A new crystalline form of cabozantinib

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a new crystal form of cabozantinib, a preparation method and application thereof. The new crystal form provided by the application is a cabozantinib-amino sulfonic acid-methanol co-crystal, wherein one molecule of cabozantinib, one molecule of amino sulfonic acid and one molecule of methanol form a basic unit of the crystal form, and great improvement is achieved in stability, solubility and the like, the preparation method is simple in operation, good in reproducibility and suitable for industrialized production.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically to a new crystal form of cabozantinib, its preparation method, and its application. Background Technology

[0002] Cabozantinib, chemically named N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide, has the following structure:

[0003]

[0004] Cabozantinib is a tyrosine kinase inhibitor. In vitro biochemical and / or cellular assays have shown that cabozantinib can specifically inhibit, regulate, and / or modulate the signaling of kinases, particularly Ret, c-Met, and VEGFR2, and therefore can be used as a drug for the treatment or prevention of conditions associated with abnormal cell proliferation or angiogenesis.

[0005] Currently, although there are reports on the crystal forms of cabozantinib malate, the properties of the reported crystal forms are not yet perfect and some problems still exist. For example, CN201080012656.5 discloses N-1 crystalline, N-2 crystalline, and amorphous forms of cabozantinib malate. Patent data shows that N-2 crystals have better stability than amorphous and N-1 crystals, but their solubility is low. WO2015177758A1 discloses crystal forms M1, M2, M3, and M4 of cabozantinib malate, among which crystal form M4 is the better crystal form, but it also suffers from low solubility. Therefore, extensive experimental research is still needed to provide more crystal forms with better properties.

[0006] For pharmaceuticals, in addition to the therapeutic efficacy of the active molecules, the specific form of the drug plays a crucial role in its processing, manufacturing, storage, transportation, and use. Different crystal forms can vary in a variety of physicochemical properties, including stability, solubility, bioavailability, pharmacological activity, and toxicity.

[0007] Research on different crystal forms will be of great significance for expanding the research and development of new cabozantinib formulations. Summary of the Invention

[0008] To address the shortcomings of existing cabozantinib technologies, such as poor solubility and low stability, this invention aims to provide a novel crystalline form of cabozantinib with higher solubility and stability: cabozantinib-aminosulfonate. Furthermore, this invention provides a simple, convenient method for preparing cabozantinib-aminosulfonate, suitable for industrial production.

[0009] The specific technical content of this invention is as follows:

[0010] On one hand, the present invention provides a new crystal form of cabozantinib, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at at least 13.3±0.2°, 16.7±0.2°, 22.5±0.2°, and 26.8±0.2°.

[0011] Preferably, the cabozantinib-aminosulfonate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 10.1±0.2°, 10.3±0.2°, 13.3±0.2°, 14.4±0.2°, 16.7±0.2°, 19.2±0.2°, 22.5±0.2°, and 26.8±0.2°.

[0012] Preferably, the cabozantinib-aminosulfonate is subjected to Cu-Kα radiation, and its characteristic peaks conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0013] Preferably, the cabozantinib-aminosulfonate has the molecular formula C 29 H 31 FN4O9S has the following crystallographic parameters: triclinic system, space group P-1, cell parameters: a=8.78800(10), b=9.09290(10), c=19.3132(2), α=99.8190(10), β=98.4400(10), γ=101.6230(10), and cell volume V=1463.03(3).

[0014] On the other hand, the present invention provides a method for preparing a new crystal form of cabozantinib, comprising the following steps:

[0015] Cabozantinib, aminosulfonic acid, and methanol were dissolved in an organic solvent, heated and stirred, filtered, allowed to stand at room temperature to volatilize and crystallize, and then filtered and dried to obtain cabozantinib-aminosulfonic acid salt.

[0016] Preferably, the organic solvent is selected from a mixture of ethanol, ethyl acetate, acetone and butanone, and particularly preferably one or a combination of butanone, methanol and acetone.

[0017] Preferably, the mass-to-volume ratio of cabozantinib to methanol is 1:0.05~0.12; and the mg / ml ratio is preferably 1:0.06.

[0018] Preferably, the molar ratio of cabozantinib to sulfamethoxazole is 1:1.0 to 1.5, more preferably 1:1.2.

[0019] Preferably, the heating temperature is 40~60℃, more preferably 45℃.

[0020] The crystallization time is 8 to 72 hours.

[0021] The drying temperature is 45~65℃, and the drying time is 8~12 hours.

[0022] Cabozantinib, the raw material used in the preparation method, can be prepared according to any method in the prior art or purchased from commercially available products.

[0023] Finally, the present invention provides a pharmaceutical composition comprising the cabozantinib-aminosulfonate of the present invention and other pharmaceutically feasible components.

[0024] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0025] Confirmation of crystal structure

[0026] The X-ray crystal data for the cabozantinib-sulfamate test described in this invention were collected using a Rigaku XtaLABSynergy instrument in Japan. The test temperature was 293(2) K, and Cu-Ka radiation was used. Data were collected and processed using an ω-scan method. L p-correction. The structure was analyzed using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was then refined using the least squares method.

[0027] The crystallographic data of the new cabozantinib crystal form prepared by the present invention (as shown in Table 1) are as follows: triclinic crystal system, space group P-1, cell parameters: a=8.78800(10), b=9.09290(10), c=19.3132(2), α=99.8190(10), β=98.4400(10), γ=101.6230(10), cell volume V=1463.03(3).

[0028] Table 1. Main crystallographic data of cabozantinib-sulfamic acid

[0029]

[0030] The ORTEP diagram of the novel cabozantinib-sulfamate crystal form of the present invention shows that this crystalline form contains one molecule of cabozantinib, one molecule of sulfamate, and one molecule of methanol, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of the novel cabozantinib crystal form of the present invention is attached. Figure 3 As shown. Based on the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1And Table 2.

[0031] Table 2 PXRD peaks of the new cabozantinib crystal form

[0032]

[0033] The TGA / DSC test results of the cabozantinib solvate crystals prepared by the method of the present invention are as follows: Figure 4 As shown: there is a strong endothermic peak at 105.7℃, which is approximately the result of losing one molecule of methanol; there is also a strong endothermic peak at 167.52℃, which is the melting point of the cabozantinib cocrystal.

[0034] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0035] 1. This invention provides a new crystal form of cabozantinib for the first time, which has higher solubility and stability, can significantly enhance the solubility of cabozantinib, improve oral bioavailability, and has strong pharmaceutical value.

[0036] 2. Its preparation method is simple to operate, the crystallization process is easy to control, and it has good reproducibility. Attached Figure Description

[0037] Figure 1 PXRD pattern of cabozantinib-sulfamethoxazole.

[0038] Figure 2 ORTEP plot of cabozantinib-sulfamethoxazole.

[0039] Figure 3 Hydrogen bond diagram of cabozantinib-sulfamate.

[0040] Figure 4 DSC-TGA chromatogram of cabozantinib-sulfamethoxazole Detailed Implementation

[0041] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0042] Example 1

[0043] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamic acid (11.6 mg, 0.12 mmol) were dissolved in a mixed solvent of 3 mL methanol and 0.5 mL butanone. The solution was heated and stirred in a water bath at 45 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a new crystal form of cabozantinib. The purity was 99.93%.

[0044] Example 2

[0045] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamethoxazole (9.7 mg, 0.1 mmol) were dissolved in a mixed solvent of 2.5 mL methanol and 2 mL ethanol. The solution was heated and stirred in a water bath at 40 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a new crystal form of cabozantinib. The yield was 96.5% and the purity was 99.71%.

[0046] Example 3

[0047] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamic acid (14.5 mg, 0.15 mmol) were dissolved in a mixed solvent of 6 mL methanol and 2 mL ethyl acetate. The solution was heated and stirred in a water bath at 60 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a new crystal form of cabozantinib. The purity was 99.60%.

[0048] Example 4

[0049] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamethoxazole (9.7 mg, 0.10 mmol) were dissolved in a mixture of 2 mL methanol and 3 mL acetone. The mixture was heated and stirred in a water bath at 35 °C until completely dissolved. After filtration, the solution was allowed to stand at room temperature to evaporate and crystallize, yielding a new crystal form of cabozantinib. The yield was 86.6% and the purity was 98.95%.

[0050] Example 5

[0051] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamethoxazole (13.5 mg, 0.14 mmol) were dissolved in a mixed solvent of 7 mL methanol and 3 mL acetone. The solution was heated and stirred in a water bath at 65 °C until completely dissolved. The solution was filtered and allowed to stand at room temperature to evaporate and crystallize, yielding a new crystal form of cabozantinib. The yield was 88.5% and the purity was 98.33%.

[0052] 1. Light stability test

[0053] The crystal form obtained in Example 1 and the original reagent used were malate crystal form N-2 (prepared according to method CN201080012656.5). They were placed in the open for 10 days under high temperature test (60℃), high humidity test (25℃, relative humidity 90%±5%) and strong light irradiation test (illuminance 4500±500lx). The results are shown in Table 3 below.

[0054] Table 3 Results of photostability tests on cabozantinib crystal form

[0055]

[0056] Experiments showed that the new cabozantinib crystal forms (Examples 1-5) prepared by this invention did not exhibit significant changes in purity or appearance under light, high temperature, and high humidity conditions. However, the N-2 crystal form showed a significant decrease in purity and a marked increase in impurity content under the same experimental conditions. This demonstrates that the crystal forms prepared by this invention have good chemical stability.

[0057] 2. Solubility test

[0058] The solubility of Examples 1 and N-2 in water and solutions of different pH values ​​was determined. 10 mL of each medium (water, 0.01 mol / L HCl solution, and pH 6.8 phosphate buffer) was measured in vials, excess drug was added, the vials were sealed, and the solutions were placed in a 37°C water bath with stirring for 1 hour. The solutions were then filtered through a 2 nm filter, and the absorbance of the filtrate was measured at 200 nm to calculate the solubility of the samples. The results are shown in Table 4.

[0059] Table 4 Solubility in different media

[0060]

[0061] Solubility test results show that the cabozantinib eutectic phase prepared by this invention exhibits significantly improved solubility compared to the available crystal forms disclosed in the prior art. Further investigation revealed similar solubility test results for Examples 1-5.

[0062] 3. Hygroscopicity test

[0063] The eutectic obtained in Example 1 was used to prepare malate crystal form N-2 according to the method of CN201080012656.5, and a hygroscopicity test was performed.

[0064] The hygroscopicity test method and conditions were based on the original experimental conditions of the General Chapter 9103 of Part IV of the Chinese Pharmacopoeia 2020: temperature 25℃±1℃, relative humidity 80%±2%. The results are shown in Table 5 below.

[0065] Among them, the description of hygroscopic characteristics and the definition of hygroscopic weight gain are as follows:

[0066] Deliquescence: The process of absorbing sufficient water to form a liquid.

[0067] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%.

[0068] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0069] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0070] None or almost none hygroscopicity: moisture absorption weight gain less than 0.2%

[0071] Table 5 Results of hygroscopicity test

[0072]

[0073] Conclusion: The new crystalline form of cabozantinib obtained by this invention has little or no hygroscopicity, is not easily affected by high humidity and deliquescent, and is convenient for long-term storage of the drug. Furthermore, PXRD analysis of the hygroscopic crystalline form showed that each crystalline form remained stable.

Claims

1. A cabozantinib eutectic, characterized in that, In the crystal unit structure, the molar ratio of cabozantinib, sulfamic acid, and methanol is 1:1:

1. Using Cu-Kα radiation, X-ray powder diffraction in 2θ angles shows characteristic diffraction peaks at 6.7±0.2°, 8.3±0.2°, 10.1±0.2°, 13.3±0.2°, 16.7±0.2°, and 26.8±0.2°.

2. The cabozantinib eutectic according to claim 1, characterized in that, Using Cu-Kα radiation, at 2 θ The X-ray powder diffraction, expressed in terms of angle, shows diffraction peaks at 10.3±0.2°, 14.4±0.2°, 15.8±0.2°, 19.2±0.2°, 20.7±0.2°, 22.5±0.2°, and 24.4±0.2°.

3. The cabozantinib eutectic according to claim 1, characterized in that, The eutectic has the X-ray powder diffraction pattern shown in Figure 1.

4. The cabozantinib eutectic according to claim 1, characterized in that, Its crystallographic parameters are: triclinic system, space group P-1, cell parameters are: a=8.78800(10), b=9.09290(10), c=19.3132(2), α=99.8190(10), β=98.4400(10), γ=101.6230(10), and cell volume V=1463.03(3).

5. The method for preparing cabozantinib eutectic according to any one of claims 1-4, characterized in that, The preparation method includes the following steps: dissolving cabozantinib, sulfamic acid, and methanol in an organic solvent, heating and stirring, filtering, allowing to stand at room temperature to volatilize and crystallize, filtering and drying to obtain cabozantinib eutectic.

6. The preparation method according to claim 5, characterized in that, The molar ratio of cabozantinib to sulfamethoxazole is 1:1.0 to 1.

5.

7. The preparation method according to claim 5, characterized in that, The mass-to-volume ratio of cabozantinib to methanol is 1:0.05~0.12 mg / ml.

8. The preparation method according to claim 5, characterized in that, The organic solvent is selected from one or a mixture of ethanol, ethyl acetate, acetone and butanone.

9. The method according to claim 5, characterized in that, The heating temperature is 40~60℃.

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