Novel polymorph of cabozantinib HEMI-(s)-malate (form a) and method of preparation

Abstract

The present invention refers to a crystalline form of cabozantinib hemi-(S)-malate designated as Form A and a process for its preparation, a pharmaceutical composition comprising it, and its use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

Description

[0001] DESCRIPTION

[0002] NOVEL POLYMORPH OF CABOZANTINIB HEMI-(S)-MALATE (FORM A) AND METHOD OF PREPARATION

[0003] Technical Field

[0004] The present invention refers to a novel crystalline polymorphic form of cabozantinib hemi-(S)-malate designated as Form A and a process for its preparation.

[0005] The invention further relates to pharmaceutical compositions containing Form A and its use for the treatment of cancer.

[0006] Background Art

[0007] 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:

[0008]

[0009] Cabozantinib

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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 amorphousand a processes of preparation thereof.

[0014] In 2012, the U.S. FDA approved the company's cabozantinib malate (1:1), under the trade name COMETRIQ.

[0015] Several salts of cabozantinib including various crystalline forms are disclosed.

[0016] International (PCT) publication No. WO 2016150966 Al discloses crystalline cabozantinib hydrochloride as well as crystalline cabozantinib phosphate and process for its preparation. 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.

[0017] CN104961681 A discloses various acid addition salts of cabozantinib and process for its preparation.

[0018] CN104961680 A discloses crystal A and crystal B of hydrochloride salt of cabozantinib and process for its preparation.

[0019] PCT publication WO 2020057622 Al, discloses crystalline forms CSI and CSIII of cabozantinib-(S)-malate salt.

[0020] The structure of cabozantinib hemi- (5) -malate corresponds to the following formula:

[0021]

[0022] Cabozantinib hemi-(S)-malate

[0023] Different salts and solid state forms of an active pharmaceutical ingredient may possess different properties.

[0024] The discovery of a new salt 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.

[0025] Based on these considerations, there still appears a need for new salts 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 salts of cabozantinib with good chemical purity and improved stability characteristics, which may further improve the characteristics of cabozantinib in finished medicinal product.Summary of the invention

[0026] The object of the present invention is to provide a new polymorphic form of cabozantinib hemi-(S)-malate.

[0027] Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of cabozantinib hemi-(S)-malate.

[0028] Technical Problem

[0029] 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.

[0030] Research and development projects in the pharmaceutical industry mainly aim to investigate different possible salts, polymorphs and processes to produce active pharmaceutical ingredients.

[0031] Salt formation in general is vitally important in drug substance synthesis as well as overall pharmaceutical development and manufacture.

[0032] Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance.

[0033] 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 like melting point, thermal behaviours, X-ray powder diffraction (XRPD) pattern, Infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these tecniques may be used to distinguish different polymorphic forms of a compound. 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.

[0034] The relationship between polymorphic forms of pharmaceutically active ingredient and pharmaceutical product is well known in the pharmaceutical industry. Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active ingredient.

[0035] Discovery of new salts and polymorphic forms of an active pharmaceutical ingredient provides a new opportunity to improve solubility, dissolution rate, drug absorption and bioavailability of pharmaceutical finished product, therefore, development of new salts and polymorphic forms are always encouraged.

[0036] According to the need, studies have been done to develop novel polymorph of cabozantinib hemi-(S)-malate having advantageous properties which are useful and suitable for thepreparation of various pharmaceutical compositions.

[0037] Solution to Problem

[0038] The present disclosure includes a novel polymorph of cabozantinib hemi-(S)-malate. This new polymorph of cabozantinib hemi-(S)-malate, besides being stable, meets the pharmaceutical requirements such as storage, shelf life, solubility and high purity.

[0039] Description of embodiments

[0040] The first aspect of the present invention is to provide a novel crystalline form of cabozantinib hemi-(S)-malate and its process for the preparation thereof. This new form hereinafter designated as “Form- A”. Form A is characterized by an XRPD pattern having characteristic peaks at 12.2, 12.9, 18.4, 22.2 and 24.0 ± 0.2 degree 2-theta. Form A is characterized by an XRPD pattern, as shown in Figure 1 and 2-theta values as shown in Table 1.

[0041] Table 1. Characteristic 2-theta values of cabozantinib hemi-(S)-malate (Form A)

[0042]

[0043] Structure of cabozantinib hemi-(S) -malate is confirmed byXH,13C, and19F NMR studies (Figure 2-5).

[0044] A second aspect of the present invention relates to a process for preparing novel polymorphic Form A of cabozantinib hemi-(S)-malate.

[0045] Described is a process for the preparation of crystalline Form A of cabozantinib hemi-(S)-malate which comprises:

[0046] a) adding malic acid and / or its solution into the cabozantinib mixture at step (a),b) stirring the reaction solution at step (b) at a suitable temperature,

[0047] c) filtering to isolate the obtained solid,

[0048] d) washing the obtained solid as pure crystalline Form A with a suitable solvent.

[0049] Wherein suitable solvent in step (a), step (b) and step (e) is selected from, water, methanol, ethanol, 2-propanol, 1 -propanol, 1 -butanol, 2-butanol, tert-butyl alcohol, 1 -pentanol and 2-pentanol or mixtures thereof.

[0050] The suitable temperature used in step (c) is selected from 20 °C to 60 °C.

[0051] The degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner.

[0052] The process of the present invention affords crystalline Form A in high purity and high yield. The crystalline Form A is obtained having purity greater than 99.95% by area percentage in ultra-performance liquid chromatography (UPLC).

[0053] Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.

[0054] Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the drug substance. The changes in solid state form of the drug substance may be resulted from the conditions of manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of drug substance. These variations comprising polymorphic transformations, hydrate / solvate formations and dehydration / desolvation reactions in the solid-state form of the drug substance, may cause stability problems in finished pharmaceutical products. Therefore, crystalline stability of the drug substance has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of drug substance should be used in pharmaceutical formulations.

[0055] For a third aspect of the present invention, crystalline stability of cabozantinib hemi-(S) -malate Form A of the present disclosure was investigated under the following conditions: a sample was kept in an open flask at 105 °C for 10 days. The crystalline stability referred here, is the stability of a polymorphic form of drug substance with respect to polymorph transformations, hydration,dehydration, or amorphization through time under these conditions.

[0056] The crystalline stability of cabozantinib hemi-(S)-malate Form A was investigated and determined by X-ray powder diffraction and differential scanning calorimetry methods. Results showed that any polymorphic transformation to another crystal form or any degradation in crystalline cabozantinib hemi-(S)-malate Form A did not occur. Cabozantinib hemi-(S)-malate Form A showed crystalline stability under dry heating at 105 °C for 10 days.

[0057] The chemical stability of crystalline cabozantinib hemi-(S)-malate Form A is also important and its stability in finished product at room temperature storage can be predicted from shortterm storage under accelerated conditions at high temperature and humidity. The result indicates that crystalline cabozantinib hemi-(S)-malate Form A has good stability.

[0058] Brief description of the drawings:

[0059] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline cabozantinib hemi-(S)-malatc Form A

[0060] Figure 2 shows the1H NMR spectrum of cabozantinib hemi-(S) -malate Form A

[0061] Figure 3 shows the13C NMR spectrum of cabozantinib hemi-(S)-malate Form A

[0062] Figure 4 shows the13C DEPT NMR spectrum of cabozantinib hemi-(S)-malate Form A Figure 5 shows the19F NMR spectrum of cabozantinib hemi-(S)-malate Form A

[0063] Figure 6 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectrum of cabozantinib hemi-(S)-malate Form A

[0064] Figure 7 shows the differential scanning calorimetric (DSC) curve of cabozantinib hemi-(S)-malate Form A

[0065] Figure 8 shows the thermogravimetric analysis (TGA) of cabozantinib hemi-(S) -malate Form A

[0066] Instrumental parameters:

[0067] NMR:

[0068] NMR,13C NMR and19F NMR analyses were performed on a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-tfo) as a solvent.

[0069] FTIR:

[0070] 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.DSC:

[0071] Differential scanning calorimetry (DSC) thermogram was 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.

[0072] TGA:

[0073] Thermogravimetric analysis (TGA) thermogram was obtained by using a thermogravimetric analyzer (TA instruments TGA 550, USA) by using the following instrument parameters: Start temperature: 25 °C,

[0074] Final temperature: 1000 °C,

[0075] Heating rate: 10 °C / min, isothermal: 15 min.

[0076] PXRD:

[0077] X-Ray powder diffractograms were measured using a Shimadzu Lab-X XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using following instrument parameters: The measurement conditions were as follows:

[0078] Radiation: Cu (1.5406 A)

[0079] Filter for KP: Nickel

[0080] Voltage: 40.0 kV

[0081] Current: 30.0 mA

[0082] Auto slit: not used

[0083] Divergence slit: 1.0°

[0084] Scatter slit: 1.0°

[0085] Receiving slit: 0.30 mm with a Graphite monochromatic

[0086] Drive axis: Theta-2Theta

[0087] Scan range: 3.00 -40.00°

[0088] Scan mode: continuous scan

[0089] Scan speed: 1.0° / min

[0090] Sampling pitch: 0.02°

[0091] Following examples are 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.

[0092] EXAMPLE-1

[0093] Preparation of cabozantinib hemi-(S)-malate Form A

[0094] A reactor was charged with cabozantinib (30.0 g, 59.8 mmol, 1.0 equiv.) and malic acid (4.0 g, 29.8 mmol, 0.5 equiv.) were added into acetone (500 mL) and stirred at 20 - 25 °C for 2 - 3 h.After completion of the reaction, the mixture was filtered and product crystals were washed with acetone to afford white to off-white cabozantinib hemi-(S)-malate crystal Form A (amount: 30.0 g, yield: 88.2%, KF: 0.21%).

Claims

CLAIMS1. A crystalline Form A of cabozantinib hemi-(S) -malate wherein the X-ray powder diffraction pattern is as defined by the following table:

2. The crystalline Form A of cabozantinib hemi-(S)-malate according to claim 1, wherein the X-ray powder diffraction pattern is as shown in Figure 1.

3. A process for the synthesis of crystalline Form A of cabozantinib hemi-(S) -malate according to claim 1 or 2 comprising:a) dissolving and / or suspending cabozantinib in a suitable solvent and / or solvent mixture, b) adding malic acid and / or its solution 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 hemi (S)-malate designated as Form A with a suitable solvent.

4. A pharmaceutical composition comprising crystalline Form A of cabozantinib hemi-(S)- malate and optionally at least one pharmaceutically acceptable excipient.

5. A medicament for the treatment of cancer comprising administering a therapeutically effective amount of crystalline Form A of cabozantinib hemi- (S) -malate.

6. A method of treating cancer comprising administering a therapeutically effective amount of crystalline Form A of cabozantinib hemi-(S)-malate, wherein the crystalline Form A of cabozantinib hemi- (S) -malate is characterized by an XPRD pattern having 2-theta valuesas shown in Figure 1.

7. The use of crystalline Form A of cabozantinib hemi-(S)-malate according to any one of the claims 1 to 7 in the manufacture of a medicament for the treatment of cancer disease.

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