Cabozantinib isophthalic 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 as well as a preparation method and application thereof. The novel crystal form provided by the invention is a cabozantinib-isophthalic acid eutectic crystal, the cabozantinib-isophthalic acid eutectic crystal contains basic units of a monomolecular cabozantinib and a monomolecular isophthalic acid crystal form, the stability, the 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 isophthalic acid, its preparation method, and its application. Background Technology

[0002] 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.

[0003] 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, CN102388024A 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.

[0004] 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.

[0005] Research on different crystal forms will be of great significance for expanding the research and development of new cabozantinib formulations. Summary of the Invention

[0006] 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: the cabozantinib-isophthalic acid crystal form. Furthermore, this invention provides a simple, convenient method for preparing the cabozantinib-isophthalic acid crystal form, suitable for industrial production.

[0007] The specific technical content of this invention is as follows:

[0008] On one hand, the present invention provides a cabozantinib isophthalic acid crystal form, characterized in that, using Cu-Kα radiation, the X-ray diffraction pattern expressed in 2θ has characteristic peaks at at least 4.2±0.2°, 8.5±0.2°, 9.8±0.2°, 12.8±0.2°, 14.6±0.2°, 21.1±0.2°, 21.4±0.2°, and 23.1±0.2°.

[0009] Preferably, the cabozantinib-isophthalic acid crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 4.2±0.2°, 8.5±0.2°, 9.8±0.2°, 10.8±0.2°, 12.8±0.2°, 14.2±0.2°, 14.6±0.2°, 17.6±0.2°, 19.4±0.2°, 19.8±0.2°, 21.1±0.2°, 21.4±0.2°, 23.1±0.2°, 26.4±0.2°, 39.2±0.2°, and 40.1±0.2°.

[0010] Preferably, the cabozantinib-isophthalic 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.

[0011] Preferably, the cabozantinib-isophthalic acid crystal form has the molecular formula C2. 36 H 30 FN3O9 has the following crystallographic parameters: triclinic system, space group P-1, cell parameters: a = 8.4847(2), b = 9.5194(4), c = 21.1853(7), α = 77.720(3), β = 84.394(2), γ = 73.013(3), and cell volume V = 1597.87(10).

[0012] On the other hand, the present invention provides a method for preparing cabozantinib-isophthalic acid crystal form, comprising the following steps:

[0013] Cabozantinib and isophthalic acid were dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand to volatilize and crystallize, and then filtered and dried to obtain the cabozantinib-isophthalic acid crystal form.

[0014] Preferably, the solvent is selected from a mixture of methanol, isopropanol, acetonitrile, ethanol, ethyl acetate, acetone, and butanone, and particularly preferably one or a combination of ethanol, acetone, and methanol.

[0015] Preferably, the mass-to-volume ratio of cabozantinib to organic solvent is 50.1:4-8; more preferably 50.1:5-6.

[0016] Preferably, the molar ratio of cabozantinib to terephthalic acid is 1:0.5 to 1.5, more preferably 1:1.

[0017] Preferably, the heating temperature is 40-60°C, and more preferably 50°C.

[0018] The cooling crystallization temperature is 10-30°C, preferably 10-15°C.

[0019] The crystallization time is 8 to 72 hours.

[0020] The drying temperature is 45–65°C, and the drying time is 8–12 hours.

[0021] 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.

[0022] Finally, the present invention provides a pharmaceutical composition comprising the cabozantinib-isophthalic acid crystal form described herein and other pharmaceutically feasible components.

[0023] Preferably, the other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0024] Confirmation of crystal structure

[0025] The X-ray crystal data for the cabozantinib-isophthalic acid crystal form test described in this invention were collected using a Rigaku XtaLABSynergy 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.

[0026] The crystallographic data (as shown in Table 1) of the cabozantinib-isophthalic acid crystal form prepared in this invention were tested and analyzed. The crystal system is triclinic, space group is P-1, and the cell parameters are: a = 8.4847 (2), b = 9.5194 (4), c = 21.1853 (7), α = 77.720 (3), β = 84.394 (2), γ = 73.013 (3), and the cell volume V = 1597.87 (10).

[0027] Table 1. Major crystallographic data of cabozantinib-isophthalic acid

[0028]

[0029] The ORTEP diagram of the novel cabozantinib-isophthalic acid crystal form of the present invention shows that this crystalline form contains one molecule of cabozantinib and one molecule of isophthalic acid, as shown in the attached diagram. Figure 2 As shown. The hydrogen bond diagram of cabozantinib-isophthalic 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.

[0030] Table 2 PXRD peaks of the new crystal form of cabozantinib-isophthalic acid

[0031]

[0032]

[0033] The TGA / DSC thermal analysis test conditions for the crystal form described in this invention are as follows: Mettler Toledo TGA / DSC thermal analyzer (model: TGA / DSC3+), dynamic temperature range: 30~400℃, heating rate: 10℃ / min, programmed gas N2, flow rate: 50ml / min, crucible: 40μl aluminum crucible.

[0034] The TGA / DSC test results of cabozantinib-isophthalic acid crystals prepared by the method of the present invention are as follows: Figure 4 As shown, there is a strong endothermic peak in the range of 215.15–218.63 °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 as follows:

[0036] This invention provides, for the first time, cabozantinib-isophthalic acid, a preparation method that is simple to operate, with easily controlled crystallization process and 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

[0037] Figure 1 PXRD pattern of cabozantinib-isophthalic acid.

[0038] Figure 2 ORTEP plot of cabozantinib-isophthalic acid.

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

[0040] Figure 4 DSC-TGA image of cabozantinib-isophthalic acid. 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 isophthalic acid (16.6 mg, 0.1 mmol) were dissolved in 3 mL of methanol and 2 mL of acetone. The mixture was heated and stirred in a water bath at 50 °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 isophthalic acid. The purity was 99.97%.

[0044] Example 2 (Lower Limit)

[0045] Cabozantinib (50.1 mg, 0.1 mmol) and isophthalic acid (8.3 mg, 0.05 mmol) were dissolved in 2 mL of isopropanol and 2 mL of butanone. The mixture 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 isophthalic acid. The purity was 99.72%.

[0046] Example 3 (Upper Limit)

[0047] Cabozantinib (50.1 mg, 0.1 mmol) and isophthalic acid (24.9 mg, 0.15 mmol) were dissolved in 6 mL of isopropanol, heated and stirred in a water bath at 60 °C until completely dissolved, filtered, and allowed to stand at room temperature to evaporate and crystallize to obtain a new crystal form of cabozantinib isophthalic acid. Yield: 97.5%, purity: 99.65%.

[0048] Example 4 (outside the lower limit)

[0049] Cabozantinib (50.1 mg, 0.1 mmol) and isophthalic acid (5.0 mg, 0.03 mmol) were dissolved in 2 mL of butanone and 1 mL of ethyl acetate. 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 isophthalic acid. The purity was 98.87%.

[0050] Example 5 (Outside the Upper Limit)

[0051] Cabozantinib (50.1 mg, 0.1 mmol) and isophthalic acid (33.2 mg, 0.2 mmol) were dissolved in 5 mL of acetonitrile and 5 mL of methanol. The mixture was heated and stirred in a water bath at 65 °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 isophthalic acid. The purity was 98.40%.

[0052] Verification test

[0053] 1. Light stability test

[0054] 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 15 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.

[0055] Table 3 Results of light stability tests on cabozantinib crystal form

[0056]

[0057]

[0058] 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.

[0059] 2. Solubility test

[0060] 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.

[0061] Table 4 Solubility in different media

[0062]

[0063] 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.

[0064] 3. In vitro dissolution test

[0065] 1. Experimental Materials: Cabozantinib terephthalic 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:

[0066]

[0067]

[0068] 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.

[0069] 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.

[0070] Table 5 Dissolution rates of tablets from each example

[0071]

[0072] 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.

[0073] In summary, the cabozantinib terephthalic 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, The molar ratio of cabozantinib to isophthalic acid in the crystal unit structure is 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 4.2±0.2°, 8.5±0.2°, 9.8±0.2°, 12.8±0.2°, 14.6±0.2°, 21.1±0.2°, 21.4±0.2°, and 23.1±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 4.2±0.2°, 8.5±0.2°, 9.8±0.2°, 10.8±0.2°, 12.8±0.2°, 14.2±0.2°, 14.6±0.2°, 17.6±0.2°, 19.4±0.2°, 19.8±0.2°, 21.1±0.2°, 21.4±0.2°, 23.1±0.2°, 26.4±0.2°, 39.2±0.2°, and 40.1±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=8.4847(2), b=9.5194(4), c=21.1853(7), α=77.720(3), β=84.394(2), γ=73.013(3), and cell volume V=1597.87(10).

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: dissolving cabozantinib and isophthalic acid in a mixed solvent, heating and stirring, filtering, cooling and allowing to stand to volatilize and crystallize, filtering and drying to obtain cabozantinib-isophthalic acid crystal form.

7. The preparation method according to claim 6, characterized in that, The molar ratio of cabozantinib to isophthalic acid is 1:0.5 to 1.

5.

8. The preparation method according to claim 6, characterized in that, The mixed solvent is selected from methanol, isopropanol, acetonitrile, ethanol, ethyl acetate, acetone, butanone, or a mixture thereof.

9. The preparation method according to claim 6, characterized in that, The mass-to-volume ratio of cabozantinib to organic solvent is 50.1:4-8; mg / ml.

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

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