CN114685437B - Eutectic crystal of axitinib and saccharin - Google Patents
Eutectic crystal of axitinib and saccharin Download PDFInfo
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- C07D401/00—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
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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Abstract
The invention provides an axitinib-saccharin eutectic and relates to the technical field of crystal form drug molecules. The eutectic uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 12.53 +/-0.2 degrees, 14.71 +/-0.2 degrees, 15.05 +/-0.2 degrees, 19.12 +/-0.2 degrees, 23.32 +/-0.2 degrees, 23.40 +/-0.2 degrees, 25.87 +/-0.2 degrees and 26.16 +/-0.2 degrees; the crystallography measurement parameters were: triclinic system, chiral space group is P-1; the unit cell parameters are:
α =110.421 (3) ° β =102.340 (3) ° γ =95.395 (3) ° unit cell volume
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, in particular to an axitinib and saccharin eutectic crystal.
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 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 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, permeability 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 research on crystalline forms of axitinib, and discloses a plurality of 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, but solubility of axitinib is not greatly changed by simply changing the crystalline form of axitinib, for example, the solubility of crystalline form IV in an aqueous solution with the pH of about 1 is about 0.55mg/ml, the solubility of crystalline form IV in an aqueous solution with the pH of about 2 is only 0.157mg/ml, and the solubility of crystalline form IV in an aqueous solution with the pH of about 6.5 is only 2 μ 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 axitinib salt compounds are obviously degraded when exposed to high-intensity light and are photosensitive axitinib salts. 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.
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 in order to achieve the safety and effectiveness of the medicine, the preparation process adopting the shading process is still unavoidable.
In addition, patent WO2015067224A1 further characterizes 7 axitinic acid salts by powder diffraction data on the basis of the 7 axitinic acid formula salt compounds available as disclosed in patent WO2006048751 A1. Patent CN201510509413.7 discloses the preparation of crystalline axitinib fumarate. And then, a plurality of 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 medicine 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 of 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.
In view of the above problems, further research into advantageous crystalline forms of axitinib suitable for pharmaceutical use remains a problem to be solved.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an axitinib saccharin eutectic which has exact crystallography main parameters and atom space positions; the invention also provides a preparation method of the eutectic crystal.
The specific technical scheme of the invention is as follows:
in a first aspect, the invention provides an axitinib-saccharin eutectic, wherein the molar ratio of axitinib to saccharin is 1:
preferably, the axitinib-saccharin eutectic has characteristic peaks at 12.53 +/-0.2 degrees, 14.71 +/-0.2 degrees, 15.05 +/-0.2 degrees, 19.12 +/-0.2 degrees, 23.32 +/-0.2 degrees, 23.40 +/-0.2 degrees, 25.87 +/-0.2 degrees and 26.16 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the axitinib-saccharin eutectic has characteristic peaks at 12.53 +/-0.2 °,14.71 +/-0.2 °,15.05 +/-0.2 °,16.97 +/-0.2 °,17.21 +/-0.2 °,19.12 +/-0.2 °,20.52 +/-0.2 °,21.90 +/-0.2 °,23.32 +/-0.2 °,23.40 +/-0.2 °,25.87 +/-0.2 °,26.16 +/-0.2 °,26.99 +/-0.2 ° and 29.61 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the axitinib-saccharin co-crystal uses Cu-Ka radiation, and the characteristic peak of the axitinib-saccharin co-crystal accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the axitinib-saccharin eutectic has the crystallographic parameters of: triclinic system, chiral space group is P-1; the unit cell parameters are:
α =110.421 (3) ° β =102.340 (3) ° γ =95.395 (3) ° unit cell volume
In a second aspect, the invention provides a preparation method of axitinib-saccharin eutectic, which comprises the following steps:
dissolving the axitinib and the saccharin in the mixed solvent, heating and dissolving, then controlling the temperature and carrying out reflux reaction, cooling and crystallizing, filtering, washing, and drying to obtain the axitinib-saccharin eutectic.
Preferably, the feeding molar ratio of the axitinib to the saccharin is 1.
Preferably, the mixed solvent is a mixed solvent of an organic solvent and water, wherein the organic solution is preferably one or two of tetrahydrofuran, methanol, ethanol, isopropanol, acetone, DMF, DMSO and ethyl acetate; the mixed solvent is more preferably one of tetrahydrofuran-methanol-water, ethyl acetate-water, tetrahydrofuran-ethanol-water, DMF-methanol-water, DMF-acetone-water, and DMSO-isopropanol-water.
Preferably, the volume ratio of the organic solvent to the water in the mixed solvent is 2-4; if the organic solvent is a mixture of two solvents, the volume ratio of the more polar solvent to the less polar solvent is preferably 1.
Preferably, the mass-to-volume ratio of the axitinib to the mixed solvent is 2-5.
Preferably, the heating and dissolving temperature is 50-70 ℃.
Preferably, the temperature-controlled reflux time is 3 to 8 hours.
Preferably, the cooling crystallization temperature is 0-30 ℃; preferably 15 to 25 ℃.
In a preferred scheme, the cooling mode is program cooling, and the cooling rate is preferably 0.5-1 ℃/min.
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-saccharin co-crystal 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-saccharin eutectic serving as an active ingredient in preparation of anti-tumor drugs.
The invention has the beneficial effects that:
the axitinib-saccharin eutectic prepared by the invention is greatly improved in the aspects of stability, solubility, permeability and the like, and after the light stability is investigated, the axitinib impurity is slightly increased, and the light stability of the eutectic is good. The preparation method of the axitinib-saccharin eutectic is simple and is suitable for industrial production; the obtained eutectic crystal has regular crystal form, uniform grain size, definite crystal form and crystal water number, definite crystallography main parameters and definite atom space positions, and single crystal diffraction data shows that the eutectic 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: axitinib-saccharin eutectic X-ray powder diffraction pattern.
FIG. 2: axitinib-saccharin eutectic ORTEP diagram.
FIG. 3: acertinib-saccharin eutectic 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 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, and can also be purchased; all materials used in the other experiments without sources and specifications are commercially available analytically pure or chemically pure.
Example 1
About 0.4g of axitinib, 0.22g of saccharin was added to 120ml of ethyl acetate/water (V) Ethyl acetate :V Water (I) Heating to 60-65 ℃ for dissolving in the mixed solution of = 3), stirring, refluxing and reacting for 5 hours, cooling to 20 ℃ at the speed of 0.5 ℃/min, controlling the temperature to crystallize, filtering, washing the filter cake with methanol, and drying to obtain the axitinib-saccharin eutectic with the purity of 99.54%.
Example 2
About 0.4g of axitinib, 0.18g of saccharin was added to 100ml of tetrahydrofuran/methanol/water (V) Tetrahydrofuran (THF) :V Methanol :V Water (W) Heating to 50-60 ℃ for dissolving in a mixed solution of = 3.
Example 3
About 0.4g of axitinib, 0.27g of saccharin was added to 200ml of DMSO/isopropanol/water (V) DMSO :V Isopropanol (I-propanol) :V Water (W) Heating to 65-70 ℃ for dissolving in a mixed solution of =1 and 2).
Example 4
About 0.4g of axitinib, 0.22g of saccharin was added to 80ml of DMF/acetone/water (V) DMF :V Acetone (II) :V Water (W) Heating to 60-65 ℃ for dissolving in a mixed solution of = 1.
Example 5
About 0.4g of axitinib, 0.22g of saccharin was added to 150ml of tetrahydrofuran/ethanol/water (V) Tetrahydrofuran (THF) :V Ethanol :V Water (W) 1) =2After reacting for 4 hours, cooling to 20-30 ℃, controlling the temperature to crystallize, filtering after crystallization, washing filter cakes with ethanol, and drying to obtain the axitinib-saccharin eutectic with the purity of 99.52%.
Characterization of axitinib-saccharin cocrystal
The X-ray powder diffraction test instrument and 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; 1, an anti-scattering slit; 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-saccharin co-crystal PXRD peaks
The axitinib-saccharin eutectic 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 obtained by testing and analyzing the axitinib-saccharin eutectic prepared by the invention are as follows: triclinic system, chiral space group is P-1; the unit cell parameters are:
α =110.421 (3) °, β =102.340 (3) °, γ =95.395 (3) °, unit cell volume
ORTEP figure 2 of the axitinib-saccharin co-crystal of the present invention shows that one molecule of axitinib combines with one molecule of saccharin to form a co-crystal. The stacking diagram of the axitinib-saccharin eutectic disclosed by the invention is shown in the attached figure 3.
Table 2 main crystallographic data of axitinib-saccharin cocrystal
The samples of examples 1 to 5 all had the same X-ray powder diffraction pattern, crystallographic parameters.
Comparative example 1 preparation of axitinib-resveratrol co-crystal complex, reference may be made to the following procedure:
taking the screened 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:
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 6 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 axitinib crystalline form XXV, the following procedure can be referenced:
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 dried under vacuum 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 clearing, adding acetone (200 ml), continuously keeping the temperature, stirring for reacting for 2 hours, filtering, reducing the filtrate to-10-0 ℃ at the speed of 0.5 ℃/min, stirring for crystallization, filtering after crystallization is finished, and drying to obtain the axitinib acetone solvate with the purity of 99.47%.
The verification example:
according to the invention, 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, 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 crystalline forms prepared in example 1 and comparative examples 1 to 7 were taken, respectively, stored under exposure to intense light irradiation (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-saccharin eutectic prepared by the invention has good light stability. Examination revealed that examples 1 to 5 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 crystalline form relative humidity stability results
Note that: v represents the stability under the storage condition and the unchanged PXRD spectrum; the gamma group indicates instability under such storage conditions.
The results of the Relative Humidity (RH) stability comparisons show that the crystalline form of axitinib fumarate exhibits instability in relative humidity.
Solubility test
The test method comprises the following steps: the obtained axitinib prepared in example 1 and comparative examples 1 to 7 was added in excess to a medium comprising water and 0.01mol/L hydrochloric acid solution and PBS buffer solution (pH6.8), and the mixture was 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 in the prior art, the axitinib-saccharin eutectic prepared by the invention has remarkably improved solubility. Examination revealed that examples 1 to 5 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 crystalline axitinib forms prepared in example 1 and comparative examples 1 to 7 (10 mg based on axitinib) were taken from the donor room and suspended in 2ml of distilled water; the acceptor chamber was filled with phosphate buffer (pH = 7.4), kept at room temperature, bubbled, 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 result of the permeability test shows that the permeability of the axitinib is obviously improved after the axitinib and the saccharin are eutectic.
The axitinib-saccharin eutectic prepared by the invention has beneficial effects in the aspects of light stability, solubility, permeability and the like, and the comprehensive performance of the axitinib-saccharin eutectic is remarkably improved compared with the axitinib crystal form reported in the prior art. Compared with the crystal form XLI on the market, the penetration capacity of the axitinib-saccharin eutectic is remarkably improved, the bioavailability of the medicine can be effectively increased, and the medicine effect is improved. The good light stability effect reduces the use of opacifier auxiliary materials in the preparation of the preparation formulation, reduces the toxic and side effects of the auxiliary materials, reduces the production cost and is beneficial to the long-term storage of the medicament. The ORTEP chart of the axitinib crystal form shows that the crystal form does not contain organic solvents, is safer for medical use compared with the organic solvate of the axitinib, and is more suitable for pharmaceutical preparations.
Claims (6)
1. The axitinib eutectic is characterized in that the eutectic is composed of an active pharmaceutical ingredient axitinib and eutectic ligand saccharin; the eutectic uses Cu-Ka radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 12.53 +/-0.2 degrees, 14.71 +/-0.2 degrees, 15.05 +/-0.2 degrees, 16.97 +/-0.2 degrees, 17.21 +/-0.2 degrees, 19.12 +/-0.2 degrees, 20.52 +/-0.2 degrees, 21.90 +/-0.2 degrees, 23.32 +/-0.2 degrees, 23.40 +/-0.2 degrees, 25.87 +/-0.2 degrees, 26.16 +/-0.2 degrees, 26.99 +/-0.2 degrees and 29.61 +/-0.2 degrees.
2. The axitinib-saccharin cocrystal of claim 1, wherein the molar ratio of axitinib to saccharin in the cocrystal is 1: triclinic system, chiral space group ofP-1(ii) a The unit cell parameters are: a = 7.6162 (3) a, b = 14.9539 (5) a, c = 15.1253 (6) a, α =110.421 (3) degree, β =102.340 (3) degree, γ =95.395 (3) degree, unit cell volume V = 1550.12 (11) a 3 The structure is as follows:
3. the axitinib-saccharin co-crystal of claim 1, wherein the co-crystal has an X-ray powder diffraction pattern as shown in figure 1.
4. A method of preparing the axitinib-saccharin co-crystal of any of claims 1-3, comprising the steps of: dissolving the axitinib and the saccharin in a mixed solvent, heating for dissolving, performing temperature-controlled reflux reaction, cooling for crystallization, filtering, washing, and drying to obtain an axitinib-saccharin eutectic crystal; the mixed solvent is a mixture of an organic solvent and water, and the organic solution is one or two of tetrahydrofuran, methanol, ethanol, isopropanol, acetone, DMF, DMSO and ethyl acetate; the heating and dissolving temperature is 50 to 70 ℃; the temperature for cooling and crystallizing is 0 to 30 ℃.
5. The preparation method of the axitinib-saccharin eutectic crystal according to claim 4, wherein the feeding molar ratio of the axitinib to saccharin is 1 to 1.5.
6. Use of the axitinib-saccharin co-crystal according to any of claims 1 to 3 as an active ingredient for the preparation of an anti-tumor medicament.
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| 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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| 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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