CN114685434B - Acetinib and glutaric acid eutectic crystal - Google Patents
Acetinib and glutaric acid eutectic crystal Download PDFInfo
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Abstract
The invention provides an acitinib glutarate eutectic crystal, and relates to the technical field of crystal form drug molecules. The eutectic uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 7.78+/-0.2 degrees, 13.01+/-0.2 degrees, 13.83+/-0.2 degrees, 19.29+/-0.2 degrees, 20.30+/-0.2 degrees, 23.98+/-0.2 degrees and 26.04+/-0.2 degrees; the crystallographic measurement parameters were: triclinic system, chiral space group is P-1; the unit cell parameters are:α= 111.5610 (10) °, β= 91.4540 (10) °, γ= 94.1680 (10) °, unit cell volume
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to an acitinib-glutaric acid eutectic crystal.
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.
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 indissolvable drugs is paid attention to in recent years by a eutectic technology, which is a novel technology capable of improving the physicochemical properties of drugs such as stability, solubility and bioavailability without changing the molecular structure of the drugs and improving the drug properties. For example, after the flavonoid compound quercetin, caffeine, theobromine and isonicotinamide are prepared into eutectic, the bioavailability is improved by 2.5-10 times.
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. Patent WO2006048751A1 attempts at the study of the crystalline forms of acitinib and discloses that the various crystalline forms of acitinib, crystalline form ii, crystalline form iii, crystalline form IV, crystalline form vi, crystalline form vii, crystalline form viii, etc., but the solubility of the pure crystalline forms of acitinib is not greatly improved, for example, the solubility of the available crystalline form IV is about 0.55mg/ml in an aqueous solution with a pH of about 1, the solubility is only 0.157mg/ml in an aqueous solution with a pH of about 2, and the solubility is only 2 μg/ml in an aqueous solution with a pH of about 6.5; meanwhile, 7 types of acid salt compounds of the acytinib are reported to be prepared for improving the water solubility of the acytinib, wherein the solubility of the acid salt compounds is improved, but the acid salt compounds are obviously degraded when exposed to high-intensity light and are photosensitive acytinib salts. 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.
According to the current report, from the aspects of bioavailability, stability, manufacturability and the like, among a plurality of published crystal forms of the acitinib, only crystal form IV and crystal form XLI can be used, and due to the extremely unstable light exposure of the crystal form IV, the original spodumene company finally selects the crystal form XLI with relatively low light exposure degradation amount as a 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 crystal form XLI is still unstable to light, and a preparation process using a shading process is unavoidable in order to achieve safety and effectiveness of medicines.
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. Then, the crystal forms of the solvate of the acytinib, the crystal forms of the acytinib acid salt and the new crystal forms of the acytinib, which are developed and researched continuously, have defects in the aspects of safety, solubility, bioavailability or photostability of the patent medicine.
At present, research reports on the co-crystal of the acitinib are rare, and only patent CN201910657224.2 reports a series of eutectic compounds formed by resveratrol serving as a histamine release inhibitor and a protein kinase inhibitor, wherein the eutectic compounds comprise a eutectic compound formed by resveratrol and the acitinib in a molar ratio of 0.494, and an attempt is made to prepare a eutectic with a synergistic antihistaminic effect; however, the report does not give explicit structural information about the resveratrol complex, and the mode of action of the API and CCF in the complex cannot be determined.
In view of the above problems, 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
Aiming at the problems in the prior art, the invention provides an acitinib-glutaric acid eutectic crystal which has definite main crystallographic parameters and atomic space positions; in another aspect, the invention provides a method of preparing the co-crystal.
The specific technical scheme of the invention is as follows:
in a first aspect, the invention provides an acitinib-glutaric acid eutectic crystal, wherein in the eutectic crystal, the mol ratio of the acitinib to the glutaric acid is 1:1, and one molecule of acitinib, one molecule of glutaric acid and one molecule of formic acid form a basic unit of a crystal form, and the specific structure is shown as a formula I:
preferably, the acitinib-glutaric acid co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed in 2 theta has characteristic peaks at 7.78+/-0.2 degrees, 13.01+/-0.2 degrees, 13.83+/-0.2 degrees, 19.29+/-0.2 degrees, 20.30+/-0.2 degrees, 23.98+/-0.2 degrees and 26.04+/-0.2 degrees.
Preferably, the acitinib-formic acid-glutaric acid eutectic uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed in terms of 2 theta has characteristic peaks at 7.78+/-0.2 degrees, 13.01+/-0.2 degrees, 13.83+/-0.2 degrees, 17.51+/-0.2 degrees, 17.94+/-0.2 degrees, 19.29+/-0.2 degrees, 19.64+/-0.2 degrees, 20.30+/-0.2 degrees, 21.88+/-0.2 degrees, 23.98+/-0.2 degrees, 26.04+/-0.2 degrees, 26.17+/-0.2 degrees and 27.27+/-0.2 degrees.
Preferably, the acitinib-glutaric acid co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern as shown in figure 1.
Preferably, the axitinib-glutaric acid co-crystal has the following crystallographic parameters: triclinic system, chiral space group is P-1; the unit cell parameters are:α= 111.5610 (10) °, β= 91.4540 (10) °, γ= 94.1680 (10) °, unit cell volume +.>
In a second aspect, the invention provides a preparation method of an acitinib-glutaric acid eutectic crystal, comprising the following steps:
and (3) dissolving the acitinib and the glutaric acid in a mixed solvent, heating and dissolving, controlling the temperature for reflux reaction, cooling for crystallization, filtering, washing and drying to obtain the acitinib-glutaric acid eutectic.
Preferably, the charging mole ratio of the acitinib to the glutaric acid is 1:1.0-1.5, preferably 1:1.2.
Preferably, the mixed solvent is a mixed solvent of an organic solvent and formic acid, wherein the organic solution is preferably one or two of methanol, ethanol, isopropanol and acetone; the mixed solvent is further preferably methanol-formic acid, ethanol-formic acid, acetone-formic acid, isopropanol-formic acid.
Preferably, the volume ratio of the organic solvent to the formic acid in the mixed solvent is 1-5:1.
Preferably, the mass-volume ratio of the acitinib to the mixed solvent is 2-6:1, 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 time is 2-10 hours.
Preferably, the temperature reduction crystallization temperature is 10-30 ℃; preferably 15 to 20 ℃.
Preferably, the washing solvent is one or a combination of methanol, ethanol and isopropanol.
In a third aspect, the present invention provides a pharmaceutical composition comprising the co-crystal of acitinib-glutaric acid and other pharmaceutically acceptable components according to the invention.
Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers, and the like, which 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 formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
Preferably, the pharmaceutical composition is spray, tablet, capsule, powder injection, liquid injection and the like.
In a fourth aspect, the invention provides an application of an acitinib-glutaric acid eutectic as an active ingredient in preparing a therapeutic anti-tumor drug.
The invention has the beneficial effects that:
the invention has the advantages that the prepared acitinib-glutaric acid eutectic is greatly improved in the aspects of stability, solubility, permeability and the like, and after the photostability is inspected, the increase of the acitinib impurity is little, and the photostability of the eutectic is good. The acitinib-glutaric acid eutectic crystal has regular crystal form, uniform grain size, definite main crystallographic parameters and definite atomic space position, and the preparation method is simple and is suitable for industrial production and large-scale popularization and application.
Drawings
Fig. 1: acetinib-glutaric acid co-crystal X-ray powder diffraction pattern.
Fig. 2: an actetinib-glutaric acid co-crystal ORTEP diagram.
Fig. 3: a eutectic stacking diagram of acitinib and glutaric acid.
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 acytinib, 0.16g of glutaric acid are added to 100ml of isopropanol/formic acid (V Isopropyl alcohol :V Formic acid In the mixed solution of the component=3:1), heating to 55-60 ℃ for dissolution, stirring and refluxing for reaction for 4 hours, cooling to 15-20 ℃, controlling Wen Xijing, after crystallization, filtering, washing a filter cake with isopropanol, and drying to obtain the acitinib-glutaric acid eutectic with the purity of 99.52%.
Example 2
About 0.4g of acytinib, 0.13g of glutaric acid are added to 120ml of methanol/formic acid (V Methanol :V Formic acid In the mixed solution of the component=2:1), heating to 50-60 ℃ for dissolution, stirring and refluxing for reaction for 5 hours, cooling to 10-15 ℃, controlling Wen Xijing, after crystallization, filtering, washing a filter cake with methanol, and drying to obtain the acitinib-glutaric acid eutectic with the purity of 99.48%.
Example 3
About 0.4g of acytinib, 0.20g of glutaric acid are added to 180ml of ethanol/formic acid (V Ethanol :V Formic acid In the mixed solution of the component=5:1), heating to 65-70 ℃ for dissolution, stirring and refluxing for reaction for 5 hours, cooling to 20-30 ℃, controlling Wen Xijing, after crystallization, filtering, washing a filter cake with ethanol, and drying to obtain the acitinib-formic acid-glutaric acid eutectic with the purity of 99.46%.
Example 4
About 0.4g of acitinib and 0.15g of glutaric acid were added to 70ml of acetone/formic acid (V) Acetone (acetone) :V Formic acid In the mixed solution of the component=1:1), heating to 55-60 ℃ for dissolution, stirring and refluxing for reaction for 8 hours, cooling to 10-15 ℃, controlling Wen Xijing, after crystallization, filtering, washing a filter cake with isopropanol, and drying to obtain the acitinib-glutaric acid eutectic with the purity of 99.50%.
Characterization of the co-crystal of acitinib and glutaric acid
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-glutarate Co-Crystal PXRD Peak
The acitinib-glutaric acid eutectic crystal 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 axitinib-glutaric acid eutectic prepared by the invention are as follows: triclinic system, chiral space group is P-1; the unit cell parameters are:α= 111.5610 (10) °, β= 91.4540 (10) °, γ= 94.1680 (10) °, unit cell volume +.>ORTEP of the axitinib-formic acid-glutaric acid co-crystals of the invention figure 2 shows that one molecule of axitinib, one molecule of formic acid, one molecule of glutaric acid combine to form a co-crystal. The stacking diagram of the acitinib-glutaric acid eutectic crystal is shown in figure 3.
TABLE 2 principal crystallographic data of Acxitinib-glutarate cocrystals
The samples of examples 1 to 4 all have the same X-ray powder diffraction pattern, crystallographic parameters.
Comparative example 1 preparation of an axitinib-resveratrol eutectic compound, reference can be made to the following method:
sieving the mixture of the acitinib and the resveratrol (the mass ratio of the acitinib to the resveratrol is 1:3.8), adding the mixture into a hot-melt extruder (the temperature area of a hot-melt extruder module 1-6 is 140 ℃, 180 ℃, 200 ℃, 260 ℃, 192 ℃ and the rotating speed is 10r/min in sequence, feeding the mixture at the speed of 3g/min after the temperature is stabilized for 10min, sequentially performing feeding, transmission, melt mixing and output) preparation, collecting the extrudate, grinding, sieving, recrystallizing the obtained solid isopropanol, and obtaining the acitinib-resveratrol eutectic compound with the purity of 99.48 percent
Comparative example 2 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 3 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 4 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 5 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 6 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 7 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 acitinib crystal forms in 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 7 were stored under exposure to intense light (4500 lx.+ -. 500 Lx) at 25 ℃ (RH 45%), sampled over 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 prepared acitinib-glutaric acid eutectic crystal has good photostability. Examples 1 to 4 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 7 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
The Relative Humidity (RH) stability test results show that the acitinib-glutaric acid eutectic crystal has stable relative humidity.
Solubility test
The testing method comprises the following steps: the excess of the acitinib prepared in example 1 and comparative examples 1 to 7 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 available crystal XLI disclosed by the prior art, the prepared axitinib-glutaric acid eutectic phase has significantly improved solubility. Examples 1 to 4 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 to 7 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), kept at room temperature, air bubbles removed, and magnetically stirred at 45±5 RPM; the permeation accumulation was tested after 24 hours.
TABLE 6 Acetinib osmotic cumulative amount (mg/cm) 2 )
From the above-described permeability test results, it was found that the eutectic crystalline acixitinib-glutaric acid permeability of the present invention was good.
The prepared acixitinib-glutaric acid eutectic crystal has the beneficial effects on the aspects of light stability, solubility, permeability and the like, and the comprehensive performance of the acixitinib-glutaric acid eutectic crystal is remarkably improved compared with the crystal forms of the acixitinib reported in the prior art, and is more suitable for pharmaceutical preparations.
Claims (7)
1. An acitinib co-crystal, characterized in that the co-crystal is composed of an active pharmaceutical ingredient of acitinib and co-crystal ligand glutaric acid, and the co-crystal has an X-ray powder diffraction pattern shown in figure 1.
2. The axitinib co-crystal according to claim 1, wherein the molar ratio of axitinib to glutaric acid in the co-crystal is 1:1, and the co-crystal basic unit consists of one molecule of axitinib, one molecule of glutaric acid and one molecule of formic acid, and the crystallographic parameters are: triclinic system with chiral 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= 7.68920 (10) a, b= 13.7952 (2) a, c= 13.8246 (2) a, α= 111.5610 (10) °, β= 91.4540 (10) °, γ= 94.1680 (10) °, and unit cell volume v= 1358.07 (3) a 3 The structure is as follows:
3. a process for preparing the co-crystal of acitinib according to any one of claims 1-2, characterized in that it comprises the steps of: and dissolving the acitinib and the glutaric acid in a mixed solvent of an organic solvent and formic acid, heating and dissolving, controlling temperature for reflux reaction, cooling for crystallization, filtering, washing and drying to obtain the acitinib-glutaric acid eutectic.
4. The method for preparing an acitinib co-crystal according to claim 3, wherein the charging molar ratio of the acitinib to the glutaric acid is 1:1.0-1.5.
5. The method for preparing an axitinib co-crystal according to claim 3, wherein the organic solution is one or two of methanol, ethanol, isopropanol and acetone.
6. The method for preparing an acitinib cocrystal according to claim 3, wherein the heating dissolution temperature is 50-70 ℃; the temperature reduction crystallization temperature is 10-30 ℃.
7. Use of the acitinib co-crystal according to any one of claims 1-2 as an active ingredient for the preparation of an antitumor drug.
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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 |
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 |
CN112174933A (en) * | 2020-08-07 | 2021-01-05 | 天津理工大学 | Novel crystal form of axitinib fumarate and preparation method thereof |
WO2022000265A1 (en) * | 2020-06-30 | 2022-01-06 | 天津理工大学 | Cocrystals of axitinib and glutaric acid, and preparation method therefor |
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CN101048398A (en) * | 2004-11-02 | 2007-10-03 | 辉瑞大药厂 | Polymorphic forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-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 |
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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