WO2025090032A1 - Novel polymorph of cabozantinib l-tartrate (form a) and method of preparation - Google Patents

Abstract

The present invention refers to a crystalline form of cabozantinib L-tartrate 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

NOVEL POLYMORPH OF CABOZANTINIB L-TARTRATE (FORM A) AND METHOD OF PREPARATION Technical Field The present invention refers to a novel crystalline polymorphic form of cabozantinib L-tartrate designated as Form A and a process for its preparation. The invention further relates to pharmaceutical compositions containing Form A and its use for the treatment of cancer. Background Art Cabozantinib is chemically known as N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide (CAS No: 849217-68-1) and represented by the following structural formula:

Cabozantinib 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. 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. 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. 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. In 2012, the U.S. FDA approved the company's cabozantinib malate (1:1), under the trade name COMETRIQ. Several salts of cabozantinib including various crystalline forms are disclosed. 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 M1, M2, M3 & M4 of (L)-malate salt of cabozantinib and processes of preparation thereof. CN104961681 A discloses various acid addition salts of cabozantinib and process for its preparation. CN104961680 A discloses crystal A and crystal B of hydrochloride salt of cabozantinib and process for its preparation. PCT publication WO 2020057622 Al, discloses crystalline forms CSI and CSIII of cabozantinib (S)-malate salt. PCT publication WO 2020075196 Al, discloses crystalline forms C2, C3, C4 and C5 of cabozantinib (S)-malate salt. The structure of cabozantinib L-tartrate corresponds to the following formula:

Cabozantinib L-tartrate 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. 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. Summary of the invention The object of the present invention is to provide a new polymorphic form of cabozantinib L-tartrate and process for the preparation of this novel polymorphic form of cabozantinib L-tartrate. Another object of the present invention is to provide pharmaceutical compositions comprising new polymorphic form of cabozantinib L-tartrate. Technical Problem 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. 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. Salt forms of drug substances have significant effects on physicochemical properties of the drug influencing its quality, safety, and performance. 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 distinquish 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. 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. Discovery of new salts and polymorphic forms of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, therefore, development of new salts and polymorphic forms are always encouraged. 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. Solution to Problem In an embodiment invention relates to novel solid state form of cabozantinib L-tartrate. This new polymorph of cabozantinib L-tartrate, besides being stable, meets the pharmaceutical requirements such as storage, shelf life, solubility and high purity. Description of embodiments A first aspect of the present invention relates to a novel crystalline form of cabozantinib L-tartrate. This new form hereinafter is designated as Form A. Form A is monohydrate and characterized by an XRPD pattern having characteristic peaks at 8.7, 12.2, 14.3, 17.4, 22.9, 24.7, 27.1, 27.6 and 25.8 ± 0.2 degree 2-theta. Furthermore, Form A can be characterized by an XRPD pattern with characteristic peaks at 16.3, 19.2, 22.3, 23.6 and 28.9 ± 0.2 degree 2-theta. The crystalline Form A can be further characterized by XRPD pattern described in the following Table 1: Table 1. Characteristic 2-theta values of cabozantinib L-tartrate (Form A)

Form A is characterized by an XRPD pattern, as shown in Figure 1 and 2-theta values as shown in Table 1. Structure of cabozantinib L-tartrate is confirmed ¹H, ¹³C, and ¹⁹F NMR studies (Figure 3-5). Crystalline Form A can be further characterized by ¹H, ¹³C and ¹⁹F NMR described in the following Table 2:

Table 2. Interpretation of NMR Spectra (DMSO-d₆,) 1 P

26 – 149.3 (C) – ^{19 1 1} F NMR (375 P

Form A is also characterized by an Infrared (IR) spectrum (Table 3), as shown in Figure 6 and characterized by differential scanning calorimetry (DSC) thermogram, as shown in Figure 7. Table 3. Interpretation of FTIR Spectrum ν 3 1 1 1 1 1 1 1 1 8

A second aspect of the present invention relates to a process for preparing novel polymorphic Form A of cabozantinib L-tartrate. Described is a process for the preparation of crystalline Form A of cabozantinib L-tartrate which comprises: a) dissolving and/or suspending cabozantinib in a suitable solvent and/or solvent mixture, b) adding tartaric 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 Form A with a suitable solvent. 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. The suitable temperature used in step (c) is selected from 20 °C to 60 °C. 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. The process of the present invention affords crystalline Form A in high purity and high yield. The crystaline Form A is obtained having purity greater than 99.95% by area percentage in ultra- performance liquid chromatography (UPLC). 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. 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. For a third aspect of the present invention, crystalline stability of cabozantinib L-tartrate 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. The crystalline stability of cabozantinib L-tartrate 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 L-tartrate Form A did not occur. Cabozantinib L-tartrate Form A showed crystalline stability under dry heating at 105 °C for 10 days. The chemical stability of crystalline cabozantinib L-tartrate Form A is also important and its stability in finished product at room temperature storage can be predicted from short-term storage under accelerated conditions at high temperature and humidity. For a forth aspect of the present invention, a study was conducted to show that cabozantinib L- tartrate Form A is more stable than cabozantinib S-malate Form N-1 as reference polymorph. The XRPD pattern of cabozantinib S-malate Form N-1 is displayed in FIG. 1 of U.S Patent No. 8,877,776. In the present invention, samples of obtained crystalline cabozantinib L-tartrate Form A and cabozantinib S-malate Form N-1 were kept under dry heating in open flask at 105 °C for 10 days in an oven in stability chambers to test chemical stability. The chemical stability of the samples was determined by UPLC method. It can be concluded that there is difference between cabozantinib L-tartrate Form A and cabozantinib S-malate Form N-1 in terms of stability. Cabo-N-oxide and Desfluoro-Cabo impurities did not detected in cabozantinib L-tartrate Form A, but said impurities were present in cabozantinib S-malate Form N-1. In addition, unknown impurities were also detected in higher amounts in cabozantinib S-malate Form N-1. (Table 4). The result indicates that crystalline cabozantinib L-tartrate Form A has good stability and it was also found to be more stable than cabozantinib-S-malate Form N-1.

Table 4. Chemical stability assessment of cabozantinib L-tartrate Form A versus cabozantinib S- malate Form N-1 Cabozantinib L-tartrate Cabozantinib S-malate T C A X R S (

ND: Not detected * Unknown impurities below 0.10% was not evaluated.

dimethoxyquinoline 1-oxide Impurity B: N,N'-bis(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide Impurity C: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide A fifth aspect of the present invention relates to pharmaceutical compositions comprising crystalline cabozantinib L-tartrate Form A along with a pharmaceutically acceptable carrier. Brief description of the drawings: Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline cabozantinib L-tartrate Form A Figure 2 shows the X-ray powder diffraction (XRPD) pattern of crystalline cabozantinib S-malate Form N-1 is displayed in FIG.1 of U.S. Patent No.8,877,776 B2 (reference crystalline form) Figure 3 shows the ¹H nuclear magnetic resonance (¹H NMR) spectrum of cabozantinib L-tartrate Form A Figure 4 shows the ¹³C nuclear magnetic resonance (¹³C NMR) spectrum of cabozantinib L-tartrate Form A Figure 5 shows the ¹⁹F nuclear magnetic resonance (¹⁹F NMR) spectrum of cabozantinib L-tartrate Form A Figure 6 shows the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of crystalline cabozantinib L-tartrate Form A Figure 7 shows the differential scanning calorimetry (DSC) thermogram of cabozantinib L-tartrate Form A Figure 8 shows the thermogravimetric analysis (TGA) of cabozantinib L-tartrate Form A Instrumental parameters: NMR: ¹H NMR, ¹³C NMR and ¹⁹F NMR analyses were performed on a 400 MHz NMR spectrometer (JEOL Ltd., Tokyo, Japan) using deuterated dimethyl sulfoxide (DMSO-d6) as a solvent. FTIR: 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^–1 with 20 scans and 2 cm^–1 resolution. DSC: 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: Thermogravimetric analysis (TGA) thermograms were obtained by using a thermogravimetric analzer (TA instruments TGA 550, USA) by using the following instrument parameters: Start temperature: 25 °C, Final temperature: 1000 °C, Heating rate: 10 °C/min, isothermal: 15 min. PXRD: X-Ray powder diffractograms were measured using a Shimadzu LabX XRD-6100 X-ray diffractometer (Shimadzu Corporation, Japan) by using following instrument parameters: The measurement conditions were as follows: Radiation: Cu (1.5406 Å) Filter for Kβ: Nickel Voltage: 40.0 kV Current: 30.0 mA Auto slit: not used Divergence slit: 1.0° Scatter slit: 1.0° Receiving slit: 0.30 mm with a Graphite monochromator Drive axis: Theta-2Theta Scan range: 3.00 – 40.00° Scan mode: continuous scan Scan speed: 1.0°/min Sampling pitch: 0.02° 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. EXAMPLE-1 Preparation of cabozantinib L-tartrate Form A A reactor was charged with cabozantinib (7.10 kg, 14.15 mmol, 1.0 equiv.) and tartaric acid (2.56 kg, 17.06 mmol, 1.2 equiv.) were added into a methanol/water (145 L / 11 L) 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 methanol/water (1/1) to afford white to off-white cabozantinib L-tartrate monohydrate crystal Form A (8.75 kg, 92.4%).

Claims

CLAIMS 1. A crystalline Form A of cabozantinib L-tartrate wherein the X-ray powder diffraction pattern is as defined by the following table: 2-Theta (±0.2°) Relative Intensity (%)

. 2. The crystalline Form A of cabozantinib L-tartrate according to claim 1, wherein the X-ray powder diffraction pattern is as shown in FIG.1. 3. A process for the synthesis of crystalline Form A of cabozantinib L-tartrate according to claim 1 or 2 comprising: a) dissolving and/or suspending cabozantinib in a suitable solvent and/or solvent mixture, b) adding tartaric 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 L-tartrate designated as Form A with a suitable solvent. 5. A pharmaceutical composition comprising crystalline Form A of cabozantinib L-tartrate and optionally at least one pharmaceutically acceptable excipient. 6. A medicament for the treatment of cancer comprising administering a therapeutically effective amount of crystalline Form A of cabozantinib L-tartrate. 7. A method of treating cancer comprising administering a therapeutically effective amount of crystalline Form A of cabozantinib L-tartrate, wherein the crystalline Form A of cabozantinib L-tartrate is characterized by an XPRD pattern having 2-theta values as shown in Fig.1. 8. The use of crystalline Form A of cabozantinib L-tartrate according to any one of the claims 1 to 8 in the manufacture of a medicament for the treatment of cancer disease.