Polymorphs of cabozantinib salts and process thereof

Abstract

Disclosed herein are novel polymorphs of Cabozantinib salts and to the process for preparation thereof.

Description

[0001] POLYMORPHS OF CABOZANTINIB SALTS AND PROCESS THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel polymorphs of Cabozantinib salts and to the process for preparation thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. Cabozantinib is used in two forms. The capsule form (Cometriq) is used to treat medullary thyroid cancer and the tablet form (Cabometyx) is used to treat renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid carcinoma.

[0006] It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET.

[0007] Chemically, Cabozantinib is N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'- (4-fluorophenyl)cyclopropane-l,l-di carboxamide with the following structure;

[0008] Cabozantinib is disclosed in W02005030140 to inhibit, regulate and / or modulate kinase receptor, particularly c-Met, KDR, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities. The basic drug though exhibits therapeutic efficacy, there is always a scope to provide a suitable form of the drug that has properties such as improved solubility, dissolution, bioavailablity, stability, ease of processing and manufacturing.

[0009] W02010083414 discloses amorphous forms of Cabozantinib L- and D-malate as well as the N-l and N-2 polymorphs of crystalline Cabozantinib L- and D-malate. The present inventors surprisingly found that polymorphs of various salts of Cabozantinib have suitable properties for use as anticancer agents and that the salt forms may exist as crystalline and amorphous forms.

[0010] SUMMARY OF THE INVENTION

[0011] The primary objective of the present invention is to provide novel polymorphs of Cabozantinib salts and to the process for preparation thereof.

[0012] The other objective is to provide polymorphs of Cabozantinib salts that may exist as crystalline and amorphous forms respectively.

[0013] In accordance with the above, the present invention discloses the crystalline polymorphs of Cabozantinib salts, wherein the salts are selected from maleate, Citrates and the like.

[0014] In an aspect, the present invention discloses Cabozantinib Maleate salt Form Cl characterized by PXRD peaks as depicted in Fig 1.

[0015] In another aspect, the present invention discloses Cabozantinib Maleate salt Form Cl characterized by DSC as depicted in Fig 2.

[0016] In yet another aspect, the present invention discloses Cabozantinib Maleate salt Form Cl characterized by TGA as depicted in Fig 3. In another aspect, the present invention discloses Cabozantinib Maleate salt Form Cl characterized by DVS as depicted in Fig 4

[0017] In another aspect, the present invention discloses Cabozantinib Citrate salt Form Cl characterized by PXRD peaks as depicted in Fig 5.

[0018] In yet another aspect, the present invention discloses the Cabozantinib Citrate salt Form Cl characterized by DSC as depicted in Fig 6.

[0019] In another aspect, the present invention discloses a process for manufacturing polymorphic forms comprising;

[0020] 1. Suspending the mixture of Cabozantinib and suitable acid in a suitable solvent;

[0021] 2. Stirring, filtering, washing and drying under vacuum to obtain desired polymorphic Forms.

[0022] In an aspect, the present invention discloses a process for preparation of Cabozantinib Maleate Form Cl comprising; i. Suspending a mixture of Cabozantinib and maleic acid in C1-C5 alcohol; ii. Stirring the above mixture at a temperature ranging between 25°C to 55°C followed by filtering and washing the mass with C1-C5 alcohol and suck drying under vacuum to obtain the material; iii. Drying the material under vacuum at a temperature in the range of 40- 50°C for 10-25 hours; optionally drying in a tray dryer at a temperature in the range of 55-65°C for 30-36 hours to obtain desired product.

[0023] In yet another alternate process, the present invention discloses a process for preparation of Cabozantinib Maleate Form Cl comprising; i. Suspending a mixture of Cabozantinib in a mixture of C1-C5 alcohol and water; ii. Charging Cabozantinib Maleate seed to the above suspension followed by adding maleic acid solution at a temperature ranging between 25-35°C; iii. Heating the above mixture to a temperature ranging between 70- 75°C; and iv. Cooling the reaction mixture to a temperature ranging between 25- 35°C, filtering and drying to obtain the desired product.

[0024] In yet another aspect, the present invention discloses a process for preparation of Cabozantinib citrate Form Cl comprising;

[0025] Suspending a mixture of Cabozantinib and citric acid in C1-C5 alcohol; ii. Stirring the above mixture at a temperature ranging between 25°C to 55°C followed by filtering and washing the mass with C1-C5 alcohol and suck drying under vacuum to obtain the material; iii. Drying the material under vacuum at a temperature in the range of 40- 50°C for 10-25 hours; optionally drying in a tray dryer at a temperature in the range of 55-65°C for 30-36 hours to obtain desired product

[0026] In an aspect, Cabozantinib base is prepared by a known process.

[0027] In yet another aspect, the present invention provides a pharmaceutical composition comprising the polymorphic forms of Cabozantinib acid salts with one or more pharmaceutically acceptable excipients.

[0028] DESCRIPTION OF THE FIGURES

[0029] Fig 1: Depicts the PXRD of Cabozantinib maleate Form Cl

[0030] Fig 2: Depicts the DSC of Cabozantinib Maleate Form Cl

[0031] Fig 3: Depicts the TGA of Cabozantinib Maleate Form Cl

[0032] Fig 4: Depicts the DVS of Cabozantinib Maleate Form Cl Fig 5: Depicts the PXRD of Cabozantinib Citrate Form Cl

[0033] Fig 6 Depicts the DSC of Cabozantinib Citrate Form Cl

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035] The invention will now be described in detail in its preferred and optional embodiments however should not be construed to limit the scope of the invention. Unless stated to the contrary, any of the words “contains”, “containing”, “including”, “includes” “comprising”’ “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.

[0036] The present invention relates to novel polymorphs of Cabozantinib salts and to the process for preparation thereof. The polymorphs of Cabozantinib salts of the present invention may exist as crystalline and amorphous forms respectively.

[0037] In an embodiment, the present invention relates to the crystalline polymorphs of Cabozantinib salts, wherein the salts are selected from maleate, Citrates and the like.

[0038] In an embodiment, the present invention relates to Cabozantinib Maleate Form Cl characterized by an X-ray powder diffraction pattern comprising of the peaks at 4.78, 12.11, 13.56, 16.97, 23.63 and 26.04 ± 0.2°.

[0039] In yet another embodiment, the Cabozantinib Maleate salt Form Cl of the present invention has an X-ray powder diffraction (XRPD) spectrum substantially in accordance with the pattern depicted in FIG. 1. In another embodiment, the Cabozantinib Maleate Form Cl of the present invention exhibits the DSC having the thermogram as depicted in Fig 2. Accordingly, the DSC exhibits the endothermic peak at 201.68°C

[0040] In yet another embodiment, the present invention discloses Cabozantinib Maleate salt Form Cl characterized by TGA as depicted in Fig 3. Accordingly, the TGA depicts the weight loss of 0.065%

[0041] In another aspect, the present invention discloses Cabozantinib Maleate salt Form Cl characterized by DVS as depicted in Fig 4.

[0042] In another embodiment, the present invention relates to Cabozantinib Citrate Form Cl characterized by an X-ray powder diffraction pattern comprising of the peaks at 6.34, 9.8, 12.75, 15.35, 19.3, 23.8 and 26.40 ± 0.2°.

[0043] In yet another embodiment, the Cabozantinib Citrate Form Cl of the present invention has X-ray powder diffraction (XRPD) spectrum substantially in accordance with the pattern depicted in FIG. 5.

[0044] In another embodiment, the Cabozantinib Citrate Form Cl of the present invention exhibits the DSC having the thermogram as depicted in Fig 6. The endothermic peak is seen at 192.49°C.

[0045] In another embodiment, the present invention relates to a process for manufacturing polymorphic forms comprising;

[0046] 1. Suspending the mixture of Cabozantinib and suitable acid in a suitable solvent;

[0047] 2. Stirring, filtering, washing and drying under vacuum to obtain desired polymorphic Forms. In an aspect, Cabozantinib base is prepared by a known process.

[0048] The suitable acids in the process are selected from maleic acid, citric acid and the like in suitable amounts.

[0049] The solvent for the process is selected from water, lower alcohols, ketones, ethers, nitriles, esters, and the like alone or mixture thereof.

[0050] In an embodiment, the present invention relates to a process for manufacturing Cabozantinib maleate Form Cl comprising;

[0051] 1. Suspending a mixture of Cabozantinib and maleic acid in C1-C5 alcohol;

[0052] 2. Stirring the above mixture at a temperature ranging between 25°C to 55°C followed by filtering and washing the mass with lower alcohol and suck drying under vacuum to obtain the material;

[0053] 3. Drying the material under vacuum at a temperature in the range of 40- 50°C for 10-25 hours; optionally drying in a tray dryer at a temperature in the range of 55-65°C for 30-36 hours to obtain desired product.

[0054] In yet another alternate process, the present invention discloses a process for preparation of Cabozantinib Maleate Form Cl comprising; i. Suspending a mixture of Cabozantinib in a mixture of C1-C5 alcohol and water; ii. Charging Cabozantinib Maleate seed to the above suspension followed by adding maleic acid solution at a temperature ranging between 25-35°C; iii. Heating the above mixture to a temperature ranging between 70- 75°C; and iv. Cooling the reaction mixture to a temperature ranging between 25- 35°C, filtering and drying to obtain the desired product. In yet another embodiment, the present invention relates to a process for manufacturing Cabozantinib Citrate Form Cl comprising;

[0055] 1. Suspending a mixture of Cabozantinib and maleic acid in C1-C5 alcohol;

[0056] 2. Stirring the above mixture at room temperature followed by filtering and washing the mass with C1-C5 alcohol and suck drying under vacuum to obtain the material;

[0057] 3. Drying the material under vacuum at a temperature in the range of 40- 50°C for about 24 hours followed by drying in a tray dryer at a temperature in the range of 55-65°C for 30- 36 hours to obtain desired product.

[0058] In an embodiment, the Cabozantinib maleate Form Cl of the present invention is stable at accelerated conditions, under UV and visible light , at high temperature amd pressure as depicted in table 1 below.

[0059] In an embodiment, the Cabozantinib maleate Form Cl of the present invention is stable for a period of 6months at accelerated conditions as depicted in table 2 below.

[0060] In another embodiment, the present invention relates to a pharmaceutical composition comprising Cabozantinib maleate Form Cl along with pharmaceutically acceptable excipients.

[0061] In another embodiment, the present invention relates to a pharmaceutical composition comprising Cabozantinib Citrate Form Cl along with pharmaceutically acceptable excipients.

[0062] The following examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way. Example 1: Preparation of Cabozantinib Maleate salt Form Cl

[0063] Cabozantinib (5g), and Maleic acid (1.27g) are suspended in 50.0 mL of methanol. The suspension is stirred at room temperature for about 4 hrs. The resulted reaction mass is filtered, then washed with 10 ml of methanol, and suck dried under vacuum for 30 min; unloaded the material and dried the material under vacuum at 45°C for 24 hrs, followed by drying at 60 °C in air tray dryer for 36 hrs to get the title compound.

[0064] Yield: 4.6 gm

[0065] Example 2: Preparation of Cabozantinib Maleate salt Form Cl

[0066] Cabozantinib (60 g), and Maleic acid (15.2 g) are suspended in 1200.0 mL of Ethanol. The suspension is heated to 50°C and stirred at this temperature for about 4-6 hr, then cool the reaction mass to room temperature and stir at this temperature for 1-2 hr. Filtered the reaction mass, washed with 60 ml of Ethanol, and suck dried under vacuum for 30 min. unload the material and dried the material under vacuum at 50 °C for 10 hrs to get the titled compound.

[0067] Yield: 62 gm

[0068] PXRD 20-peak positions for Cabozantinib Maleate salt Form Cl Set (20 °): 4.78, 12.11, 13.56, 16.97, 23.63 and 26.04 ± 0.2°.

[0069] Example 3: Preparation of Cabozantinib Maleate salt Form Cl

[0070] Cabozantinib base (180.0 gm ) suspended in 1800.0 ml of Ethanol and 54.0 ml of purified water at 25-30 °C. Charged 1.8 gm of Cabozantinib Maleate seed to the above suspension. Added Maleic acid solution (dissolved 45.72 gm of Maleic acid in 450.0 ml of Ethanol) to the cabozantinib suspension at 27±5°C and stirred at same temperature for 1 hour, then heat to 70±5 °C and maintained at this temperature for 5 hr, further cooled the reaction mass to 27±5 °C and maintained the reaction mass at this temperature for 2 hr fallowed by filtration and dried the material at 60±5°C for 10 hrs to get to get the titled compound. Yield: 211.9 gm

[0071] Water content: 0.49% w / w

[0072] Maleic acid content: 19.0 % w / w

[0073] Example 4: Preparation Cabozantinib Citrate salt Form Cl:

[0074] Cabozantinib (5g), and Citric acid (2.07 g) are suspended in 50.0 mL of Methanol. The suspension is stirred at room temperature for about 7 to 9 hrs. The resulted reaction mass is filtered, washed with 10 ml of Methanol and suck dried under vacuum for 30 min. unload the material and dried under vacuum at 45 °C for 24 hrs, followed by drying at 60 °C in air tray dryer for 36 hrs to get the title compound.

[0075] Yield: 4.6gm

[0076] PXRD 20-peak positions for Cabozantinib Citrate salt Form Cl

[0077] Set (20 °): 6.34, 9.8, 12.75, 15.35, 19.3, 23.8 and 26.40 ± 0.2°.

[0078] Example 5: SSFD data of Cabozantinib maleate form Cl

[0079] Table 1:

[0080] Example 6: Stability of Cabozantinib maleate Form Cl

[0081] Table 2:

[0082] Although the invention has been described in detail in the foregoing for the purposeof illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Claims

We Claim;1. Cabozantinib polymorphic salts comprising;(i) Cabozantinib Maleate Form Cl; and(ii) Cabozantinib citrate Form Cl.

2. The Cabozantinib polymorphic salts as claimed in claim 1, wherein the Cabozantinib polymorphic salt is Cabozantinib Maleate Form Cl characterized by X-ray powder diffraction pattern having peaks at 4.78, 12.11, 13.56, 16.97, 23.63 and 26.04 ± 0.2°.

3. A process for preparation of Cabozantinib Maleate Form Cl comprising; i. Suspending a mixture of Cabozantinib and maleic acid in C1-C5 alcohol; ii. Stirring the above mixture at a temperature ranging between 25°C to 55°C followed by filtering and washing the mass with C1-C5 alcohol and suck drying under vacuum to obtain the material; iii. Drying the material under vacuum at a temperature in the range of 40-50°C for 10-25 hours; optionally drying in a tray dryer at a temperature in the range of 55-65°C to obtain desired product.

4. A process for preparation of Cabozantinib Maleate Form Cl comprising; i. Suspending a mixture of Cabozantinib in a mixture of C1-C5 alcohol and water; ii. Charging Cabozantinib Maleate seed to the above suspension followed by adding maleic acid solution at a temperature ranging between 25-35°C; iii. Heating the above mixture to a temperature ranging between 70- 75°C; andiv. Cooling the reaction mixture to a temperature ranging between 25- 35°C, filtering and drying to obtain the desired product.

5. The Cabozantinib polymorphic salts as claimed in claim 1, wherein the Cabozantinib polymorphic salt is Cabozantinib Citrate Form Cl characterized by X-ray powder diffraction pattern having peaks at 6.34, 9.8, 12.75, 15.35, 19.3, 23.8 and 26.40 ± 0.2°.

6. A process for preparation of Cabozantinib citrate Form Cl comprising; i. Suspending a mixture of Cabozantinib and citric acid in C1-C5 alcohol; ii. Stirring the above mixture at a temperature ranging between 25°C to 55°C followed by filtering and washing the mass with C1-C5 alcohol and suck drying under vacuum to obtain the material; and iii. Drying the material under vacuum at a temperature in the range of 40-50°C for 10-25 hours; optionally drying in a tray dryer at a temperature in the range of 55-65°C to obtain desired product7. A pharmaceutical composition comprising Cabozantinib maleate Form Cl as claimed in any one of the preceding claims 1 to 6 along with pharmaceutically acceptable excipients.

8. A pharmaceutical composition comprising Cabozantinib maleate Form Cl as claimed in any one of the preceding claims 1 and 4 to 6 along with pharmaceutically acceptable excipients.

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