CN114685438B - Novel salt of acitinib malate - Google Patents
Novel salt of acitinib malate Download PDFInfo
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- CN114685438B CN114685438B CN202011585244.2A CN202011585244A CN114685438B CN 114685438 B CN114685438 B CN 114685438B CN 202011585244 A CN202011585244 A CN 202011585244A CN 114685438 B CN114685438 B CN 114685438B
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Abstract
The invention provides an acitinib malate crystal form, and relates to the technical field of crystal form drug molecules. The crystal form uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 8.15+/-0.2 degrees, 11.99+/-0.2 degrees, 14.42+/-0.2 degrees, 20.33+/-0.2 degrees, 24.34+/-0.2 degrees and 24.87+/-0.2 degrees; the crystallographic measurement parameters were: monoclinic system, the space group is P-1; the unit cell parameters are:
α=90°, β= 93.1110 (10) °, γ=90°, unit cell volume
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to an acitinib malate crystal form.
Background
Acetinib is white or off-white powder, and the chemical name is: 6- [2- (methylcarbamoyl) phenylsulfanyl group]-3-E- [2- (pyridin-2-yl) vinyl]Indazoles of formula C 22 H 18 N 4 OS, molecular weight 386.48, CAS number 319460-85-0, structure as follows:
the acitinib former mill was american-type-part company, first receiving FDA approval in the united states at 1 in 2012. At 29 months of 2015, acytinib was CFDA approved for adult patients with Renal Cell Carcinoma (RCC) in the advanced stage of failure to receive treatment with a tyrosine kinase inhibitor or cytokine. Acxitinib is currently marketed in multiple countries, including the United states, europe, canada, australia, korea, japan, etc., and has become one of the standard treatment regimens for advanced renal cancer. Acxitinib is a novel oral Tyrosine Kinase Inhibitor (TKI), can effectively and selectively inhibit vascular endothelial growth factor receptors VEGFR-l, VEGFR-2 and VEGFR-3, inhibit the neogenesis of blood vessels and lymphatic vessels, inhibit the growth and metastasis of tumors, and exert antitumor activity. The composition can inhibit tumor growth and cancer progression by blocking protein kinase during tumor growth. In a randomized, open, international multicenter phase III clinical trial, acytinib significantly prolonged progression free survival compared to sorafenib and showed overall good safety in previously treated patients with advanced renal cell carcinoma.
As is well known, the crystal form of the drug has great influence on the stability, dissolution, permeability, bioavailability and the like of a solid preparation of the drug, and the crystal form which is excellent and suitable for preparing the solid preparation generally needs to meet the requirements of the stability, the dissolution, the bioavailability and the like.
Various forms of acitinib have been reported, and patent WO2006048751A1 discloses various forms of acitinib, form I, form ii, form iii, form IV, form vi, form vii, form viii, etc., and discloses that form IV has a solubility of about 0.55mg/ml in an aqueous solution at a pH of about 1, a solubility of only 0.157mg/ml in an aqueous solution at a pH of about 2, and a solubility of only 2 μg/ml in an aqueous solution at a pH of about 6.5; meanwhile, 7 acid salt compounds of the acytinib are reported to be prepared for improving the water solubility of the acytinib, and the solubility of the acid salt compounds is improved, but the acid salt compounds are obviously degraded when exposed to high-intensity light. Patent CN200880016453 discloses that various forms of form XXV, form XVI, form XLI, form IX, form XII and form XV, both of which are not greatly improved in terms of solubility and bioavailability.
Furthermore, patent WO2015067224A1 further characterizes 7 acitinib acid salts by powder diffraction data on the basis of the 7 available acitinib acid salt compounds disclosed in patent WO2006048751 A1. Patent CN201510509413.7 discloses the preparation of an acitinib fumarate crystal.
Because of the problems of photosensitivity, indissolvable property and the like of the acitinib, people in the art try to develop different crystal forms to obtain the crystal form of the acitinib which is more suitable for medicines. However, according to the present report, from the aspects of bioavailability, stability and manufacturability, among many of the disclosed crystal forms of acitinib, only crystal form IV and crystal form XLI can be used, and due to the extremely unstable light exposure of crystal form IV, the original schigy company finally selects the crystal form XLI with relatively low degradation amount of light exposure as the crystal form on the market (see CHMP evaluation report). However, as reported in patent CN200880016453, the potency of the crystal form XLI on the market after light exposure is reduced to 89%, and the preparation process using the shading process is unavoidable in order to achieve the pharmaceutical safety and effectiveness. And then, the subsequent development and research of some of the crystal forms of the solvate of the acytinib, the crystal form of the acytinib acid salt and the novel crystal form of the acytinib still have defects in the aspects of safety, solubility, bioavailability or photostability of the patent medicine.
In summary, further research and development of dominant crystalline forms of acitinib suitable for pharmaceutical use is still a problem to be solved at present.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel pharmaceutical salt crystal form of the acitinib and a preparation method thereof.
The specific technical scheme of the invention is as follows:
the crystal form of the axitinib malate comprises a mol ratio of 1:1 of the axitinib to the malic acid, wherein one molecule of the axitinib, one molecule of the malic acid and one molecule of water form a basic unit of the crystal form, and the specific structure is as follows:
preferably, the crystal form of the acitinib malate adopts Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 8.15+/-0.2 degrees, 11.99+/-0.2 degrees, 14.42+/-0.2 degrees, 20.33+/-0.2 degrees, 24.34+/-0.2 degrees and 24.87+/-0.2 degrees.
Preferably, the crystal form of the acitinib malate uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 7.77+/-0.2 degrees, 8.15+/-0.2 degrees, 11.99+/-0.2 degrees, 14.42+/-0.2 degrees, 15.59+/-0.2 degrees, 15.87+/-0.2 degrees, 18.23+/-0.2 degrees, 18.64+/-0.2 degrees, 19.61+/-0.2 degrees, 20.05+/-0.2 degrees, 20.33+/-0.2 degrees, 24.34+/-0.2 degrees, 24.87+/-0.2 degrees, 25.17+/-0.2 degrees and 26.02 +/-0.2 degrees.
Preferably, the crystalline form of acitinib malate, using Cu-ka radiation, has characteristic peaks conforming to the X-ray powder diffraction pattern as shown in fig. 1.
Preferably, the crystal form of the acitinib malate has the following crystallographic parameters: monoclinic system, the space group is P-1; the unit cell parameters are:
α=90°, β= 93.1110 (10) °, γ=90°, unit cell volume +.>
The preparation method of the crystal form of the acitinib malate comprises the following steps:
and (3) dissolving the acitinib and the malic acid in the solvent A, heating and dissolving, controlling the temperature to reflux for reaction, cooling and crystallizing, filtering, washing and drying to obtain the crystal form of the acitinib malate.
Preferably, the solvent A is a mixed solvent of acid, alcohol and water, wherein the acid solution is preferably formic acid and acetic acid; the alcohol solution is preferably methanol, ethanol or isopropanol.
Preferably, the volume ratio of the acid to the alcohol to the water in the solvent A mixed solvent is 1:5-10:1-5, preferably 1:8:3.
Further, the solvent a is preferably one or a combination of formic acid/ethanol/water, formic acid/methanol/water, formic acid/isopropanol/water, acetic acid/ethanol/water, acetic acid/methanol/water, acetic acid/isopropanol/water.
Preferably, the charging molar ratio of the acitinib to the malic acid is 1:1-2, preferably 1:1.4.
Preferably, the mass-to-volume ratio of the acitinib to the solvent A is 2-5:1, wherein the mass is in mg and the volume is in mL.
Preferably, the heating dissolution temperature is 50 to 70 ℃.
Preferably, the temperature-controlled reflux reaction time is 3 to 5 hours.
Preferably, the temperature reduction crystallization temperature is 0-30 ℃; preferably 15 to 25 ℃.
The crystal form of the acitinib malate can be used as an active ingredient and applied to the preparation of antitumor drugs.
A pharmaceutical composition comprising the crystalline form of acitinib malate according to the present invention, admixed with other components.
Preferably, the preparation method of the pharmaceutical composition of the invention is as follows: the compounds of the present invention are formulated into useful dosage forms by combining them with a pharmaceutically acceptable solid or liquid carrier, and optionally with a pharmaceutically acceptable excipient, using standard and conventional techniques.
Preferably, the other components include other active ingredients, fillers, diluents, binders, disintegrants, lubricants, etc., which may be used in combination.
More preferably, the diluent is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol and sorbitol; the adhesive is one or more selected from methylcellulose, hydroxypropyl cellulose, hypromellose, sodium hydroxymethyl cellulose, ethylcellulose and povidone; the disintegrating agent is one or more selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; the lubricant is one or more selected from magnesium stearate, aerosil, talcum powder and sodium dodecyl sulfate.
Preferably, the pharmaceutical composition is a tablet, a capsule, a granule, a pill, etc.
The invention has the beneficial effects that:
the crystal form of the acitinib malate prepared by the invention has good stability, and after light stability investigation, the impurity of the acitinib is slightly increased, so that the technical problem of unstable illumination of the prior art of the crystal form of the acitinib is solved, and when the crystal form of the acitinib is applied to a solid preparation, a special opacifier is not needed to be added for good illumination stability, so that the cost is saved, and the toxic and side effects of clinical application of auxiliary materials are reduced. The crystal form of the acitinib malate has good solubility, and solves the problem of low solubility of the acitinib in the prior art, thereby greatly improving the bioavailability. In addition, the preparation method is simple, and the solvents used in the preparation process are low-toxicity or nontoxic solvents, so that the preparation method is more suitable for industrial production; the obtained crystal has regular crystal form, uniform grain size, definite crystal form and crystal water number, definite main crystallographic parameters and definite atomic space position, and single crystal diffraction data indicate that the crystal does not contain an organic solvent, and the non-solvate crystal form is safer in medicinal use and suitable for large-scale popularization and application.
Drawings
Fig. 1: x-ray powder diffraction pattern of the crystalline form of acitinib malate.
Fig. 2: and (3) an ORTEP diagram of an acitinib malate crystal form.
Fig. 3: stacking diagram of acitinib malate crystal forms.
Fig. 4: DSC-TGA profile of the crystalline form of acitinib malate.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The materials used in the experiment: acetinib is commercially available and can also be prepared by the method disclosed in patent WO 2006048745; the crystal forms of the acitinib required by the comparative test can be prepared by referring to the prior art and can also be purchased; the materials used in this other experiment were not of the indicated source and specification, either commercially available analytical or chemical purity.
Example 1
About 0.4g of acitinib, 0.19g of malic acid were added to 120ml of formic acid/methanol/water (V Formic acid :V Methanol :V Water and its preparation method Heating the mixed solution of (1:8:3) to 55-60 ℃ for dissolution, stirring and refluxing for 4 hours, cooling to 15-25 ℃ for crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib malate with the purity of 99.61%.
Example 2
Will be about 0.4g of acitinib0.26g of malic acid was added to 200ml of formic acid/ethanol/water (V Formic acid :V Ethanol :V Water and its preparation method Heating the mixed solution of (1:10:5) to 55-60 ℃ for dissolution, stirring and refluxing for reaction for 5 hours, cooling to 10-20 ℃ for crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib malate with the purity of 99.57 percent.
Example 3
About 0.4g of acitinib, 0.14g of malic acid were added to 80ml of formic acid/isopropanol/water (V Formic acid :V Isopropyl alcohol :V Water and its preparation method Heating the mixed solution of (1:5:1) to 55-60 ℃ for dissolution, stirring and refluxing for reaction for 5 hours, cooling to 15-25 ℃ for crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib malate with the purity of 99.55%.
Example 4
About 0.4g of acitinib, 0.20g of malic acid were added to 100ml of acetic acid/ethanol/water (V Acetic acid :V Ethanol :V Water and its preparation method Heating the mixed solution of (1:6:2) to 60-65 ℃ for dissolution, stirring and refluxing for reaction for 3 hours, cooling to 10-20 ℃ for crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib malate with the purity of 99.52%.
Example 5
About 0.4g of acitinib, 0.19g of malic acid were added to 150ml of acetic acid/isopropanol/water (V Acetic acid :V Isopropyl alcohol :V Water and its preparation method Heating the mixed solution of (1:8:1) to 50-55 ℃ for dissolution, stirring and refluxing for reaction for 5 hours, cooling to 0-10 ℃ for crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib malate with the purity of 99.50%.
Example 6
About 0.4g of acitinib, 0.19g of malic acid were added to 120ml of acetic acid/methanol/water (V Acetic acid :V Methanol :V Water and its preparation method Heating the mixed solution of (1:6:1) to 65-70 ℃ for dissolution, stirring and refluxing for reaction for 3 hours, cooling to 20-30 ℃ for crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib malate with the purity of 99.53%.
Crystal form characterization of acitinib malate
The X-ray powder diffraction test instrument and test conditions related in the invention: PANalytical EMPYREA X-ray powder diffractometer; cu-K alpha; sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of the divergent slit; an anti-scattering slit 1; a cable pull slit of 0.04rad; step size: 0.5s; scanning range: 3-50 deg. The corresponding characteristic peaks in the X-ray secretion diffraction pattern (Cu-K alpha) are shown in the accompanying figure 1 and the table 1.
TABLE 1 Acxitinib malate crystalline form PXRD peak
The crystal form of the acitinib malate provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffractometer and the testing conditions related by the invention are as follows: the temperature 293 (2) K was measured using a XtaLAB Synergy X-ray single crystal diffractometer, and data was collected by omega scanning using CuKa radiation and corrected for Lp. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic parameters obtained by testing and analyzing the crystal form of the axitinib malate prepared by the invention are as follows: monoclinic system, the space group is P-1; the unit cell parameters are:
α=90°, β= 93.1110 (10) °, γ=90°, unit cell volume +.>
ORTEP figure 2 of the crystalline form of acitinib malate of the present invention shows that one molecule of acitinib binds to one fractionSub-malic acid and a molecule of water. The stacking diagram of the crystal forms of the acitinib malate of the present invention is shown in fig. 3.
Table 2 major crystallographic data for the crystalline form of acitinib malate
TGA/DSC thermal analysis tester and test conditions in the invention: TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC < 3+ >; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/mIVn; procedure section gas N 2 The method comprises the steps of carrying out a first treatment on the surface of the Gas flow rate: 50mL/mIVn; crucible: 40 μl of aluminum crucible.
The TGA/DSC test result of the co-crystal of the acitinib and the malic acid prepared by the method is shown in figure 4, and the DSC detection result has two endothermic peaks, wherein the peaks are 126.99 ℃ and 193.14 ℃.
The samples of examples 1 to 6 all have the same X-ray powder diffraction pattern, crystallographic parameters, DSC pattern.
Comparative example 1 preparation of acitinib mesylate reference is made to the following procedure:
about 0.25g of acitinib is added into 10ml of isopropanol, heated to 50 ℃ and stirred for dissolution; adding 126 μl of methanesulfonic acid into 1ml of isopropanol to prepare methanesulfonic acid isopropanol solution; and (3) dropwise adding the methanesulfonic acid isopropanol solution into the acitinib isopropanol solution at the temperature of 50 ℃, sealing, stirring for 1 hour at the temperature of 50 ℃, cooling to room temperature, stirring overnight, filtering and drying to obtain the acitinib mesylate with the purity of 99.54%.
Comparative example 2 preparation of acitinib sulfate, reference can be made to the following procedure:
about 0.25g of acitinib is added into 5ml of isopropanol, heated to 50 ℃ and stirred for dissolution; 36. Mu.l of sulfuric acid solution (concentration: about 96%) was added to 0.5ml of isopropyl alcohol to prepare an isopropyl sulfate solution; and (3) dropwise adding sulfuric acid isopropanol solution into the acitinib isopropanol solution at the temperature of 50 ℃, sealing, stirring for 1 hour at the temperature of 50 ℃, cooling to room temperature, stirring overnight, filtering and drying to obtain the acitinib sulfate with the purity of 99.48%.
Comparative example 3 preparation of acitinib fumarate, reference can be made to the following procedure:
about 1g of acitinib was added to 15ml of ethanol and about 0.35g of fumaric acid was added with stirring; heating to 65-70 ℃ and stirring for 1 hour, cooling to 25 ℃, crystallizing, filtering, and vacuum drying at 100-120 ℃ to obtain the acytinib fumarate with the purity of 99.45%.
Comparative example 4 preparation of crystalline form XLI of acitinib reference can be made to the following procedure:
about 4g of crude acitinib is added into 40ml of isopropanol, heated to 60 ℃ for 3 hours, cooled to ambient temperature, filtered, and the solid is separated, washed with about 12ml of isopropanol, dried for 2 hours by nitrogen purging, and further dried in vacuum at 55-65 ℃ for 18 hours; the solid is added into 40ml of absolute ethyl alcohol, heated and refluxed, distilled to remove the solvent for about 1/3, continuously refluxed for 2 hours, cooled to room temperature and stirred for 1 hour, filtered, washed by about 12ml of absolute ethyl alcohol, and the filter cake is dried in vacuum for 24 hours at 50-60 ℃ to obtain the XLI crystal form with the purity of 99.53 percent.
Comparative example 5 preparation of crystalline form XXV of acitinib reference can be made to the following process:
about 2g of the acitinib isopropyl alcohol solvate was added to 40ml of ethanol (denatured with 1% methanol), the slurry was heated to 77-78 ℃ under nitrogen protection for 24 hours, cooled to room temperature for granulating for 1 hour, filtered, the filter cake was rinsed with about 4ml of absolute ethanol, and the solid was dried in vacuo at 50-55 ℃ for 16 hours to give the acitinib XXV form with 99.45% purity.
Comparative example 6 preparation of acitinib acetone solvate reference may be made to the following procedure:
about 1g of acitinib is added into 40ml of N, N-dimethylformamide, after heating to 50 ℃ and stirring and clearing, acetone (200 ml) is added, the heat preservation and stirring reaction is continued for 2 hours, the reaction is finished, the filtration is carried out, the filtrate is reduced to-10 to 0 ℃ at the speed of 0.5 ℃/min, the stirring crystallization is carried out, the crystallization is finished, the filtration and the drying are carried out, and the acitinib acetone solvate with the purity of 99.47% is obtained.
Verification example:
the invention examines the prepared crystal forms of the acitinib in the aspects of stability, solubility, permeability and the like, and the specific implementation contents are as follows:
the invention is worth to be explained, according to the prior art method, 7 types of acitinib acid salt forms (benzenesulfonic acid, methanesulfonic acid, 4-chlorobenzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, sulfuric acid) prepared by implementation are found through stability, solubility and other property inspection tests, wherein the salt form with the optimal solubility is acitinib mesylate, the stability is optimal is acitinib sulfate, and after the photostability inspection of other 6 types of acid salt forms except for the acitinib sulfate form is carried out for 10 days, the total impurities are higher than 10%.
Light stability test
The crystal forms prepared in example 1 and comparative examples 1 to 6 were stored under exposure to intense light (4500 lx.+ -. 500 Lx) at 25 ℃ (RH 45%), sampled for 5 days and 10 days, respectively, and checked for purity by HPLC. The results are shown in Table 3.
TABLE 3 photo stability test results of Acxitinib crystalline forms
The photo stability test result shows that after 10 days under the condition of strong light irradiation, the total impurity content of the crystal form XLI of the acitinib and the total impurity content of the mesylate of the acitinib are both more than 5 percent. The crystal form of the acitinib malate prepared by the invention has good light stability. Examples 1 to 6 were examined and found to have similar stability test results.
Relative Humidity (RH) stability comparison
The crystal forms of acitinib prepared in example 1 and comparative examples 1 to 6 were respectively taken, and after being stored for 1 week at 25 ℃ under different humidity conditions (25%, 60%, 75%, 95%), PXRD detection was performed to test the relative humidity stability of each crystal form, and the results are shown in table 4.
Table 4 results of relative humidity stability of acitinib crystalline forms
Annotation: v denotes stable under this storage condition, PXRD pattern is unchanged; and gamma represents instability under such storage conditions.
The Relative Humidity (RH) stability test results show that the crystal form of the acitinib malate is stable in relative humidity. Examples 1 to 6 were examined and found to have the same stability test results.
Solubility test
The testing method comprises the following steps: the excess of the acitinib prepared in example 1 and comparative examples 1 to 6 was added to the medium by using water, a 0.01mol/L hydrochloric acid solution and a PBS buffer solution having a pH of 6.8, respectively, and stirred at 37℃for 72 hours. Sampling repeatedly for three times, filtering, taking a proper amount of filtrate, diluting, and detecting by HPLC to obtain the solubility in each medium.
TABLE 5 solubility of Acetinib in different media (mg/ml)
The solubility test result shows that compared with the available crystal form XLI disclosed by the prior art, the crystal form of the acitinib malate prepared by the invention has obviously improved solubility. Examples 1 to 6 were examined and found to have similar solubility test results.
Permeability test
Test conditions: permeability tests were performed using Franz diffusion Chi Fa at (37±0.5) deg.c water temperature.
Dialysis membrane (model: MW 14000Da, himedia, india): treating with 10% sodium bicarbonate solution, 10mM EDTA solution, and deionized water at 70deg.C for 20min; the treated dialysis membrane was packed into a diffusion cell (effective surface area 4.15cm 2 ) The method comprises the steps of carrying out a first treatment on the surface of the Taking the crystal forms of the acitinib prepared in the example 1 and the comparative examples 1-6 respectively from a donor room (10 mg based on the amount of the acitinib) to suspend in 2ml of distilled water; the receptor chamber was filled with phosphate buffer (ph=7.4) and protectedMaintaining the room temperature, removing bubbles, and magnetically stirring at 45+/-5 RPM; the permeation accumulation was tested after 24 hours.
TABLE 6 Acetinib osmotic cumulative amount (mg/cm) 2 )
As shown by the permeability test results, the permeability of the crystal form of the acitinib malate disclosed by the invention is obviously improved.
The prepared acitinib malate has the beneficial effects on the aspects of light stability, solubility, permeability and the like, and the comprehensive performance of the acitinib malate is remarkably improved compared with that of an acitinib crystal form reported in the prior art; the acitinib malate disclosed by the invention does not contain an organic solvent, is safer in medicinal use and more suitable for a medicinal preparation compared with an acitinib solvate.
Claims (6)
1. The crystal form of the axitinib malate is characterized in that the mol ratio of the axitinib to the malic acid in the malate crystal form is 1:1, and an X-ray diffraction pattern expressed by 2 theta is 7.77+/-0.2 degrees, 8.15+/-0.2 degrees, 11.99+/-0.2 degrees, 14.42+/-0.2 degrees, 15.59+/-0.2 degrees, 15.87+/-0.2 degrees, 18.23+/-0.2 degrees, 18.64+/-0.2 degrees, 19.61+/-0.2 degrees, 20.05+/-0.2 degrees, 20.33+/-0.2 degrees, 24.34+/-0.2 degrees, 24.87+/-0.2 degrees, 25.17+/-0.2 degrees and 26.02 +/-0.2 degrees.
2. The crystalline form of axitinib malate of claim 1, wherein said malate crystalline form base unit is comprised of one molecule of axitinib, one molecule of malic acid, one molecule of water, and wherein the crystallographic parameters are: monoclinic system with space group ofP-1The method comprises the steps of carrying out a first treatment on the surface of the The unit cell parameters are:a=7.56220(10)Å ，b=14.8985(2)Å，c=22.9743(2)Å，α=90°，β=93.1110(10)°，γunit cell volume =90°V=2584.59(5)Å 3 The structure is as follows:
3. the crystalline form of acitinib malate of claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in figure 1.
4. A process for preparing the crystalline form of acitinib malate according to any one of claims 1-3, comprising the steps of: dissolving the acitinib and malic acid in a solvent A, heating and dissolving, controlling temperature for reflux reaction, and cooling for crystallization to obtain an acitinib malate crystal form; wherein the solvent a is one or a combination of formic acid/ethanol/water, formic acid/methanol/water, formic acid/isopropanol/water, acetic acid/ethanol/water, acetic acid/methanol/water, acetic acid/isopropanol/water; the heating and dissolving temperature is 50-70 ℃; the temperature of the cooling crystallization is 0-30 ℃.
5. The method for preparing an acitinib malate crystal form according to claim 4, wherein the charging molar ratio of the acitinib to the malic acid is 1:1-2.
6. Use of the crystalline form of acitinib malate according to any one of claims 1 to 3 as active ingredient for the preparation of an antitumor drug.
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