Novel crystal form of cabozantinib

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cabozantinib as well as a preparation method and application thereof. The novel crystal form provided by the invention is a cabozantinib-sulfamic acid-methanol eutectic crystal, contains basic units of crystal forms of one molecule of cabozantinib, one molecule of sulfamic acid and one molecule of methanol, and is greatly improved in the aspects of stability, solubility and the like, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a new crystal form of cabozantinib, its preparation method and application. Background Art

[0002] Cabozantinib, chemically named N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, has the structure shown in the following formula:

[0003]

[0004] Cabozantinib is a tyrosine kinase inhibitor. In vitro biochemical and / or cell assays indicate that cabozantinib can specifically inhibit, regulate, and / or modulate the signal transduction of kinases (especially including Ret, c-Met, and VEGFR2), and thus can be used as a drug for treating or preventing diseases related to 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 there are still some problems. For example, CN201080012656.5 discloses the N-1 crystalline form, N-2 crystalline form, and amorphous form of cabozantinib malate. Patent data shows that the N-2 crystal has better stability compared to the amorphous and N-1 crystals, but its solubility is relatively low. WO2015177758A1 discloses the crystal forms M1, M2, M3, and M4 of cabozantinib malate, among which the crystal form M4 is a relatively superior crystal form, but this crystal form also has the problem of poor solubility. Therefore, a large number of experimental studies are still needed to provide more crystal forms with better properties.

[0006] For drugs, in addition to the therapeutic efficacy of the active molecule, the specific form of the drug also plays a crucial role in the processing, manufacturing, storage, transportation, and use of the drug. Different crystal forms may have differences in various physicochemical properties, including stability, solubility, bioavailability, pharmacological activity, and toxicity.

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

[0008] Aiming at the disadvantages of poor solubility and low stability of cabozantinib provided by the prior art, the present invention aims to provide a new crystal form of cabozantinib with high solubility and stability, namely cabozantinib sulfamate. In addition, the present invention provides a method for preparing cabozantinib sulfamate, which is simple, convenient, and suitable for industrial production.

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

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

[0011] Preferably, for the cabozantinib-aminosulfonate, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 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, for the cabozantinib-aminosulfonate using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern as Figure 1 shown.

[0013] Preferably, for the cabozantinib-aminosulfonate, its molecular formula is C 29 H 31 FN 4 O 9 S, and the crystallographic parameters are: triclinic system, space group P-1, unit 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 unit 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] Dissolve cabozantinib, aminosulfonic acid, and methanol in an organic solvent, heat and stir, filter, allow to stand at room temperature for volatilization and crystallization, and filter and dry to obtain cabozantinib-aminosulfonate.

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

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

[0018] Preferably, the molar ratio of cabozantinib to aminosulfonic acid is 1:1.0 to 1.5, and preferably 1:1.2.

[0019] Preferably, the heating temperature is 40 to 60 °C, preferably 45 °C.

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

[0021] The drying temperature is 45 to 65 °C, and the drying time is 8 to 12 hours.

[0022] In the preparation method, the raw material cabozantinib can be prepared by any method in the prior art or purchased from commercially available products.

[0023] Finally, the present invention provides a pharmaceutical composition, which contains the cabozantinib-sulfamate of the present invention and other pharmaceutically acceptable components.

[0024] Preferably, the other pharmaceutically acceptable components may be pharmaceutically active ingredients that can be used in combination and / or pharmaceutically acceptable excipient components.

[0025] Confirmation of crystal structure

[0026] In the test of the cabozantinib-sulfamate of the present invention, the X-ray crystal data was collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K, using Cu-Kα radiation, collecting data in ω scan mode and performing Lp correction. The structure was solved by the direct method, and all non-hydrogen atoms were located by difference Fourier methods. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.

[0027] The crystallographic data (as shown in Table 1) of the new crystal form of cabozantinib prepared in the present invention are: triclinic system, space group P-1, unit 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), unit cell volume V = 1463.03(3).

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

[0029]

[0030] The ORTEP diagram of the new crystal form of cabozantinib-sulfamic acid of the present invention shows that this crystalline form contains one molecule of cabozantinib, one molecule of sulfamic acid and one molecule of methanol, as shown in the appendix. Figure 2 As shown. The hydrogen bond diagram of the new crystal form of cabozantinib of the present invention, as shown in the appendix. Figure 3 As shown. According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in detail in the appendix. Figure 1and Table 2.

[0031] PXRD Peaks of the New Crystal Form of Cabozantinib in Table 2

[0032]

[0033]

[0034] The TGA / DSC test results of the cabozantinib solvate crystal prepared by the method of the present invention are as Figure 4 shown: there is a strong endothermic peak at 105.7 °C, approximately corresponding to the loss of one molecule of methanol; there is a strong endothermic peak at 167.52 °C, which is the melting point of the cabozantinib cocrystal.

[0035] Compared with the prior art, the technical effects achieved by the present invention are:

[0036] 1. The present 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 drug-forming value.

[0037] 2. Its preparation method is simple in operation, easy to control the crystallization process, and has good reproducibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 . PXRD spectrum of cabozantinib - sulfamic acid.

[0039] Figure 2 . ORTEP diagram of cabozantinib - sulfamic acid.

[0040] Figure 3 . Hydrogen bond diagram of cabozantinib - sulfamic acid.

[0041] Figure 4 . DSC - TGA diagram of cabozantinib - sulfamic acid. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0042] The present invention will be further illustrated below by examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than limiting the present invention. Therefore, any simple improvement to the present invention under the premise of the method of the present invention falls within the scope of protection of the present invention.

[0043] Example 1

[0044] 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 of methanol and 0.5 mL of methyl ethyl ketone, heated and stirred in a water bath at 45 °C until completely dissolved, filtered, and allowed to stand at room temperature to volatilize and crystallize to obtain the new crystal form of cabozantinib, with a yield of 98.3% and a purity of 99.93%.

[0045] Example 2

[0046] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamic acid (9.7 mg, 0.1 mmol) were dissolved in a mixed solvent of 2.5 mL of methanol and 2 mL of ethanol. The mixture was heated and stirred in a water bath at 40 °C until completely dissolved, filtered, and allowed to stand at room temperature to volatilize and crystallize to obtain a new crystal form of cabozantinib. Yield: 96.5%, Purity: 99.71%.

[0047] Example 3

[0048] 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 of methanol and 2 mL of ethyl acetate. The mixture was heated and stirred in a water bath at 60 °C until completely dissolved, filtered, and allowed to stand at room temperature to volatilize and crystallize to obtain a new crystal form of cabozantinib. Yield: 97.1%, Purity: 99.60%.

[0049] Example 4

[0050] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamic acid (9.7 mg, 0.10 mmol) were dissolved in a mixed solvent of 2 mL of methanol and 3 mL of acetone. The mixture was heated and stirred in a water bath at 35 °C until completely dissolved, filtered, and allowed to stand at room temperature to volatilize and crystallize to obtain a new crystal form of cabozantinib. Yield: 86.6%, Purity: 98.95%.

[0051] Example 5

[0052] Cabozantinib (50.1 mg, 0.1 mmol) and sulfamic acid (13.5 mg, 0.14 mmol) were dissolved in a mixed solvent of 7 mL of methanol and 3 mL of acetone. The mixture was heated and stirred in a water bath at 65 °C until completely dissolved, filtered, and allowed to stand at room temperature to volatilize and crystallize to obtain a new crystal form of cabozantinib. Yield: 88.5%, Purity: 98.33%.

[0053] 1. Photo-stability test

[0054] The crystal form obtained in Example 1 and the malate crystal form N-2 used in the original research formulation (prepared according to the method of CN201080012656.5) were respectively placed under the conditions of high temperature test (60 °C), high humidity test (25 °C, relative humidity 90% ± 5%) and strong light irradiation test (illuminance 4500 ± 500 lx) and left open for 10 days, and then samples were taken for testing. The results are shown in Table 1 below.

[0055] Table 1 Results of photo-stability test of cabozantinib crystal forms

[0056] Placement conditions Placement time Example 1 N-2 Properties Granular crystals Granular crystals Sample before placement 99.98％ 99.58％ High temperature test 10 99.97％ 99.26％ High humidity experiment 10 99.95％ 99.08％ Strong light irradiation experiment 10 99.96％ 99.12％

[0057] After experiments, the purity and appearance of the novel cabozantinib crystal forms (Examples 1-5) prepared by the present invention did not change significantly under the conditions of light, high temperature, and high humidity. However, for the N-2 crystal form, its purity decreased significantly and the impurity content increased significantly under the same experimental conditions. It can be seen that the crystal forms prepared by the present invention have good chemical stability.

[0058] 2. Solubility Test

[0059] The solubilities of Example 1 and N-2 in water and solutions with different pH values were measured. Respectively, 10 mL of the media (water, 0.01 mol / L HCl solution, and phosphate buffer solution with pH 6.8) were measured and placed in a vial, an excessive amount of the drug was added, the vial was sealed and placed in a 37 °C water bath for constant temperature stirring for 1 hour, filtered through a 2 nm filter membrane, and the absorbance of the subsequent filtrate was measured at a wavelength of 200 nm to calculate the solubility of the sample. The results are shown in Table 2.

[0060] Table 2 Solubility in Different Media

[0061]

[0062] The solubility test results show that the cabozantinib cocrystal prepared by the present invention has made significant progress in solubility compared with the available crystal forms disclosed in the prior art. It was found through investigation that Examples 1-5 have similar solubility test results.

[0063] 3. Hygroscopicity Experiment

[0064] The cocrystal obtained in Example 1 was taken, and the malate crystal form N-2 was prepared according to the method of CN201080012656.5 for the hygroscopicity test.

[0065] The method and conditions of the hygroscopicity test refer to the General Principles 9103 of the Fourth Part of the Chinese Pharmacopoeia 2020 for the Guidance on the Hygroscopicity Test of Drugs. The experimental conditions are: temperature 25 °C ± 1 °C, relative humidity 80% ± 2%. The results are shown in Table 3 below;

[0066] Among them, the description of the hygroscopicity characteristics and the definition of the hygroscopicity weight gain:

[0067] Deliquescence: Absorbing sufficient moisture to form a liquid.

[0068] Highly hygroscopic: The hygroscopicity weight gain is not less than 15%.

[0069] Hygroscopic: The hygroscopicity weight gain is less than 15% but not less than 2%.

[0070] Slightly hygroscopic: The hygroscopicity weight gain is less than 2% but not less than 0.2%.

[0071] Non-hygroscopic or almost non-hygroscopic: The hygroscopicity weight gain is less than 0.2%

[0072] Results of the investigation on hygroscopicity in Table 3

[0073]

[0074] Conclusion: The new crystal form of cabozantinib obtained in the present invention has no or almost no hygroscopicity, is not easily affected by high humidity and deliquesces, which is convenient for the long-term storage of the drug. In addition, the PXRD test was carried out on the crystal form after moisture absorption, and each crystal form was tested to be stable and unchanged.

Claims

1. A cabozantinib cocrystal, characterized in that The molar ratio of cabozantinib, aminosulfonic acid, and methanol in the crystal unit structure is 1:1:

1.

2. The cabozantinib cocrystal according to claim 1, characterized in that Using Cu-K α Radiation, 2 θ The X-ray powder diffraction expressed by angles has 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°.

3. The cabozantinib cocrystal according to claim 1, characterized in that Using Cu-K α Radiation, 2 θ The X-ray powder diffraction expressed by angles has 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°.

4. The cabozantinib cocrystal according to claim 1, characterized in that The crystal form has an X-ray powder diffraction pattern as shown in FIG1 .

5. The cabozantinib cocrystal according to claim 1, characterized in that Its crystallographic parameters are: triclinic system, space group P-1, unit 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), unit cell volume V=1463.03(3).

6. The method for preparing the cabozantinib cocrystal according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: dissolving cabozantinib and aminosulfonic acid and methanol in an organic solvent, heating and stirring, filtering, standing at room temperature for volatilization and crystallization, filtering and drying to obtain cabozantinib cocrystal.

7. The method according to claim 6, characterized in that The feeding molar ratio of cabozantinib to aminosulfonic acid is 1:1.0-1.

5.

8. The method according to claim 6, characterized in that The mass volume ratio of cabozantinib to methanol is 1:0.05-0.12, mg / ml.

9. The method according to claim 6, characterized in that The organic solvent is selected from one or a mixed solvent of ethanol, ethyl acetate, acetone and butanone.

10. The method according to claim 6, characterized in that The heating temperature is 40-60°C.

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