Novel polymorph of cabozantinib base (form e) and method of preparation

Abstract

The present invention provides a new crystalline form of Cabozantinib free base, Formula (I), which is chemically known as N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide and preparation of its novel crystalline polymorph Form E, Formula (II).

Description

[0001] NOVEL POLYMORPH OF CABOZANTINIB BASE (FORM E) AND METHOD OF PREPARATION

[0002] Technical Field

[0003] The present invention refers to a novel crystalline polymorphic form of Cabozantinib base designated as Form E and a process for its preparation. Form E is THF / H2O solvate of Cabozantinib base.

[0004] Background Art

[0005] Cabozantinib is chemically known as W(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-M-(4- fluorophenyl)cyclopropane- 1,1 -dicarboxamide (CAS No: 849217-68-1) and represented by the following structural formula:

[0006] Cabozantinib

[0007] Cabozantinib is marketed in the United States under the trade name COMETRIQ® and CABOMETYX® by Exelixis Inc. COMETRIQ® is indicated for use in the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and CABOMETYX® is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy.

[0008] CABOMETYX (Cabozantinib) tablets are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of Cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of Cabozantinib (S)-malate, respectively.

[0009] International (PCT) publication No. WO 2005030140 Al first disclosed Cabozantinib. Further the application discloses processes for the preparation of Cabozantinib, pharmaceutical preparation of Cabozantinib and therapeutic application thereof.

[0010] International (PCT) publication No. WO 2010083414 Al, discloses (L)-malate salt of Cabozantinib and further claims said salt is in the crystalline forms (N-l), (N-2) and amorphous and a processes of preparation thereof.

[0011] In 2012, the U.S. FDA approved the company's Cabozantinib malate (1:1), under the trade name COMETRIQ.

[0012] Several salts of Cabozantinib including various crystalline forms are disclosed.

[0013] International (PCT) publication No. WO 2016150966 Al discloses crystalline Cabozantinib hydrochloride as well as crystalline Cabozantinib phosphate and process for its preparation.

[0014] U.S. Patent No. 9,815,789 B2, discloses crystalline forms Ml, M2, M3 & M4 of (L)-malate salt of Cabozantinib and processes of preparation thereof.

[0015] CN104961681 A discloses various acid addition salts of Cabozantinib and process for its preparation.

[0016] CN104961680 A discloses crystal A and crystal B of hydrochloride salt of Cabozantinib and process for its preparation.

[0017] PCT publication WO 2020057622 Al, discloses crystalline forms CSI and CSIII of Cabozantinib (S)-malate salt.

[0018] PCT publication WO 2020075196 Al, discloses crystalline forms C2, C3, C4 and C5 of Cabozantinib (S)-malate salt.

[0019] PCT publication WO 2015123639 Al, discloses crystalline forms Form III, Form XXVIII, Form XXX and Form XXXXI of Cabozantinib free base.

[0020] IN343563 B, discloses crystalline Form I of Cabozantinib free base and process for its preparation.

[0021] PCT publication WO 2015177758 Al, discloses crystalline forms Mi, M2, M3 of Cabozantinib free base and processes of preparation thereof.

[0022] The discovery of a new polymorph of an active substance provides an opportunity to improve its characteristics, increasing the possibilities available to a formulation specialist when developing a new pharmaceutical form, a drug with a particular release profile or a specific dissolution degree.

[0023] Based on these considerations, there still appears a need for new polymorphs of Cabozantinib having further improved physical and / or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically novel polymorphs of Cabozantinib with good chemical purity and improved stability characteristics, which may further improve the characteristics of Cabozantinib in finished medicinal product.

[0024] Summary of the invention The object of the present invention is to provide a new polymorphic form of Cabozantinib base and process for the preparation of this novel polymorphic form of Cabozantinib base.

[0025] Technical Problem

[0026] Active pharmaceutical ingredients are individual components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.

[0027] Research and development projects in the pharmaceutical industry mainly aim to investigate different possible salts, polymorphs and processes to produce these APIs.

[0028] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties. Difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.

[0029] The pharmaceutical industry widely recognizes the correlation between the polymorphic forms of a pharmaceutically active substance and the resulting pharmaceutical product. The specific polymorphic form significantly influences the formulation of pharmaceutical products.

[0030] The solid state form of an active pharmaceutical ingredient may affect its stability as in finished product.

[0031] Stability of active pharmaceutical ingredients (APIs) is the key factor in stability evaluation of finished pharmaceutical products (FPPs). On this ground, stability testing of API in FPP must be conducted.

[0032] From a storage perspective, the relative humidity and / or temperature of the environment may cause increase in impurity amount of API. Hence, stable polymorph which does not change on storage and does not require any special conditions for storage, is always preferred.

[0033] The exploration and identification of new polymorphic forms for an active pharmaceutical ingredient present a promising avenue to enhance the performance attributes of the final pharmaceutical product.

[0034] According to the need, studies have been done to develop novel polymorph of Cabozantinib having advantageous properties which are useful and suitable for the preparation of various pharmaceutical compositions.

[0035] Solution to Problem In an embodiment invention relates to novel solid state form of Cabozantinib base.

[0036] This new polymorph of Cabozantinib base, besides being stable, meets the pharmaceutical requirements such as high purity.

[0037] Description of embodiments A first aspect of the present invention relates to a novel crystalline form of Cabozantinib base. This new form hereinafter is designated as Form E. Form E is THF / H2O solvate form and it is characterized by an XRPD pattern having characteristic peaks at 10.9, 12.9, 14.8, 17.5, 20.2, 21.8, 22.4, 24.1, 24.7, 25.1 and 26.8 ± 0.2 degree 2-theta. Form E can be further characterized by an XRPD pattern having characteristic peaks at 6.5, 8.7, 11.6, 12.1, 18.0, 28.2 and 28.3 ± 0.2 degree 2-theta. Furthermore, Form E can be characterized by an XRPD pattern with characteristic peaks at 7.4, 13.9, 16.3, 18.8, 26.0 and 27.1 ± 0.2 degree 2-theta.

[0038] Form E is characterized by an XRPD pattern, as shown in Figure 1.

[0039] Structure of Cabozantinib base is confirmed byXH,13C, and19F NMR studies (Figure 2-4).

[0040] Crystalline Form E can be further characterized byXH,13C and19F NMR described in the following Table 1:

[0041] Table 1. Interpretation of NMR Spectra (DMSO-tfo,)

[0042] Form E is also characterized by an Infrared (IR) spectrum (Table 2), as shown in Figure 5 and characterized by differential scanning calorimetry (DSC) thermogram, as shown in Figure 6. Table 2. Interpretation of FTIR Spectrum

[0043] A second aspect of the present invention relates to a process for preparing novel polymorphic Form E of Cabozantinib base. Described is a process for the preparation of crystalline Form E of Cabozantinib base which comprises: a) dissolving Cabozantinib in a in mixture of tetrahydrofuran / water, b) adding water into the Cabozantinib mixture at step (a) c) stirring the reaction solution at step (b) at a suitable temperature, d) filtering to isolate the obtained solid, e) washing the obtained solid as pure crystalline Cabozantinib base designated as Form E with a suitable solvent.

[0044] The suitable temperature used in step (c) is selected from 20 °C to 30 °C.

[0045] The process of the present invention affords crystalline Form E in high purity and high yield. The crystalline Form E is obtained having purity greater than 99.95% by area percentage in ultra-performance liquid chromatography (UPLC).

[0046] Brief description of the drawings:

[0047] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form E

[0048] Figure 2 shows the1H nuclear magnetic resonance ( ’ H NMR) spectrum of Form E

[0049] Figure 3 shows the13C nuclear magnetic resonance (13C NMR) spectrum of Form E

[0050] Figure 4 shows the19F nuclear magnetic resonance (19F NMR) spectrum of Form E

[0051] Figure 5 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline Form E

[0052] Figure 6 shows the differential scanning calorimetry (DSC) thermogram of Form E

[0053] Figure 7 shows the thermogravimetric analysis (TGA) of Form E

[0054] Instrumental parameters:

[0055] NMR:

[0056] 1H NMR,13C NMR and19F NMR analyses were performed on a 400 MHz NMR spectrometer (JEOE Etd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-de) as a solvent.

[0057] FTIR:

[0058] Samples were measured as neat by ATR (attenuated total reflectance) on Shimadzu FTIR Spectrometer IR Spirit (Shimadzu Corporation, Kyoto, Japan) in the range of 400 - 4000 cm-1with 20 scans and 2 cm-1resolution.

[0059] DSC:

[0060] Differential scanning calorimetry (DSC) thermograms were obtained using a differential scanning calorimeter (TA instruments DSC 250, USA) by using following instrument parameters: Start temperature: 25 °C, final temperature: 350 °C, heating rate: 10 °C / min. TGA:

[0061] Thermogravimetric analysis (TGA) thermograms were obtained by using a thermogravimetric analyzer (TA instruments TGA 550, USA) by using the following instrument parameters: Start temperature: 25 °C, Final temperature: 200 °C,

[0062] Heating rate: 10 °C / min, isothermal: 15 min.

[0063] PXRD:

[0064] X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using following instrument parameters:

[0065] The measurement conditions were as follows:

[0066] Radiation: Cu (1.5406 A)

[0067] Filter for KP: Nickel

[0068] Voltage: 40.0 kV

[0069] Current: 30.0 mA

[0070] Auto slit: not used

[0071] Divergence slit: 1.0°

[0072] Scatter slit: 1.0°

[0073] Receiving slit: 0.30 mm with a Graphite monochromator

[0074] Drive axis: Theta-2Theta

[0075] Scan range: 3.00 - 40.00°

[0076] Scan mode: continuous scan

[0077] Scan speed: 1.0° / min

[0078] Sampling pitch: 0.02°

[0079] The Cabozantinib free base Form E disclosed herein may be included in formulations prescribed for the treatment of medullary thyroid cancer and progressive, metastatic medullary thyroid cancer, in particular. The Cabozantinib free base Form E disclosed herein may be formulated as a solid dosage form, such as a capsule, containing about 20 mg to about 80 mg per capsule for administration to patients.

[0080] Following example is provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

[0081] EXAMPLE ! Preparation of Cabozantinib THF / H2O solvate Form E

[0082] A reactor was charged with l-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (5.27 g), 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (6.29 g), A,A,A',A'-tctramcthyl-O-( l / 7- benzotriazol-l-yl)uronium hexafluorophosphate (9.35 g) and AW-di methyl formamide (40 mL). Afterwards, trimethylamine (2.38 g) is added to the reaction mixture at 20 - 30 °C and stirred for reaction. After 1 h stirring, reaction mixture is heated and stirred at 40 - 50 °C until reaction is completed. Mixture of sodium carbonate (2.4 g), water (60 mL) and methanol (20 mL) is prepared. After completion of the reaction, mixture is cooled. Sodium carbonate solution is added and stirred at 20 - 30 °C for 16 h. Product crystals were filtered and washed with tetrahydrofuran / water (1 / 1, v / v). Obtained product is dissolved in mixture of tetrahydrofuran and water (95 / 9, v / v). Water (95 mL) is added for crystallization. Cabozantinib base product crystals were filtered and washed with tetrahydrofuran / water (1 / 1, v / v). Product is dried by air flow in the fume hood for 16 h. (yellowish crystal Form E, 9.38 g, and HPLC purity: 99.5%, Water content: 6.3%).

Claims

CLAIMS1. A crystalline form of Cabozantinib free base designated Form E wherein the characteristic diffraction lines (29 in angular degrees 0.2°) in the X-ray diffraction pattern thereof: 6.5 ± 0.2, 7.4 ± 0.2, 8.7 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2, 12.1 ± 0.2, 12.9 ± 0.2, 13.9 ± 0.2, 14.8 ± 0.2 16.3 ± 0.2, 17.5 ± 0.2, 18.0 ± 0.2, 18.8 ± 0.2, 20.2 ± 0.2, 21.8 ± 0.2, 22.4 ± 0.2, 24.1 ± 0.2, 24.7 ± 0.2, 25.1 ± 0.2, 26.0 ± 0.2, 26.8 ± 0.2, 27.1 ± 0.2, 28.2 ± 0.2 and 28.3 degree 2-theta.

2. The crystalline Form E of Cabozantinib free base according to claim 1, wherein the X-ray powder diffraction pattern is as shown in FIG. 1.

3. The crystalline Form E of Cabozantinib free base according to claim 1, where in NMR spectrums are as shown in FIG. 2-4.

4. The crystalline Form E of Cabozantinib free base according to claim 1, where in the FTIR spectrum pattern is as shown in FIG. 5.

5. The crystalline Form E of Cabozantinib free base according to claim 1, where in the DSC thermogram pattern is as shown in FIG. 6.

6. The crystalline Form E of Cabozantinib free base according to claim 1, where in the TGA spectrum is as shown in FIG. 7.

7. A process for the synthesis of crystalline Form E of Cabozantinib base according to claim 1 or 2 comprising: a) dissolving cabozantinib in a mixture of tetrahydrofuran and water, b) adding water into the Cabozantinib mixture at step (a) c) stirring the reaction solution at step (b) at a suitable temperature, d) filtering to isolate the obtained solid, e) washing the obtained solid as pure crystalline Cabozantinib base designated as Form E with a suitable solvent.

8. The use of crystalline Form E of Cabozantinib base according to any one of the claims 1 to 6 in the manufacture of the synthesis of Cabozantinib salts and polymorphs thereof.

9. Use of crystalline Form E of Cabozantinib according to any one of claims 1-6 in the preparation of a pharmaceutical composition or a formulation comprising Cabozantinib.

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