Amorphous form of cabozantinib sulfate monohydrate and method of preparation

Abstract

The present invention refers to an amorphous form of cabozantinib sulphate monohydrate 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] AMORPHOUS FORM OF CABOZANTINIB SULFATE MONOHYDRATE AND METHOD OF PREPARATION

[0003] Technical Field

[0004] The present invention refers to amorphous form of cabozantinib and processes for preparation thereof, and pharmaceutical composition thereof.

[0005] Background Art

[0006] 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:

[0007]

[0008] Cabozantinib

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] In 2012, the U.S. FDA approved the company's cabozantinib malate (1:1), under the trade name COMETRIQ.

[0014] CN104961681 A discloses various acid addition salts of cabozantinib and process for its preparation.

[0015] CN104961680 A discloses crystal A and crystal B of hydrochloride salt of cabozantinib and process for its preparation.

[0016] PCT publication WO 2020057622 Al, discloses crystalline forms CSI and CSIII of cabozantinib (S)-malate salt.

[0017] PCT publication WO 2020075196 Al, discloses crystalline forms C2, C3, C4 and C5 of cabozantinib (S)-malate salt.

[0018] Different salts and solid state forms of an active pharmaceutical ingredient may possess different properties.

[0019] The discovery of a new salt or a solid state form 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.

[0020] Based on these considerations, there still appears a need for new salts or solid state forms 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 solid state forms of cabozantinib with good chemical purity and improved stability characteristics, which may further improve the characteristics of cabozantinib in finished medicinal product.

[0021] Summary of the invention

[0022] The object of the present invention is to provide solid state form of cabozantinib sulphate, processes for preparation thereof, and pharmaceutical compositions thereof.

[0023] Technical Problem

[0024] 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.

[0025] Research and development projects in the pharmaceutical industry mainly aim to investigate different possible salts, polymorphs and processes to produce active pharmaceutical ingredients.Salt formation in general is vitally important in drug substance synthesis as well as overall pharmaceutical development and manufacture.

[0026] Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance.

[0027] Polymorphism, the occurrence of different solid state forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of solid state forms having distinct crystal structures and physical properties like melting point, thermal behaviors, X-ray powder diffraction (XRPD) pattern, Infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. Difference in the physical properties of different solid state results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.

[0028] 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.

[0029] 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.

[0030] According to the need, studies have been done to develop novel salts of cabozantinib and novel solid state form of cabozantinib having advantageous properties which are useful and suitable for the preparation of various pharmaceutical compositions.

[0031] Solution to Problem

[0032] The present disclosure includes amorphous form of cabozantinib sulphate, besides being stable, meets the pharmaceutical requirements such as storage, shelf life and high purity.

[0033] Description of embodiments

[0034] The first aspect of the present invention is to provide an amorphous form of cabozantinib sulphate and its process for the preparation thereof.

[0035] Amorphous cabozantinib sulphate is monohydrate and characterized by an XRPD pattern, as shown in Figure 1.

[0036]

[0037] Cabozantinib sulfate monohydrate

[0038] A second aspect of the present invention relates to a process for preparing cabozantinib sulfate monohydrate.

[0039] Described is a process for the preparation of Cabozantinib sulfate monohydrate which comprises:

[0040] a) dissolving and / or suspending cabozantinib in a suitable solvent and / or solvent mixture, b) adding sulfuric acid and / or its solution into the cabozantinib mixture at step (a), c) stirring the reaction solution at step (b) at a suitable temperature,

[0041] d) filtering to isolate the obtained solid,

[0042] e) washing the obtained solid as pure with a suitable solvent.

[0043] 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.

[0044] The suitable temperature used in step (c) is selected from 20 °C to 60 °C.

[0045] 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.

[0046] The process of the present invention affords amorphous cabozantinib sulphate monohydrate in high purity and high yield. The cabozantinib sulphate monohydrate is obtained having purity greater than 99.95% by area percentage in ultra-performance liquid chromatography (UPLC).

[0047] Brief description of the drawings:

[0048] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of cabozantinib sulfate monohydrate (amorphous form)

[0049] Figure 2 shows the1H nuclear magnetic resonance (’ H NMR) spectrum of cabozantinib sulfate monohydrate.

[0050] Figure 3 shows the13C nuclear magnetic resonance (13C NMR) spectrum of cabozantinib sulfate monohydrate

[0051] Figure 4 shows the19F NMR spectrum of cabozantinib sulfate monohydrateFigure 5 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of cabozantinib sulfate monohydrate

[0052] Figure 6 shows the differential scanning calorimetry (DSC) thermogram of cabozantinib sulfate monohydrate (amorphous form)

[0053] Figure 7 shows the thermogravimetric analysis (TGA) of cabozantinib sulfate monohydrate (amorphous form)

[0054] Instrumental parameters:

[0055] NMR:

[0056] 1H 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.

[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) 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.

[0061] TGA:

[0062] 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,

[0063] Final temperature: 1000 °C,

[0064] Heating rate: 10 °C / min, isothermal: 15 min.

[0065] PXRD:

[0066] 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:

[0067] Radiation: Cu (1.5406 A)

[0068] Filter for KP: Nickel

[0069] Voltage: 40.0 kV

[0070] Current: 30.0 mA

[0071] Auto slit: not used

[0072] Divergence slit: 1.0°Scatter slit: 1.0°

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

[0074] Drive axis: Theta-2Theta

[0075] Scan range: 3.00 -40.00°

[0076] Scan mode: continuous scan

[0077] Scan speed: 1.07min

[0078] Sampling pitch: 0.02°

[0079] 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.

[0080] EXAMPLE !

[0081] Preparation of cabozantinib sulfate monohydrate (Amorphous form)

[0082] A reactor was charged with sulfuric acid and water. The reactor was added into cabozantinib and stirred at 20 - 25 °C for 16 - 17 h. After completion of the reaction, the mixture was filtered and product was washed with water to afford white to off-white amorphous form of cabozantinib sulfate monohydrate (amount: 2.17 g; yield: 90.8% KF: 3.84%).

Claims

CLAIMS1. An amorphous form of cabozantinib sulphate monohydrate.

2. The amorphous form of cabozantinib sulphate monohydrate according to claim 1, wherein the X-ray powder diffraction pattern is as shown in Figure 1.

3. A process for the synthesis of amorphous form of cabozantinib sulphate monohydrate according to claim 1 or 2 comprising:a) dissolving and / or suspending cabozantinib in a suitable solvent and / or solvent mixture, b) adding sulphuric acid 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 amorphous form of cabozantinib sulphate monohydrate with a suitable solvent.

4. A pharmaceutical composition comprising amorphous form of cabozantinib sulphate monohydrate and optionally at least one pharmaceutically acceptable excipient.

5. A medicament for the treatment of cancer comprising administering a therapeutically effective amount of amorphous form of cabozantinib sulphate monohydrate.

6. A method of treating cancer comprising administering a therapeutically effective amount of amorphous form of cabozantinib sulphate monohydrate, wherein the amorphous form of cabozantinib sulphate monohydrate is characterized by an XPRD pattern as shown in Figure 1.

7. The use of amorphous form of cabozantinib sulphate monohydrate according to any one of the claims 1 to 6 in the manufacture of a medicament for the treatment of cancer disease.

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