DESC:FIELD OF THE INVENTION
The present invention relates to novel Lenvatinib salt or polymorphic forms and the process for preparation thereof.

BACKGROUND OF THE INVENTION
Lenvatinib chemically known as 4-[3-chloro-4-(cyclopropylcarbamoylamino) phenoxy]-7-methoxyquinoline-6-carboxamide is an inhibitor of receptor tyrosine kinases (RTKs) that targets the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Additionally, Lenvatinib inhibits various other RTKs that are involved in pathogenic angiogenesis, tumor growth, and cancer progression, as well as their normal cellular functions. These include fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFRa), KIT, and RET.

Formula I

Lenvatinib was first disclosed in US7253286 effective for prevention and treatment of various diseases associated with abnormal angiogenesis.

US7612208 discloses crystal of 4-(3-chloro-4-(cyclopropyl amino carbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate, hydrates or a solvate and to the process of preparation thereof. Accordingly, US’208 discloses crystalline form viz. Form A, Form B, Form C of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide methanesulfonate; a crystalline form (Form F) of a hydrate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide; a crystalline form (Form I) of an acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide; a crystalline form (Form I) of an acetic acid solvate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide methanesulfonate; a crystalline form (Form a) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide ethanesulfonate; a crystalline form (Form ß) of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide ethanesulfonate.

US7550483 discloses amorphous form of Lenvatinib and process for its preparation.

US10562855 discloses crystalline form of Lenvatinib mesylate characterized by its XRD data and the process for its synthesis.

WO2017221215 describes various salts of Lenvatinib such as Lenvatinib acetate, L-proline, maleate, citrate, salicylate, succinate, L-pyroglutamate and their polymorphs.

A need in the art still exists to provide the compound in its salt forms as polymorphs which is physically and chemically stable at storage conditions and has sufficient solubility and bioavailability.

The present inventors surprisingly found that the salt forms of Lenvatinib as novel polymorphs have good physical and chemical properties and further provides the process of preparation thereof. This remains the object of the invention.

SUMMARY OF THE INVENTION
In accordance with the above, the present invention provides novel Lenvatinib salt polymorphic forms which is physically and chemically stable at storage conditions and has sufficient solubility and bioavailability and to the process for preparation thereof.

In an aspect, the present invention provides novel Lenvatinib succinate polymorph Form C1 characterized by its PXRD peaks as shown in Fig 1 as per example 1.

In another aspect, the present invention provides novel Lenvatinib succinate polymorph Form C1 characterized by its PXRD peaks as shown in Fig 2 as per example 2.

In an aspect, the present invention provides novel Lenvatinib succinate polymorph Form C2 characterized by its PXRD peaks as shown in Fig 3.

In another aspect, the present invention provides novel Lenvatinib succinate polymorph Form C3 characterized by its PXRD peaks as shown in Fig 4.

In yet another aspect, the present invention provides novel Lenvatinib succinate polymorph Form C4 characterized by its PXRD peaks as shown in Fig 5.

In another aspect, the present invention provides novel Lenvatinib L-malate, D-malate and DL-malate salts.

In yet another aspect, the present invention provides novel Lenvatinib L-malate characterized by PXRD peaks as shown in Fig 6.

In an aspect, the present invention provides novel polymorph Form C1 Lenvatinib D-malate, according to example 8 characterized by PXRD peaks as shown in Fig 7.

In another aspect, the present invention provides novel polymorph Form C2 Lenvatinib D-malate according to example 9 characterized by PXRD peaks as shown in Fig 8.

In an aspect, the present invention provides novel Lenvatinib DL-malate polymorph Form C1 characterized by PXRD peaks as shown in Fig 9.

In another aspect, the present invention provides Lenvatinib DL-malate polymorph Form C2 characterized by PXRD peaks as shown in Fig 10.

In yet another aspect, the present invention provides novel Lenvatinib DL-malate polymorph Form C3 characterized by PXRD peaks as shown in Fig 11.

In another aspect, the present invention provides a process for preparation of novel polymorphs of Lenvatinib succinate, Lenvatinib L-malate, Lenvatinib D-malate and Lenvatinib DL-malate respectively.

In yet another aspect, the present invention provides a pharmaceutical composition comprising novel salts of Lenvatinib or novel polymorph of the salts and pharmaceutically acceptable excipients.

In an aspect, the present invention provides the pharmaceutical composition for use in various cancers.

DESCRIPTION OF THE FIGURES
Fig.1: illustrates the PXRD data of Lenvatinib succinate polymorph Form C1 as per example 1.
Fig 2: illustrates the PXRD data of Lenvatinib succinate polymorph Form C1 as per example 2.
Fig 3: illustrates the PXRD data of Lenvatinib succinate polymorph Form C2.
Fig 4: illustrates the PXRD data of Lenvatinib succinate polymorph Form C3.
Fig 5: illustrates the PXRD data of Lenvatinib succinate polymorph Form C4.
Fig 6: illustrates the PXRD data of Lenvatinib L-malate.
Fig 7: illustrates the PXRD data of Polymorph Form C1 Lenvatinib D malate according to example 8.
Fig 8: illustrates the PXRD data of polymorph Form C2 Lenvatinib D-malate according to example 9.
Fig 9: illustrates the PXRD data of Lenvatinib DL-malate polymorph Form C1.
Fig 10: illustrates the PXRD data of Lenvatinib DL-malate polymorph Form C2.
Fig 11: illustrates the PXRD data of Lenvatinib DL-malate polymorph Form C3.
Fig 12: illustrate the solubility of Lenvatinib mesylate and Lenvatinib succinate Form C1 in 0.1 N HCl.
Fig 13: illustrate the solubility of Lenvatinib mesylate and Lenvatinib succinate Form C1 in pH 1.2 buffer.
Fig 14: illustrate the solubility of Lenvatinib mesylate and Lenvatinib succinate Form C1 in pH 4.5 buffer.
Fig 15: illustrate the solubility of Lenvatinib mesylate and Lenvatinib succinate Form C1 in pH 6.8 buffer.

DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be explained in detail with reference to its various preferred as well as optional embodiments, which, however, should not be construed to limit the scope of the invention.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.

Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

In an embodiment, the present invention discloses Lenvatinib salt forms, its polymorphs and the process for preparation thereof.

Accordingly, the present invention discloses novel polymorphs of Lenvatinib salts such as Lenvatinib succinate, Lenvatinib malate, Lenvatinib L-malate, Lenvatinib D-malate and Lenvatinib DL-malate.

In an embodiment, the novel Lenvatinib succinate polymorph Form C1 is characterized by PXRD data having peaks at 7.27, 12.34, 17.49, 20.17, 22.67, 26.54 ± 0.2°? according to Fig 1 & Fig 2.

In an embodiment, the novel Lenvatinib succinate polymorph C2 is characterized by PXRD data having peaks at 8.2, 10.92, 11.6, 14.56, 16.49, 24.49 ± 0.2°? according to Fig 3.

In yet another embodiment, the novel Lenvatinib succinate polymorph C3 is characterized by PXRD data having peaks at 8.18, 10.94, 11.6, 14.49, 16.52, 24.64 ± 0.2°? according to Fig 4.

In an embodiment, the novel Lenvatinib succinate polymorph C4 is characterized by PXRD data having peaks at 15.63, 16.78, 18.69, 22.71 & 23.96 ± 0.2°? according to Fig 5.
In an embodiment, Lenvatinib and succinic acid may be in the ratio 1:1 or 1:0.5.

In another embodiment, the present invention discloses novel Lenvatinib L-malate, D-malate and DL-malate salts.

In yet another embodiment, the novel Lenvatinib L-malate is characterized by PXRD data having peaks at 7.35, 9.39, 12.39, 16.50, 25.87 ± 0.2°?.

In an embodiment, the novel polymorph Form C1 of Lenvatinib D-malate according to Example 8 is characterized by PXRD data having peaks at 7.3, 9.42, 12.42, 14.34, 14.85, 16.53, 21.54 ± 0.2° ?.

In another embodiment, the novel polymorph Form C2 of Lenvatinib D-malate according to Example 9 is characterized by PXRD data having peaks at 7.42, 9.49, 12.46, 14.35, 14.94, 16.58, 18.18, 21.67 ± 0.2° ?.

In an embodiment, the novel Lenvatinib DL-malate of polymorph Form C1 is characterized by PXRD data having peaks at 7.38, 9.44, 12.45, 16.57, 27.89 ± 0.2°?.

In another embodiment, the novel Lenvatinib DL-malate of polymorph C2 is characterized by PXRD data having peaks at 6.61, 10.29, 15.21, 17.85, 18.98, 26.65 ± 0.2°?.

In another embodiment, the novel Lenvatinib DL-malate of polymorph C3 is characterized by PXRD data having peaks at 7.60, 10.95, 11.52, 12.63, 22.07, 24.00 ± 0.2°?.

In an embodiment, Lenvatinib and D or L or DL malic acid may be in the ratio 1:1 or 1:0.5.

In an embodiment, the present invention discloses process for preparation of Lenvatinib salt forms comprising:
a) Suspending Lenvatinib and suitable acid in a solvent; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield the corresponding salt.

The Lenvatinib base used in the process for synthesis of any of the salts may be in any form amorphous or crystalline form available in the art.

The suitable acid may be selected from succinic acid or malic acid.

The solvent according to step a) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

The stirring of the reaction mixture according to step b) is carried out at a temperature ranging from 25°C to 50°C.

The filtration, washing, and drying steps are carried out by the processes known in the art.

In an embodiment, the present invention discloses a process for preparation of Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 and Form C4 comprising;
a) Suspending Lenvatinib and succinic acid in suitable solvent at a suitable temperature; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield Lenvatinib succinate polymorphs.

The suitable solvent according to step a) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

The reaction is carried out at a temperature ranging between 20 to 40?C, preferably at room temperature.
In an alternate embodiment, Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 and Form C4 may be prepared by the process comprising;
a) Suspending Lenvatinib in a first solvent at suitable temperature;
b) Suspending succinic acid in a second solvent at suitable temperature;
c) Adding succinic acid solution to Lenvatinib solution or vice versa; and
d) Stirring and heating and cooling the reaction mixture in cycles; and
e) Filtering the reaction mass of step d) followed by washing and drying to obtain Lenvatinib succinate polymorphs.

The suitable solvent according to step a) and step b) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

In an embodiment, the addition of succinic acid solution or Lenvatinib solution may be a slow addition.

In yet another alternate embodiment, the mixture may be stirred for the time ranging from 30 minutes to 40 hours.

The suitable temperature of addition may be selected from 10 to 50°C, preferably 20 to 40°C, more preferably 30 to 35°C.

In an optional embodiment, the Lenvatinib seed can be added to the reaction mixture.

The reaction mixture may then be heated to suitable temperature and maintained for time ranging from 10 to 15 hours, preferably 8 to 10 hours.

The suitable temperature may be selected from 40 to 50°C, preferably 50 to 55°C, more preferably 55 to 65°C.

The reaction mass may then be further cooled at suitable temperature and maintained for the time ranging from 30 minutes to 6 hours, preferably 1 to 4 hours.

The suitable temperature of cooling may be selected from 40 to 50°C, preferably 30 to 45°C, more preferably 25 to 35°C.

The precipitate obtained may be filtered by the processes known in the art and may be washed with suitable solvent which may be selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

The solid obtained after filtration may be dried by the known processes at suitable temperature and for suitable period of time.

The suitable temperature of drying may be selected from 20 to 60°C for the time ranging from 3 hours to 40 hours.

In an embodiment, the present invention discloses a process for preparation of Lenvatinib succinate polymorph Form C1 comprising;
a) Suspending Lenvatinib and succinic acid in ethyl acetate at room temperature; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield the desired polymorph.

In an alternate embodiment, Lenvatinib succinate polymorph Form C1 is prepared by the process comprising;
a) Suspending Lenvatinib base in ethyl acetate and heating to 30-35?C to obtain Lenvatinib solution;
b) Suspending succinic acid in methanol at a temperature of 30-35?C and clarifying the solution under vacuum;
c) Adding slowly the succinic acid solution of step b) into Lenvatinib solution of step a) or vice versa;
d) Seeding the above mixture of step c) with Lenvatinib succinate (C1) followed by stirring and heating and cooling the reaction mixture in cycles; and
e) Filtering the reaction mass of step d) followed by washing and drying to obtain Lenvatinib succinate polymorph Form C1.

The Lenvatinib succinate Form C1 obtained by the process of the present invention is anhydrous.

The bulk and tapped densities are important in formulation of the Active pharmaceutical ingredient into suitable dosage forms. These tests are carried out as per any Pharmacopeia such as US Pharmacopeia or European Pharmacopeia or British Pharmacopeia.

In an embodiment, the bulk density (g/ml) and tapped density (g/ml) of Lenvatinib succinate polymorph Form C1 was compared to the bulk density and tapped density of approved Lenvatinib mesylate as shown in table 1 below. The Lenvatinib succinate Form C1 was observed to have comparable bulk and tapped and densities with the approved Lenvatinib mesylate salt.

The inventors of the present invention carried out certain experiments and observed that Lenvatinib succinate Form C1 also has good physical and chemical properties which can be used for formulation of this form in solid dosage forms.

In an embodiment, Lenvatinib succinate Form C1 is stable for a period of 6 months at 2-8°C. Further, Lenvatinib Succinate (C1) is stable for 6 months at accelerated conditions of 25°C/60% RH as shown in the table 6 and table 7 below.

In yet another embodiment, the present invention discloses process for preparation of Lenvatinib L-malate comprising;
a) Suspending Lenvatinib and L-malic acid in the ratio 1:1 in a solvent; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield Lenvatinib L-malate.

The suitable solvent according to step a) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

In an embodiment, the present invention discloses process for preparation of Lenvatinib D-malate polymorphs:
a) Suspending Lenvatinib and D-malic acid in suitable solvent; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield Lenvatinib D-malate polymorphs.
The solvent according to step a) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

In an embodiment, the present invention discloses process for preparation of Lenvatinib DL-malate polymorphs comprising;
a) Suspending Lenvatinib and DL-malic acid in a solvent; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield Lenvatinib DL-malate polymorphs.

The solvent according to step a) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.

The reaction is carried out at a temperature ranging between 40 to 50°C, preferably 30 to 45°C, more preferably 25 to 35°C

In yet another embodiment, the present invention relates to pharmaceutical composition comprising Lenvatinib succinate polymorphs Form C1, Form C2 Form C3 and/or Form C4 alone or in combination together with pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to pharmaceutical composition comprising Lenvatinib L-malate, Lenvatinib D-malate, Lenvatinib DL-malate, alone or in combination together with pharmaceutically acceptable excipients.

In an embodiment, a method of treating cancer comprising administration of Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 or Form C4 of the present invention or its pharmaceutical composition,alone or in combination to the patient in a therapeutically effective amount.
In yet another embodiment, the present invention relates to a method of treating cancer comprising administration of Lenvatinib L-malate, Lenvatinib D-malate, Lenvatinib DL-malate or polymorphs thereof or its pharmaceutical composition, alone or in combination to the patient in a therapeutically effective amount.

In yet another embodiment, the Lenvatinib salt forms of the present invention alone or in combination are used for treatment of cancer.

Examples:
The invention will now be further described by the following working example(s), which are preferred embodiments of the invention. All temperatures are in degrees Celsius (°C) unless otherwise indicated. These examples are illustrative rather than limiting and it is to be understood that there may be other embodiments that fall within the spirit and scope of the invention appended hereto.

Example 1 : Process of Preparation of Lenvatinib succinate polymorph Form C1
Lenvatinib (5 g), and succinic acid (1.93 g) were taken in a clean round bottom flask and suspended in 100 mL of ethyl acetate. The suspension was stirred at 20 -25°C for about 6 to 8 hours. 25 ml of ethyl acetate was added to the above suspension and the reaction mass were maintained for about 14 to 16 hours at RT. The reaction mixture was filtered and washed with 25ml of ethyl acetate, and then suck dried under vacuum for about 30 minutes at 20-25°C. The obtained solid was dried at 45°C for about 23 to 25 hours and was analyzed by PXRD (Figure 1). Yield: 5 g

Example 2 : Process of Preparation of Lenvatinib succinate polymorph Form C1
100 g of Lenvatinib base, 3.5 lit of ethyl acetate were taken in a clean 15 lit glass reactor and the contents were heated to 30-35°C and maintained for 30 minutes. In a separate reactor 41.49 g of succinic acid was dissolved in 300 ml of methanol at 30-35 °C and the solution was clarified under vacuum. Slowly the succinic acid solution was added into the Lenvatinib suspension. Further, 2 g of Lenvatinib succinate (C1) seed was added into the above reaction mass and the contents were heated to 55-60°C and maintained for 8-10 hours. The reaction mass was cooled to 20-25°C and maintained for 4 to 5 hours. Again, the reaction mass was heated to 55-60°C and maintained for 2 to 3 hours. The reaction mass then cooled to 20-25°C and maintained for 2 to 3 hours. Then the reaction mass was filtered under vacuum. The bed was washed with 50 ml of Ethyl acetate and suck dried for 1 hour. The solid obtained was dried at 30-35 °C for 5 hours and then further dried at 40-45 °C for about 12 to 15 hours and was analyzed by PXRD.
Yield: 120 g

Example 3 : Process of Preparation of Lenvatinib succinate polymorph Form C2
Lenvatinib (0.5 g) and succinic acid (0.194 g) were taken in a clean round bottom flask and suspended in 10 mL of methanol. The suspension was stirred at 20 - 25°C for about 30 min and then 10 ml of methanol was added to it and further the reaction mass was maintained for about 8 to 10 hours at 20 - 25°C. The reaction mixture was filtered and washed with 5 ml of methanol, and then suck dried under vacuum for about 30 min at 20 - 25°C and was analyzed by PXRD (Figure 2).

Example 4 : Process of Preparation of Lenvatinib succinate polymorph Form C3
The solid obtained in Example 2 was dried at 45 °C for about 18 to 20 hours and was analyzed by PXRD (Figure 3). Yield: 0.38 g

Example 5 : Process of Preparation of Lenvatinib succinate polymorph Form C4
Charged 1 g of Lenvatinib base, 20 ml of ethyl acetate in a round bottom flask (RBF). Dissolved 0.387 g (1.4 eq) of succinic acid in 10.0 ml of acetone at 55 °C and clarified the solution and washed with 2 ml of acetone. Cooled the succinic acid solution to 20 - 25°C and slowly added this solution into the Lenvatinib suspension. Stirred the reaction mass for 10 to 12 hours at 20 - 25°C. Filtered the reaction mass under vacuum and washed the bed with 10 ml of Ethyl acetate and suck dried for 1 hr. The obtained solid was dried at 25 °C for 5 hours and then dried at 45 °C for about 12 to 15 hours and was analyzed by PXRD.

Example 6 : Process of Preparation of Lenvatinib L-malate
Lenvatinib (0.5 g), and L-malic acid (0.157 g) were taken in a clean round bottom flask and suspended in 10 mL of ethyl acetate. The suspension was stirred at 20 -25°C for about 3 hours. 5 ml of ethyl acetate was added into the above flask and the reaction mixture was maintained for 10 to 12 hours at 20 - 25°C. The reaction mixture was then filtered, and suck dried under vacuum for about 1 hour at 20 - 25°C. The obtained solid was dried at 45°C for about 18 to 22 hours and was analyzed by PXRD. Yield: 0.43 g

Example 7 : Process of Preparation of Lenvatinib L-malate
Lenvatinib (4g), and L-malic acid (1.26 g) were taken in a clean round bottom flask and suspended in 80 mL of ethyl acetate. The suspension was stirred at 20 - 25°C for about 8 to 10 hours. The reaction mixture was filtered and washed with 35 ml of ethyl acetate, and then suck dried under vacuum for about 1 hour at 20 - 25°C. The obtained solid was dried at 45 °C for about 28 to 32 hours and was analyzed by PXRD (Figure 7). Yield: 4.35 g

Example 8 : Process of Preparation of Lenvatinib D-malate polymorph Form C1
Lenvatinib (5 g), and D-malic acid (1.57 g) were taken in a clean round bottom flask and suspended in 100 mL of ethyl acetate. The suspension was stirred at 20 -25°C for about 30 min and then 0.5 ml of water was charged into it. The reaction mass was maintained for 3 to 5 hours at 20 - 25°C. The reaction mixture was filtered and washed with 25 ml of ethyl acetate, and then suck dried under vacuum for about 1 hour at 20 - 25°C. The obtained solid was dried at 45 °C for about 20 to 22 hours and was analyzed by PXRD (Figure 8). Yield: 5.3 g

Example 9 : Process of Preparation of Lenvatinib D-malate polymorph Form C2
Lenvatinib (5 g), and D-malic acid (1.57 g) were taken in a clean round bottom flask and suspended in 100 mL of ethyl acetate. The suspension was stirred at 20 - 25°C for about 6 hours and then 25 ml of ethyl acetate was added to it and further the reaction mass was maintained for about 10 hours at RT. The reaction mass was heated to 50 ? and maintained for 6 hours. 25 ml of ethyl acetate was added to the reaction mass and further the reaction mass was maintained for about 6 hours at 50 ?. The reaction mixture was filtered and washed with 25 ml of ethyl acetate, and then suck dried under vacuum for about 30 minutes at 20 - 25°C. The obtained solid was dried at 45 °C for about 16 to 18 hours and was analysed by PXRD (Figure 9). Yield: 4.5 g

Example 10 : Process of preparation of Lenvatinib DL-malate polymorph Form C1
Lenvatinib (0.5g), and DL-malic acid (0.157g) were taken in a clean round bottom flask and suspended in 10 mL of ethyl acetate. The suspension was stirred at 20 - 25°C for about 3 hours and then 5 ml of ethyl acetate was charged into it. The reaction mass was maintained for 10 to 12 hours at 20 - 25°C. The reaction mixture was filtered and washed with 8 ml of ethyl acetate and then suck dried under vacuum for about 1 hour at 20 - 25°C. The obtained solid was dried at 45 °C for about 18 to 20 hours and was analyzed by PXRD. Yield: 0.42 g

Example 11 : Process of Preparation of Lenvatinib DL-malate polymorph Form C1
Lenvatinib (4 g), and DL-malic acid (1.26 g) were taken in a clean round bottom flask and suspended in 80 mL of ethyl acetate. The suspension was stirred at 20 - 25°C for about 8 to 10 hours. The reaction mixture was filtered and washed with 40 ml of ethyl acetate, and then suck dried under vacuum for about 1 hour at 20 - 25°C. The obtained solid was dried at 45 °C for about 28 to 32 hours and was analyzed by PXRD (Figure 10 ). Yield: 4.35 g

Example 12: Process of Preparation of Lenvatinib DL-malate polymorph Form C2
Lenvatinib (0.5g), and DL-malic acid (0.157 g) were taken in a clean round bottom flask (RBF) and suspended in 10 mL of acetone. The suspension was stirred at 20 - 25°C for about 3 to 5 hours. 0.157 g of DL-malic acid was charged into the above RBF and continued the stirring for 1 hour. 5 ml of acetone was charged into it and maintained for 20 to 23 hours at 20 - 25°C. The reaction mixture was filtered and washed the bed with 5 ml of acetone then suck dried it under vacuum for about 1 hour at 20 - 25°C. The obtained solid was dried at 45 °C for about 18 to 20 hours and was analysed by PXRD (Figure 11). Yield: 0.23 g

Example 13 : Process of Preparation of Lenvatinib DL-malate polymorph Form C3
Lenvatinib (0.5g), and DL-malic acid (0.314 g) were taken in a clean round bottom flask and suspended in 10 mL of methanol. The suspension was stirred at 20 - 25°C for about 30 minutes and then 10 ml of methanol was added to it and further the reaction mass was maintained for about 6 hours. Further DL-malic acid (471 mg) was added into the above suspension and maintained for 8 to 10 hours at 20 - 25°C. The reaction mixture was filtered and washed with 5 ml of methanol, and then suck dried under vacuum for about 30 minutes at20 -25°C. The obtained solid was dried at 45 °C for about 18 to 20 hours and was analyzed by PXRD (Figure 12). Yield: 0.39 g

Example 14: Characteristics of Lenvatinib Succinate polymorph Form C1
Example 14a: Bulk density and tapped density
Bulk and tapped densities are important in formulation of the Active pharmaceutical ingredient into suitable dosage forms. These tests are carried out as per any Pharmacopeia such as US Pharmacopeia or European Pharmacopeia or British Pharmacopeia.
Table 1:
Lenvatinib Mesylate Lenvatinib Succinate (C1)
Bulk density (g/ml) 0.20 0.20
Tapped density (g/ml) 0.39 0.32

Inference: Above data indicates that Lenvatinib succinate Form C1 has comparable tapped and bulk densities with that of Lenvatinib mesylate which is an approved salt.
Example 14b: pH SOLUBILITY
Following method were used for this test: An excess amount of the sample, equivalent to 150 mg of Lenvatinib base, was added to 900 ml of selected media and stirred in a dissolution apparatus at 37? for 1 hour. At specified time intervals, approximately 5 ml of the solution was taken and filtered through a 0.45 µm filter. The filtrate was then analyzed spectrophotometrically using HPLC to determine the concentration of Lenvatinib.

SOLUBILITY IN 0.1 N HCL
Table 2:
Time (min) Solubility (mg/ml)
Lenvatinib Mesylate Lenvatinib Succinate (C1)
5 0.004 0.002
10 0.006 0.004
15 0.008 0.005
20 0.009 0.006
30 0.012 0.008
60 0.020 0.014

The graphical representation of these values is provided in figure 12.
Inference: Lenvatinib mesylate and Lenvatinib Succinate (C1) are having comparable solubility in 0.1 N HCl.
SOLUBILITY IN pH 1.2 BUFFER
Table 3:
Time (min) Solubility (mg/ml)
Lenvatinib Mesylate Lenvatinib Succinate (C1)
10 0.0085 0.0070
20 0.0145 0.0133
30 0.0205 0.0190
60 0.0369 0.0336

The graphical representation of these values is provided in figure 13.
Inference: Lenvatinib mesylate and Lenvatinib Succinate (C1) are having comparable solubility in pH 1.2 buffer.

SOLUBILITY IN pH 4.5 BUFFER
Table 4:
Time (min) Solubility (mg/ml)
Lenvatinib Mesylate Lenvatinib Succinate (C1)
10 0.0070 0.0015
20 0.0127 0.0018
30 0.0191 0.0022
60 0.0374 0.0031

The graphical representation of these values is provided in figure 14.
Inference: Lenvatinib mesylate and Lenvatinib Succinate (C1) are having comparable solubility in pH 4.5 buffer.

SOLUBILITY IN pH 6.8 BUFFER
Table 5:
Time (min) Solubility (mg/ml)
Lenvatinib Mesylate Lenvatinib Succinate (C1)
10 0.0007 0.0006
20 0.0007 0.0003
30 0.0009 0.0003
60 0.0010 0.0004

The graphical representation of these values is provided in figure 15.
Inference: Lenvatinib mesylate and Lenvatinib Succinate (C1) are having comparable solubility in pH 6.8 buffer.

Example 15: STABILITY DATA
Example 15a: STABILITY DATA OF LENVATINIB SUCCINATE (C1) (STORAGE CONDITION: 2-8°C)
Table 6:
Time interval Description XRD
INITIAL Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
1 MONTH Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
2 MONTHS Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
3 MONTHS Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
6 MONTHS Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
Inference: Lenvatinib Succinate (C1) is stable for 6 months at 2-8°C.
Example 15b: STABILITY DATA OF LENVATINIB SUCCINATE (C1) (STORAGE CONDITION: 25°C ± 2°C / 60% ± 5%RH)
Table 7:
Time interval Description XRD
INITIAL Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
1 MONTH Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
2 MONTHS Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
3 MONTHS Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
6 MONTHS Off white colour powder Comparable with Lenvatinib Succinate (C1) standard
Inference: Lenvatinib Succinate (C1) is stable for 6 months at 25°C/60% RH.
It will be understood that the above description is intended to be illustrative and not restrictive. The embodiments will be apparent to those in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description but should instead be determined by the appended claims along with full scope of equivalents to which such claims are entitled.
,CLAIMS:1. Lenvatinib succinate polymorphs comprising Form C1, Form C2, Form C3 and Form C4..
2. The Lenvatinib succinate polymorph as claimed in claim 1, wherein
• Lenvatinib succinate polymorph Form C1 characterized by PXRD having peaks at 7.27, 12.34, 17.49, 20.17, 22.67, 26.54 ± 0.2°?;
• Lenvatinib succinate polymorph Form C2 characterized by PXRD having peaks at 8.2, 10.92, 11.6, 14.56, 16.49, 24.49 ± 0.2°?;
• Lenvatinib succinate polymorph Form C3 characterized by PXRD having peaks at 8.18, 10.94, 11.6, 14.49, 16.52, 24.64 ± 0.2°?;
• Lenvatinib succinate polymorph Form C4 characterized by PXRD having peaks at 15.63, 16.78, 18.69, 22.71 & 23.96 ± 0.2°?.
3. A process for preparation of Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 and Form C4 as claimed in claim 2, comprising;
a) Suspending Lenvatinib base and succinic acid in a solvent; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield Lenvatinib succinate polymorphs.
4. The process for preparation of Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 and Form C4 as claimed in claim 2 may be carried out by the process comprising;
a) Suspending Lenvatinib in a first solvent at suitable temperature;
b) Suspending succinic acid in a second solvent at suitable temperature;
c) Adding succinic acid solution to Lenvatinib solution or vice versa;
d) Optionally seeding with Lenvatinib seed; and
e) Stirring and heating and cooling the reaction mixture in cycles; and
f) Filtering the reaction mass of step d) followed by washing and drying to obtain Lenvatinib succinate polymorphs.
5. The process as claimed in claim 3 or claim 4, wherein the solvent is selected from polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.
6. The process as claimed in claim 3, wherein the reaction is carried out at a temperature ranging between 20 to 40?C.
7. The process as claimed in claim 4, wherein addition of succinic acid solution or Lenvatinib solution in step c) may be a slow addition.
8. The process as claimed in claim 4, wherein the reaction is carried out at a temperature ranging between 10 to 50?C, preferably 20 to 40°C, more preferably 30 to 35°C.
9. The process as claimed in claim 4, wherein the seeding with Lenvatinib seed is followed by heat-cool cycle to obtain the reaction mass.
10. The process as claimed in claim 3, wherein Lenvatinib succinate polymorph Form C1 is prepared by the process comprising;
a) Suspending Lenvatinib and succinic acid in ethyl acetate at room temperature; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield the desired polymorph.
11. The process as claimed in claim 4, wherein Lenvatinib succinate polymorph Form C1 is prepared by the process comprising;
a) Suspending Lenvatinib base in ethyl acetate and heating to 30-35?C to obtain Lenvatinib solution;
b) Suspending succinic acid in methanol at a temperature of 30-35?C and clarifying the solution under vacuum;
c) Adding slowly the succinic acid solution of step b) into Lenvatinib solution of step a) or vice versa;
d) Seeding the above mixture of step c) with Lenvatinib succinate (C1) followed by stirring and heating and cooling the reaction mixture in cycles, and
e) Filtering the reaction mass of step d) followed by washing and drying to obtain Lenvatinib succinate polymorph Form C1.
12. A pharmaceutical composition comprising Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 and Form C4 as claimed in any one of the preceding claims, and a pharmaceutically acceptable excipients.
13. A method of treating cancer comprising administration of Lenvatinib succinate polymorphs Form C1, Form C2, Form C3 or Form C4 or its pharmaceutical composition, alone or in combination to the patient in a therapeutically effective amount.
14. Lenvatinib malate salts comprising L-malate, D-malate and DL-malate salts or polymorphs thereof.
15. The Lenvatinib malate salt as claimed in claim 13, wherein;
Lenvatinib L-malate characterized by PXRD data having peaks at 7.35, 9.39, 12.39, 16.50, 25.87 ± 0.2°?;
Lenvatinib D-malate polymorph Form C1 characterized by PXRD data having peaks at 7.3, 9.42, 12.42, 14.34, 14.85, 16.53, 21.54 ± 0.2° ?;
Lenvatinib D-malate polymorph Form C2 characterized by PXRD data having peaks at 7.42, 9.49, 12.46, 14.35, 14.94, 16.58, 18.18, 21.67 ± 0.2° ?;
Lenvatinib DL-malate polymorph Form C1 characterized by PXRD data having peaks at 7.38, 9.44, 12.45, 16.57, 27.89 ± 0.2° ?;
Lenvatinib DL-malate polymorph C2 characterized by PXRD data having peaks at 6.61, 10.29, 15.21, 17.85, 18.98, 26.65 ± 0.2°?;
Lenvatinib DL-malate polymorph C3 characterized by PXRD data having peaks at 7.60, 10.95, 11.52, 12.63, 22.07, 24.00 ± 0.2°?.
16. A process for preparation of Lenvatinib L-malate as claimed in claim 15, comprising;
a) Suspending Lenvatinib and L-malic acid, D-malic acid, DL-malic acid in the ratio 1:1 in a solvent; and
b) Stirring the reaction mixture of step a) followed by filtration, washing and drying to yield the product.
17. The process as claimed in claim 16, wherein the solvent in step a) is selected from but not limited to polar aprotic solvents such as esters, ketones, ethers; non-polar solvents such as hydrocarbons; protic polar solvents such as alcohols and the like alone or in combination thereof.
18. The process as claimed in claim 16, wherein the reaction is carried out at a temperature ranging between 40 to 50°C, preferably 30 to 45°C, more preferably 25 to 35°C.
19. A pharmaceutical composition comprising Lenvatinib malate salts comprising L-malate, D-malate and DL-malate salts or polymorphs thereof as claimed in any one of the preceding claims 13 to 16 and a pharmaceutically acceptable excipients.
20. A method of treating cancer comprising administration of Lenvatinib L-malate, Lenvatinib D-malate, Lenvatinib DL-malate or polymorphs thereof or its pharmaceutical composition, alone or in combination to the patient in a therapeutically effective amount.