Cabozantinib-5-sulfosalicylic acid crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cabozantinib-5-sulfosalicylic acid as well as a preparation method and application of the novel crystal form. The novel crystal form of cabozantine-5-sulfosalicylic acid provided by the invention contains basic units of crystal forms of one molecule of cabozantinib, one molecule of 5-sulfosalicylic acid and one molecule of methanol, the stability, solubility and the like are greatly improved, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically the crystal form of cabozantinib-5-sulfosalicylic acid, 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 been shown to inhibit the tyrosine kinase activity of RET, MET, VEGFR-1, VEGFR-2, VEGFR-3, KIT, TRKB, FLT-3, AXL, and TIE-2 receptors. It is a multi-target, broad-spectrum anticancer drug, and its structure is shown below:

[0003]

[0004] In November 2012, the U.S. FDA approved cabozantinib malate (1:1) developed by Exelixis for marketing under the brand name COMETRIQ. The company's Chinese patent application CN102388024A disclosed three solid forms of cabozantinib L-malate: N-1 crystalline, N-2 crystalline, and amorphous (non-crystalline). Patent data shows that N-2 crystalline has better stability than amorphous and N-1 crystalline, but its solubility is lower.

[0005] Patent application WO2015177758A1 discloses crystal forms M1, M2, M3, and M4 of cabozantinib malate, among which crystal form M4 is the preferred crystal form. However, this crystal form 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. Summary of the Invention

[0007] 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-5-sulfosalicylic acid. Furthermore, this invention provides a simple, convenient method for preparing the cabozantinib-5-sulfosalicylic acid crystalline form, suitable for industrial production.

[0008] The specific technical content of this invention is as follows:

[0009] On one hand, the present invention provides a cabozantinib-5-sulfosalicylic acid crystal form, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern represented by 2θ has characteristic peaks at at least 5.4±0.2°, 10.7±0.2°, 15.4±0.2°, 16.0±0.2°, and 24.5±0.2°.

[0010] Preferably, the cabozantinib-5-sulfosalicylic acid crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (represented by 2θ) at at least 5.4±0.2°, 10.7±0.2°, 12.3±0.2°, 13.6±0.2°, 14.4±0.2°, 14.9±0.2°, 15.4±0.2°, 16.0±0.2°, 16.9±0.2°, 20.1±0.2°, 21.4±0.2°, 22.1±0.2°, 24.5±0.2°, and 26.1±0.2°.

[0011] Preferably, the cabozantinib-5-sulfosalicylic acid crystal form is obtained using Cu-Kα radiation, and its characteristic peaks conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0012] Preferably, the cabozantinib-5-sulfosalicylic acid crystal form has the molecular formula C36H34FN3O12S, and the crystallographic parameters are: triclinic crystal system, space group P-1, and the cell parameters are: a=8.4492(3), b=12.6738(3), c=17.2623(5), α=93.351(2), β=93.560(2), γ=100.956(2), and the cell volume V=1806.65(9).

[0013] On the other hand, the present invention provides a method for preparing cabozantinib-5-sulfosalicylic acid crystal form, comprising the following steps:

[0014] Cabozantinib and 5-sulfosalicylic acid were added to a mortar and pestle, and an organic solvent was added dropwise for the first grinding. Then methanol was added for the second grinding to obtain a transparent solution. The solution was allowed to stand at a controlled temperature to crystallize, filtered, and dried under vacuum to obtain cabozantinib-5-sulfosalicylic acid.

[0015] Preferably, the molar ratio of cabozantinib to 5-sulfosalicylic acid is 1:1.1 to 2; more preferably 1:1.2.

[0016] Preferably, the organic solvent is selected from one or a combination of butanone, acetonitrile, acetone, methanol, and ethanol; more preferably, one or a combination of methanol and acetone.

[0017] Preferably, the mass-to-volume ratio of cabozantinib to the organic solvent used in the first milling is 50.1:1.0-5.0, mg / ml.

[0018] Preferably, the volume ratio of methanol used in the first grinding to the second grinding is 1:2 to 5.

[0019] Preferably, the first grinding time is 30-50 minutes, and the second grinding time is 10-20 minutes.

[0020] Preferably, the crystallization temperature is 5–10°C.

[0021] Preferably, the crystallization time is 48 to 72 hours.

[0022] Preferably, the drying temperature is 50-60°C and the drying time is 8-12 hours.

[0023] 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.

[0024] Finally, the present invention provides a pharmaceutical composition comprising the cabozantinib-5-sulfosalicylic acid crystal form described herein and other pharmaceutically feasible components.

[0025] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0026] Confirmation of crystal structure

[0027] The X-ray crystal data for the eutectic test of cabozantinib-5-sulfosalicylic acid described in this invention were collected on a Rigaku XtaLAB Synergy instrument in Japan at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected in an ω-scan manner with Lp correction. The structure was resolved using a direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained through theoretical hydrogenation. The structure was refined using the least squares method.

[0028] The crystallographic data (as shown in Table 1) of the crystalline form of cabozantinib-5-sulfosalicylic acid prepared in this invention were tested and analyzed. The crystal system is triclinic, space group is P-1, and the cell parameters are: a = 8.4492 (3), b = 12.6738 (3), c = 17.2623 (5), α = 93.351 (2), β = 93.560 (2), γ = 100.956 (2), and the cell volume V = 1806.65 (9).

[0029] Table 1. Main crystallographic data of cabozantinib-5-sulfosalicylic acid

[0030]

[0031] The ORTEP diagram of the novel crystalline form of cabozantinib-5-sulfosalicylic acid of the present invention shows that this crystalline form contains one molecule of cabozantinib, one molecule of 5-sulfosalicylic acid, and one molecule of methanol, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of cabozantinib-5-sulfosalicylic acid 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 1 And Table 2.

[0032] Table 2 PXRD peaks of the new crystal form of cabozantinib-5-sulfosalicylic acid

[0033]

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

[0035] This invention provides cabozantinib-5-sulfosalicylic acid for the first time. Its preparation method is simple, the crystallization process is easy to control, and it has good reproducibility. The formation of a co-crystal between the two significantly enhances the solubility of cabozantinib and improves its oral bioavailability, demonstrating strong pharmaceutical value. Attached Figure Description

[0036] Figure 1 PXRD pattern of cabozantinib-5-sulfosalicylic acid.

[0037] Figure 2 ORTEP plot of cabozantinib-5-sulfosalicylic acid.

[0038] Figure 3 Hydrogen bond diagram of cabozantinib-5-sulfosalicylic acid. Detailed Implementation

[0039] 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.

[0040] Example 1

[0041] Cabozantinib (50.1 mg, 0.1 mmol) and 5-sulfosalicylic acid (26.2 mg, 0.12 mmol) were added to a mortar, 2 mL of methanol was added dropwise, and the mixture was ground thoroughly for 40 min. Then, 6 mL of methanol was added and the mixture was ground for another 15 min to obtain a clear solution. The solution was allowed to stand at 5–10 °C for 48 h to crystallize. After filtration, the solution was dried under vacuum at 55 °C to obtain cabozantinib-5-sulfosalicylic acid crystals with a yield of 98.2% and a purity of 99.98%.

[0042] Example 2

[0043] Cabozantinib (50.1 mg, 0.1 mmol) and 5-sulfosalicylic acid (24.0 mg, 0.11 mmol) were added to a mortar, 1 mL of acetone was added dropwise, and the mixture was ground thoroughly for 30 min. Then, 2 mL of methanol was added and the mixture was ground for another 10 min to obtain a clear solution. The solution was allowed to stand at 5–10 °C for 48 h to crystallize. After filtration, the solution was dried under vacuum at 50 °C to obtain cabozantinib-5-sulfosalicylic acid crystals with a yield of 95.3% and a purity of 99.75%.

[0044] Example 3

[0045] Cabozantinib (50.1 mg, 0.1 mmol) and 5-sulfosalicylic acid (43.6 mg, 0.2 mmol) were added to a mortar, and 5 mL of butanone was added dropwise. The mixture was ground thoroughly for 50 min, and then 10 mL of methanol was added and the mixture was ground for another 20 min to obtain a clear solution. The solution was allowed to stand at 5–10 °C for 72 h to crystallize. After filtration, the solution was dried under vacuum at 60 °C to obtain cabozantinib-5-sulfosalicylic acid crystals with a yield of 96.5% and a purity of 99.68%.

[0046] Example 4

[0047] Cabozantinib (50.1 mg, 0.1 mmol) and 5-sulfosalicylic acid (48.0 mg, 0.22 mmol) were added to a mortar, and 7 mL of methanol was added dropwise. The mixture was ground thoroughly for 60 min, and then 14 mL of methanol was added and the mixture was ground for another 25 min to obtain a clear solution. The solution was allowed to stand at 5–10 °C for 74 h to crystallize. After filtration, the solution was dried under vacuum at 65 °C to obtain cabozantinib-5-sulfosalicylic acid crystals with a yield of 98.3% and a purity of 98.93%.

[0048] Example 5

[0049] Cabozantinib (50.1 mg, 0.1 mmol) and 5-sulfosalicylic acid (21.8 mg, 0.1 mmol) were added to a mortar, and 0.8 mL of methanol was added dropwise. The mixture was ground thoroughly for 25 min, and then 1.5 mL of methanol was added and the mixture was ground for another 8 min to obtain a clear solution. The solution was allowed to stand at 5–10 °C for 45 h to crystallize. After filtration, the solution was dried under vacuum at 45 °C to obtain cabozantinib-5-sulfosalicylic acid crystals with a yield of 88.3% and a purity of 99.12%.

[0050] Verification test

[0051] 1. Light stability test

[0052] 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 1 below.

[0053] Table 1. Results of light stability tests on cabozantinib crystal form

[0054] 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 test 10 99.96％ 99.08％ Strong light irradiation experiment 10 99.96％ 99.12％

[0055] 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.

[0056] 2. Solubility test

[0057] 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 2.

[0058] Table 2 Solubility in different media

[0059]

[0060] 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.

[0061] 3. In vitro dissolution test

[0062] 1. Experimental Materials: Cabozantinib-5-sulfosalicylic acid crystal form and cabozantinib malate obtained in the examples were prepared into tablets using the same conventional wet granulation process in the art. In vitro dissolution was tested. The formulation is as follows:

[0063] Table 3 Cabozantinib Prescriptions

[0064]

[0065] Dissolution conditions: Determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Standard medium (pH 2.0 hydrochloric acid medium): 900 ml of a hydrochloric acid solution containing 0.5% Triton, adjusted to pH 2.00 ± 0.1 with hydrochloric acid, was used as the dissolution medium. The dissolution method was paddle dissolution at a speed of 75 rpm. Sampling time points were 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min.

[0066] Dissolution chromatographic conditions: An octadecylsilane-bonded silica gel column was used as the packing material; the mobile phase was 0.02 mol / L ammonium acetate solution (adjusted to pH 5.2 with glacial acetic acid)-acetonitrile (48:52); the flow rate was 1.0 mL / min; the column temperature was 35 °C; and the detection wavelength was 241 nm. The injection volume was 10 μL. The theoretical plate number, calculated based on the cabozantinib peak, was not less than 2000.

[0067] Table 4 Dissolution rates of tablets from each example

[0068]

[0069]

[0070] The novel crystal form of cabozantinib presented in this application exhibits excellent solubility and in vitro dissolution, providing a new option for the development of cabozantinib formulations.

[0071] In summary, the cabozantinib-5-sulfosalicylic acid crystal form prepared by this invention has better solubility, stability, and dissolution rate, and is better suited for cabozantinib formulations.

Claims

1. A novel crystal form of cabozantinib, characterized in that, In the crystal unit structure, the molar ratio of cabozantinib, 5-sulfosalicylic acid, and methanol is 1:1:

1.

2. The new crystal form of cabozantinib according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in terms of angle, has characteristic diffraction peaks at 5.4±0.2°, 10.7±0.2°, 15.4±0.2°, 16.0±0.2°, and 24.5±0.2°.

3. The new crystal form of cabozantinib according to claim 1, characterized in that, Using Cu-K α Radiation, at 2 θ The X-ray powder diffraction, expressed in angles, shows diffraction peaks at 5.4±0.2°, 10.7±0.2°, 12.3±0.2°, 13.6±0.2°, 14.4±0.2°, 14.9±0.2°, 15.4±0.2°, 16.0±0.2°, 16.9±0.2°, 20.1±0.2°, 21.4±0.2°, 22.1±0.2°, 24.5±0.2°, and 26.1±0.2°.

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

5. The new crystal form of cabozantinib according to claim 1, characterized in that, Its crystallographic parameters are: triclinic system, space group P-1, cell parameters are: a=8.4492(3), b=12.6738(3), c=17.2623(5), α=93.351(2), β=93.560(2), γ=100.956(2), and cell volume V=1806.65(9).

6. A method for preparing the new crystal form of cabozantinib according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: cabozantinib and 5-sulfosalicylic acid are added to a mortar, an organic solvent is added dropwise for the first grinding, and then methanol is added for the second grinding to obtain a transparent solution. The solution is allowed to stand at a controlled temperature to crystallize, filtered, and vacuum dried to obtain cabozantinib-5-sulfosalicylic acid.

7. The preparation method according to claim 6, characterized in that, The molar ratio of cabozantinib to 5-sulfosalicylic acid is 1:1.1 to 2.

8. The preparation method according to claim 6, characterized in that, The organic solvent is selected from one or a combination of butanone, acetonitrile, acetone, methanol, and ethanol.

9. The preparation method according to claim 6, characterized in that, The mass-to-volume ratio of cabozantinib to the organic solvent used in the first milling process is 50.1:1.0–5.0, mg / ml.

10. The preparation method according to claim 6, characterized in that, The volume ratio of the organic solvent used in the first grinding to the methanol used in the second grinding is 1:2 to 5.

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