CN111777551A - Eutectic of regorafenib and suberic acid and preparation method thereof - Google Patents
Eutectic of regorafenib and suberic acid and preparation method thereof Download PDFInfo
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- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 239000002138 L01XE21 - Regorafenib Substances 0.000 title claims abstract description 92
- 229960004836 regorafenib Drugs 0.000 title claims abstract description 92
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- 238000002360 preparation method Methods 0.000 title abstract description 20
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- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a regorafenib and suberic acid eutectic crystal and a preparation method thereof. The molar ratio of regorafenib to suberic acid in the eutectic is 1: 1, and the eutectic X-ray powder diffraction pattern has characteristic peaks at 2theta values of 11.2 +/-0.2 degrees, 13.8 +/-0.2 degrees, 14.6 +/-0.2 degrees, 16.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 21.3 +/-0.2 degrees and 22.2 +/-0.2 degrees. The preparation method of the eutectic crystal provided by the invention has the advantages of simple process, easy control of the crystallization process, good reproducibility and suitability for industrial production. The eutectic regorafenib monohydrate has lower hygroscopicity and higher apparent solubility, and is beneficial to improving the stability and the oral absorption efficiency of regorafenib.
Description
Technical Field
The invention relates to the technical field of medical chemistry, in particular to a regorafenib and suberic acid eutectic crystal and a preparation method thereof.
Background
The pharmaceutically active ingredient is usually present in crystalline forms, such as polymorphs, hydrates, solvates, salts, co-crystals and the like. Different crystalline forms have different physicochemical properties for the same pharmaceutically active ingredient. Therefore, obtaining a suitable crystalline form of a drug is of great importance in the pharmaceutical industry. The medicament exists in a eutectic form, can improve the stability, solubility, processability and the like of active ingredients of the medicament, and has remarkable advantages. Therefore, the pharmaceutical co-crystal is an effective means for improving the physicochemical properties of the active ingredients of the drugs.
Regorafenib (Regorafenib) having the chemical name 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenoxy } -N-methylpyridine-2-carboxamide, the chemical formula of which is:
regorafenib is a new drug approved by the U.S. FDA in month 9 2012 for the treatment of metastatic colorectal cancer, and its new indication (advanced gastrointestinal stromal tumor) in month 2 2013 was approved by the FDA priority review procedure. Regorafenib is a novel multi-kinase inhibitor capable of blocking a variety of enzymes that promote tumor growth, developed by Bayer corporation under the tradename Stivarga, marketed as the monohydrate of regorafenib free base. Patent CN101547903B discloses regorafenib monohydrate and a preparation method thereof. However, regorafenib monohydrate has poor water solubility and certain hygroscopicity, so that the application of regorafenib monohydrate in preparation is limited. In addition, the imported regorafenib on the market in China is expensive and difficult to bear by many patients, so that the clinical application of the regorafenib is further limited. Therefore, it is necessary to find and develop a new crystal form of regorafenib to improve its water solubility and hygroscopicity, reduce the process threshold of the preparation, and realize the replacement of import for localization. The inventor obtains the eutectic of regorafenib and suberic acid through a large amount of eutectic screening, and can effectively improve the solubility and the hygroscopicity of regorafenib.
Disclosure of Invention
One of the purposes of the invention is to provide a regorafenib and suberic acid eutectic crystal; the second purpose of the invention is to provide a preparation method of the eutectic crystal of regorafenib and suberic acid; the invention also aims to provide the application of the regorafenib and suberic acid eutectic.
Through a large number of experimental researches, the inventor tries to perform a eutectic screening experiment on regorafenib, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid and the like, and finally successfully finds the eutectic of regorafenib, malonic acid, glutaric acid, pimelic acid and suberic acid, can effectively reduce the hygroscopicity of regorafenib, improves the solubility of regorafenib, and provides a material basis for improving the stability and oral absorption of regorafenib.
The technical scheme adopted by the invention is as follows:
the invention provides a regorafenib and suberic acid eutectic crystal.
A regorafenib and suberic acid eutectic crystal has a structural formula shown in a formula (I):
in the eutectic, the molar ratio of regorafenib to suberic acid is 2: 1; the X-ray powder diffraction pattern of the eutectic measured by Cu Kalpha ray has characteristic peaks at diffraction angles 2theta of 11.2 +/-0.2 degrees, 13.8 +/-0.2 degrees, 14.6 +/-0.2 degrees, 16.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 21.3 +/-0.2 degrees and 22.2 +/-0.2 degrees.
Preferably, the X-ray powder diffraction pattern of the eutectic crystal of regorafenib and suberic acid measured by Cu Ka ray also has characteristic peaks at one or more of diffraction angles 2theta of 5.7 +/-0.2 degrees, 7.4 +/-0.2 degrees, 8.5 +/-0.2 degrees, 9.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 23.6 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.1 +/-0.2 degrees and 25.8 +/-0.2 degrees.
The invention provides a preparation method of the regorafenib and suberic acid eutectic crystal.
A preparation method of a regorafenib and suberic acid eutectic crystal comprises the following steps: feeding regorafenib and suberic acid according to the molar ratio of 2: 1, adding a proper amount of solvent, and grinding to obtain the eutectic crystal.
Preferably, in the preparation method of the eutectic crystal, the solvent is at least one of alcohol solvents. Wherein, the alcohol solvent includes but is not limited to methanol, ethanol; further preferably, the solvent is at least one selected from methanol and ethanol.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the regorafenib and the suberic acid to the using amount of the solvent during grinding is 1g to (100-200) mu L.
In some preferred embodiments of the present invention, the preparation method of the eutectic is specifically as follows: feeding regorafenib and suberic acid according to the molar ratio of 2: 1, adding a solvent, and grinding to obtain the eutectic crystal.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the regorafenib and the suberic acid to the using amount of the solvent during stirring is 1g to (2-28) mL.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the regorafenib and the suberic acid to the using amount of the solvent during grinding is 1g to (100-200) mu L.
The invention provides a pharmaceutical composition, which comprises the regorafenib and suberic acid eutectic crystal and a pharmaceutically acceptable excipient.
In the present invention, the pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, mixture or solvent related to the consistency of the administration form or pharmaceutical composition. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition.
Preferably, the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers.
The invention also provides application of the regorafenib and suberic acid eutectic in preparation of a medicament for preventing and/or treating cancer.
The invention has the beneficial effects that:
according to the invention, regorafenib is converted into a brand new regorafenib and suberic acid eutectic for the first time, and the eutectic has lower hygroscopicity and higher apparent solubility than regorafenib monohydrate, so that a material basis is provided for improving the stability and oral absorption efficiency of regorafenib.
The preparation method of the regorafenib-suberic acid eutectic crystal disclosed by the invention is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.
The regorafenib and suberic acid eutectic crystal has wide application prospect in preparation of medicaments for preventing and/or treating cancers.
Drawings
Fig. 1 is an X-ray powder diffraction pattern of a eutectic of regorafenib and suberic acid prepared in example 1;
fig. 2 is a differential scanning calorimetry trace of a eutectic of regorafenib and suberic acid prepared in example 1;
fig. 3 is a graph showing thermogravimetric analysis of eutectic crystals of regorafenib and suberic acid obtained in example 1;
fig. 4 is a fourier transform infrared spectrum of a eutectic of regorafenib and suberic acid prepared in example 1;
fig. 5 is a nuclear magnetic resonance hydrogen spectrum of a regorafenib eutectic crystal with suberic acid prepared in example 1;
fig. 6 is a dynamic moisture adsorption profile of the regorafenib co-crystal with suberic acid, regorafenib monohydrate prepared in example 1;
fig. 7 is a powder elution profile of a regorafenib co-crystal with suberic acid, regorafenib monohydrate obtained in example 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials used in the examples are, unless otherwise specified, commercially available from conventional sources.
Example 1
Weighing 1000mg of regorafenib and 180mg of suberic acid, adding the weighed regorafenib and 180mg of suberic acid into a ball milling tank, then adding 150 mu L of methanol, grinding for 60min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the regorafenib and suberic acid eutectic crystal.
Example 2
Weighing 30mg of regorafenib and 5.5mg of suberic acid, adding the weighed regorafenib and 5.5mg of suberic acid into a ball milling tank, then adding 5 mu L of methanol, grinding for 60min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the regorafenib and suberic acid eutectic crystal.
Example 3
Weighing 30mg of regorafenib and 5.5mg of suberic acid, adding the weighed regorafenib and 5.5mg of suberic acid into a ball milling tank, then adding 5 mu L of ethanol, grinding for 60min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the regorafenib and suberic acid eutectic crystal.
Comparative example
Weighing 1000mg regorafenib, adding 10mL acetonitrile and 10mL water to obtain a suspension, placing the suspension at room temperature, stirring for 24h, filtering, and drying the obtained white solid at room temperature to obtain a solid sample of regorafenib monohydrate.
Characterization analysis
The regorafenib and suberic acid eutectic crystal provided by the invention is characterized by methods such as X-ray powder diffraction, differential scanning calorimetry analysis, thermogravimetric analysis, Fourier transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum and the like.
The solid sample of the eutectic crystal of regorafenib and suberic acid obtained in example 1 was subjected to X-ray powder diffraction analysis using a diffractometer of Rigaku MiniFlex 600 model, manufactured by Nippon science Ltd., Cu K α ray
The voltage is 40 kilovolts, the current is 15 milliamps, the step length is 0.01 degrees, the scanning speed is 20 degrees/min, the scanning range is 5.0-40.0 degrees, and the test temperature is room temperature. The analysis results are shown in the X-ray powder diffraction diagram of figure 1, and the X-ray powder diffraction data are shown in Table 1.
Table 1X-ray powder diffraction data for the regorafenib co-crystal with suberic acid of example 1
The X-ray powder diffraction data of the solid sample of the eutectic crystal of regorafenib and suberic acid prepared in example 2 based on the same X-ray powder diffraction test method as example 1 are shown in table 2.
Table 2X-ray powder diffraction data for the regorafenib co-crystal with suberic acid of example 2
The X-ray powder diffraction data of the solid sample of the eutectic crystal of regorafenib and suberic acid prepared in example 3 based on the same X-ray powder diffraction test method as example 1 are shown in table 3.
Table 3X-ray powder diffraction data for the regorafenib co-crystal with suberic acid of example 3
It is well known to those skilled in the art that crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction patterns typically vary with the test conditions of the instrument. It is particularly noted that the relative intensities of the X-ray diffraction patterns may vary with the experimental conditions, so that the relative intensity order of the X-ray diffraction peaks cannot be the sole or determining factor in the characterization of crystalline material. In addition, the peak angle is usually allowed to have an error of ± 0.2 °, and due to the influence of experimental factors such as sample height and test temperature, the peak angle is shifted as a whole, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of the eutectic of regorafenib and suberic acid according to the present invention does not necessarily correspond exactly to the X-ray diffraction pattern in the present embodiment, and any situation having the same or similar characteristic peaks in this pattern is within the scope of the present invention. The skilled person will be able to compare the profile given in the present invention with a profile of an unknown substance to confirm whether the unknown substance is or is not the regorafenib co-crystal with suberic acid as described in the present invention.
Differential scanning calorimetry was performed on the solid sample of the eutectic crystal of regorafenib and suberic acid prepared in example 1, and the differential scanning calorimetry was performed by using a DSC 214 type differential calorimeter of Germany Chinesemedicine instruments, Inc., wherein the atmosphere was nitrogen, and the temperature rise rate was 10 ℃/min. The analysis result is shown in the differential scanning calorimetry diagram of figure 2. As shown in fig. 2, the eutectic crystal of regorafenib and suberic acid shows a melting endothermic peak at 144 ℃.
The solid sample of the eutectic crystal of regorafenib and suberic acid prepared in example 1 was subjected to thermogravimetric analysis using a model TG 209F 3 thermogravimetric analyzer from german chi-resistant scientific instruments ltd under nitrogen atmosphere at a temperature rise rate of 10 ℃/min. The analysis result is shown in the thermogravimetric analysis chart of FIG. 3. As shown in fig. 3, the eutectic of regorafenib and suberic acid heated to around 150 ℃ started to decompose and there was no weight loss until this temperature.
Infrared spectrum analysis is carried out on the regorafenib and suberic acid eutectic crystal sample prepared in the example 1, and the regorafenib and suberic acid eutectic crystal sample is detected by a Vertex 70 Fourier transform infrared spectrometer of Bruker company of Germany, wherein the detection range is 4000-500 cm-1The analysis result is shown in the Fourier transform infrared spectrogram of figure 4. As can be seen from FIG. 4, the characteristic peak position of the infrared spectrum is (cm)-1)：3373、3348、3294、3205、3141、3112、3070、3018、2954、2935、2871、2669、2582、1741、1710、1641、1616、1593、1546、1487、1409、1386、1352、1326、1305、1265、1224、1197、1166、1126、1031、997、968、914、894、860、823、786、696、661、570。
The hydrogen nuclear magnetic resonance spectroscopy analysis of the regorafenib and suberic acid eutectic sample prepared in example 1 is carried out by using a Vertex 70 fourier transform infrared spectrometer of Bruker, germany, and the analysis result is shown in the hydrogen nuclear magnetic resonance spectroscopy of fig. 5. The peaks of regorafenib are:1h NMR (400MHz, DMSO-d6)9.54(s, 1H), 8.88-8.72(m, 2H), 8.54(d, J ═ 5.6Hz, 1H), 8.22-8.09(m, 2H), 7.70-7.58(m, 2H), 7.46-7.30(m, 2H), 7.20(dd, J ═ 5.6, 2.6Hz, 1H), 7.09(d, J ═ 8.7Hz, 1H), 2.80(d, J ═ 4.8Hz, 3H), the peak of suberic acid is:1h NMR (400MHz, DMSO-d6)11.99(s, 2H), 2.19(t, J ═ 7.3Hz, 4H), 1.47(d, J ═ 6.5Hz, 4H), 1.26(s, 4H), from the results of integration of the characteristic peaks, the stoichiometric ratio of regorafenib to suberic acid in the co-crystal was 2: 1.
Dynamic moisture adsorption analysis
Dynamic moisture adsorption comparative analysis is carried out on powder samples of regorafenib eutectic and suberic acid and regorafenib monohydrate.
The source of the test sample is: the regorafenib and suberic acid eutectic is prepared by the method provided by embodiment 1 of the invention; regorafenib monohydrate is prepared by the process provided by the comparative examples of the present invention.
Grinding powder samples of regorafenib and suberic acid eutectic and regorafenib monohydrate, and respectively sieving the powder samples with 100-200 meshes of sieve, wherein the particle size is controlled to be 75-150 mu m. A DVS Intrasic dynamic moisture adsorption instrument of the British SMS company is adopted, the temperature is kept at 25 ℃, the system is kept in balance under the nitrogen flow with the relative humidity of 0% until the quality is kept unchanged, then the relative humidity is controlled to operate for a cycle according to the range of 0% -95% -0% in a gradient of 10%, and the change condition of the weight of the sample along with the humidity is tested. The analytical results are shown in the dynamic moisture adsorption/desorption isotherm of fig. 6. As can be seen from fig. 6, regorafenib monohydrate is dry balanced at a relative humidity of 0%, when the relative humidity is increased to 10%, the moisture absorption is increased by 1.54%, the relative humidity is continuously increased to 95%, the quality is maintained stable, and no obvious weight increase occurs; when the relative humidity is reduced, the moisture desorption curve and the adsorption curve are basically overlapped. In contrast, the hygroscopicity of the regorafenib eutectic with suberic acid is significantly improved. Along with the increase of the relative humidity, the regorafenib and suberic acid eutectic crystal slowly absorbs moisture and increases weight, when the relative humidity reaches 80%, the moisture absorption weight increase is 0.07%, the relative humidity continues to rise, the water absorption rate is accelerated, and when the relative humidity reaches 95%, the moisture absorption weight increase is 0.12%; when the relative humidity is reduced, the moisture desorption curve and the adsorption curve are basically overlapped.
Evaluation of solubility
Powder dissolution data of regorafenib co-crystal with suberic acid and regorafenib monohydrate were compared.
The source of the test sample is: the regorafenib and suberic acid eutectic is prepared by the method provided by embodiment 1 of the invention; regorafenib monohydrate is prepared by the process provided by the comparative examples of the present invention.
Powder dissolution test method: grinding powder samples of regorafenib and suberic acid eutectic and regorafenib monohydrate, and respectively sieving the powder samples with 100-200 meshes of sieve, wherein the particle size is controlled to be 75-150 mu m. Respectively weighing 21mg regorafenib monohydrate, 27mg regorafenib and suberic acid eutectic, adding into 65mL dissolution medium, taking 0.5mL solution at intervals, filtering through a 0.45 mu m microporous membrane, diluting to proper times, monitoring the drug concentration at each time point by using high performance liquid chromatography, and finally obtaining the powder dissolution curve of each sample.
Powder dissolution conditions:
dissolution medium: acetic acid-sodium acetate buffer solution of pH 4.5 containing 0.1% SDS;
stirring speed: 150 revolutions per minute;
dissolution temperature: 37 plus or minus 0.5 ℃;
sampling time: 1, 2, 3, 5, 10, 30, 60, 120, 240 minutes;
liquid phase conditions:
the instrument comprises the following steps: SHIMADZU LC-2030C 3D;
a chromatographic column: inertsil ODS C18 column (4.6 mm. times.150 mm, 5 μm);
ultraviolet detection wavelength: 261 nm;
mobile phase: acetonitrile to 0.1% trifluoroacetic acid in water 60: 40;
column temperature: 40 ℃;
flow rate: 1 mL/min;
sample introduction amount: 20 μ L.
The results are shown in the powder dissolution profile of figure 7. As shown in fig. 7, the maximum apparent solubilities of regorafenib monohydrate and the co-crystal of regorafenib and suberic acid were 0.28 ± 0.034 and 1.21 ± 0.04 μ g/mL, respectively. It can be seen that the apparent solubility of the eutectic of regorafenib and suberic acid is unexpectedly and significantly better than that of regorafenib monohydrate, and the value of the eutectic is 4.32 times that of regorafenib monohydrate.
The regorafenib and suberic acid eutectic provided by the invention can be applied to preparation of a medicament for preventing and/or treating cancers, and has a wide application prospect.
The above embodiments are only examples of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be regarded as equivalent substitutions, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. A regorafenib and suberic acid eutectic crystal is characterized in that: the structural formula of the eutectic is shown as the formula (I):
in the eutectic, the molar ratio of regorafenib to suberic acid is 2: 1; the X-ray powder diffraction pattern of the eutectic measured by Cu Kalpha rays has characteristic peaks at diffraction angles 2theta of 11.2 +/-0.2 degrees, 13.8 +/-0.2 degrees, 14.6 +/-0.2 degrees, 16.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 21.3 +/-0.2 degrees and 22.2 +/-0.2 degrees.
2. The co-crystal of claim 1, wherein: the X-ray powder diffraction pattern of the eutectic also has characteristic peaks at one or more of diffraction angles 2theta of 5.7 +/-0.2 degrees, 7.4 +/-0.2 degrees, 8.5 +/-0.2 degrees, 9.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 23.6 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.1 +/-0.2 degrees and 25.8 +/-0.2 degrees.
3. A method of preparing a co-crystal according to any one of claims 1 to 2, wherein: the method comprises the following steps of feeding regorafenib and suberic acid according to the molar ratio of 2: 1, adding a proper amount of solvent, and grinding to obtain the eutectic crystal.
4. The production method according to claim 3, characterized in that: the solvent is at least one of alcohol solvents.
5. The production method according to claim 3, characterized in that: during grinding, the total mass of regorafenib and suberic acid and the dosage of the solvent are in a ratio of 1g to (100-200) mu L.
6. A pharmaceutical composition characterized by: comprising a co-crystal according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.
7. Use of a co-crystal according to any one of claims 1 to 2 in a medicament for the treatment of cancer.
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