WO2022000265A1

WO2022000265A1 - Cocrystals of axitinib and glutaric acid, and preparation method therefor

Info

Publication number: WO2022000265A1
Application number: PCT/CN2020/099269
Authority: WO
Inventors: 陈嘉媚; 任伯颖
Original assignee: 天津理工大学
Priority date: 2020-06-30
Filing date: 2020-06-30
Publication date: 2022-01-06

Abstract

Disclosed in the present invention are cocrystals of axitinib and glutaric acid, and a preparation method therefor. In the cocrystals of axitinib and glutaric acid, the molar ratio of axitinib to glutaric acid is 1:1. The preparation method of the cocrystals of axitinib and glutaric acid features simple technology, an easy-control crystallization process, and good reproducibility, and is suitable for industrial production. Compared with axitinib, the cocrystals of axitinib and glutaric acid have a greater apparent solubility and a faster dissolution rate, and facilitate improving the oral bioavailability of axitinib.

Description

A kind of co-crystal of Axitinib and glutaric acid and preparation method thereof

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a co-crystal of axitinib and glutaric acid and a preparation method thereof.

Background technique

Pharmaceutically active ingredients usually exist in crystalline forms such as polymorphs, hydrates, solvates, salts, co-crystals, and the like. For the same active pharmaceutical ingredient, different crystalline forms have different physicochemical properties. Therefore, in the pharmaceutical industry, it is of great significance to obtain suitable crystalline forms of drugs. Drugs exist in the form of co-crystals, which have significant advantages in improving the stability, solubility and processability of active pharmaceutical ingredients. Therefore, drug co-crystals are an effective means to improve the physicochemical properties of active pharmaceutical ingredients.

The chemical name of Axitinib is N-methyl-2-[[3-[(1E)-2-(2-pyridyl)vinyl]-1H-indazol-6-yl]sulfanyl ] benzamide, its chemical structural formula is:

Axitinib is a second-generation VEGFR inhibitor that selectively inhibits the activities of vascular endothelial growth factor VEGF-1, VEGF-2, and VEGF-3 receptors to exert anti-cancer effects. The drug was developed by Pfizer under the trade name

It was approved by the FDA on January 27, 2012 for the treatment of early-stage to advanced kidney cancer, and was approved by the EMA in September of the same year for marketing in Europe. Currently, the drug is used to treat advanced renal cell carcinoma in several countries. Pfizer has built a strict crystal form patent barrier for axitinib. Patent US20060094763 discloses crystal forms I, II, III, IV, VI, VII, VIII and other crystal forms of axitinib; patent CN 103626739 discloses crystal forms XXV, XVI, XLI, IX of axitinib , XII, XV and other crystal forms. At present, the axitinib used in China is imported, which is expensive and unbearable for ordinary patients, which limits its clinical application. In addition, axitinib is a BCS class II drug with poor water solubility, limiting its oral bioavailability. Therefore, in order to break through the crystal form patent of the original pharmaceutical company and improve its dissolution properties, we carried out a co-crystal study of axitinib.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to provide a co-crystal of axitinib and glutaric acid; the second of the objects of the present invention is to provide a preparation method of this co-crystal of axitinib and glutaric acid; The third is to provide the application of this co-crystal of axitinib and glutaric acid.

After a large number of experimental studies, the inventors have tried the co-crystal screening experiments of axitinib and various dicarboxylic acid compounds, including succinic acid, glutaric acid, adipic acid, pimelic acid and the like. Finally, a co-crystal of axitinib and glutaric acid was successfully discovered, which can effectively improve the dissolution properties of axitinib and provide a material basis for improving the oral bioavailability of axitinib.

The technical scheme adopted by the present invention is:

The invention provides a co-crystal of axitinib and glutaric acid.

A co-crystal of axitinib and glutaric acid, the structural formula of the co-crystal is shown in formula (I):

In this co-crystal, the molar ratio of axitinib to glutaric acid is 1:1; the X-ray powder diffraction pattern of this co-crystal measured by Cu Kα radiation is 7.7±0.2°, 12.8± There are characteristic peaks at 0.2°, 14.1±0.2°, 15.4±0.2°, 17.3±0.2°, 19.2±0.2°, 21.4±0.2°, and 25.5±0.2°.

Preferably, the X-ray powder diffraction pattern of the co-crystal of axitinib and glutaric acid also has diffraction angles 2θ of 16.1±0.2°, 17.9±0.2°, 18.2±0.2°, 20.1±0.2°, 22.1±0.2 One or more of °, 22.7±0.2°, 23.2±0.2°, 24.1±0.2°, and 24.7±0.2° have characteristic peaks.

The present invention provides a preparation method of the co-crystal of axitinib and glutaric acid.

A preparation method of axitinib and glutaric acid co-crystal, comprising the following steps: feeding axitinib and glutaric acid according to a molar ratio of 1:1, adding an appropriate amount of solvent, and then stirring or grinding to obtain a co-crystal.

Preferably, in the preparation method of the co-crystal, the solvent is at least one of alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents, and alkane solvents. Wherein, alcohol solvents include but are not limited to methanol, ethanol, isopropanol; ester solvents include but are not limited to methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate; ketone solvents include but are not limited to acetone; Ether-based solvents include but are not limited to diethyl ether, isopropyl ether, and tetrahydrofuran; nitrile-based solvents include but are not limited to acetonitrile; alkane-based solvents include but are not limited to n-hexane, n-heptane, and cyclohexane; further preferably, the solvent is selected from methanol , one or more of ethanol, isopropanol, ethyl acetate, acetonitrile, acetone, isopropyl ether, tetrahydrofuran, n-heptane.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of axitinib and glutaric acid to the amount of solvent during stirring is 1 g: (2-20) mL; when grinding, axitinib and glutaric acid are The ratio of the total mass of the solvent to the amount of the solvent is 1 g: (20-200) uL.

In some preferred embodiments of the present invention, the preparation method of this co-crystal is as follows: feeding axitinib and glutaric acid in a molar ratio of 1:1, adding a solvent, stirring, filtering, and drying the obtained solid product , to obtain a eutectic.

In some other preferred embodiments of the present invention, the preparation method of the co-crystal is as follows: feeding axitinib and glutaric acid in a molar ratio of 1:1, adding a solvent and grinding to obtain a co-crystal.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of axitinib and glutaric acid to the amount of solvent used during stirring is 1 g: (4-20) mL.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of axitinib and glutaric acid to the amount of solvent used during grinding is 1 g: (100-200) uL.

The present invention provides a pharmaceutical composition comprising the co-crystal of axitinib and glutaric acid and a pharmaceutically acceptable excipient.

In the present invention, pharmaceutically acceptable excipients refer to pharmaceutically acceptable materials, mixtures or vehicles that are related to the consistency of dosage forms or pharmaceutical compositions. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition.

Preferably, the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents Agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants , preservatives, stabilizers, surfactants and buffers.

The invention also provides the application of the co-crystal of axitinib and glutaric acid in the preparation of a medicament for preventing and/or treating cancer and other angioproliferative diseases.

The beneficial effects of the present invention are:

The present invention converts axitinib into a new co-crystal of axitinib and glutaric acid for the first time, and the co-crystal of axitinib and glutaric acid has a faster dissolution rate and larger The apparent solubility of axitinib provides a material basis for improving the oral bioavailability of axitinib.

The preparation method of the co-crystal of axitinib and glutaric acid disclosed by the invention has simple process, easy control of the crystallization process, good reproducibility, and is suitable for industrial production.

The co-crystal of axitinib and glutaric acid of the present invention has broad application prospects in the preparation of medicines for preventing and/or treating cancer and other vascular proliferation diseases.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern of axitinib and glutaric acid co-crystal;

Figure 2 is a differential scanning calorimetry analysis diagram of axitinib and glutaric acid co-crystal;

Fig. 3 is the thermogravimetric analysis diagram of axitinib and glutaric acid co-crystal;

Fig. 4 is the Fourier transform infrared spectrum of axitinib and glutaric acid co-crystal;

Fig. 5 is the hydrogen nuclear magnetic resonance spectrum of co-crystal of Axitinib and glutaric acid;

Fig. 6 is the powder dissolution curve diagram of axitinib crystal form IV, axitinib and glutaric acid co-crystal;

Figure 7 is a graph showing the characteristic dissolution curves of axitinib crystal form IV and axitinib co-crystal with glutaric acid.

detailed description

The content of the present invention will be further described in detail below through specific embodiments. The raw materials used in the examples can be obtained from conventional commercial channels unless otherwise specified.

Example 1

Weigh 386 mg of Axitinib and 132 mg of glutaric acid, add 10 mL of n-heptane and 50 μL of ethanol to obtain a suspension, stir the suspension at room temperature for 4 h, filter, and dry the obtained white solid at 40 ° C to obtain Axitinib A solid sample of the co-crystal of cititinib and glutaric acid in 92.5% yield.

Example 2

38.6 mg of axitinib and 13.2 mg of glutaric acid were weighed, 1 mL of n-heptane and 10 μL of acetone were added to obtain a suspension, the suspension was stirred at room temperature for 24 h, filtered, and the obtained white solid was dried at 40 ° C to obtain Solid samples of axitinib and glutaric acid co-crystals.

Example 3

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add 1 mL of anisole to obtain a suspension, stir the suspension at room temperature for 24 h, filter, and dry the obtained white solid at 40 ° C to obtain axitinib A solid sample of the co-crystal of nitric acid and glutaric acid.

Example 4

38.6 mg of axitinib and 13.2 mg of glutaric acid were weighed, 1 mL of n-heptane and 10 μL of ethanol were added to obtain a suspension, the suspension was stirred at room temperature for 4 h, filtered, and the obtained white solid was dried at 40 ° C to obtain Solid samples of axitinib and glutaric acid co-crystals.

Example 5

38.6 mg of axitinib and 13.2 mg of glutaric acid were weighed, 1 mL of n-heptane and 10 μL of ethyl acetate were added to obtain a suspension, the suspension was stirred at room temperature for 24 h, filtered, and the obtained white solid was dried at 40 °C , a solid sample of axitinib and glutaric acid co-crystal was obtained.

Example 6

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add 1 mL of ether to obtain a suspension, stir the suspension at room temperature for 24 h, filter, and dry the obtained white solid at 40 ° C to obtain axitinib and Solid sample of glutaric acid co-crystal.

Example 7

38.6 mg of axitinib and 13.2 mg of glutaric acid were weighed, and 1 mL of methyl tert-butyl ether was added to obtain a suspension. The suspension was stirred at room temperature for 24 h, filtered, and the obtained white solid was dried at 40 °C to obtain Solid samples of axitinib and glutaric acid co-crystals.

Example 8

38.6 mg of axitinib and 13.2 mg of glutaric acid were weighed, and 1 mL of isopropyl ether was added to obtain a suspension. The suspension was stirred at room temperature for 24 h, filtered, and the obtained white solid was dried at 40 °C to obtain axitinib. A solid sample of the co-crystal of nitric acid and glutaric acid.

Example 9

154.4 mg of axitinib and 52.8 mg of glutaric acid were weighed, added to 1 mL of n-heptane and 10 μL of ethanol to obtain a suspension, the suspension was stirred at room temperature for 24 h, filtered, and the obtained white solid was dried at 40 °C, A solid sample of axitinib and glutaric acid co-crystal was obtained in 92.5% yield.

Example 10

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add it to a ball-milling jar, then add 10 μL of acetone, and grind at 20 Hz for 30 min. crystalline solid samples.

Example 11

Weigh 38.6 mg of Axitinib and 13.2 mg of glutaric acid, add them to a ball-milling jar, then add 10 μL of methyl acetate, grind at 20 Hz for 30 min, and dry the obtained white solid at 40 °C to obtain axitinib and glutaric acid. Solid samples of acid co-crystals.

Example 12

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add it to a ball-milling jar, then add 10 μL of methanol, and grind at 20 Hz for 30 min. crystalline solid samples.

Example 13

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add it to a ball-milling jar, then add 10 μL of acetonitrile, and grind at 20 Hz for 30 min. crystalline solid samples.

Example 14

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add it to a ball-milling jar, then add 10 μL of ether, and grind at 20 Hz for 30 min. crystalline solid samples.

Example 15

Weigh 38.6 mg of Axitinib and 13.2 mg of glutaric acid, add them to a ball-milling jar, then add 10 μL of isopropyl ether, grind at 20 Hz for 30 min, and dry the obtained white solid at 40 °C to obtain axitinib and glutaric acid. Solid samples of acid co-crystals.

Example 16

Weigh 38.6 mg of axitinib and 13.2 mg of glutaric acid, add them to a ball-milling jar, then add 10 μL of n-hexane, and grind at 20 Hz for 30 min. The obtained white solid is dried at 40 °C to obtain axitinib and glutaric acid. Eutectic solid samples.

Characterization Analysis

The co-crystal of axitinib and glutaric acid provided by the invention is analyzed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, Fourier transform infrared spectroscopy ( FTIR), hydrogen nuclear magnetic resonance (HNMR) and other methods.

X-ray powder diffraction analysis was carried out on the solid sample of the co-crystal of Axitinib and glutaric acid prepared in Example 1, using a diffractometer of Rigaku Mini Flex 600 of Japan Rigaku Co., Ltd., Cu Kα rays, and a voltage of 40 thousand volts, the current is 15 mA, the step size is 0.01°, the scanning speed is 20°/min, the scanning range is 5.0-40.0°, and the test temperature is room temperature. The analysis results are shown in the X-ray powder diffraction (XRPD) diagram of FIG. 1 , and the X-ray powder diffraction data are shown in Table 1.

Table 1 Axitinib and glutaric acid co-crystal X-ray powder diffraction data of Example 1

Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of axitinib and glutaric acid prepared in Example 2 are shown in Table 2.

Table 2 Axitinib and glutaric acid co-crystal X-ray powder diffraction data of Example 2

Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of axitinib and glutaric acid prepared in Example 3 are shown in Table 3.

Table 3 Axitinib and glutaric acid co-crystal X-ray powder diffraction data of Example 3

It is well known to those skilled in the art that crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction pattern will generally vary with the testing conditions of the instrument. In particular, the relative intensities of X-ray diffraction patterns may vary with experimental conditions, so the relative intensity order of X-ray diffraction peaks cannot be used as the sole or decisive factor for the characterization of crystalline substances. In addition, the peak angle is usually allowed to have an error of ±0.2°. Due to the influence of experimental factors such as sample height and test temperature, the overall peak angle will be shifted, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of the co-crystal of axitinib and glutaric acid described in the present invention does not have to be completely consistent with the X-ray diffraction pattern in this example. The cases where the characteristic peaks in the same or similar are all within the scope of the present invention. Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown substance to confirm that the unknown substance is or is not the co-crystal of axitinib and glutaric acid according to the present invention.

The solid sample of axitinib and glutaric acid co-crystal obtained in Example 1 was subjected to differential scanning calorimetry analysis, which was detected by a DSC 214 differential calorimeter of Germany NETZSCH Scientific Instruments Co., Ltd., and the atmosphere was nitrogen. , and the heating rate was 10 °C/min. The analysis results are shown in the differential scanning calorimetry (DSC) analysis chart of FIG. 2 . The DSC curve showed that no obvious endothermic or exothermic phenomenon was found in the co-crystal of axitinib and glutaric acid before thermal decomposition.

Thermogravimetric analysis was carried out on the solid sample of the co-crystal of Axitinib and glutaric acid prepared in Example 1, using a TG209F3 thermogravimetric analyzer from German NETZSCH Scientific Instruments Co., Ltd., the atmosphere was nitrogen, and the heating rate was 10 °C /min. The analysis results are shown in the thermogravimetric (TG) analysis chart of FIG. 3 . The TG curve shows that the co-crystal of axitinib and glutaric acid is heated to around 170°C and begins to decompose, and there is no weight loss before this temperature. During the heating process from 170°C to 500°C, there is a multi-stage weight loss phenomenon.

The co-crystal sample of axitinib and glutaric acid prepared in Example 1 was analyzed by infrared spectroscopy, which was detected by ALPHA II Fourier transform infrared spectrometer of Bruker Company, and the detection range was 4000-500 cm ^-1 . See Figure 4 of the Fourier Transform Infrared (FTIR) spectrum. It can be seen from Figure 4 that the characteristic peak positions of its infrared spectrum are (cm ^-1 ): 3247, 2973, 2938, 2905, 2884, 2361, 2340, 2322, 2206, 2188, 2126, 2111, 1994, 1963, 1700 , 1640, 1557, 1458, 1434, 1337, 1267, 1236, 1150, 1085, 1065, 1052, 1020, 960, 861, 803, 754, 729, 702, 655, 608, 591, 515.

The Axitinib and glutaric acid co-crystal samples prepared in Example 1 were subjected to 1H NMR spectrum analysis, and were detected by an Avance III 400M NMR spectrometer from Bruker, Germany. The analysis results were shown in the 1H NMR spectrum of accompanying drawing 5. ( ¹ HNMR) spectrum. As can be seen from Figure 5, the peaks of axitinib are: ¹ HNMR (400MHz, DMSO) δ 13.38 (s, 1H), 8.61 (d, J=4.0Hz, 1H), 8.43 (d, J= 4.6Hz, 1H), 8.22 (d, J=8.5Hz, 1H), 7.96 (d, J=16.4Hz, 1H), 7.82 (td, J=7.7, 1.7Hz, 1H), 7.67 (d, J= 7.8Hz, 1H), 7.6 (m, 1H), 7.50 (dd, J=7.3, 1.6Hz, 2H), 7.30 (m, J=14.8, 7.4, 2.5Hz, 3H), 7.19 (d, J=8.5 Hz, 1H), 7.10 (m, 1H), 2.78 (d, J=4.6Hz, 3H). The peaks for glutaric acid are: ¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.11 (s, 2H), 2.24 (t, J=7.4 Hz, 4H), 1.70 (p, J=7.4 Hz, 2H). According to the integration results of the characteristic peaks, the stoichiometric ratio of axitinib and glutaric acid in the co-crystal of axitinib and glutaric acid is 1:1.

Solubility evaluation

The powder dissolution data and intrinsic dissolution data of axitinib and glutaric acid co-crystal and the pharmaceutical crystal form IV of axitinib were compared.

Source of test sample: Axitinib and glutaric acid co-crystal were prepared by the method provided in Example 1 of the present invention; Axitinib crystal form IV was purchased from Shanghai Shengde Pharmaceutical Technology Co., Ltd., with a purity of 99%.

Powder dissolution test method: Axitinib and glutaric acid co-crystal and axitinib crystal form IV were ground and passed through 100 and 200 mesh sieves, respectively, and the particle size of the powder was controlled to be 75-150 μm. Weigh 100 mg of axitinib crystal form IV, 134.2 mg of axitinib and glutaric acid co-crystal, add them to 15 mL of dissolution medium, take 0.2 mL of the solution at regular intervals, filter through a 0.45 μm microporous membrane, and Dilute to an appropriate multiple, monitor the solution concentration at each time point with high performance liquid chromatography, and finally obtain the powder dissolution curve of each sample.

Powder dissolution conditions:

Dissolution medium: 0.01N hydrochloric acid solution;

Stirring speed: 50 rpm;

Dissolution temperature: 37±0.5℃;

Sampling time: 0.5, 1, 2, 5, 10, 20, 40, 60, 120, 240 minutes;

Liquid phase conditions:

Instrument: SHIMADZU LC-2030C 3D;

Chromatographic column: Inertsil ODS C18 column (4.6mm×150mm, 5μm);

UV detection wavelength: 330nm;

Mobile phase: acetonitrile: 0.03M pH 4.6 sodium acetate-acetic acid solution=40:60;

Column temperature: 40℃;

Flow rate: 0.8mL/min;

Injection volume: 5 μL.

Characteristic dissolution test method: The powder samples were ground and passed through 100-mesh and 200-mesh sieves, respectively, and the particle size of the powder was controlled at 75-150 μm. Weigh 100 mg of the powder and press it for 10 s at a pressure of 1 MPa to make a round tablet with a diameter of 5 mm, seal one side with solid wax and expose the other side, and place it in 500 mL of dissolution medium. Add 1 mL of solution, filter through a 0.45 μm microporous membrane, monitor the concentration of the solution at each time point with high performance liquid chromatography, and finally obtain the characteristic dissolution curve of each sample.

Intrinsic Dissolution Conditions:

Dissolution medium: 0.01N hydrochloric acid solution;

Stirring speed: 100 rpm;

Dissolution temperature: 37±0.5℃;

Sampling time: 5, 10, 15, 20, 25, 30 minutes;

Liquid phase conditions:

Instrument: SHIMADZU LC-2030C 3D;

Chromatographic column: Inertsil ODS C18 column (4.6mm×150mm, 5μm);

UV detection wavelength: 330nm;

Column temperature: 40℃;

Flow rate: 0.8mL/min;

Injection volume: 20 μL.

The experimental results are shown in the powder dissolution curve diagram of FIG. 6 and the characteristic dissolution curve of FIG. 7 . As shown in Figure 6, the maximum apparent solubility of axitinib crystal form IV and axitinib co-crystal with glutaric acid were 276.1 ± 40.54 μg/mL and 919.4 ± 144.1 μg/mL, respectively. Sitinib crystal form IV increased by 3.3 times. As shown in Figure 7, the intrinsic dissolution rates of axitinib Form IV and axitinib-glutaric acid co-crystal within 30 minutes were 0.0098 mg·cm ⁻² ·min ⁻¹ and 0.0579 mg·cm ^{− , respectively. 2} ·min ^-1 , the co-crystal was 5.9 times higher than that of axitinib crystal form IV.

The co-crystal of axitinib and glutaric acid provided by the invention can be used for preparing medicines for preventing and/or treating cancer and other vascular proliferation diseases, and has broad application prospects.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims

A co-crystal of Axitinib and glutaric acid, characterized in that: the structural formula of the co-crystal is shown in formula (I):

In the co-crystal, the molar ratio of axitinib and glutaric acid is 1:1; the X-ray powder diffraction pattern of the co-crystal measured by Cu Kα rays at the diffraction angle 2θ is 7.7±0.2°, 12.8± There are characteristic peaks at 0.2°, 14.1±0.2°, 15.4±0.2°, 17.3±0.2°, 19.2±0.2°, 21.4±0.2°, and 25.5±0.2°.
The eutectic according to claim 1, wherein the X-ray powder diffraction pattern of the eutectic measured by Cu Kα rays is 16.1±0.2°, 17.9±0.2°, 18.2±0.2°, 2θ at the diffraction angle 2θ. One or more of 20.1±0.2°, 22.1±0.2°, 22.7±0.2°, 23.2±0.2°, 24.1±0.2°, and 24.7±0.2° have characteristic peaks.
A method for preparing a co-crystal according to any one of claims 1 to 2, characterized in that it comprises the following steps: charging axitinib and glutaric acid according to a molar ratio of 1:1, adding an appropriate amount of solvent, and then passing Stir or grind to obtain co-crystals.
The preparation method according to claim 3, wherein the solvent is at least one of alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents, and alkane solvents.
The preparation method according to claim 3, characterized in that: during the stirring, the ratio of the total mass of axitinib and glutaric acid to the dosage of the solvent is 1 g: (4-20) mL.
The preparation method according to claim 3, characterized in that: during the grinding, the ratio of the total mass of axitinib and glutaric acid to the dosage of the solvent is 1 g: (100-200) uL.
A pharmaceutical composition, characterized in that it comprises the co-crystal of axitinib and glutaric acid according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.
Application of the co-crystal of axitinib and glutaric acid according to any one of claims 1 to 2 in the preparation of a medicament for preventing and/or treating cancer and other angioproliferative diseases.