a process according to the process described above. The process produces crystalline Form C8 in high yield and purity.

According to eighth aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate acetonitrile solvate, wherein the said solvate is referred to as “Form C9”.

The crystalline Form C9 is relatively stable towards moisture and humidity, thereby representing a crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C9 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C9 may be characterized by having an XRPD diffractogram comprising peaks at 7.24, 11.0, 14.6, 17.36, 19.40, 20.25, 22.62 and 24.72 ± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 12.68, 23.16, 25.72 and 26.89± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 8.

Those skilled in the art would recognize that Form C9 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C9, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and acetonitrile; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 80 hours ; g) isolating the precipitated crystalline Form C9 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C9 prepared by a process according to the process described above. The process produces crystalline Form C9 in high yield and purity.

According to nineth aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate DMSO solvate. Preferably, the DMSO solvate is in hydrated form. Suitably, the 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate is a 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate DMSO solvate hydrate wherein the said solvate is referred to as “Form C10”.

The crystalline Form C10 is relatively stable towards moisture and humidity, thereby representing a stable crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

In an embodiment, the DMSO content in 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate may vary in ratio depending on the conditions applied, more specifically depending on the temperature of the crystal form.

Conveniently, 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate forms a crystalline sesquihydrate with DMSO and water wherein the molar ratio of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate to DMSO to water is approximately 1:1.5:1.5.

The crystalline Form C10 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C10 may be characterized by having an XRPD diffractogram comprising peaks at 4.53, 9.02, 17.18, 19.87, 20.45 and 25.18 ± 0.2 °2?. The XRPD diffractogram may comprise further peaks at 13.57, 21.11 and 26.84± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 9.

Those skilled in the art would recognize that Form C10 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C10, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base, DMSO and water; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) heating the mixture at a temperature and for a sufficient period to effect complete dissolution, preferably at about 40°C to about 70°C, more preferably at 50° C to about 60°C; d) cooling the reaction mass to a temperature ranging from around 20°C to around 30°C; preferably ranging from around 25°C to around 30°C; f) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 7 hours ; g) isolating the precipitated crystalline Form C10 and h) drying under reduced pressure at 30-80°C, preferably at 30-60°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C10 prepared by a process according to the process described above. The process produces crystalline Form C10 in high yield and purity.

According to tenth aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate. Preferably, the crystalline form is in anhydrate form wherein the anhydrous form is referred to as “Form C11”

The crystalline Form C11 is relatively stable towards moisture and humidity, thereby representing a stable crystalline form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C11 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C11 may be characterized by having an XRPD diffractogram comprising peaks at 5.93, 7.33, 14.93, 17.38 and 19.38± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 10.

Those skilled in the art would recognize that Form C11 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C11, the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and acetonitrile; b) cooling the reaction mass to a temperature ranging from around -15°C to around 0°C; preferably ranging from around -10°C to around -5°C; c) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; d) stirring the reaction mass at a temperature ranging from -10°C to -5°C, for at least 5 hours; fallowed by holding the reaction mass for about 48 hrs at 25°C ; g) isolating the precipitated crystalline Form C11 and h) drying under reduced pressure at 30-80°C, preferably at 30-60°C for at least 8 hrs.

The 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7,253,286 B2 which is incorporated herein by reference.

According to another aspect of the present invention, there is provided crystalline Form C11 prepared by a process according to the process described above. The process produces crystalline Form C11 in high yield and purity.

According to eleventh aspect, the present invention provides the crystalline 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate hydrate, wherein the said hydrate is referred to as “Form C12”.

The crystalline Form C12 is relatively stable towards moisture and humidity, thereby representing a stable crystalline form of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline Form C12 according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form C12 may be characterized by having an XRPD diffractogram comprising peaks at
4.50, 6.09, 8.96, 10.46 and 19.70 ± 0.2 °2?. The XRPD diffractogram may be as depicted in Figure 11.

Those skilled in the art would recognize that Form C12 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.

According to another aspect of the present invention, there is provided a process for preparing crystalline Form C12, the process comprising, a) combining 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and water to form a mixture b) stirring the mixture at a temperature and for a sufficient period to obtain gel type suspension, preferably at about 20°C to about 100°C, more preferably at 25° C to about 80°C for about 30 minutes to about 30 hours, preferably for about 1 hour to about 24 hours ; c) drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs and d) isolating the precipitated crystalline Form C12 .

The process of invention may be used as a method for purifying any form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, as well as for the preparation of the new polymorphic forms.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising novel polymorphic forms of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as described above, together with one or more pharmaceutically acceptable excipients. The (4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate used in the preparation of pharmaceutical compositions may substantially consist of one of forms C2, C3, C4, C5, C6, C7, C8, C9, C10 C11 or C12 described above, or may substantially consist of a combination of two or more of said forms.
In one preferred aspect, the invention provides pharmaceutical compositions comprising the crystalline Form C10 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, optionally comprising one or more pharmaceutically acceptable excipients.

According to yet another aspect of the present invention there is provided use of polymorphic Forms of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as described above, in the preparation of a medicament useful in treating or preventing tumor.
In a further aspect, the invention provides a method for the prevention or treatment of tumor which method comprises administering crystalline Form C10 of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate in therapeutically effective amounts optionally in association with one or more pharmaceutically acceptable excipients to a patient in need thereof.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

EXAMPLES:

Example 1
Process to prepare Form-C2 (Hydrate):
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide, mesylate dissolved in a mixture of methanol (50ml), acetone (50ml) and purified water (6ml) at 50-55°C. The solvent was removed completely at 55-60°C under vacuum. The residue was stirred in 20ml of diethyl ether and 20ml of n-Heptane. The reaction mass was cooled to 25°C and maintained at the same temperature for 24 to 48 hours. The solids were isolated by filtration and dried at 25-30°C. Crystalline Form C2 was analyzed by XRD and as depicted in Figure 1.

Example 2
Process to prepare Form-C3 (Benzyl alcohol solvate):
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in benzyl alcohol (10 ml) at 25°C. To the above suspension was slowly added 0.2ml of Methane sulfonic acid and the reaction mass was heated to 50°C. The above clear solution was added to 30ml of MTBE. The reaction mass was cooled to 0-5°C and maintained for 2hours. The solids were isolated by filtration and dried at 40-45°C. Crystalline Form C3 was analyzed by XRD and as depicted in Figure 2.

Example 3
Process to prepare Form-C4 (3-Methyl 2-Butanol solvate):
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy) _7-methoxy-6-quinoline carboxamide base was suspended in 3-methyl-2-Butanol (40 ml) at 25°C. To the above suspension was slowly added 0.2ml of Methane sulfonic acid and the reaction mass was maintained at 25°C for 12hours. The solids were isolated by filtration and dried at 40°C. Crystalline Form C4 was analyzed by XRD and as depicted in Figure 3.

Example 4
Process to prepare Form-C5 (1,3-Propane diol solvates):
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in 1,3-propane diol (10 ml) and DMF (10 ml) at 25°C and the reaction mass was cooled to 0-5°C. To the above suspension was slowly added 0.2ml of methane sulfonic acid and the reaction mass was maintained at 0-5°C for 2hours. The solids were isolated by filtration and dried at 40°C. Crystalline Form C5 was analyzed by XRD and as depicted in Figure 4.

Example 5
Process to prepare Form-C6 (4-Methyl pentane 2-one solvate):
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy) 7-methoxy-6-quinoline carboxamide base was suspended in 4-methyl pentane 2-one (15 ml) at 25°C.To the above suspension was slowly added 0.2ml of methane sulfonic acid and the reaction mass was maintained at 25-28°C for about 8 hours. The solids were isolated by filtration and dried at 25°C. Crystalline Form C6 was analyzed by XRD and as depicted in Figure 5.

Example 6
Process to prepare Form-C7 (Propylene glycol solvate):
6g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in propylene glycol (120 ml) at 25°C.To the above suspension was slowly added 1.2ml of methane sulfonic acid and the reaction mass was maintained at 25-28°C for 30 minutes. The above clear solution was slowly added to MTBE (350 ml) and the reaction mass was maintained further at 25°C for 2 hrs. The solids were isolated by filtration and dried at 50°C. Crystalline Form C7 was analyzed by XRD and as depicted in Figure 6.

Example 7
Process to prepare Form-C8 (Acetonitrile(-10°C)):
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in acetonitrile (20 ml) at 25°C and the reaction mass was cooled to -8°C. To the above suspension was slowly added 0.2ml of methane sulfonic acid and the reaction mass was maintained at -10°C for 30 minutes. The temperature of the reaction mass was raised to 25°C and maintained for 3 days at 25°C. The solids were isolated by filtration and dried at 25°C. Crystalline Form C8 was analyzed by XRD and as depicted in Figure 7.

Example 8
Process to prepare Form-C9 (Acetonitrile (RT) ):
2 g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in acetonitrile (240 ml) at 25°C.To the above suspension was slowly added 0.58ml of methane sulfonic acid and the reaction mass was maintained at 25°C for 80hrs. The solids were isolated by filtration and dried at 50°C. Crystalline Form C9 was analyzed by XRD and as depicted in Figure 8.

Example 9
Process to prepare Form-C10 (DMSO/water solvate):
5 g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in DMSO (80 ml) and Water (20 ml) at 25°C. To the above suspension was slowly added 2 ml of methane sulfonic acid and the reaction mass was maintained at 45°C for 15 min. The clear solution was slowly cooled to 25°C and the reaction was maintained at the same temperature for 7 hrs. The solids were isolated by filtration and dried at 50°C. Crystalline Form C10 was analyzed by XRD and as depicted in Figure 9.

Example 10
Process to prepare Form-C11:
2 g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide base was suspended in acetonitrile (100 ml). The suspension was cooled to -10°C and 0.4ml of methane sulfonic acid (MSA) was slowly added. The reaction mass was maintained at -10°C for 5hrs and the temperature was raised to 25°C. The reaction mass was held at 25°C, without agitation for 46 hrs. The solids were isolated by filtration and dried at 60°C. Crystalline Form C11 was analyzed by XRD and as depicted in Figure 10.

Example 11
Process to prepare Form-C12:
10 g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide, mesylate was suspended in water (100 ml) at 25-30?C. The mixture was stirred for about 4 hours. The resulting gel type suspension was dried under reduced pressure in a Buchi -rotavapor at 40-45°C for about 15-20 hours . Crystalline Form C12 was analyzed by XRD and as depicted in Figure 11.
Yield: 9.5 g

Example 12
Process to prepare Form-C12:
1g of (4-[3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)_7-methoxy-6-quinoline carboxamide, mesylate was suspended in water (10 ml) at 25-30°C. The mixture was stirred for about 2 hours. The resulting gel type suspension was dried in a vacuum tray dryer at 25-30°C for about 24 -30 hours. Crystalline Form C12 was analyzed by XRD and as depicted in Figure 11.
Yield: 0.8 g
,CLAIMS:1. Crystalline polymorphic forms of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate selected from the group consisting of Form C2, Form C3, Form C4, Form C5, Form C6, Form C7, Form C8, Form C9, Form C10, Form C11 and Form C12.

2. The crystalline Form C2 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1, characterized by having an XRPD diffractogram comprising peaks at 4.82, 9.82, 10.82 and 25.63 ± 0.2 °2?, substantially as depicted in Figure 1.

3. A crystalline Form C3 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1, characterized by having an XRPD diffractogram comprising peaks at 4.59, 9.0, 18.74, 21.6 and 24.84 ± 0.2 °2? and further peaks at 12.3, 18.0, 12.50 and 23.51± 0.2 °2?, substantially as depicted in Figure 2.
4. A crystalline Form C4 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1, characterized by having an XRPD diffractogram comprising peaks at 7.260, 9.34, 18.10 and 21.80± 0.2 °2?; and further peaks at 12.04, 22.62 and 23.24 ± 0.2 °2?,substantially as depicted in Figure 3.

5. A crystalline Form C5 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1 characterized by having an XRPD diffractogram comprising peaks at 4.73, 9.30, 12.82,15.68, 23.02 and 26.09 ± 0.2 °2? and further peaks at 10.26, 11.14, 18.57, 19.40 and 27.26 ± 0.2 °2?, substantially as depicted in Figure 4.

6. A crystalline Form C6 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1 characterized by having an XRPD diffractogram comprising peaks at 8.08, 14.19, 14.98, 15.70, 19.64 and 24.90± 0.2 °2? and further peaks at 11.46, 20.69, 21.88 and 26.24 ± 0.2 °2? substantially as depicted in Figure 5.

7. A crystalline Form C7 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1 characterized by having an XRPD diffractogram comprising peaks at 7.02, 9.04, 13.38, 17.91, 19.60 and 21.75 ± 0.2 °2? and further peaks at 16.74, 22.44 and 24.30± 0.2 °2? substantially as depicted in Figure 6.

8. A crystalline Form C8 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate characterized by having an XRPD diffractogram comprising peaks at 7.53, 9.82, 11.40, 14.93, 17.59, 19.60 and 26.72± 0.2 °2? and further peaks at 13.02, 20.56 and 28.60± 0.2 °2? substantially as depicted in Figure 7.

9. A crystalline Form C9 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1 characterized by having an XRPD diffractogram comprising peaks at 7.24, 11.0, 14.6, 17.36, 19.40, 20.25, 22.62 and 24.72 ± 0.2 °2? and further peaks at 12.68, 23.16, 25.72 and 26.89± 0.2 °2?, substantially as depicted in Figure 8.

10. A crystalline Form C10 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1 characterized by having an XRPD diffractogram comprising peaks at 4.53, 9.02, 17.18, 19.87, 20.45 and 25.18 ± 0.2 °2?.

11. The crystalline Form C10 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 10, having an XRPD diffractogram comprising further peaks at 13.57, 21.11 and 26.84± 0.2 °2?.

12. The crystalline Form C10 as claimed in claims 10 and 11, characterized by the powder X-ray diffraction pattern as depicted in Figure 9.

13. A crystalline Form C11 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1, characterized by having an XRPD diffractogram comprising peaks at 5.93, 7.33, 14.93, 17.38 and 19.38± 0.2 °2?, substantially as depicted in Figure 10.

14. A crystalline Form C12 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate as claimed in claim 1 characterized by having an XRPD diffractogram comprising peaks at 4.50, 6.09, 8.96, 10.46 and 19.70 ± 0.2 °2? substantially as depicted in Figure 11.

15. A process for preparing crystalline Form C2 as claimed in claim 2, wherein, the process comprises, a) combining 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol (IPA) and a mixture of acetone and water to form a mixture b) heating the mixture at a temperature and for a sufficient period to obtain dissolution, preferably at about 40° C to about 100° C, more preferably at 50° C to about 80° C; c) removing the solvent under reduced pressure to obtain a residue; d) stirring the residue in a mixture of solvent selected from the group consisting of diethylether and n-heptane or n-hexane; d) stirring for at about 20 hours to about 50 hours and e) isolating the precipitated crystalline Form C2 and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

16. A process for preparing crystalline Form C3 as claimed in claim 3, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and benzyl alcohol; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) heating the mixture at a temperature and for a sufficient period to effect complete dissolution, preferably at about 40°C to about 100°C, more preferably at 50° C to about 80°C; d) adding the clear solution into MTBE solution; e) cooling the reaction mass to a temperature ranging from around 0°C to around 30°C; preferably ranging from around 0°C to around 10°C; f) stirring for at least 2hours ; g) isolating the precipitated crystalline Form C3 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

17. A process for preparing crystalline Form C4 as claimed in claim 4, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and 3-methyl 2-butanol; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 12hours ; g) isolating the precipitated crystalline Form C4 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

18. A process for preparing crystalline Form C5 as claimed in claim 5, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and 1,3- propane diol in a solvent selected from the group consisting of DMF to form a mixture; b) cooling the reaction mass to a temperature ranging from around 0°C to around 30°C; preferably ranging from around 0°C to around 10°C; c) adding methane sulfonic acid at a temperature ranging from 0°C to 10°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; d) stirring the reaction mass at a temperature ranging from 0°C to 10°C, for at least 2 hours ; e) isolating the precipitated crystalline Form C5 and f) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

19. A process for preparing crystalline Form C6 as claimed in claim 6, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and 4-methyl pentane 2-one; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 8 hours ; g) isolating the precipitated crystalline Form C6 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

20. A process for preparing crystalline Form C7 as claimed in claim 7, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and propylene glycol ; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) adding the clear solution into MTBE solution; d) f) stirring for at least 2 hours ; g) isolating the precipitated crystalline Form C7 and h) drying under reduced pressure at 30-80°C, preferably at 30-60°C for at least 8 hrs.

21. A process for preparing crystalline Form C8 as claimed I claim 8, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarbox-amide base and acetonitrile to form a mixture; b) cooling the reaction mass to a temperature ranging from around -15°C to around 0°C; preferably ranging from around - 10°C to around -5°C; c) adding methane sulfonic acid at a temperature ranging from -10°C to -5°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; d) stirring the reaction mass at a temperature ranging from -10°C to -5°C, for at least 30 minutes to around 2 hours; e) allowing the reaction mass to stand at a temperature ranging from 25°C to 30°C, for at least 30 minutes to around 4 days , preferably from around 60 minutes to around 3.5 days, more preferably for a time of around 1 days to 3 days; e) isolating the precipitated crystalline Form C8 and f) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

22. A process for preparing crystalline Form C9 as claimed in claim 9, wherein the process comprising a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and acetonitrile; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 80 hours ; g) isolating the precipitated crystalline Form C9 and h) drying under reduced pressure at 30-80°C, preferably at 30-50°C for at least 8 hrs.

23. A process for preparing crystalline Form C10 as claimed in claim 10, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base, DMSO and water; b) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; c) heating the mixture at a temperature and for a sufficient period to effect complete dissolution, preferably at about 40°C to about 70°C, more preferably at 50° C to about 60°C; d) cooling the reaction mass to a temperature ranging from around 20°C to around 30°C; preferably ranging from around 25°C to around 30°C; f) stirring the reaction mass at a temperature ranging from 20°C to 30°C, for at least 7 hours ; g) isolating the precipitated crystalline Form C10 and h) drying under reduced pressure at 30-80°C, preferably at 30-60°C for at least 8 hrs.

24. A process for preparing crystalline Form C11 as claimed claim 13, wherein the process comprises a) combining 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide base and acetonitrile; b) cooling the reaction mass to a temperature ranging from around -15°C to around 0°C; preferably ranging from around -10°C to around -5°C; c) adding methane sulfonic acid at a temperature ranging from 20°C to 30°C, over a period of ranging from around 20 minutes to around 2 hours, preferably from around 30 minutes to around 1.5 hours, more preferably for a time of around 40 minutes to 1.2 hour, for example over a period of around 60 minutes; d) stirring the reaction mass at a temperature ranging from -10°C to -5°C, for at least 5 hours; fallowed by holding the reaction mass for about 48 hrs at 25°C ; g) isolating the precipitated crystalline Form C11 and h) drying under reduced pressure at 30-80°C, preferably at 30-60°C for at least 8 hrs.

25. A process for preparing crystalline Form C12 as claimed in claim 14, wherein the process comprises, a) combining 4-(3-chloro-4-(cyclopropyl aminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate and water to form a mixture b) stirring the mixture at a temperature and for a sufficient period to obtain gel type suspension, preferably at about 20°C to about 100°C, more preferably at 25° C to about 80°C for about 30 minutes to about 30 hours, preferably for about 1 hour to about 24 hours ; c) drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs and d) isolating the precipitated crystalline Form C12 .

26. A pharmaceutical compositions comprising the crystalline Form C10 of 4-(3-chloro-4-(cyclopropyl aminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, optionally comprising one or more pharmaceutically acceptable excipients.

27. A method for the prevention or treatment of tumor which method comprises administering crystalline Form C10 of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate in therapeutically effective amounts to a patient in need thereof.