CN114685431A - Crystalline form of axitinib citrate - Google Patents
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Abstract
The invention provides an axitinib citrate crystal form, and relates to the technical field of crystal form drug molecules. The crystal form uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 15.22 +/-0.2 degrees, 18.08 +/-0.2 degrees, 19.31 +/-0.2 degrees, 20.28 +/-0.2 degrees, 24.24 +/-0.2 degrees and 27.09 +/-0.2 degrees; the crystallography measurement parameters were: triclinic system, space group is P-1; the unit cell parameters are:
α is 67.1430(10) °, β is 82.3600(10) °, γ is 88.3800(10) °, unit cell volume
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to an axitinib citrate crystal form.
Background
Axitinib is a white or off-white powder with the chemical name: 6- [2- (methylcarbamoyl) phenylsulfanyl]-3-E- [2- (pyridin-2-yl) ethenyl]IndazolesMolecular formula is C22H18N4OS, molecular weight 386.48, CAS number 319460-85-0, structure as follows:
the axitinib raw mill was the united states pyroxene company, which 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 for patients with advanced renal cell carcinoma who had previously received treatment, and showed overall good safety.
As is well known, the crystal form of a drug has a great influence on the stability, dissolution rate, bioavailability and the like of a solid pharmaceutical preparation, and the excellent crystal form suitable for preparing the solid pharmaceutical preparation generally needs to meet the requirements of stability, dissolution rate, bioavailability and the like.
Various crystalline forms of axitinib have been reported at present, and patent WO2006048751a1 discloses various crystalline forms of axitinib, such as crystalline form I, crystalline form ii, crystalline form iii, crystalline form IV, crystalline form vi, crystalline form vii, crystalline form viii, and the like, and discloses that the solubility of crystalline form IV is about 0.55mg/ml in an aqueous solution with the pH of about 1, the solubility is only 0.157mg/ml in an aqueous solution with the pH of about 2, and the solubility is only 2 μ g/ml in an aqueous solution with the pH of about 6.5; it was also reported that in order to improve the water solubility of axitinib, 7 axitinic acid salt compounds were prepared, which had improved solubility but which showed significant degradation upon exposure to high intensity light. Patent CN200880016453 discloses various crystal forms of crystal form XXV, crystal form XVI, crystal form XLI, crystal form IX, crystal form XII and crystal form XV, which are not greatly improved in terms of solubility and bioavailability.
In addition, patent WO2015067224a1 further characterized 7 axitinic acid salts by powder diffraction data on the basis of the 7 axitinic acid formula compounds available as disclosed in patent WO2006048751a 1. Patent CN201510509413.7 discloses the preparation of a crystalline axitinib fumarate.
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. However, according to the current reports, from the aspects of bioavailability, stability, manufacturability and the like, only crystal form IV and crystal form XLI can be used in many disclosed axitinib crystal forms, and due to the extreme instability of light exposure of the crystal form IV, original research pfeiffei company finally selects the crystal form XLI with relatively small light exposure degradation amount as the 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 in order to achieve the safety and effectiveness of the medicine, the preparation process adopting the shading process is still unavoidable. Some series of axitinib solvate crystal forms, axitinic acid salt crystal forms and axitinib new crystal forms which are developed and researched in the following have defects in the aspects of patent drug safety, solubility, bioavailability or photostability and the like.
In conclusion, further research and development of advantageous crystalline forms of axitinib suitable for pharmaceutical use still remain problems to be solved at present.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a new medicinal salt crystal form of axitinib and a preparation method thereof.
The specific technical scheme of the invention is as follows:
in the citrate crystal form, the molar ratio of axitinib to citric acid (1 hydrate) is 1:1, and one molecule of axitinib, one molecule of citric acid and one molecule of water form a basic unit of the crystal form, and the specific structure is as shown in formula I:
preferably, the axitinib citrate crystal form has characteristic peaks at 15.22 +/-0.2 degrees, 18.08 +/-0.2 degrees, 19.31 +/-0.2 degrees, 20.28 +/-0.2 degrees, 24.24 +/-0.2 degrees, 27.09 +/-0.2 degrees by using Cu-Ka radiation and an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the axitinib citrate crystal form has characteristic peaks at 7.61 +/-0.2 °, 12.22 +/-0.2 °, 13.46 +/-0.2 °, 15.22 +/-0.2 °, 18.08 +/-0.2 °, 19.31 +/-0.2 °, 20.28 +/-0.2 °, 21.48 +/-0.2 °, 24.24 +/-0.2 °, 27.09 +/-0.2 °, 27.17 +/-0.2 ° and 27.93 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the crystalline form of axitinib citrate, using Cu-ka radiation, has characteristic peaks according to the X-ray powder diffraction pattern shown in figure 1.
Preferably, the crystalline form of axitinib citrate has the crystallographic parameters of: triclinic system, space group is P-1; the unit cell parameters are:
a is 67.1430(10) °, β is 82.3600(10) °, γ is 88.3800(10) °, unit cell volume
A preparation method of the axitinib citrate crystal form comprises the following steps:
dissolving the axitinib and citric acid in the solvent A, heating and dissolving, performing temperature-controlled reflux reaction, cooling and crystallizing, filtering, washing, and drying to obtain the axitinib citrate crystal form.
Preferably, the solvent A is a mixed solvent of acid and alcohol, 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 in the solvent A mixed solvent is 1: 1-10, preferably 1: 5.
Further, the solvent A is preferably one or a combination of formic acid/ethanol, acetic acid/ethanol, formic acid/methanol, acetic acid/methanol, formic acid/isopropanol and acetic acid/isopropanol.
Preferably, the feeding molar ratio of the axitinib to the citric acid is 1: 1-1.5, preferably 1: 1.2.
Preferably, the mass-to-volume ratio of axitinib to solvent A is 3-7: 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 reaction time is 3-5 hours.
Preferably, the cooling crystallization temperature is 0-30 ℃; preferably 10 to 20 ℃.
The axitinib citrate crystal form can be used as an active ingredient and applied to preparation of antitumor drugs.
A pharmaceutical composition comprising the crystalline form of axitinib citrate according to the invention, in admixture with other ingredients.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable excipients using standard and conventional techniques to prepare useful dosage forms.
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 selected from one or more of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium hydroxymethyl cellulose, ethyl cellulose and polyvidone; the disintegrant is selected from one or more of carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; the lubricant is selected from one or more of magnesium stearate, superfine silica gel powder, talcum powder and sodium dodecyl sulfate.
Preferably, the pharmaceutical composition is tablets, capsules, granules, pills and the like.
The invention has the beneficial effects that:
the axitinib citrate crystal form prepared by the invention has good stability, after the photostability investigation, the addition of the axitinib impurity is slightly less, the technical problem of unstable illumination existing in the axitinib crystal form in the prior art is solved, when the solid preparation is applied, the good illumination stability does not need special opacifier addition, the cost is saved, and the clinical application toxic and side effects of auxiliary materials are reduced. The crystalline form of the axitinib citrate has good solubility, and the problem of low solubility of the axitinib in the prior art is solved, so that the bioavailability is greatly improved. In addition, the preparation method is simple, and the solvents used in the preparation process are all low-toxicity or non-toxic solvents, so that the preparation method is more suitable for industrial production; the obtained crystal has regular crystal form, uniform grain size, definite crystallography main parameters and exact atom space positions, and single crystal diffraction data shows that the crystal does not contain organic solvent, so that the non-solvate crystal form is safer for medicine use and is suitable for large-scale popularization and application.
Drawings
FIG. 1: crystalline form X-ray powder diffraction pattern of axitinib citrate.
FIG. 2: a crystal form ORTEP of axitinib citrate.
FIG. 3: alitinib citrate crystal form stacking diagram
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 be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Materials used in the experiment: axitinib is available commercially and can also be prepared by the method disclosed in patent WO 2006048745; the citric acid used in the invention is commercially available citric acid monohydrate. 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 0.4g of axitinib, 0.25g of citric acid were added to 80ml of acetic acid/ethanol (V)Acetic acid：VEthanolHeating to 60-65 ℃ for dissolving in the mixed solution of 1:5), stirring, refluxing, reacting for 4 hours, cooling to 10-20 ℃ for crystallization, filtering after crystallization is finished, washing filter cakes with ethanol, and drying to obtain the crystalline form of axitinib citrate with the purity of 99.57%.
Example 2
About 0.4g of axitinib, 0.21g of citric acid were added to 60ml of acetic acid/ethanol (V)Acetic acid：VEthanolHeating the mixed solution of 1:1) to 50-55 ℃ for dissolution, stirring, refluxing and reacting for 5 hours, cooling to 0-10 ℃ for crystallization, filtering after crystallization is finished, washing filter cakes with ethanol, and drying to obtain the crystalline form of the axitinib citrate with the purity of 99.45%.
Example 3
About 0.4g of axitinib, 0.32g of citric acid were added to 130ml of acetic acid/ethanol (V)Acetic acid：VEthanolHeating to 65-70 ℃ for dissolving in the mixed solution of 1:10), stirring, refluxing, reacting for 4 hours, cooling to 10-20 ℃ for crystallization, filtering after crystallization is finished, washing filter cakes with ethanol, and drying to obtain the axitinib citrate crystal form with the purity of 99.53%.
Example 4
About 0.4g of axitinib, 0.25g of citric acid were added to 80ml of formic acid/methanol (V)Formic acid：VMethanolHeating to 60-65 ℃ for dissolving in the mixed solution of 1:7), stirring, refluxing, reacting for 3 hours, cooling to 20-30 ℃ for crystallization, filtering after crystallization is finished, washing filter cakes with methanol, and drying to obtain the crystalline form of the axitinib citrate with the purity of 99.54%.
Example 5
About 0.4g of axitinib, 0.25g of citric acid was added to 100ml of acetic acid/isopropanol (V)Acetic Acid (AA)：VEthanolHeating to 65-70 ℃ for dissolving in the mixed solution of 1:9), stirring, refluxing, reacting for 4 hours, cooling to 10-20 ℃ for crystallization, filtering after crystallization is finished, washing filter cakes with isopropanol, and drying to obtain the axitinib citrate crystal form with the purity of 99.48%.
Crystalline form characterization of axitinib citrate
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 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04rad of rope pulling slit; step length: 0.5 s; 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 citrate crystalline form PXRD peaks
The axitinib citrate crystal form 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 chemistry XtaLAB Synergy X-ray single crystal diffractometer measures the temperature 293(2) K, uses CuKa radiation, collects data in an omega scanning mode and carries out Lp correction. 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 crystalline form of the axitinib citrate prepared by the invention are as follows: triclinic system, space group is P-1; cell parametersComprises the following steps:
α is 67.1430(10) °, β is 82.3600(10) °, γ is 88.3800(10) °, unit cell volume
ORTEP figure 2 of the crystalline form of axitinib citrate of the present invention shows that one molecule of axitinib binds one molecule of citric acid and one molecule of water. The stacking diagram of the crystalline form of axitinib citrate of the invention is shown in the attached figure 3.
Table 2 major crystallographic data for crystalline form of axitinib citrate
The samples of examples 1 to 5 all had the same X-ray powder diffraction pattern and crystallographic parameters.
Comparative example 1 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 2 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 prepare 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 3 preparation of axitinib fumarate, reference may be made to the following procedure:
adding about 1g of axitinib to 15ml of ethanol, and adding about 0.35g of fumaric acid while 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 4 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; and 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 with about 12ml of absolute ethyl alcohol, and vacuum-drying the filter cake at 50-60 ℃ for 24 hours to obtain an XLI crystal form with the purity of 99.53%.
Comparative example 5 preparation of crystalline form XXV of axitinib, reference may be made to the following method:
adding about 2g of axitinib isopropanol solvate into 40ml of ethanol (denatured by 1% methanol), heating the slurry to 77-78 ℃ under the protection of nitrogen for 24 hours, cooling to room temperature, granulating for 1 hour, filtering, washing a filter cake by using about 4ml of absolute ethanol, and drying the solid in vacuum at 50-55 ℃ for 16 hours to obtain axitinib XXV with the purity of 99.45%.
Comparative example 6 preparation of axitinib acetone solvate, reference may be made to the following procedure:
adding about 1g of axitinib into 40ml of N, N-dimethylformamide, heating to 50 ℃, stirring for dissolving, adding acetone (200ml), continuing to perform heat preservation and stirring for reaction 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 an 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, bioavailability and the like, and the specific implementation contents are as follows:
it should be noted that, in 7 axitinic acid salt forms (benzenesulfonic acid, methanesulfonic acid, 4-chlorobenzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, sulfuric acid) prepared by the inventors by referring to the prior art method, the salt form with the best solubility is axitinib mesylate, the salt form with the best stability is axitinib sulfate, and the total impurity of other 6 salt forms except the axitinib sulfate form is higher than 10% after being subjected to photostability for 10 days.
Light stability test
The crystal forms prepared in example 1 and comparative examples 1-6 were respectively taken, stored under strong light irradiation (4500Lx ± 500Lx) 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 citrate crystal form prepared by the invention has good photostability. The examination found that examples 1 to 5 have similar stability test results.
Relative Humidity (RH) stability comparison
The axitinib crystal forms prepared in example 1 and comparative examples 1-6 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
Note that: the storage condition is stable, and the PXRD spectrum is unchanged; gamma indicates instability under such storage conditions.
The Relative Humidity (RH) stability test result shows that the crystalline form of axitinib citrate is stable in relative humidity. The examination revealed that examples 1 to 5 had the same stability test results.
Solubility test
The test method comprises the following steps: the obtained axitinib prepared in example 1 and comparative examples 1 to 6 was added in excess to a medium comprising water and 0.01mol/L hydrochloric acid solution and pH6.8 PBS buffer, 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 citrate crystal form prepared by the invention has remarkably improved solubility. The examination found that examples 1-5 have similar solubility test results.
Bioavailability test
18 healthy male rats were randomly divided into three groups, and after fasting for 1 night, the axitinib crystal form of example 1, comparative example 1 (mesylate) and comparative example 4 (XLI) was administered (calculated as axitinib) at 30mg/kg for intragastric gavage, 0.25ml of blood samples were taken from the tail vein of rats before and after administration at 10min, 30min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h and 24h, respectively, and the plasma was analyzed for axitinib concentration in liquid phase after centrifugation.
Table 6 pharmacokinetic parameters of axitinib in rats (n ═ 6)
The pharmacokinetic parameters show that compared with the crystal forms XLI and methanesulfonate, the blood concentration of the axitinib citrate crystal form prepared in example 1 of the invention is obviously improved, and the Cmax reaches 2.43 +/-0.22 mu g/ml-1。
The crystalline form of axitinib citrate prepared by the invention has beneficial effects in the aspects of stability, solubility and the like, and the comprehensive performance of the crystalline form of axitinib citrate is more remarkably improved compared with that of the crystalline form of axitinib reported in the prior art, so that the crystalline form of axitinib citrate is more suitable for being used in pharmaceutical preparations. The crystal form ORTEP of the axitinib citrate disclosed by the invention is free of organic solvents, is safer for medicine compared with an axitinib solvate, and is more suitable for pharmaceutical preparations.
Claims (10)
1. An axitinib citrate crystal form is characterized in that the molar ratio of axitinib to citric acid in the citrate crystal form is 1:1.
2. The crystalline form of axitinib citrate according to claim 1, wherein the citrate crystalline form consists of one molecule of axitinib, one molecule of citric acid and one molecule of water, and the crystallographic parameters are: triclinic system, space group is P-1; the unit cell parameters are:
a is 67.1430(10) °, β is 82.3600(10) °, γ is 88.3800(10) °, unit cell volume
The structure is as follows:
3. the crystalline form of axitinib citrate of claim 1, wherein the crystalline form has an X-ray diffraction pattern, in terms of 2 Θ, using Cu-ka radiation having characteristic peaks at 15.22 ± 0.2 °, 18.08 ± 0.2 °, 19.31 ± 0.2 °, 20.28 ± 0.2 °, 24.24 ± 0.2 °, 27.09 ± 0.2 °.
4. The crystalline form of axitinib citrate of claim 1, wherein the crystalline form has an X-ray diffraction pattern, in terms of 2 Θ, using Cu-ka radiation having characteristic peaks at 7.61 ± 0.2 °, 12.22 ± 0.2 °, 13.46 ± 0.2 °, 15.22 ± 0.2 °, 18.08 ± 0.2 °, 19.31 ± 0.2 °, 20.28 ± 0.2 °, 21.48 ± 0.2 °, 24.24 ± 0.2 °, 27.09 ± 0.2 °, 27.17 ± 0.2 °, 27.93 ± 0.2 °.
5. The crystalline form of axitinib citrate according to claim 1, wherein said crystalline form has an X-ray powder diffraction pattern as shown in figure 1.
6. A method of preparing the crystalline form of axitinib citrate of any one of claims 1-5, comprising the steps of: dissolving the axitinib and citric acid in the solvent A, heating and dissolving, performing temperature-controlled reflux reaction, and cooling and crystallizing to obtain the axitinib citrate crystal form.
7. The method for preparing a crystalline form of axitinib citrate according to claim 6, wherein the molar ratio of axitinib to citric acid is 1: 1-1.5.
8. The method for preparing the crystalline form of axitinib citrate according to claim 6, wherein the solvent A is a mixed solvent of an acid and an alcohol, preferably one or a combination of formic acid/ethanol, acetic acid/ethanol, formic acid/methanol, acetic acid/methanol, formic acid/isopropanol and acetic acid/isopropanol.
9. The method for preparing a crystalline form of axitinib citrate according to claim 6, wherein the heated dissolution temperature is 50-70 ℃; the cooling crystallization temperature is 0-30 ℃.
10. Use of the crystalline form of axitinib citrate according to any one of claims 1 to 5 as active ingredient for the preparation of an antitumor medicament.
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| WO2015067224A1 (en) * | 2013-11-08 | 2015-05-14 | Zentiva, K.S. | Salts of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethanyl] indazole |
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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 |
| WO2020212253A1 (en) * | 2019-04-18 | 2020-10-22 | Synthon B.V. | Process for preparing axitinib, process for purifying the intermediate 2-((3-iodo-1h-indazol-6-yl)thio)-n-methylbenzamide, process for purifying axitinib via the axitinib hcl salt, solid form of the axitinib hcl salt |
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| US20060094763A1 (en) * | 2004-11-02 | 2006-05-04 | Agouron Pharmaceuticals, Inc. | Polymorphic forms of 6-[2-(methylcarbomoyl) phenyl sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole |
| 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 |
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| CA2928287A1 (en) * | 2015-04-28 | 2016-10-28 | Signa S.A. De C.V. | Solid form of axitinib |
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| CN106467512A (en) * | 2015-08-19 | 2017-03-01 | 浙江九洲药业股份有限公司 | A kind of Axitinib fumarate and its crystal form and preparation method |
| WO2020212253A1 (en) * | 2019-04-18 | 2020-10-22 | Synthon B.V. | Process for preparing axitinib, process for purifying the intermediate 2-((3-iodo-1h-indazol-6-yl)thio)-n-methylbenzamide, process for purifying axitinib via the axitinib hcl salt, solid form of the axitinib hcl salt |
| 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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