Pharmaceutical compositions comprising crystalline form alpha of axitinib and uses thereof

Abstract

The present application relates to pharmaceutical preparations, the field of pharmaceutical crystal form, specifically relates to the crystal form alpha of axitinib, the pharmaceutical composition and purposes containing the crystal form alpha of axitinib.The crystal form alpha of axitinib provided by the present application has excellent solubility, stability, hygroscopicity and fluidity, and the crystal form alpha of axitinib and the pharmaceutical composition containing the crystal form alpha of axitinib both have significantly improved bioavailability.The preparation method of the crystal form alpha described in the present application is simple, reproducible, high-yield, easy to operate, green and environmentally friendly, requires small amount of solvent and is conducive to recycling, can effectively reduce reagent cost, and is easy to realize scale-up production.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical formulations and pharmaceutical crystal forms, specifically to crystal form α of axitinib, pharmaceutical compositions containing crystal form α of axitinib, and their uses. Background Technology

[0002] Axitinib is a tyrosine kinase inhibitor that effectively and selectively inhibits vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3, thereby inhibiting angiogenesis and lymphatic vessel formation, suppressing tumor growth and metastasis, and exerting anti-tumor activity. Axitinib is currently widely used as a second-line treatment for advanced renal cell carcinoma and has shown potential in clinical studies of other solid tumors. Its structural formula is shown in formula (I):

[0003]

[0004] (I)

[0005] Axitinib belongs to the Biopharmaceutics Class II (low solubility, high permeability) drugs, and its oral bioavailability is often limited by the rate and extent of dissolution of the active pharmaceutical ingredient in the gastrointestinal tract. The solid form of a drug, especially its crystal form, is a key factor affecting the physicochemical properties of the drug (such as solubility, stability, hygroscopicity, and processability) and even the bioavailability of the final formulation.

[0006] Patent WO2006048751A1 discloses multiple crystal forms of axitinib, including crystal form I, crystal form II, crystal form III, crystal form IV, crystal form VI, crystal form VII, and crystal form VIII, and discloses that amorphous form IV is the most thermodynamically stable crystal form. Patent CN103626739B discloses multiple crystal forms, including crystal form XXV, crystal form XVI, crystal form XLI, crystal form IX, crystal form XII, and crystal form XV, among which crystal form XLI is the crystal form used in commercially available products. In this patent, only crystal forms XLI and XXV are amorphous and their stability under light conditions is significantly better than that of crystal form IV. However, crystal forms XXV and XLI do not overcome the solubility defects of axitinib and have low solubility.

[0007] Patents CN113943270B and CN113943271B disclose a new crystal form of axitinib, which has good light stability and improved solubility, but do not involve the investigation of properties such as high temperature and high humidity stability and hygroscopicity.

[0008] In summary, there is still a need in the art to provide a new crystal form of axitinib with good high temperature, high humidity and light stability, good solubility, high bioavailability and low moisture absorption, as well as a pharmaceutical composition containing the new crystal form. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention, through systematic screening and research, provides an axitinib crystal form α, a pharmaceutical composition containing this crystal form α, and its uses. The axitinib crystal form α exhibits good stability under high temperature, high humidity, and light conditions, high bioavailability, good solubility, and low moisture absorption, making it suitable for pharmaceutical crystal form development.

[0010] The first aspect of the present invention provides a crystal form α of axitinib, characterized in that the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at least at 2θ angles of 8.2±0.2° and 9.2±0.2°.

[0011] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 18.5±0.2°, 22.5±0.2° and 27.3±0.2°.

[0012] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2° and 18.9±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2° and 24.7±0.2°.

[0014] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 17.5±0.2°, 18.5±0.2° and 18.9±0.2°.

[0015] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 17.5±0.2°, 18.9±0.2° and 23.9±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2° and 24.7±0.2°.

[0017] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2° and 24.7±0.2°.

[0018] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2° and 23.9±0.2°.

[0019] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.9±0.2°, 23.9±0.2° and 24.7±0.2°.

[0020] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 18.5±0.2°, 22.5±0.2°, 23.3±0.2°, and 27.3±0.2°.

[0021] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 15.4±0.2°, 17.5±0.2°, 18.5±0.2°, 22.5±0.2°, 23.3±0.2°, 26.0±0.2°, and 27.3±0.2°.

[0022] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.9±0.2°, and 24.7±0.2°.

[0023] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, and 27.3±0.2°.

[0024] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.3±0.2°, and 27.3±0.2°.

[0025] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 15.4±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, and 27.3±0.2°.

[0026] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.0±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, 26.0±0.2°, 27.3±0.2°, 29.9±0.2°, and 30.8±0.2°.

[0027] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18.5±0.2°, 20.9±0.2°, 22.5±0.2°, 23.0±0.2°, 23.3±0.2°, 23.9±0.2°, 26.0±0.2°, 27.3±0.2°, 29.9±0.2°, and 30.8±0.2°.

[0028] In some embodiments, the X-ray powder diffraction pattern of the crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 20.9±0.2°, 22.5±0.2°, 23.0±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, 26.0±0.2°, 27.3±0.2°, 29.9±0.2°, and 30.8±0.2°.

[0029] In some specific embodiments, the X-ray powder diffraction pattern of the crystal form α is basically as follows: Figure 1 As shown.

[0030] In some specific embodiments, the TGA chart of the crystal form α is basically as follows: Figure 2 As shown.

[0031] A second aspect of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises axitinib crystal form α and pharmaceutically acceptable excipients.

[0032] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 18.5±0.2°, 22.5±0.2°, and 27.3±0.2°.

[0033] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, and 18.9±0.2°.

[0034] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of the axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 17.5±0.2°, 18.5±0.2°, and 18.9±0.2°.

[0035] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of the axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 17.5±0.2°, 18.9±0.2°, and 23.9±0.2°.

[0036] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, and 24.7±0.2°.

[0037] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and pharmaceutically acceptable excipients, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, and 24.7±0.2°.

[0038] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, and 23.9±0.2°.

[0039] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.9±0.2°, 23.9±0.2°, and 24.7±0.2°.

[0040] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 18.5±0.2°, 22.5±0.2°, 23.3±0.2°, and 27.3±0.2°.

[0041] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 22.5±0.2°, 23.3±0.2°, 24.7±0.2°, and 27.3±0.2°.

[0042] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, and 27.3±0.2°.

[0043] In some embodiments, the pharmaceutical composition comprises axitinib crystalline form α and a pharmaceutically acceptable excipient, wherein the X-ray powder diffraction pattern of axitinib crystalline form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.0±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, 26.0±0.2°, 27.3±0.2°, 29.9±0.2°, and 30.8±0.2°.

[0044] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and pharmaceutically acceptable excipients, wherein the X-ray powder diffraction pattern of crystal form α is substantially as shown in the figure. Figure 1 As shown.

[0045] In some embodiments, the pharmaceutical composition comprises axitinib crystal form α and pharmaceutically acceptable excipients, wherein the TGA chromatogram of crystal form α is substantially as shown in the figure. Figure 2 As shown.

[0046] In some embodiments, the pharmaceutically acceptable excipients include, but are not limited to, one or more of fillers, diluents, binders, solubilizers, flow aids, disintegrants, lubricants, etc.

[0047] A third aspect of this invention provides a method for preparing axitinib crystal form α, characterized by comprising the following steps:

[0048] Step 1: Mix axitinib with methanol;

[0049] Step 2: Suspension crystallization, drying, to obtain axitinib crystal form α.

[0050] In some embodiments, the mass-to-volume ratio (g / mL) of axitinib to methanol is 1:5-40; in some embodiments, the mass-to-volume ratio (g / mL) of axitinib to methanol is 1:5-15, or 1:8-30, or 1:5-10, or 1:10-40; preferably, the mass-to-volume ratio (g / mL) of axitinib to methanol is 1:10.

[0051] In some embodiments, the temperature of the suspension in step 2 is 25-50°C, preferably 40±5°C;

[0052] In some embodiments, the suspension time in step 2 is 4-24 h, preferably 8-15 h, and more preferably 10±2 h.

[0053] A fourth aspect of the present invention provides the use of a pharmaceutical composition comprising axitinib α crystal form in the preparation of a medicament for treating renal cell carcinoma.

[0054] The crystal form α described in this invention is an amorphous form.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] 1. The axitinib crystal form α of the present invention and / or the crystal form α prepared by the preparation method of the present invention have significantly improved solubility, low hygroscopicity, good pharmacokinetic characteristics and good stability. The crystal form can maintain stability under the influence of high temperature, high humidity and light, and the bioavailability is significantly improved, making it suitable for development as a pharmaceutical crystal form.

[0057] 2. The axitinib crystal form α of the present invention and / or the crystal form α prepared by the preparation method of the present invention have high purity and can remain stable under strong light conditions without significant impurity growth.

[0058] 3. The present invention provides a pharmaceutical composition containing axitinib crystal form α, wherein crystal form α has good formulation stability and does not undergo crystal transformation or degradation during preparation and storage, and the pharmaceutical composition has significantly improved bioavailability.

[0059] 4. This invention provides a method for preparing axitinib crystal form α, using all third-class solvents (methanol), with high yield, mild process conditions, simple operation, and stable large-scale industrial production. Attached Figure Description

[0060] Figure 1 XRD pattern of axitinib α crystal form;

[0061] Figure 2 TGA spectrum of axitinib α crystal form;

[0062] Figure 3 The stability of axitinib crystal form α was investigated by comparing crystal forms over 15 days. Detailed Implementation

[0063] To make the present invention easier to understand, the present invention will be described in detail below with reference to embodiments. These embodiments are for illustrative purposes only and are not limited to the scope of application of the present invention. Any person skilled in the art can make some modifications or alterations to the technical content disclosed in the present invention to obtain equivalent embodiments without departing from the scope of the technical solution of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention shall still fall within the scope of the technical solution of the present invention.

[0064] The terms used in this invention are explained as follows:

[0065] XRD: X-ray powder diffraction

[0066] The X-ray powder diffraction (XRD) measurements described in this invention were performed using a Malvern-Panaco Empyrean X-ray powder diffractometer, with specific parameters as shown in the table below:

[0067] Table 1

[0068]

[0069] In this article, "X-ray powder diffraction patterns are basically as follows" Figure 1 "As shown" refers to the X-ray powder diffraction pattern and Figure 1 The term "substantially identical" in X-ray powder diffraction patterns means that representative peak positions and intensity variations are taken into account.

[0070] TGA: Thermogravimetric Analysis

[0071] The thermogravimetric analysis (TGA) of the present invention was performed using a METTLER TOLEDO TGA-2 instrument with a heating rate of 10℃ / min and a temperature range of 30-300℃. The nitrogen purging rate during the test was 20mL / min.

[0072] The error of TGA can be within approximately ±0.5% of mass. In this paper, "TGA spectra are basically as follows..." Figure 2 "As shown" refers to the TGA chart and Figure 2Essentially the same; the TGA term "essentially the same" means that this variation in error is taken into account.

[0073] Unless otherwise specified, percentage content mentioned in this article refers to mass percentage (wt%).

[0074] Example 1: Preparation of axitinib crystal form α

[0075] 10.0 g of axitinib was weighed and suspended in 100 mL of methanol at 40 °C for 10 h. After filtration and drying, 9.5 g of α-crystalline form was obtained. X-ray powder diffraction and thermogravimetric analysis were performed on the obtained solid. The XRD pattern is shown below. Figure 1 As shown, the TGA spectrum is as follows Figure 2 As shown in Table 2, the characteristic peak data of the XRD pattern are as follows:

[0076] Table 2

[0077] 8.1903 7963.51 10.78657 57.80 9.1847 3757.33 9.62086 27.27 13.5446 1030.66 6.53218 7.48 15.4088 2801.70 5.74584 20.33 16.0103 1822.14 5.53128 13.22 16.4023 13778.34 5.39997 100.00 17.4551 3046.87 5.07656 22.11 18.0180 388.29 4.91922 2.82 18.4586 1101.55 4.80277 7.99 18.9127 615.26 4.68848 4.47 20.9494 4930.57 4.23704 35.78 22.5139 2149.77 3.94602 15.60 22.9597 2222.85 3.87039 16.13 23.2987 2407.57 3.81484 17.47 23.9384 3740.30 3.71433 27.15 24.7292 665.44 3.59731 4.83 25.9507 4913.82 3.43070 35.66 26.7508 322.88 3.32987 2.34 27.2975 575.82 3.26440 4.18 27.9923 278.92 3.18494 2.02 28.5671 184.50 3.12215 1.34 29.0829 302.25 3.06794 2.19 29.4608 215.72 3.02944 1.57 29.9498 1508.67 2.98108 10.95 30.5361 496.97 2.92517 3.61 30.8256 811.82 2.89835 5.89 32.8194 144.26 2.72668 1.05 33.1490 160.22 2.70032 1.16 33.6763 97.37 2.65924 0.71 34.0639 131.39 2.62986 0.95 34.7451 452.78 2.57985 3.29 37.2193 428.25 2.41383 3.11 37.9498 185.88 2.36903 1.35 38.8205 109.68 2.31787 0.80

[0078] The error of the 2θ diffraction angle is ±0.2°.

[0079] Example 2: Preparation of axitinib crystal form α

[0080] 10.0 g of axitinib was weighed and suspended in 50 mL of methanol at 25 °C for 4 h. After stirring, the mixture was filtered and dried to obtain 9.7 g of α-crystalline form. X-ray powder diffraction (XRD) was performed on the obtained solid using Cu-Ka rays. The obtained XRD pattern is basically as shown below. Figure 1 As shown.

[0081] Example 3: Preparation of axitinib crystal form α

[0082] 10.0 g of axitinib was weighed and suspended in 400 mL of methanol at 50 °C for 24 h. After filtration and drying, 9.1 g of α-crystalline form was obtained. X-ray powder diffraction (XRD) was performed on the obtained solid using Cu-Ka rays. The obtained XRD pattern was basically as shown in the figure. Figure 1 As shown.

[0083] Experimental Example 1: Stability Test

[0084] The α-crystal obtained in Example 1 was placed at 60°C and under light irradiation (4500 lx ± 500 lx) for 15 days to investigate its crystal form and purity stability. The results are detailed in [link to relevant documentation]. Figure 3 And Table 3.

[0085] Table 3. Experimental results on the α-stability of axitinib crystal form.

[0086]

[0087] Stability test results show that the axitinib α crystal form of the present invention has good crystal form and purity stability under the investigated conditions.

[0088] Experiment Example 2: Solubility Investigation Experiment

[0089] The α-crystal obtained in Example 1 of this invention was placed in different media and stirred at 37°C for 72 hours. The samples were taken three times, filtered, and an appropriate amount of the filtrate was taken, diluted, and the solubility was detected by HPLC to determine the purity.

[0090] Table 4. Solubility data of axitinib α crystal form in different media

[0091] pure water 2.23 pH 1.2 3.05 pH 4.5 2.05 pH 6.8 1.89

[0092] Experimental results show that the axitinib α crystal form of the present invention has good solubility in different media.

[0093] Experimental Example 3: Pharmacokinetic Study

[0094] Animal experiments were conducted on axitinib crystal form α, CN113943270B, CN113943271B and crystal form XLI obtained in Example 1, respectively.

[0095] A precise amount of the test drug was weighed and mixed with 0.5% methylcellulose solution to prepare a suspension for oral administration. Twenty-four male rats were divided into four groups (n=6) and administered a single oral dose of 20 mg / kg of the test drug. Whole blood was collected before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration. Plasma was obtained after centrifugation. The concentration of the drug in the rat plasma samples was quantitatively determined using LC-MS / MS, and pharmacokinetic parameters were calculated.

[0096] Table 5. Pharmacokinetic parameters of axitinib crystal forms α, CN113943270B, CN113943271B, and XLI.

[0097] α crystal form 3.1±0.56 2.43±1.08 5.43±2.85 CN113943270B crystal form 4.1±1.11 1.55±0.78 4.12±2.03 CN113943271B crystal form 3.9±0.98 1.57±0.59 4.29±1.95 Crystal form XLI 5.1±1.45 0.97±0.12 2.31±1.87

[0098] The experimental results showed that the pharmacokinetic properties of axitinib crystal form α in male rats were superior to those of crystal forms CN113943270B, CN113943271B, and XLI.

[0099] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0100] Those skilled in the art will recognize that the scope of this application is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, all of which fall within the protection scope of this application.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises axitinib crystal form α and pharmaceutically acceptable excipients. The X-ray powder diffraction pattern of axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2° and 18.9±0.2°. The X-ray powder diffraction pattern of crystal form α is basically shown in Figure 1.

2. The pharmaceutical composition according to claim 1, characterized in that, The X-ray powder diffraction pattern of the axitinib crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.9±0.2°, 23.9±0.2° and 24.7±0.2°.

3. The pharmaceutical composition according to any one of claims 1-2, wherein the TGA diagram of the crystal form α is substantially as shown in Figure 2.

4. A crystal form α of axitinib, characterized in that, The X-ray powder diffraction pattern of crystal form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2° and 18.9±0.2°. The X-ray powder diffraction pattern of crystal form α of axitinib is basically shown in Figure 1.

5. The crystal form α according to claim 4, characterized in that, The X-ray powder diffraction pattern of the crystalline form α has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2° and 24.7±0.2°.

6. The crystal form α according to claim 4, characterized in that, The X-ray powder diffraction pattern of the α-crystal form has characteristic peaks at 2θ angles of 8.2±0.2°, 9.2±0.2°, 13.5±0.2°, 15.4±0.2°, 17.5±0.2°, 18.5±0.2°, 18.9±0.2°, 22.5±0.2°, 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, and 27.3±0.2°.

7. The crystal form α according to any one of claims 4-6, characterized in that, The TGA diagram of the crystal form α is basically shown in Figure 2.

8. The composition according to any one of claims 1-3, characterized in that, The method for preparing the α-crystal form includes the following steps: Step 1: Mix axitinib with methanol solvent; Step 2: Suspension crystallization, drying, to obtain axitinib crystal form α.

9. The composition according to claim 8, characterized in that, The mass-to-volume ratio of axitinib to methanol is 1:5-40 (g / mL).

10. The composition according to claim 9, characterized in that, The mass-to-volume ratio of axitinib to methanol is 1:10 (g / mL).

11. The crystal form α according to any one of claims 4-7, characterized in that, The method for preparing the α-crystal form includes the following steps: Step 1: Mix axitinib with methanol solvent; Step 2: Suspension crystallization, drying, to obtain axitinib crystal form α.

12. The crystal form α according to claim 11, characterized in that, The mass-to-volume ratio of axitinib to methanol is 1:5-40 (g / mL).

13. The crystal form α according to claim 12, characterized in that, The mass-to-volume ratio of axitinib to methanol is 1:10 (g / mL).

14. Use of the composition according to any one of claims 1-3 or 8-10 in the preparation of a medicament for treating renal cell carcinoma.

15. Use of the α-crystal form according to any one of claims 4-7 or 11-13 in the preparation of a medicament for treating renal cell carcinoma.

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