FIELD OF THE INVENTION

The present invention relates a novel crystalline form of Cabozantinib and Cabozantinib malate, process for its preparation and pharmaceutical compositions comprising it.

BACKGROUND OF THE INVENTION

Cabozantinib malate is inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis. The generic name cabozantinib malate is marketed by EXELIXIS under the brand name Cometriq®.

Cabozantinib is chemically, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-l,l-dicarboxamideand has the structural formula:

Cabozantinib and its malate salt were disclosed in U.S. Patent No. 7,579,473.

Process for the preparation of cabozantinib malate was disclosed in International patent application publication nos. WO 2012/109510 and WO 2013/059788.

International patent application publication no. WO 2010/083414 disclosed crystalline Form N-l and Form N-2 of cabozantinib malate. This publication also described amorphous cabozantinib malate.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.

Cabozantinib and its malate salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

The present inventors have found a novel polymorph of Cabozantinib. The polymorph of Cabozantinib. is stable, reproducible and so, the polymorph of Cabozantinib is suitable for pharmaceutical preparations.

The present inventors have found a novel process for the preparation of cabozantinib. The process of the present invention is simple, inexpensive, reproducible and is well suited for industrial scale.

The present inventors have found a novel crystalline polymorph of Cabonzatinib malate. The polymorph of Cabozantinib malate is stable, reproducible and so, the polymorph of Cabozantinib malate is suitable for pharmaceutical preparations.

The novel polymorph of cabozantinib is useful as an intermediate for the preparation of cabozantinib malate.

The present inventors have found a novel process for preparation of amorphous cabozantinib malate. The amorphous cabozantinib malate is stable, reproducible and so, the amorphous cabozantinib malate is suitable for pharmaceutical preparations.

Object of the Invention

One object of the present invention is to provide novel process for the preparation of Cabozantinib.

Another object of the present invention is to provide novel crystalline Form of cabozantinib, process for its preparation and pharmaceutical compositions comprising it.

Another object of the present invention is to provide novel crystalline form of Cabozantinib malate, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide novel process for the preparation of amorphous Cabozantinib malate.

Summary of the Invention

In one aspect, the present invention provides a process for the preparation of Cabozantinib, which comprises:

a) dissolving l-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid in an ether solvent;

b) adding dimethylformamide or dimethylacetamide to the solution;

c) adding thionyl chloride to the solution;

d) dissolving 6,7-dimethoxy-4-(4-aminophenoxy)quinolone in an ether solvent;

e) adding a base and water to the solution obtained in step (d);

f) adding a solution obtained in step (c) to the reaction mass obtained in step (e); and

g) isolating Cabozantinib.

In another aspect of the present invention provides a crystalline Form of Cabozantinib designated as Form 1 characterized by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 8.8, 11.3, 13.2, 13.7, 14.0, 15.1, 15.6, 22.1 and 24.3 ± 0.2 degrees.

In another aspect, the present invention provides a process for the preparation of Cabozantinib crystalline Form 1, which comprises:

a) dissolving Cabozantinib in an alcoholic solvent, a chlorinated solvent or mixture thereof;

b) removing the solvents from the solution; and

c) isolating Cabozantinib crystalline Form 1.

In another aspect, the present invention provides a pharmaceutical composition comprising crystalline Form 1 of Cabozantinib and pharmaceutically acceptable excipients.

In another aspect, the present invention provides a crystalline Form of Cabozantinib malate designated as Form HI characterized by peaks in the powder x-ray diffraction spectrum having 26 angle positions at about 7.6, 9.4, 10.8, 13.4, 15.4, 15.3, 22.9 and 25.9 ± 0.2 degrees.

In another aspect, the present invention provides a crystalline Form of Cabozantinib malate designated as Form HI characterized by solid state 13C NMR spectrum with peaks at 24.8, 28.2, 29.4, 57.4, 101.6, 121.8, 123.8, 137.1, 156.0, 168.8±0.2 ppm.

In another aspect, the present invention provides a process for the preparation of Cabozantinib malate crystalline Form HI, which comprises

a) treating Cabozantinib with L- malic acid in a mixture of solvents selected from polar aprotic solvents

b) heating to 60 deg C and optionlly adding water;

c) maintaining for 1 hour at 60 to 65 deg C ;

d) cooling to 25 to 35 deg C;

e) and isolating Cabozantinib malate Form H1.

In another aspect of the present invention provides a process for the preparation of amorphous cabozantinib malate, which comprises:

a) dissolving cabozantinib malate in an alcoholic solvent, a chlorinated solvent or mixture thereof; and

b) removing the solvents from the solution to obtain amorphous cabozantinib malate. In yet another aspect of the present invention provides a process for the preparation of amorphous cabozantinib malate, which comprises:

a) dissolving cabozantinib in an alcoholic solvent, a chlorinated solvent or mixture thereof;

b) adding L-malic acid to the solution; and

c) removing the solvents from the solution to obtain amorphous cabozantinib malate.

Brief Description of the Drawing

Figure 1 is a powder X-ray diffractogram pattern of Cabozantinib crystalline Form 1.

Figure 2 is a powder X-ray diffractogram pattern of amorphous Cabozantinib malate.

Figure 3 is a powder X-ray diffractgram pattern of Cabozantinib malate crystalline Form HI
Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper-Ka radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.

Detailed Description of the Invention

The term "room temperature" refers to temperature at about 25 to 35 C. According to one aspect of the present invention, there is provided a process for the preparation of Cabozantinib, which comprises:

a) dissolving l-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid in an ether solvent;

b) adding dimethylformamide or dimethylacetamide to the solution;

c) adding thionyl.chloride to the solution to obtain a solution;

d) dissolving 6,7-dimethoxy-4-(4-aminophenoxy)quinolone in an ether solvent;

e) adding a base and water to the solution obtained in step (d);

f) adding a solution obtained in step (c) to the reaction mass obtained in step (e); and

g) isolating cabozantinib.

Preferably the ether solvent used in step (a) and (d) may preferably be a solvent or a mixture of solvents selected from tetrahydrofuran, diethyl ether, diisopropyl ether and tert-butyl methyl ether. More preferably the ether solvent is tetrahydrofuran.

The base used in step (e) may preferably be an organic base or an inorganic base. More preferably the base is inorganic base selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate or calcium bicarbonate. Still more preferably the base is potassium carbonate.

Isolation of cabozantinib in step (g) can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent and the like.

According to another aspect of the present invention, there is provided a crystalline Form of cabozantinib designated as Form 1 characterized by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 8.8, 11.3, 13.2, 13.7, 14.0, 15.1, 15.6, 22.1 and 24.3 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of cabozantinib crystalline Form 1 is shown in figure 1.

According to another aspect of the present invention, there is provided a process for the preparation of cabozantinib crystalline Form 1. which comprises:

a) dissolving cabozantinib in an alcoholic solvent, a chlorinated solvent or mixture thereof;

b) removing the solvents from the solution; and

c) isolating cabozantinib crystalline Form 1.

Cabozantinib used in step (a) may preferably be cabozantinib obtained by the known process.

The alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.

The chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.

The solvents may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg.

The term "Spray drying" refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.

Isolation of Cabozantinib crystalline Form 1 in step (c) can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent and the like.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline Form 1 of Cabozantinib and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The crystalline Form 1 may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided a crystalline Form of Cabozantinib malate designated as Form HI characterized by peaks in the powder x-ray diffraction spectrum having 29 angle positions at about 7.6, 9.4, 10.8, 13.4, 15.1, 15.3, 22.9 and 25.9 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of cabozantinib crystalline Form HI is shown in figure 3.

In another aspect, the present invention provides a crystalline Form of Cabozantinib malate designated as Form HI characterized by solid state 13C NMR spectrum with peaks at 24.8, 28.2, 29.4, 57.4, 101.6, 121.8, 123.8, 137.1, 156.0, 168.8±0.2ppm

In another aspect, the present invention provides a process for the preparation of Cabozantinib malate crystalline Form HI, which comprises
a) treating Cabozantinib with L-malic acid in a mixture of solvents selected from polar aprotic solvents;
b) heating to 60 deg C and optionally adding water;

c) maintaining for 1 hour at 60 to 65 deg C;

d) cooled to 25 to 35 deg C; and

e) isolating Cabozantinib malate Form H1.

The polar aprotic solvents in step (a) may preferably be a solvent or a mixture of solvents selected from organic nitriles, dimethyl sulfoxide, dimethylformamide dimethylacetamide, More preferably the nitrile solvent is acetonitrile and dimethyl formamide.

According to another aspect of the present invention, there is provided a process for the purification of Cabozantinib malate, which comprises:

a) dissolving Cabozantinib in dimethylacetamide, dimethylformamide or dimethyl sulfoxide;

b ) adding a nitrile solvent to the solution;

c) adding L-malic acid to the solution;

d) adding water; and

e) isolating pure Cabozantinib malate.

The term '"pure Cabozantinib malate" refers to Cabozantinib malate having the purity greater than about 98.5% by weight, preferably greater than about 99% by weight, and more preferably greater than about 99.5% by weight.
Cabozantinib used in step (a) may preferably be Cabozantinib obtained by the known process or Cabozantinib crystalline Form 1.

The nitrile solvent used in step (b) may preferably be a solvent or a mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile. More preferably the nitrile solvent is acetonitrile.
The highly pure Cabozantinib malate may be isolated in step (e) by known methods such as filtration or centrifugation.

The contents of cabozantinib malate and the impurities are determined by High performance liquid chromatography (HPLC).

According to another aspect of the present invention, there is provided a process for the preparation of amorphous cabozantinib malate, which comprises:

a) dissolving Cabozantinib malate in an alcoholic solvent, a chlorinated solvent or mixture thereof; and

b) removing the solvents from the solution to obtain amoiphous cabozantinib malate.

Preferably the alcoholic solvent used in step (a) may be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.

The chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.

The solvents may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

According to another aspect of the present invention, there is provided a process for the preparation of amorphous Cabozantinib malate, which comprises:

a) dissolving Cabozantinib in an alcoholic solvent, a chlorinated solvent or mixture thereof;

b) adding L-malic acid to the solution; and

c) removing the solvents from the solution to obtain amoiphous cabozantinib malate. The alcoholic solvent used in step (a) may preferably be a solvent or a mixture of
. solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol, and more preferably the alcoholic solvent is methanol.

Preferably the chlorinated solvent used in step (a) may be a solvent or a mixture of solvents selected from methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride. More preferably the chlorinated solvent is methylene chloride.

The solvents may be removed from the solution in step (c) by known methods, for example, distillation or spray drying.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

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

Reference example Preparation of Cabozantinib
l-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (10 gm) was dissolved in tetrahydrofuran (60 ml) and dimethyformamide (0.3 ml) was then added. To the solution was added a solution of oxalyl chloride (6 ml) in tetrahydrofuran (15 ml) and stirred for 30 minutes. To a mixture of 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (10 gm), terahydrofuran (140 ml), potassium carbonate (25 gm) and water (75 ml) was added a solution thus obtained above at 15 to 20 C. The temperature of the reaction mass was raised to room temperature and stirred for 45 minutes. To the reaction mass was added water (400 ml) and stirred for 14 hours. The separated solid was filtered and then dried to obtain 16 gm of Cabozantinib.

Examples

Example 1:

Preparation of Cabozantinib
l-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (10 gm) was dissolved in tetrahydrofuran (60 ml) and dimethyformamide (0.5 ml) was then added. To the solution was added a solution of thionyl chloride (6 ml) in tetrahydrofuran (15 ml) and stirred for 30 minutes. To a mixture of 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (10 gm), terahydrofuran (140 ml), potassium carbonate (23 gm) and water (75 ml) was added a solution thus obtained above at 15 to 20 C. The temperature of the reaction mass was raised to room temperature and stirred for 45 minutes. To the reaction mass was added water (400 ml) and stirred for 14 hours. The separated solid was filtered and then dried to obtain 16 gm of Cabozantinib. Chromatographic purity of cabozantinib: 99.91%.

Example 2:

Preparation of Cabozantinib crystalline Form 1
Cabozantinib (20 gm) as obtained in example 1 was dissolved in methanol (100 ml) and methylene chloride (100 ml) at room temperature. The resulting solution was subjected to carbon treatment and stirred for 15 minutes. The mass was filtered through hi-flow bed and the solvent was distilled off under vacuum below 50 C. The reaction mass was cooled to 20 to 25 C and stirred for 1 hour. The separated solid was filtered and then dried to obtain 18 gm of crystalline Cabozantinib.

Example 3:

Preparation of Cabozantinib crystalline Form 1
Example 2 was repeated using ethanol solvent instead of methanol solvent to obtain Cabozantinib crystalline Form 1.

Example 4:
Preparation of Cabozantinib crystalline Form 1
Example 2 was repeated using isopropyl alcohol solvent instead of methanol solvent to obtain Cabozantinib crystalline Form 1.

Example 5:
Preparation of Cabozantinib crystalline Form 1

Example 2 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain Cabozantinib crystalline Form 1.

Example 6:
Preparation of Cabozantinib malate
A mixture of cabozantinib (25 gm), dimethylacetamide (80 ml), acetonitrile (230 ml) and L-malic acid (10 gm) were added at room temperature to obtain a clear solution. The resulting solution was subjected to carbon treatment and filtered through hi-flow bed. The filtrate thus obtained was added water (450 ml) slowly for 1 hour and stirred for 2 hours. The separated solid was filtered and then dried to obtain 22 gm of pure Cabozantinib malate. Chromatographic purity: 99.91%.

Example 7:
Preparation of Cabozantinib malate
A mixture of cabozantinib crystalline Form 1 (250 gm) as obtained in example 2, dimethylacetamide (800 ml), acetonitrile (2300 ml) and L-malic acid (100 gm) were added at room temperature to obtain a clear solution. The resulting solution was subjected to carbon treatment and filtered through hi-flow bed. The filtrate thus obtained was added water (4500 ml) slowly for 1 hour and stirred for 2 hours. The separated solid was filtered and then dried to obtain 225 gm of pure Cabozantinib malate. Chromatographic purity: 99.92%.

Example 8:

Preparation of Cabozantinib malate
Example 6 was repeated using dimethylformamide solvent instead of dimethylacetamide solvent to obtain pure Cabozantinib malate.

Example 9:

Preparation of Cabozantinib malate

Example 6 was repeated using dimethyl sulfoxide solvent instead of dimethylacetamide solvent to obtain pure Cabozantinib malate.
Example 10:
Preparation of Cabozantinib malate
A mixture of Cabozantinib (25 gm), tetrahydrofuran (80 ml), methanol (160 ml) and L-malic acid (10 gm) were added at room temperature. The contents were heated to 60 to 65 C and stirred for 1 hour. The reaction mass was cooled to 25 to 30°C, stirred for 1 hour and filtered. To the crude solid thus obtained was added a mixture of tetrahydrofuran (80 ml) and methanol (160 ml), and then heated to 60 to 65°C. The solution was stirred for 1 hour at 60 to 65°C and then cooled to 25 to 30°C. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was dried to obtain 22 gm of pure Cabozantinib malate. Chromatographic purity: 99.87%.

Example 11:
Preparation of amorphous Cabozantinib malatc
Cabozantinib malate (10 gm) was dissolved in methanol (100 ml) and methylene chloride (100 ml) under stirring. The solution was filtered through hi-flow bed and the solvents were distilled off under vacuum below 50°C to obtain 10 gm of amorphous Cabozantinib malate.

Example 12:
Preparation of amorphous Cabozantinib malate
Cabozantinib malate (10 gm) was dissolved in ethanol (100 ml) and methylene chloride (100 ml) under stirring. The solution was filtered through hi-flow bed and the solvents were distilled off under vacuum below 50°C to obtain 10.gm of amoiphous Cabozantinib malate.

Example 13:
Preparation of amorphous Cabozantinib malate
Example 11 was repeated using isopropyl alcohol solvent instead of methanol solvent to obtain amorphous Cabozantinib malate.
Example 14:
Preparation of amorphous Cabozantinib malate
Example 11 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain amorphous Cabozantinib malate.

Example 15:
Preparation of amorphous Cabozantinib malate
Example 12 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain amorphous cabozantinib malate.

Example 16:
Preparation of amorphous Cabozantinib malate

A mixture of cabozantinib (10 gm), methanol (100 ml), methylene chloride (100 ml) and L-malic acid (4 gm) were added and stirred for 20 minutes at room temperature. The solution was filtered through hi-flow bed and the solvents were distilled off under vacuum below 50°C to obtain 10 gm of amorphous Cabozantinib malate.

Example 17:
Preparation of amorphous Cabozantinib malate
Example 16 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous Cabozantinib malate.

Example 18:
Preparation of amorphous Cabozantinib malate
Example 16 was repeated using isopropyl alcohol solvent instead of methanol solvent to obtain amorphous Cabozantinib malate. Example 19: Preparation of amorphous Cabozantinib malate
Example 16 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain amorphous Cabozantinib malate.
Example 20:
Preparation of Cabozantinib malate crystalline Form HI
A mixture of Cabozantinib (100 gm), dimethylacetamide (400 ml), acetonitrile (1000 ml) and L-malic acid (10 gm) were added at room temperature. Heated to 60 to 65 deg C and added water. Stirred for lhour at 60 - 65°C and cooled to 25 to 30 deg C, The product thus obtained was filtered, washed with acetonitrile (80 ml) and dried to yield 87 gm of Cabozantinib malate Form HI.

We claim:

1. A process for the preparation of Cabozantinib, which comprises: a) dissolving 1-[(4-flucrophenyl)carbamoyl]cyclopropanecarboxylic acid in an ether solvent; b) adding dimethylformamide or dimethylacetamide to the solution; c) adding thionyl chloride to the solution to obtain a solution; d) dissolving 6,7-dimethoxy-4-(4-aminophenoxy)quinolone in an ether solvent; e) adding a base and water to the solution obtained in step (d); f) adding a solution obtained in step (c) to the reaction mass obtained in step (e); and isolating cabozantinib. Wherein base is selected from sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate or calcium bicarbonate.

2. Cabozantinib crystalline Form I which is characterized by Powder x-ray diffraction spectrum having 26 angle peaks at about 8.8, 11.3, 13.2, 13.7, 14.0, 15.1, 15.6, 22.1 and 24.3 ± 0.2 degrees.

3. A process for the preparation of Cabozantinib crystalline Form 1 as claimed in claim 2, which comprises a) dissolving Cabozantinib in a solvent b) removing the solvents from the solution; and c) isolating Cabozantinib crystalline Form 1; wherein the solvent is comprising of alcoholic solvent, chlorinated solvent and mixtures thereof.
4. The process as claimed in claim 3, wherein the alcoholic solvent selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol, isobutyl alcohol; chlorinated solvent selected from methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride.

5. Cabozantinib Malate crystalline Form HI, which is characterized by Powder x-ray diffraction spectrum having 20 angle peaks at 7.6, 9.4, 10.8, 13.4, 15.1, 15.3, 22.9 and 25.9 ± 0.2 degrees.

6. A process for the preparation of Cabozantinib Malate crystalline Form HI as claimed in claim 5, which comprises a) treating Cabozantinib with L- malic acid in a solvent b) heating to 60 deg C and adding water; c) maintaining for 1 hour at 60 to 65 deg C d) cooling to 25 to 35 deg C; and e) isolating Cabozantinib malate Form HI; wherein the solvent is comprising of polar aprotic solvents and mixtures thereof.

7. The process claimed in claim 6, wherein polar aprotic solvents selected from acetonitrile, dimethyl sulfoxide, dimethyl fonnamide, dimethyl acetamide.

8. A process for the preparation of amorphous Cabozantinib malate, which comprises; a) dissolving Cabozantinib malate in a solvent; and b) removing the solvent from the solution to obtain amorphous Cabozantinib malate; wherein the solvent is comprising of alcoholic solvent, chlorinated solvent and mixtures thereof.

9. A process for the preparation of amorphous Cabozantinib malate. which comprises; a) dissolving Cabozantinib in a solvent; and b) adding L-malic acid to the solution; and removing the solvent from the solution to obtain amorphous Cabozantinib malate; wherein the solvent is comprising of alcoholic solvent, chlorinated solvent and mixtures thereof.

10. The process as claimed in claim 8 and 9, wherein the alcoholic solvent selected from methanol, ethanol, isopropyl alcohol, ten-butyl alcohol, n-butanol, isobutyl alcohol; chlorinated solvent selected from methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride.