CN114685433B - Apolitinib vanillic acid eutectic salt and preparation thereof - Google Patents
Apolitinib vanillic acid eutectic salt and preparation thereof Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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Abstract
The invention provides axitinib-vanillic acid eutectic salt, and relates to the technical field of crystal form drug molecules. The eutectic salt uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 7.94 +/-0.2 degrees, 9.38 +/-0.2 degrees, 11.96 +/-0.2 degrees, 12.89 +/-0.2 degrees, 16.53 +/-0.2 degrees, 17.20 +/-0.2 degrees, and 27.03 +/-0.2 degrees; the crystallography measurement parameters were: triclinic system, space group is P-1; the unit cell parameters are:
α =68.228 (2) °, β =65.302 (3) °, γ =73.341 (3) °, unit cell volume
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to axitinib-vanillic acid eutectic salt.
Background
Axitinib is a white or off-white powder with the chemical name: 6- [2- (methylcarbamoyl) phenylsulfanyl]-3-E- [2- (pyridin-2-yl) ethenyl]Indazole of formula C 22 H 18 N 4 OS, molecular weight 386.48, CAS number 319460-85-0, structure as follows:
the axitinib former manufacturer was the american pfeiri company, who first obtained FDA approval in the united states in month 1 of 2012. Ashitabine was approved for CFDA on day 29/4 of 2015 for use in adult patients who had previously received advanced Renal Cell Carcinoma (RCC) for which treatment with one of the tyrosine kinase inhibitors or cytokines failed. Axitinib is currently marketed in several countries, including the united states, europe, canada, australia, korea, japan, etc., and has become one of the standard treatment regimens for advanced kidney cancer. The axitinib 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 play a role in antitumor activity. The medicine has the effects of inhibiting tumor growth and cancer progression by blocking protein kinase in tumor growth process. In a randomized, open, international multicenter phase III clinical trial, axitinib significantly extended progression-free survival compared to sorafenib in a previously treated patient with advanced renal cell carcinoma, and showed overall good safety.
According to statistics, more than 40% of candidate drugs in the drug development process cannot enter clinical research due to poor water solubility, poor permeability and low bioavailability; for these indissolvable drugs, the problem of indissolvability of the drugs has been particularly noticed in recent years by eutectic technology, which is a new technology capable of improving the physicochemical properties of the drug molecules, such as stability, solubility and bioavailability, and improving the drug potency without changing the molecular structure of the drug. As the research reports that the bioavailability is improved by 2.5 to 10 times after the flavonoid compound quercetin, caffeine, theobromine and isonicotinamide are prepared into eutectic.
Due to the problems of photosensitivity, insolubility and the like of axitinib, the technicians in the field try to develop different crystal forms to obtain the axitinib crystal form more suitable for medicine. Patent WO2006048751A1 tries axitinib crystal form research, and discloses axitinib crystal forms I, II, III, IV, VI, VII, VIII and the like, but the solubility of the axitinib crystal form is not greatly improved by simply changing the crystal form, for example, the solubility of the crystal form IV in an aqueous solution with the pH of about 1 is about 0.55mg/ml, the solubility of the crystal form IV in an aqueous solution with the pH of about 2 is only 0.157mg/ml, and the solubility of the crystal form IV in an aqueous solution with the pH of about 6.5 is only 2 mu g/ml; meanwhile, 7 axitinic acid salt compounds are prepared in order to improve the water solubility of axitinib, the solubility of the axitinic acid salt compounds is improved, but the axitinic acid salt compounds are obviously degraded when exposed to high-intensity light and are photosensitive axitinib salts. Patent CN200880016453 discloses various crystal forms such as crystal form XXV, crystal form XVI, crystal form XLI, crystal form IX, crystal form XII, and crystal form XV, and crystal form XXV and crystal form XLI are not greatly improved in solubility and bioavailability.
According to the current report, from the aspects of bioavailability, stability, manufacturability and the like, only crystal form IV and crystal form XLI can be used in a plurality of disclosed axitinib crystal forms, and because of the extreme instability of light exposure of the crystal form IV, original research whether XLI with relatively small light exposure degradation amount is finally selected by the company of Peveride is used as a crystal form on the market (visible CHMP evaluation report). However, as reported by CN200880016453, the potency of XLI in the market after light exposure is reduced to 89%, and the XLI is still unstable to light, so that the preparation process adopting a shading process is unavoidable in order to achieve the safety and effectiveness of medicine.
In addition, patent WO2015067224A1 further characterizes 7 axitinic acid salts by powder diffraction data based on the 7 axitinic acid salt compounds available as disclosed in patent WO2006048751 A1. Patent CN201510509413.7 discloses preparation of axitinib fumarate crystals. Then, some series of axitinib solvate crystal forms, axitinic acid salt crystal forms and axitinib new crystal forms which are researched and developed still have defects in the aspects of patent drug safety, solubility, bioavailability or photostability and the like.
At present, research reports of axitinib co-crystal are rare, and only patent CN201910657224.2 reports a series of co-crystal compounds formed by resveratrol and protein kinase inhibitors, wherein the co-crystal compounds comprise a co-crystal compound formed by resveratrol and axitinib in a molar ratio of 0.494, and the co-crystal with synergistic antihistaminic effect is attempted to be prepared; however, the report does not give clear structural information of the resveratrol complex, and the mode of action of the API and CCF in the complex cannot be judged.
In view of the above problems, further research and development of advantageous crystalline forms of axitinib suitable for pharmaceutical use still remain problems to be solved.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the axitinib-vanillic acid eutectic salt which has exact crystallography main parameters and atom space positions; the invention also provides a preparation method of the eutectic salt.
The specific technical scheme of the invention is as follows:
in a first aspect, the invention provides axitinib-vanillic acid eutectic salt, wherein the molar ratio of axitinib to vanillic acid is 2:1, two molecules of axitinib, one molecule of vanillic acid, one molecule of formic acid and two molecules of water form a basic unit of a crystal form, and the specific structure is as shown in formula I:
preferably, the axitinib-vanillic acid eutectic salt has characteristic peaks at 7.94 +/-0.2 degrees, 9.38 +/-0.2 degrees, 11.96 +/-0.2 degrees, 12.89 +/-0.2 degrees, 16.53 +/-0.2 degrees, 17.20 +/-0.2 degrees and 27.03 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the axitinib-formic acid-vanillic acid eutectic salt has an X-ray diffraction spectrum expressed by 2 theta and having characteristic peaks at 7.94 +/-0.2 degrees, 9.38 +/-0.2 degrees, 10.21 +/-0.2 degrees, 11.96 +/-0.2 degrees, 12.89 +/-0.2 degrees, 14.47 +/-0.2 degrees, 16.53 +/-0.2 degrees, 17.20 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.08 +/-0.2 degrees, 25.39 +/-0.2 degrees, 27.03 +/-0.2 degrees by using Cu-Kalpha radiation.
Preferably, the axitinib-vanillic acid eutectic salt, using Cu-ka radiation, has characteristic peaks according to the X-ray powder diffraction pattern as shown in figure 1.
Preferably, the axitinib-vanillic acid eutectic salt has crystallographic parameters of: triclinic system, space group is P-1; the unit cell parameters are:
α =68.228 (2) °, β =65.302 (3) °, γ =73.341 (3) °, unit cell volume
In a second aspect, the invention provides a preparation method of axitinib-vanillic acid eutectic salt, which comprises the following steps:
dissolving the axitinib and the vanillic acid in a mixed solvent, heating and dissolving, then carrying out temperature-controlled reflux reaction, cooling and crystallizing, filtering, washing, and drying to obtain the axitinib-vanillic acid eutectic salt.
Preferably, the feeding molar ratio of the axitinib to the vanillic acid is 1.
Preferably, the mixed solvent is a mixture of an organic solvent, formic acid and water, wherein the organic solution is preferably one or two of methanol, ethanol, isopropanol and acetone; the mixed solvent is more preferably methanol-formic acid-water, ethanol-formic acid-water, acetone-formic acid-water, or isopropanol-formic acid-water.
Preferably, the volume ratio of the organic solvent, the formic acid and the water in the mixed solvent is 1-10.
Preferably, the mass-to-volume ratio of the axitinib to the mixed solvent is 5-8:1, wherein the mass is mg and the volume is mL.
Preferably, the heating and dissolving temperature is 50-70 ℃.
Preferably, the temperature-controlled reflux time is 3 to 10 hours.
Preferably, the temperature for cooling and crystallization is 0-30 ℃; preferably 10 to 20 ℃.
Preferably, the washing solvent is one of methanol, ethanol, isopropanol or a combination thereof.
In a third aspect, the present invention provides a pharmaceutical composition comprising the axitinib-vanillic acid eutectic salt of the present invention and other pharmaceutically acceptable components.
Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition of the present invention can be prepared using the following method: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.
Preferably, the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, a liquid injection and the like.
In a fourth aspect, the invention provides an application of axitinib-vanillic acid eutectic salt serving as an active ingredient in preparation of anti-tumor drugs.
The invention has the beneficial effects that:
the axitinib-vanillic acid eutectic salt prepared by the invention is greatly improved in the aspects of stability, solubility, permeability and the like, and after the photostability investigation, the axitinib impurity is slightly increased, and the optical stability of the eutectic salt is good. The axitinib-vanillic acid eutectic salt has a regular crystal form, uniform particle size, definite crystallography main parameters and definite atom space positions, and the preparation method is simple and is suitable for industrial production and large-scale popularization and application.
Drawings
FIG. 1: a powder X-ray diffraction pattern of axitinib-vanillic acid eutectic salt.
FIG. 2 is a schematic diagram: ORTEP diagram of axitinib-vanillic acid eutectic salt.
FIG. 3: a stacking diagram of axitinib-vanillic acid eutectic salt.
FIG. 4: DSC-TGA chart of axitinib-vanillic acid eutectic salt.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are all within the scope of the present invention as claimed.
Materials used in the experiment: axitinib is commercially available and can also be prepared by the method disclosed in patent WO 2006048745. The axitinib crystal form required by the comparative test can be prepared by referring to the prior art or can be purchased; all materials used in the other experiments, which do not have the indicated sources and specifications, are commercially available analytically pure or chemically pure.
Example 1
About 0.8g axitinib, 0.27g vanillic acid was added to 120ml ethanol/formic acid/water (V) Ethanol :V Formic acid :V Water (W) Heating to 65-70 ℃ for dissolution in a mixed solution of = 5.
Example 2
About 0.8g axitinib, 0.17g vanillic acid was added to 100ml methanol/formic acid/water (V) Methanol :V Formic acid :V Water (W) Heating to 60-65 ℃ for dissolution in a mixed solution of = 1.
Example 3
About 0.8g of axitinib, 0.34g of vanillic acid was added to 160ml of isopropanol/formic acid/water (V) Isopropanol (I-propanol) :V Formic acid :V Water (W) Heating to 60-70 ℃ for dissolving in a mixed solution of = 10.
Example 4
About 0.8g axitinib, 0.30g vanillic acid was added to 150ml acetone/formic acid/water (V) Acetone (II) :V Formic acid :V Water (I) Heating to 50-60 ℃ for dissolution in a mixed solution of = 6.
Axitinib-vanillic acid eutectic salt characterization
The X-ray powder diffraction test instrument and the test conditions involved in the invention are as follows: x-ray powder diffractometer PANalytical EMPYREA; cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of divergent slit; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5s; scanning range: 3 to 50 degrees. The corresponding characteristic peak in the X-ray secretion diffraction pattern (Cu-Ka) is shown in figure 1 and table 1.
Table 1 axitinib-vanillic acid eutectic salt PXRD peaks
The axitinib-vanillic acid eutectic salt provided by the invention is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and the test conditions related by the invention are as follows: the XtaLAB Synergy X-ray single crystal diffractometer measures the temperature 293 (2) K, uses CuKa radiation, collects data in an omega scanning mode and corrects Lp. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic parameters for testing and analyzing the axitinib-vanillic acid eutectic salt prepared by the invention are as follows: triclinic system, space group is P-1; the unit cell parameters are as follows:
α =68.228 (2) °, β =65.302 (3) °, γ =73.341 (3) °, unit cell volume
ORTEP of the axitinib-vanillic acid eutectic salt of the invention figure 2 shows that two molecules of axitinib, one molecule of vanillic acid, one molecule of formic acid and two molecules of water combine to form the eutectic salt. The stacking diagram of the axitinib-vanillic acid eutectic salt is shown in the attached figure 3.
TABLE 2 Primary crystallographic data for axitinib-vanillic acid eutectic salts
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram: METTLER TOLEDO TGA/DSC3+; dynamic temperature section: 30 to 300 ℃; heating rate: 10 ℃/mIVn; segment gas N 2 (ii) a Gas flow rate: 50mL/mIVn; crucible: an aluminum crucible of 40. Mu.l.
The TGA/DSC test result of the axitinib-vanillic acid eutectic salt prepared by the method is shown in figure 4, the DSC test result has three endothermic peaks, and the peak values respectively correspond to the temperature of 86.0 ℃, 140.39 ℃ and 191.55 ℃.
The samples of examples 1 to 4 all had the same X-ray powder diffraction pattern, crystallographic parameters, DSC pattern.
Comparative example 1 preparation of axitinib-resveratrol co-crystal complex, reference may be made to the following procedure:
taking a sieving mixture of axitinib and resveratrol (the mass ratio of the axitinib to the resveratrol is 1
Comparative example 2 preparation of axitinib mesylate, reference may be made to the following procedure:
adding about 0.25g of axitinib into 10ml of isopropanol, heating to 50 ℃, and stirring to dissolve; adding 126 mu l of methanesulfonic acid into 1ml of isopropanol to prepare methanesulfonic acid isopropanol solution; and (3) dropwise adding the methanesulfonic acid isopropanol solution into the axitinib 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 axitinib mesylate with the purity of 99.54%.
Comparative example 3 axitinib sulfate preparation, the following procedure can be referenced:
adding about 0.25g of axitinib into 5ml of isopropanol, heating to 50 ℃, and stirring to dissolve; adding 36 μ l sulfuric acid solution (with concentration of about 96%) into 0.5ml isopropanol to obtain sulfuric acid isopropanol solution; and (3) dropwise adding the isopropanol sulfate solution into the isopropanol axitinib 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 axitinib sulfate with the purity of 99.48%.
Comparative example 4 preparation of axitinib fumarate, reference may be made to the following procedure:
about 1g of axitinib was added to 15ml of ethanol and about 0.35g of fumaric acid was added with stirring; heating to 65-70 ℃, stirring for 1 hour, cooling to 25 ℃, crystallizing, filtering, and vacuum drying at 100-120 ℃ to obtain the axitinib fumarate with the purity of 99.45%.
Comparative example 5 preparation of crystalline XLI axitinib, reference is made to the following procedure:
adding about 4g of crude axitinib into 40ml of isopropanol, heating to 60 ℃, keeping for 3 hours, cooling to ambient temperature, filtering, separating solid, washing with about 12ml of isopropanol, purging with nitrogen for drying for 2 hours, and further drying in vacuum at 55-65 ℃ for 18 hours; adding the solid into 40ml of absolute ethyl alcohol, heating and refluxing, distilling to remove about 1/3 of the solvent, continuously refluxing for 2 hours, cooling to room temperature, stirring for 1 hour, filtering, washing by about 12ml of absolute ethyl alcohol, and vacuum drying the filter cake for 24 hours at 50-60 ℃ to obtain an XLI crystal form with the purity of 99.53%.
Comparative example 6 preparation of crystalline form XXV of axitinib, reference may be made to the following method:
about 2g of axitinib isopropanol solvate was added to 40ml of ethanol (denatured with 1% methanol), the slurry was heated to 77-78 ℃ under nitrogen for 24 hours, cooled to room temperature and granulated for 1 hour, filtered, the filter cake was washed with about 4ml of absolute ethanol, and the solid was vacuum dried at 50-55 ℃ for 16 hours to give axitinib form XXV, purity 99.45%.
Comparative example 7 preparation of axitinib acetone solvate, reference may be made to the following procedure:
adding about 1g of axitinib into 40mlN, N-dimethylformamide, heating to 50 ℃, stirring for dissolving, adding acetone (200 ml), continuously keeping the temperature, stirring for reacting for 2 hours, after the reaction is finished, filtering, reducing the filtrate to-10-0 ℃ at the speed of 0.5 ℃/min, stirring for crystallization, after the crystallization is finished, filtering, and drying to obtain the axitinib acetone solvate with the purity of 99.47%.
Verification of the examples:
the prepared axitinib crystal form is considered in the aspects of stability, solubility, permeability and the like, and the specific implementation contents are as follows:
it should be noted that, according to the prior art method, the inventor finds that, in 7 axitinib salt forms (benzenesulfonic acid, methanesulfonic acid, 4-chlorobenzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid and sulfuric acid) prepared by the implementation, through property examination tests such as stability and solubility, the salt form with the best solubility is axitinib mesylate, the salt form with the best stability is axitinib sulfate, and the total impurity is higher than 10% after other 6 salt forms except axitinib sulfate are subjected to photostability examination for 10 days.
Photostability test
The crystalline forms prepared in example 1 and comparative examples 1 to 7 were each taken, stored under exposure to intense light (4500 Lx ± 500 Lx) at 25 ℃ (RH 45%), sampled for 5 days and 10 days, respectively, and purity was checked by HPLC. The results are shown in Table 3.
TABLE 3 photostability test results for crystalline forms of axitinib
The light stability test result shows that the total impurity content of the axitinib crystal form XLI and the axitinib mesylate exceeds 5 percent after 10 days under the condition of strong light irradiation. The axitinib-vanillic acid eutectic salt prepared by the invention has good light stability. Examination revealed that examples 1 to 4 had similar stability test results.
Relative Humidity (RH) stability comparison
The axitinib crystal forms prepared in example 1 and comparative examples 1 to 7 are respectively taken, and PXRD detection is carried out after the axitinib crystal forms are stored at 25 ℃ for 1 week under different humidity conditions (25%, 60%, 75% and 95%), and the relative humidity stability of each crystal form is tested, and the results are shown in Table 4.
Table 4 axitinib crystal form relative humidity stability results
And (3) annotation: the storage condition is stable, and the PXRD spectrum is unchanged; gamma indicates instability under such storage conditions.
The Relative Humidity (RH) stability test results show that the axitinib-vanillic acid eutectic salt of the present invention is stable relative humidity.
Solubility test
The test method comprises the following steps: the excess amounts of axitinib prepared in example 1 and comparative examples 1 to 7 were added to a medium of water and 0.01mol/L hydrochloric acid solution and PBS buffer solution (pH 6.8), respectively, and stirred at 37 ℃ for 72 hours. Sampling is repeated for three times, filtering is carried out, a proper amount of filtrate is taken, dilution is carried out, and HPLC detection is adopted, so that the solubility in each medium is obtained.
TABLE 5 solubility of axitinib in different media (mg/ml)
Solubility test results show that compared with available crystal XLI disclosed by the prior art, the axitinib-vanillic acid eutectic salt prepared by the invention has remarkably improved solubility. Examination revealed that examples 1 to 4 had similar solubility test results.
Permeability test
And (3) testing conditions: permeability tests were performed using the Franz diffusion cell method at water temperatures of (37 ± 0.5) ° c.
Dialysis membranes (model: MW 14000Da, himedia, india): respectively treating with 10% sodium bicarbonate solution, 10MmEDTA solution, and deionized water at 70 deg.C for 20min; the treated dialysis membrane was placed in a diffusion cell (effective surface area 4.15 cm) 2 ) (ii) a The axitinib crystal forms prepared in example 1 and comparative examples 1 to 7 (10 mg calculated by axitinib) were taken from the donor room and suspended in 2ml of distilled water; the receptor chamber was filled with phosphate buffer (pH = 7.4), kept at room temperature, degassed, and magnetically stirred at 45 ± 5 RPM; the permeation cumulant was measured after 24 hours.
TABLE 6 osmotic cumulative amounts (mg/cm) of axitinib 2 )
The permeability test results show that the permeability of the axitinib-vanillic acid eutectic salt is obviously improved.
The axitinib-vanillic acid eutectic salt prepared by the invention has beneficial effects in the aspects of light stability, solubility, permeability and the like, and the comprehensive performance is remarkably improved compared with the axitinib crystal form reported in the prior art, so that the axitinib-vanillic acid eutectic salt is more suitable for pharmaceutical preparations.
Claims (6)
1. The axitinib-vanillic acid eutectic salt is characterized by consisting of an active pharmaceutical ingredient axitinib and an eutectic ligand vanillic acid; the eutectic salt uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 7.94 +/-0.2 degrees, 9.38 +/-0.2 degrees, 10.21 +/-0.2 degrees, 11.96 +/-0.2 degrees, 12.89 +/-0.2 degrees, 14.47 +/-0.2 degrees, 16.53 +/-0.2 degrees, 17.20 +/-0.2 degrees, 21.93 +/-0.2 degrees, 25.08 +/-0.2 degrees, 25.39 +/-0.2 degrees and 27.03 +/-0.2 degrees.
2. As claimed inThe axitinib-vanillic acid eutectic salt obtained in claim 1, wherein the molar ratio of axitinib to vanillic acid in the eutectic salt is 2:1, the basic unit of the eutectic salt consists of two molecules of axitinib, one molecule of vanillic acid, one molecule of formic acid and two molecules of water, and the crystallographic parameters are as follows: triclinic system, space group ofP-1(ii) a The unit cell parameters are:a = 13.7686(5) Å ，b= 14.7899(4) Å，c= 15.1645 (4), α =68.228 (2) °, β =65.302 (3) °, γ =73.341 (3) °, unit cell volumeV = 2573.49(15) Å 3 The structure is as follows:
3. the axitinib-vanillic acid eutectic salt according to claim 1, wherein said eutectic salt has an X-ray powder diffraction pattern as shown in figure 1.
4. A method of preparing the axitinib-vanillic acid eutectic salt according to any one of claims 1 to 3, comprising the steps of: dissolving axitinib and vanillic acid in a mixed solvent, heating for dissolving, performing temperature-controlled reflux reaction, cooling for crystallization, filtering, washing, and drying to obtain axitinib-vanillic acid eutectic salt; wherein the mixed solvent is a mixture of an organic solvent, formic acid and water, and the organic solution is one or two of methanol, ethanol, isopropanol and acetone; the heating and dissolving temperature is 50 to 70 ℃; the temperature for cooling crystallization is 0 to 30 ℃.
5. The method for preparing axitinib-vanillic acid eutectic salt according to claim 4, wherein the molar ratio of axitinib to vanillic acid is 1.
6. Use of the axitinib-vanillic acid eutectic salt according to any one of claims 1 to 3 as an active ingredient for the preparation of an antitumor medicament.
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| CN111187253A (en) * | 2020-01-09 | 2020-05-22 | 鲁南制药集团股份有限公司 | Novel crystalline form of axitinib |
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| JP2008518904A (en) * | 2004-11-02 | 2008-06-05 | ファイザー・インク | Polymorphic form of 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] indazole |
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| CN101679356A (en) * | 2007-04-05 | 2010-03-24 | 辉瑞产品公司 | Be applicable to 6-[2-(methyl-carbamyl) the phenyl sulfenyl of treatment Mammals abnormal cell growth]-3-E-[2-(pyridine-2-yl) vinyl] crystal formation of indazole |
| CN104230886A (en) * | 2013-06-24 | 2014-12-24 | 南京华威医药科技开发有限公司 | New axitinib crystal form |
| CA2928287A1 (en) * | 2015-04-28 | 2016-10-28 | Signa S.A. De C.V. | Solid form of axitinib |
| WO2016178150A1 (en) * | 2015-05-05 | 2016-11-10 | Shilpa Medicare Limited | Novel polymorphs of axitinib |
| CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
| CN111187253A (en) * | 2020-01-09 | 2020-05-22 | 鲁南制药集团股份有限公司 | Novel crystalline form of axitinib |
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