Crystal forms, preparation methods and applications of tripterine and solvate thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemical crystallization, and particularly relates to tripterine, a crystal form of a solvate of the tripterine, a preparation method and application of the tripterine. The crystal form is a co-crystal of the tripterine and a solvent, and the ratio of the tripterine to the solvent is (45-200) mg: (1-30) mL. And the solvent is selected from C1-C4 alcohol solvents, C3-C5 ester solvents and non-polar solvents. 22 solvates and one novel polymorphic form are prepared by slurry conversion and solvent evaporation methods. The solvate is of a unique channel type structure, and solvent molecules are embedded into a three-dimensional framework constructed by a tripterine hydrogen bond network through hydrogen bonds and Van der Waals interaction. The stability of the crystal obtained by the polar solvent is obviously superior to that of the non-polar solvent, the structure-function relationship among the solvent polarity, the crystal structure and the thermal stability is clarified, and a theoretical basis and experimental guidance are provided for the preparation design of the tripterine medicine.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical crystallization, and specifically relates to a crystal form, preparation method and application of tripterygium wilfordii and a solvate thereof. Background Art

[0002] Triptolide is a natural compound with a wide range of biological activities, mainly extracted from the vine plant Tripterygium wilfordii of the Celastraceae family. The molecular formula of triptolide is C 29 H 38 O4 has a polycyclic structure, certain planarity and stability, and has multiple substituents (hydroxyl, keto, carboxyl, etc.), double bonds and chiral centers. Its structural formula is shown below: .

[0003] Tripterine has shown great potential in anti-inflammatory, anti-tumor, diabetes improvement, anti-obesity, neuroprotection, and antiviral applications. Tripterine is a natural product with significant pharmacological activity but poor water solubility and low bioavailability. The solvates it forms in different solvents significantly affect solubility and dissolution rate, thereby affecting drug processing and formulation performance. The polymorphic behavior and solvate formation mechanism of tripterine and its solvates remain underdeveloped, and the specific transformation relationship between the crystalline forms of tripterine and its solvates remains unclear. Summary of the Invention

[0004] The present invention aims to provide a crystal form, preparation method, and application of tripterygium wilfordii and its solvates, thereby overcoming the shortcomings of the prior art. The present invention uses in-depth characterization techniques such as XRPD, TGA, DSC, and HSM to clarify the structure-activity relationship between solvent polarity, crystal structure, and thermal stability. These findings provide a theoretical basis and experimental guidance for the formulation design of tripterygium wilfordii drugs.

[0005] In order to achieve the above object, the technical solution of the present invention is: In a first aspect, the present invention provides a crystalline form of a tripterygium wilfordii solvate, wherein the crystalline form is a co-crystal of tripterygium wilfordii and a solvent, wherein the mass ratio of tripterygium wilfordii to the solvent is (45-200): (1-30); The solvent is selected from one of C1-C4 alcohol solvents, C3-C5 ester solvents, dioxane, acetonitrile, acetone, methyl tert-butyl ether, petroleum ether, n-octane, n-hexane, isopropyl ether, cyclohexanone, vinyl acetate, and dimethyl carbonate.

[0006] In some other embodiments, the C1-C4 alcohol solvent includes ethanol, 1-propanol, isopropanol, 1-butanol and isobutanol; Or, C3-C5 ester solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and ethyl formate; Alternatively, the crystalline form includes ethanol solvate, 1-propanol solvate, isopropanol solvate, 1-butanol solvate, isobutanol solvate, methyl acetate solvate, ethyl acetate solvate, propyl acetate solvate, isopropyl acetate solvate, ethyl formate solvate, dioxane solvate, acetonitrile solvate, acetone solvate, methyl tert-butyl ether solvate, petroleum ether solvate, n-octane solvate, n-hexane solvate, isopropyl ether solvate, cyclohexanone solvate, vinyl acetate solvate and dimethyl carbonate solvate.

[0007] In some other embodiments, the X-ray powder diffraction pattern of the ethyl acetate solvate using Cu-Kα radiation has characteristic peaks at 2θ values ​​of 12.5°±0.2°, 13.1°±0.2°, 14.5°±0.2°, 17.3°±0.2°, 18.0°±0.2°, and 22.5°±0.2°; Or, the X-ray powder diffraction pattern of methyl acetate solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 16.2°±0.2°, 18.0°±0.2°, 20.5°±0.2°, and 23.1°±0.2°; Or, the X-ray powder diffraction pattern of the isobutanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0.°±0.2°, 16.2°±0.2°, 17.1°±0.2°, 18.0°±0.2°, and 22.1°±0.2°; Or, the X-ray powder diffraction pattern of the 1-butanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 14.3°±0.2°, 15.5°±0.2°, 16.1°±0.2°, and 22.1°±0.2°; Or, the X-ray powder diffraction pattern of the isopropanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 20.2°±0.2°, and 22.0°±0.2°; Or, the X-ray powder diffraction pattern of the 1-propanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 13.2°±0.2°, 16.1°±0.2°, 19.2°±0.2°, 21.0°±0.2°, and 22.5°±0.2°; Or, the X-ray powder diffraction pattern of the ethanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 13.1°±0.2°, 16.5°±0.2°, 19.0°±0.2°, and 21.1°±0.2°; Or, the X-ray powder diffraction pattern of methyl tert-butyl ether solvate has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 7.2°±0.2°, 11.0°±0.2°, 13.1°±0.2°, 15.0°±0.2°, 17.5°±0.2°, and 18.5°±0.2°; Alternatively, the X-ray powder diffraction pattern of acetone solvate II has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 13.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.5°±0.2°, and 21.1°±0.2°; Or, the X-ray powder diffraction pattern of acetone solvate I has characteristic peaks at 2θ values ​​of 8.5°±0.2°, 11.0°±0.2°, 14.1°±0.2°, 16.2°±0.2°, 17.1°±0.2°, and 19.0°±0.2°; Or, the 2θ values ​​of the diffraction peaks of the acetonitrile solvate are: characteristic peaks at 9.0°±0.2°, 9.5°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 16.1°±0.2°, and 16.5°±0.2°; Or, the X-ray powder diffraction pattern of the dioxane solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 12.5°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 16.1°±0.2°, and 24.0°±0.2°; Or, the X-ray powder diffraction pattern of ethyl formate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 24.0°±0.2°; Or, the X-ray powder diffraction pattern of isopropyl acetate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 26.1°±0.2°; Or, the X-ray powder diffraction pattern of propyl acetate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 18.0°±0.2°, 20.5°±0.2°, and 23.0°±0.2°; Or, the X-ray powder diffraction pattern of the dimethyl carbonate solvate has characteristic peaks at 2θ values ​​of 12.1°±0.2°, 13.0°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 17.0°±0.2°, and 19.1°±0.2°; Alternatively, the X-ray powder diffraction pattern of vinyl acetate solvate I has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 17.0°±0.2°, and 25.0°±0.2°; Alternatively, the X-ray powder diffraction pattern of vinyl acetate solvate II has characteristic peaks at 2θ values ​​of 10.0°±0.2°, 13.1°±0.2°, and 16.0°±0.2°; Or, the X-ray powder diffraction pattern of the cyclohexanone solvate has characteristic peaks at 2θ values ​​of 13.0°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 16.0°±0.2°, 17.0°±0.2°, and 18.0°±0.2°; Or, the X-ray powder diffraction pattern of the isopropyl ether solvate has characteristic peaks at 2θ values ​​of 7.0°±0.2°, 8.1°±0.2°, 12.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 17.1°±0.2°; Or, the X-ray powder diffraction pattern of the n-hexane solvate has characteristic peaks at 2θ values ​​of 5.1°±0.2°, 9.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 17.0°±0.2°, and 18.0°±0.2°; the X-ray powder diffraction pattern of the n-octane solvate has characteristic peaks at 2θ values ​​of 5.0°±0.2°, 9.0°±0.2°, 11.2°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 18.0°±0.2°; Alternatively, the X-ray powder diffraction pattern of the petroleum ether solvate has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 7.1°±0.2°, 11.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 18.0°±0.2°.

[0008] In some other embodiments, the ethanol solvate loses 5.15% of its weight when heated to 161.57° C. in a thermogravimetric analysis curve; Alternatively, the 1-propanol solvate loses 6.34% of its weight when heated to 168.71°C according to the thermogravimetric analysis curve; Alternatively, the isopropanol solvate loses 6.28% of its weight when heated to 120.21°C in the thermogravimetric analysis curve; Alternatively, the 1-butanol solvate loses 7.09% of its weight when heated to 104.25°C according to the thermogravimetric analysis curve; Alternatively, the isobutanol solvate loses 8.05% of its weight when heated to 145.49°C according to the thermogravimetric analysis curve; Alternatively, the thermogravimetric analysis curve of methyl acetate solvate shows a weight loss of 7.47% when heated to 124.24°C; Alternatively, the ethyl acetate solvate loses 8.36% of its weight when heated to 156.35°C according to the thermogravimetric analysis curve; Alternatively, the thermogravimetric analysis curve of propyl acetate solvate shows a weight loss of 5.21% when heated to 153.31°C; Alternatively, the thermogravimetric analysis curve of isopropyl acetate solvate shows a weight loss of 10.84% ​​when heated to 141.01°C; Alternatively, the thermogravimetric analysis curve of ethyl formate solvate shows a weight loss of 8.23% when heated to 126.46°C; Alternatively, the thermogravimetric analysis curve of the dioxane solvate shows a weight loss of 10.47% when heated to 171.91°C; Alternatively, the acetonitrile solvate loses 5.05% of its weight when heated to 170.54 °C in the thermogravimetric analysis curve; Alternatively, the thermogravimetric analysis curve of acetone solvate I shows a weight loss of 7.68% when heated to 142.83°C; Alternatively, the thermogravimetric analysis curve of acetone solvate II shows a weight loss of 6.25% when heated to 123.81°C; Alternatively, the thermogravimetric analysis curve of methyl tert-butyl ether solvate shows a weight loss of 16.42% when heated to 118.30°C; Alternatively, the thermogravimetric analysis curve of n-octane solvate shows a weight loss of 14.79% when heated to 124.31°C; Alternatively, the thermogravimetric analysis curve of the isopropyl ether solvate shows a weight loss of 13.71% when heated to 102.54°C; Alternatively, the thermogravimetric analysis curve of cyclohexanone solvate shows a weight loss of 23.83% when heated to 129.28°C; Alternatively, the thermogravimetric analysis curve of vinyl acetate solvate I shows a weight loss of 11.60% when heated to 198.96°C; Alternatively, the dimethyl carbonate solvate loses 8.74% of its weight when heated to 154.65° C. according to a thermogravimetric analysis curve.

[0009] In some other embodiments, the differential scanning calorimetry (DSC) curve of the ethanol solvate exhibits an endothermic peak at 161.57° C. and an exothermic peak at 216.50° C.; Alternatively, the differential scanning calorimetry (DSC) curve of the 1-propanol solvate exhibits an endothermic peak at 168.71°C and an exothermic peak at 228.83°C; Alternatively, the differential scanning calorimetry (DSC) curve of the isopropanol solvate exhibits an endothermic peak at 161.23°C and an exothermic peak at 205.07°C; Alternatively, the differential scanning calorimetry (DSC) curve of the 1-butanol solvate exhibits an endothermic peak at 104.25°C and an exothermic peak at 221.32°C; Alternatively, the differential scanning calorimetry (DSC) curve of the isobutanol solvate exhibits an endothermic peak at 145.49°C and an exothermic peak at 220.50°C; Alternatively, the differential scanning calorimetry (DSC) curve of methyl acetate solvate exhibits an endothermic peak at 124.24°C and an exothermic peak at 206.55°C; Alternatively, the differential scanning calorimetry (DSC) curve of the ethyl acetate solvate exhibits an endothermic peak at 156.35°C and an exothermic peak at 208.08°C; Alternatively, the differential scanning calorimetry (DSC) curve of propyl acetate solvate exhibits an endothermic peak at 153.31°C and an exothermic peak at 225.15°C; Alternatively, the differential scanning calorimetry (DSC) curve of isopropyl acetate solvate exhibits an endothermic peak at 141.01°C and an exothermic peak at 225.31°C; Alternatively, the differential scanning calorimetry (DSC) curve of the dioxane solvate exhibits an endothermic peak at 171.91°C and an exothermic peak at 215.75°C; Alternatively, the differential scanning calorimetry (DSC) curve of the acetonitrile solvate exhibits an endothermic peak at 191.87°C and an exothermic peak at 220.74°C; Alternatively, the differential scanning calorimetry (DSC) curve of acetone solvate I shows an endothermic peak at 142.83°C and an exothermic peak at 214.96°C; Alternatively, the differential scanning calorimetry (DSC) curve of acetone solvate II shows an endothermic peak at 123.81°C and an exothermic peak at 198.39°C; Alternatively, the differential scanning calorimetry (DSC) curve of methyl tert-butyl ether solvate exhibits an endothermic peak at 118.30°C and an exothermic peak at 198.17°C; Alternatively, the differential scanning calorimetry (DSC) curve of the n-octane solvate exhibits an endothermic peak at 124.31°C and an exothermic peak at 217.51°C in the thermogravimetric analysis curve; Alternatively, the differential scanning calorimetry (DSC) curve of the cyclohexanone solvate shows an endothermic peak at 129.28°C and an exothermic peak at 206.38°C.

[0010] In a second aspect, the present invention provides a method for preparing the crystalline form of the tripterygium wilfordii solvate according to the first aspect, characterized in that the method comprises the following steps: Add tripterygium wilfordii into the solvent, stir and mix evenly, filter out the solvent, and allow to stand to obtain the product; Among them, the ratio of tripterygium wilfordii to solvent is (45-200) mg: (1-30) mL; The solvent is selected from one of C1-C4 alcohol solvents, C3-C5 ester solvents, dioxane, acetonitrile, acetone, methyl tert-butyl ether, petroleum ether, n-octane, n-hexane, isopropyl ether, cyclohexanone, vinyl acetate, and dimethyl carbonate; The stirring time is 4 hours to 5 days, the stirring temperature is 5-80° C., and the stirring speed is 300-500 rpm; and the standing time is 1-50 days.

[0011] In some other embodiments, the ethanol solvate is prepared as follows: 101.3 mg of tripterygium wilfordii is added to 8 mL of ethanol, and the mixture is stirred at 400 rpm at room temperature for 12 hours. After stirring, the solution is filtered and then slowly evaporated, and red square single crystals begin to form after 6 days. Alternatively, the 1-propanol solvate was prepared as follows: 100.4 mg of triptolide was added to 10 mL of 1-propanol, stirred at 400 rpm at room temperature for 24 hours, filtered and the solvent was slowly evaporated, and red square single crystals appeared after 10 days; Alternatively, the isopropanol solvate was prepared as follows: 50 mg of tripterygium wilfordii was added to 8 mL of isobutanol, stirred at 80°C for 4 hours, and then filtered. The solvent was then slowly evaporated, and single crystals began to form after 25 days; Alternatively, the 1-butanol solvate was prepared as follows: 100.1 mg of triptolide was dissolved in 10 mL of 1-butanol, stirred at 400 rpm at room temperature for 24 hours, filtered, and the solvent was slowly evaporated, and red square single crystals were precipitated after 30 days; Alternatively, the isobutanol solvate was prepared as follows: 200 mg of tripterygium wilfordii was mixed with 20 mL of isobutanol, stirred at 400 rpm at room temperature for 48 hours, and then filtered. 10 mL of the filtrate was slowly evaporated, and red single crystals began to form after 15 days. Alternatively, the methyl acetate solvate was prepared as follows: 100.7 mg of tripterygium wilfordii was added to 10 mL of methyl acetate, stirred at 400 rpm at room temperature for 12 hours, filtered, and slowly evaporated, and red square single crystals appeared after 2 days; Alternatively, the ethyl acetate solvate is prepared as follows: 50 mg of tripterygium wilfordii is dissolved in 5 mL of ethyl acetate, filtered, and the solvent is slowly evaporated to precipitate red single crystals after 5 days; Alternatively, the propyl acetate solvate is prepared as follows: 100 mg of tripterygium wilfordii is added to 8 mL of propyl acetate, filtered, and slowly evaporated to form red crystals after 5 days; Alternatively, the preparation method of isopropyl acetate solvate is as follows: 50 mg of tripterygium wilfordii is dissolved in 1 mL of isopropyl acetate, placed in an environment of 5-50°C for 5 days to slowly evaporate, and crystals are precipitated after 2 days; Alternatively, the ethyl formate solvate was prepared as follows: 49.9 mg of tripterygium wilfordii was added to 8 mL of ethyl formate, stirred at 400 rpm at room temperature for 5 days, filtered and slowly evaporated, and single crystals appeared after 2 days; Alternatively, a dioxane solvate was prepared as follows: 100 mg of triptolide was dissolved in 20 mL of 1,4-dioxane, stirred at 400 rpm for 5 days, allowed to stand for 24 hours, filtered, and slowly evaporated. Single crystals formed after 20 days. Alternatively, the acetonitrile solvate was prepared as follows: 100 mg of tripterygium wilfordii was added to 30 mL of acetonitrile, stirred at 400 rpm at 80°C for 4 hours, filtered, and slowly evaporated at room temperature, and single crystals were precipitated after 2 days; Alternatively, acetone solvates I and II were prepared as follows: 100.6 mg of triptolide was dissolved in 20 mL of acetone, stirred at 400 rpm at room temperature (25 ± 2°C) for 5 days, filtered, and slowly evaporated. Two crystalline forms were observed after approximately 48 hours: red square single crystals of acetone solvate I and rhombohedral single crystal aggregates of acetone solvate II. Alternatively, the preparation method of methyl tert-butyl ether solvate is as follows: 50 mg of tripterygium wilfordii is dissolved in 10 mL of methyl tert-butyl ether, filtered, and slowly evaporated at room temperature to form bulk single crystals within 24 hours; Alternatively, the petroleum ether solvate was prepared as follows: 100 mg of triptolide was suspended in 20 mL of petroleum ether, stirred at 400 rpm at room temperature for 5 days, allowed to stand for 24 hours, filtered, and the solvent was slowly evaporated, and crystals formed after 5 days; Alternatively, the n-octane solvate was prepared as follows: 100.7 mg of triptolide was dissolved in 20 mL of n-octane, stirred continuously at 400 rpm at room temperature for 5 days, filtered, and the solvent was slowly evaporated to obtain a single crystal after 10 days; Alternatively, the n-hexane solvate was prepared as follows: 101.9 mg of tripterygium wilfordii was suspended in 20 mL of n-hexane, stirred continuously at 400 rpm at room temperature for 5 days, filtered, and the solvent was slowly evaporated, and single crystals were precipitated after 50 days; Alternatively, the preparation method of the isopropyl ether solvate is as follows: 100 mg of tripterygium wilfordii is added to 20 mL of isopropyl ether, stirred at 400 rpm at 80°C for 4 hours, filtered, and slowly evaporated at room temperature, and a crystalline product is formed after 6 days; or, the preparation method of the cyclohexanone solvate is as follows: 100 mg of tripterygium wilfordii is added to 20 mL of cyclohexanone, stirred at 400 rpm at room temperature for 5 days, allowed to stand for 24 hours, filtered, and the solvent was slowly evaporated, and crystals began to form after 15 days; Alternatively, vinyl acetate solvates I and II were prepared as follows: 0.05 g of tripterygium wilfordii was added to 8 mL of vinyl acetate, heated at 80°C and stirred at 400 rpm for 4 hours, filtered, and the solvent was slowly evaporated. After 35 days, two different vinyl acetate solvate crystal forms I and II appeared; Alternatively, the preparation method of dimethyl carbonate solvate is as follows: 0.05 g of triptolide is dissolved in 8 mL of dimethyl carbonate, stirred at 400 rpm at 80° C. for 4 hours, filtered, and then the solvent is slowly evaporated to form single crystals after 30 days.

[0012] In a third aspect, the present invention provides a solvent-free crystalline form II of tripterygium wilfordii. When Cu-Kα radiation is used, the X-ray powder diffraction pattern of the solvent-free crystalline form II of tripterygium wilfordii has characteristic peaks at 2θ values ​​of 9.4°±0.2°, 13.5°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 17.0°±0.2°, 18.2°±0.2°, 18.9°±0.2°, and 19.2°±0.2°. In the thermogravimetric analysis curve, weight loss begins when heated at 317-300°C; The differential scanning calorimetry (DSC) curve showed an endothermic peak at 191.8°C.

[0013] In a fourth aspect, the present invention provides a method for preparing the solvent-free crystal form II of tripterygium wilfordii described in the third aspect, comprising the following steps: dissolving 0.10 g of tripterygium wilfordii in 20 mL of cyclohexanone, cyclically heating and cooling at 5-50°C for 24 hours at a heating and cooling rate of 11-11.5°C / h, slowly evaporating the solvent after filtering, and forming single crystals after 10 days.

[0014] In a fifth aspect, the present invention provides the use of the crystalline form of the tripterygium wilfordii solvate described in the first aspect or the solvent-free crystalline form II of tripterygium wilfordii described in the third aspect in the preparation of anti-inflammatory, anti-tumor, diabetes-improving, anti-obesity, neuroprotective, and antiviral products.

[0015] In a sixth aspect, the present invention provides a pharmaceutical composition preparation comprising the crystalline form of the tripterygium wilfordii solvate described in the first aspect or the solvent-free crystalline form II of tripterygium wilfordii described in the fourth aspect and a pharmaceutically acceptable carrier.

[0016] Beneficial effects of the present invention: (1) The present invention discovered 22 solvates and solvent-free crystal form II, which were characterized in depth by XRPD, TGA, and DSC techniques, and the relationship between crystal structure and thermal phase transition behavior was analyzed. This can be used to improve the solubility, dissolution rate, and stability of the compound, thereby affecting drug processing. The solvates exhibit a unique channel-type structure, in which solvent molecules are embedded in the three-dimensional framework constructed by the hydrogen bond network of tripterygium wilfordii through hydrogen bonds and van der Waals interactions. The stability of the crystals obtained in polar solvents is significantly better than that in non-polar solvents, which clarifies the structure-activity relationship between solvent polarity, crystal structure, and thermal stability, and provides a theoretical basis and experimental guidance for the formulation design of tripterygium wilfordii drugs.

[0017] (2) The present invention prepares 22 solvates by slurry conversion and solvent evaporation. The preparation method is simple and can systematically explore the crystal structure of tripterygium wilfordii formed with different solvents. The solubility is 2-10 times higher than that of tripterygium wilfordii, which is convenient for improving the solubility, dissolution rate and stability of the compound, thereby facilitating drug product design and process development.

[0018] (3) The crystalline form of the tripterygium wilfordii solvate or the solvent-free crystalline form of tripterygium wilfordii of the present invention is beneficial to improving the bioavailability of tripterygium wilfordii and ensuring the quality, safety and effectiveness of the prepared products such as pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0020] Figure 1 The PXRD patterns corresponding to the tripterygium wilfordii solvate and solvent-free crystalline form of the present invention are as follows; Figure 2 This is the crystal morphology of the tripterygium wilfordii solvate of the present invention; Figure 3 The thermal analysis diagram of the tripterygium wilfordii solvate of the present invention, wherein a is S EtOH TGA and DSC diagrams, b is S 1-PrOH TGA and DSC diagrams, c is S 1-BuOH TGA and DSC diagrams, d is S IBA TGA and DSC diagrams; Figure 4The thermal analysis diagram of the tripterygium wilfordii solvate of the present invention, wherein a is S MA TGA and DSC diagrams, b is S EA TGA and DSC diagrams, c is S PA TGA and DSC diagrams, d is S IPAc TGA and DSC diagrams; Figure 5 The thermal analysis diagram of the tripterygium wilfordii solvate of the present invention, wherein a is S Dioxane TGA and DSC diagrams, b is S ACN TGA and DSC diagrams, c is S Acetone Ⅰ TGA and DSC diagrams, d is S Acetone Ⅱ TGA and DSC diagrams; Figure 6 The thermal analysis diagram of the tripterygium wilfordii solvate of the present invention, wherein a is S MTBE TGA and DSC diagrams, b is S Octane TGA and DSC diagrams, c is S IPA 、S EF and S IPE TGA diagram of d is S CYC 、S VAM Ⅰ and S DMC TGA diagram of Figure 7 For the ethanol solvate of the present invention (S ETOH ) 1H NMR spectrum; Figure 8 The crystal structure diagram of the tripterygium wilfordii crystal form II of the present invention, including (a) the asymmetric unit of the type II crystal, (b) a schematic diagram of the hydrogen bond connection of the asymmetric unit, (c) the two-dimensional chain structure observed along the b-axis, and (d) the three-dimensional chain structure observed along the c-axis. DETAILED DESCRIPTION

[0021] Those skilled in the art will understand that the following examples are intended to illustrate the present invention only and should not be construed as limiting its scope. Unless otherwise specified in the examples, the experiments were conducted under conventional conditions or manufacturer's recommendations. Components used without manufacturer identification are commercially available conventional products. The celastrol sample (CAS: 34157-83-0, purity ≥98%) was purchased from Hubei Feirui Chemical Co., Ltd. Solvents used in the experiments were obtained from commonly available commercial suppliers.

[0022] The testing instruments and methods used are as follows: Powder X-ray Diffraction (PXRD): PXRD measurements were performed using a MiniFlex600 diffractometer (CuKα radiation, wavelength 1.5405 Å). The tube voltage and current were set to 40 kV and 30 mA, respectively. The measurement angle (2θ) range was 10°–50°, with a scan rate of 8° / min and a step size of 0.02°. The obtained PXRD patterns were compared with those obtained from single crystal structure calculations to confirm the crystalline composition.

[0023] Crystal morphology (CM): The crystal morphology was observed using a WYT-ET trinocular continuous zoom stereo microscope, which allowed for clear observation of the unique surface features of each sample.

[0024] Proton nuclear magnetic resonance spectroscopy (1H NMR): 1H NMR spectra of triptolide solvate were acquired using a Bruker AVANCE III HD 400 MHz NMR spectrometer. Data were processed and analyzed using MestReNova software.

[0025] Single crystal X-ray diffraction (SCXRD): S AcetoneⅠ 、S AcetoneⅡ SCXRD measurements of SMTBE, SHeptane, SIPE, SVAM I, and SVAM II were performed on a Bruker D8 VENTURE three-circle diffractometer (CuKα radiation, λ = 1.54178 Å), equipped with a microfocus sealed X-ray tube, a mirror monochromator, and a CCD area detector. Data were integrated using the SAINT program, and absorption correction was performed using SADABS. The remaining single crystals were measured on an XtaLAB Synergy four-circle diffractometer (CuKα radiation, λ = 1.54184 Å), equipped with a microfocus sealed X-ray tube, a mirror monochromator, and a HyPix detector. Data were integrated using the Crysalispro program, and multi-scan absorption correction was performed using SCALE3 ABSPACK. The crystal structure was solved using SHELXT two-space group solution, and refined using SHELXL with full-matrix least-squares F2-based refinement (using Olex2 software). All non-hydrogen atoms were refined using anisotropic displacement parameters, and the CH hydrogen atoms were theoretically added and refined using the riding model.

[0026] Thermogravimetric analysis (TGA) was performed using a Mettler-Toledo TGA / DSC 3+ thermogravimetric analyzer (Switzerland). 5–10 mg of sample was accurately weighed and placed in a ceramic crucible. The crucible was heated from 25°C to 300°C at a rate of 10°C / min under a nitrogen atmosphere (flow rate of 10 mL / min).

[0027] Differential Scanning Calorimetry (DSC): Analyses were performed using a Mettler-Toledo DSC3 differential scanning calorimeter (Switzerland). The instrument was calibrated with indium and zinc for heat capacity and cell constant. 3–5 mg of ground sample was placed in a sealed aluminum sample pan and heated at a rate of 10°C / min from 25°C to 200°C or 300°C under a nitrogen flow of 50 mL / min.

[0028] The crystal form and preparation method of tripterygium wilfordii and its solvate prepared by the present invention are further described below in conjunction with specific embodiments: Example 1 A crystal form of tripterygium wilfordii alcohol solvate and preparation method thereof Tripterygium wilfordii alcohol solvates include S EtOH (ethanol solvate), S 1-PrOH (1-propanol solvate), S IPA (isopropyl alcohol solvate), S 1-BuOH (1-Butanol solvate) and S IBA (isobutanol solvate). The specific preparation method is as follows: S EtOH (Ethanol Solvate): 101.3 mg of triptolide was added to 8 mL of ethanol and stirred at 400 rpm at room temperature for 12 hours. After stirring, the solution was filtered and then slowly evaporated. Red, square single crystals began to form after 6 days.

[0029] S 1-PrOH (1-Propanol Solvate): Add 100.4 mg of triptolide to 10 mL of 1-propanol and stir at 400 rpm at room temperature for 24 hours. Filter and slowly evaporate the solvent. Red, square single crystals will appear after 10 days.

[0030] S IPA (Isopropanol Solvate): Add 50 mg of tripterygium wilfordii to 8 mL of isobutanol, stir at 80°C for 4 hours, filter, and slowly evaporate the solvent. Single crystals will begin to form after 25 days.

[0031] S 1-BuOH (1-Butanol Solvate): Dissolve 100.1 mg of triptolide in 10 mL of 1-butanol. Stir at 400 rpm at room temperature for 24 hours. Filter and slowly evaporate the solvent. Red, square single crystals will precipitate after 30 days.

[0032] S IBA (Isobutanol Solvate): Mix 200 mg of triptolide with 20 mL of isobutanol. Stir at 400 rpm for 48 hours at room temperature, then filter. Slowly evaporate 10 mL of the filtrate. Red single crystals will begin to form after 15 days.

[0033] Example 2 A crystal form of tripterygium wilfordii ester solvate and preparation method thereof Celastrol ester solvates include S MA (methyl acetate solvate), S EA (ethyl acetate solvate), S PA (propyl acetate solvate), S IPAc (isopropyl acetate solvate) and S EF (Ethyl formate solvate). The specific preparation method is as follows: S MA (Methyl acetate solvate): Add 100.7 mg of tripterygium wilfordii to 10 mL of methyl acetate and stir at 400 rpm for 12 hours at room temperature. Filter and evaporate slowly. Red square single crystals will appear after 2 days.

[0034] S EA (Ethyl acetate solvate): Dissolve 50 mg of tripterygium wilfordii in 5 mL of ethyl acetate, filter, and slowly evaporate the solvent. Red single crystals will precipitate after 5 days.

[0035] S PA (Propyl acetate solvate): Add 100 mg of tripterygium wilfordii to 8 mL of propyl acetate, filter, and evaporate slowly. Red crystals will form after 5 days.

[0036] S IPAc (Isopropyl acetate solvate): Dissolve 50 mg of tripterygium wilfordii in 1 mL of isopropyl acetate and allow to evaporate slowly at 5-50°C for 5 days. Crystals will precipitate after 2 days.

[0037] S EF (Ethyl formate solvate): Add 49.9 mg of tripterygium wilfordii to 8 mL of ethyl formate and stir at 400 rpm for 5 days at room temperature. Filter and evaporate slowly. Single crystals will appear after 2 days.

[0038] Example 3 A crystal form of a non-polar solvate of tripterygium wilfordii and a preparation method thereof Non-polar solvates of tripterygium wilfordii include S Dioxane (dioxane solvate), S ACN (acetonitrile solvate), S Acetone Ⅰ and S Acetone Ⅱ (acetone solvate), S MTBE (methyl tert-butyl ether solvate), S PE (petroleum ether solvate), S Octane (n-octane solvate), S Heptane (n-hexane solvate), SIPE (isopropyl ether solvate), S CYC (cyclohexanone solvate), S VAM Ⅰ and S VAM Ⅱ (vinyl acetate solvate) and S DMC (Dimethyl carbonate solvate). The specific preparation method is as follows: S Dioxane (Dioxane Solvate): Dissolve 100 mg of triptolide in 20 mL of 1,4-dioxane and stir at 400 rpm for 5 days. Allow to stand for 24 hours, then filter and evaporate slowly. Single crystals will form after 20 days.

[0039] S ACN (Acetonitrile Solvate): Add 100 mg of triptolide to 30 mL of acetonitrile and stir at 400 rpm at 80°C for 4 hours. Filter and evaporate slowly at room temperature. Single crystals will precipitate after 2 days.

[0040] S Acetone Ⅰ and S Acetone Ⅱ (Acetone solvate): 100.6 mg of tripterygium wilfordii was dissolved in 20 mL of acetone and stirred at 400 rpm for 5 days at room temperature (25±2°C). After filtration, the mixture was slowly evaporated. Two crystal forms were observed after about 48 hours: red square single crystal (S Acetone Ⅰ ) and rhombohedral single crystal aggregates (S Acetone Ⅱ ).

[0041] S MTBE (Methyl tert-butyl ether solvate): Dissolve 50 mg of triptolide in 10 mL of methyl tert-butyl ether, filter, and slowly evaporate at room temperature. Single crystals will form within 24 hours.

[0042] S PE (Petroleum ether solvate): Suspend 100 mg of triptolide in 20 mL of petroleum ether and stir at 400 rpm at room temperature for 5 days. After standing for 24 hours, filter and slowly evaporate the solvent. Crystals will form after 5 days.

[0043] S Octane (n-Octane Solvate): Dissolve 100.7 mg of triptolide in 20 mL of n-octane. Stir continuously at 400 rpm for 5 days at room temperature. Filter and slowly evaporate the solvent. Single crystals were obtained after 10 days.

[0044] S Heptane (n-Hexane Solvate): Suspend 101.9 mg of triptolide in 20 mL of n-hexane and stir continuously at 400 rpm for 5 days at room temperature. Filter and slowly evaporate the solvent. Single crystals will precipitate after 50 days.

[0045] S IPE(Isopropyl ether solvate): Add 100 mg of tripterygium wilfordii to 20 mL of isopropyl ether, stir at 400 rpm at 80°C for 4 hours, filter, and evaporate slowly at room temperature. Crystallize after 6 days.

[0046] S CYC (Cyclohexanone solvate): Add 100 mg of tripterygium wilfordii to 20 mL of cyclohexanone and stir at 400 rpm for 5 days. After standing for 24 hours, filter and slowly evaporate the solvent. Crystals will begin to form after 15 days.

[0047] S VAM Ⅰ and S VAM Ⅱ (Vinyl acetate solvate): Add 0.05 g of tripterygium wilfordii to 8 mL of vinyl acetate, heat at 80°C, and stir at 400 rpm for 4 hours. Filter and slowly evaporate the solvent. Two distinct crystalline forms (SVAM I and SVAM II) appear after 35 days.

[0048] S DMC (Dimethyl carbonate solvate): Dissolve 0.05 g of triptolide in 8 mL of dimethyl carbonate. Stir at 400 rpm at 80°C for 4 hours. Filter and slowly evaporate the solvent. Single crystals will form after 30 days.

[0049] Example 4 A solvent-free crystal form II of tripterygium wilfordii and its preparation method The preparation method of the solvent-free crystal form II of tripterygium wilfordii comprises the following steps: 0.10 g of triptolide was dissolved in 20 mL of cyclohexanone and heated and cooled in a cycle of 5-50°C for 24 hours at a heating and cooling rate of 11.2°C / h. After filtration, the solvent was slowly evaporated and single crystals were formed after 10 days.

[0050] Example 5 A solvent-free crystal form I of tripterygium wilfordii and its preparation method The preparation method of the solvent-free crystalline form I of tripterygium wilfordii comprises the following steps: S Dioxane 、S ACN 、S Acetone Ⅰ and S Acetone Ⅱ or S MTBE The solvate is heated for 6 hours and then cooled to obtain Form I.

[0051] Performance Characterization The structural complexity of the tripterygium wilfordii molecule with multiple substituents and chiral centers gives it significant potential for polymorphic diversity. The present invention systematically screened polymorphs using slurry conversion and solvent evaporation technology, successfully identifying 23 tripterygium wilfordii solvates and one new polymorph (Form II) under different solvent conditions. The corresponding PXRD patterns are shown in Figure 2. Figure 1 shown.

[0052] pass Figure 1 The diffraction peak 2θ values ​​of different crystal forms can be analyzed as follows: When using Cu-Kα radiation, the X-ray powder diffraction pattern of ethyl acetate solvate has characteristic peaks at 2θ values ​​of 12.5°±0.2°, 13.1°±0.2°, 14.5°±0.2°, 17.3°±0.2°, 18.0°±0.2°, and 22.5°±0.2°; The X-ray powder diffraction pattern of methyl acetate solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 16.2°±0.2°, 18.0°±0.2°, 20.5°±0.2°, and 23.1°±0.2°; The X-ray powder diffraction pattern of the isobutanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 16.2°±0.2°, 17.1°±0.2°, 18.0°±0.2°, and 22.1°±0.2°; The X-ray powder diffraction pattern of 1-butanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 14.3°±0.2°, 15.5°±0.2°, 16.1°±0.2°, and 22.1°±0.2°; The X-ray powder diffraction pattern of the isopropanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 20.2°±0.2°, and 22.0°±0.2°; The X-ray powder diffraction pattern of 1-propanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 13.2°±0.2°, 16.1°±0.2°, 19.2°±0.2°, 21.0°±0.2°, and 22.5°±0.2°; The X-ray powder diffraction pattern of the ethanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 13.1°±0.2°, 16.5°±0.2°, 19.0°±0.2°, and 21.1°±0.2°; The X-ray powder diffraction pattern of methyl tert-butyl ether solvate has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 7.2°±0.2°, 11.0°±0.2°, 13.1°±0.2°, 15.0°±0.2°, 17.5°±0.2°, and 18.5°±0.2°; The X-ray powder diffraction pattern of acetone solvate II has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 13.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.5°±0.2°, and 21.1°±0.2°; The X-ray powder diffraction pattern of acetone solvate I has characteristic peaks at 2θ values ​​of 8.5°±0.2°, 11.0°±0.2°, 14.1°±0.2°, 16.2°±0.2°, 17.1°±0.2°, and 19.0°±0.2°. The 2θ values ​​of the diffraction peaks of the acetonitrile solvate are: characteristic peaks at 9.0°±0.2°, 9.5°±0.2°, 12.5°±0.2°, 14.5°±0.2°, 16.1±0.2°, and 16.5°±0.2°; The X-ray powder diffraction pattern of the dioxane solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 12.5°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 16.1°±0.2°, and 24.0°±0.2°. The X-ray powder diffraction pattern of the ethyl formate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 24.0°±0.2°. The X-ray powder diffraction pattern of isopropyl acetate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 26.1°±0.2°; The X-ray powder diffraction pattern of propyl acetate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 18.0°±0.2°, 20.5°±0.2°, and 23.0°±0.2°; The X-ray powder diffraction pattern of dimethyl carbonate solvate has characteristic peaks at 2θ values ​​of 12.1°±0.2°, 13.0°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 17.0°±0.2°, and 19.1°±0.2°; The X-ray powder diffraction pattern of vinyl acetate solvate I has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 17.0°±0.2°, and 25.0°±0.2°; The X-ray powder diffraction pattern of vinyl acetate solvate II has characteristic peaks at 2θ values ​​of 10.0°±0.2°, 13.1°±0.2°, and 16.0°±0.2°; The X-ray powder diffraction pattern of cyclohexanone solvate has characteristic peaks at 2θ values ​​of 13.0°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 16.0°±0.2°, 17.0°±0.2°, and 18.0°±0.2°; The X-ray powder diffraction pattern of the isopropyl ether solvate has characteristic peaks at 2θ values ​​of 7.0°±0.2°, 8.1°±0.2°, 12.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 17.1°±0.2°; The X-ray powder diffraction pattern of the n-hexane solvate has characteristic peaks at 2θ values ​​of 5.1°±0.2°, 9.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 17.0°±0.2°, and 18.0°±0.2°; the X-ray powder diffraction pattern of the n-octane solvate has characteristic peaks at 2θ values ​​of 5.0°±0.2°, 9.0°±0.2°, 11.2°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 18.0°±0.2°; The X-ray powder diffraction pattern of petroleum ether solvate has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 7.1°±0.2°, 11.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 18.0°±0.2°.

[0053] Depend on Figure 1 The PXRD analysis results in the study show that tripterygium wilfordii (From I) exhibits highly similar diffraction peaks in solvents such as ethanol, 1-propanol, isopropanol, and methyl acetate. However, in solvents such as acetone and vinyl acetate, even under the same experimental conditions, it exhibits significantly different diffraction characteristics, suggesting that the two solvates may be isostructural and exhibit similar or even identical crystal structures.

[0054] The crystal structure was analyzed by X-ray diffraction (SCXRD) analysis, and the crystallographic information of tripterygium wilfordii and its solvate was shown in Table 1.

[0055] Table 1 Crystallographic information of tripterygium wilfordii and its solvates

[0056] As shown in Table 1 , the crystallographic data of celastrol and its solvates cover four crystal systems: monoclinic, trigonal, tetragonal, and orthorhombic, corresponding to six space groups: P21(4), P3221(154), P41212(92), P21212(19), P32(145), and P212121(19).

[0057] Single crystal X-ray diffraction (SCXRD) analysis confirmed that the present invention successfully resolved two polymorphic forms of tripterygium wilfordii and 21 solvate structures thereof. The crystallographic data were submitted to the Cambridge Crystallographic Data Center (CCDC). A comprehensive search by the CCDC revealed that the present invention successfully obtained the crystal structure of Form II for the first time.

[0058] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to systematically characterize the tripterygium wilfordii solvate, and all data are shown in Table 2. Through systematic analysis of the thermal analysis data of the solvate system, we can gain a deeper understanding of the interaction characteristics between the solvent molecules and the main drug molecules and their thermal stability differences.

[0059] Table 2 Thermal analysis results of tripterygium wilfordii solvate

[0060] Note: “ / ” in Table 2 means not detected or not tested As shown in Table 2, all solvates exhibited characteristic desolvation behaviors during heating and the desolvation behaviors of different solvates showed significant temperature dependence, as follows: alcohol solvates (S EtOH and S 1-PrOH ) exhibited the highest desolvation midpoint temperature (160-170 °C), which, combined with the higher enthalpy value of its first endothermic peak (47.13-47.56 J / g), confirmed the stable complex structure formed by strong hydrogen bonding. MTBE ) and alkanes (S Octane ) solvates desolvated over a wider temperature range (85-195°C and 90-200°C, respectively). The actual weight loss rates (16.42% and 14.79%) were highly consistent with the theoretical values ​​(16.20% and 15.98%), indicating a clear stoichiometric relationship (2:3 and 4:3, respectively). It is particularly noteworthy that S CYCThe system's actual weight loss rate was unusually high (23.83% vs. the theoretical value of 9.82%). Combined with the high desolvation enthalpy of 88.49 J / g, this suggests a unique solvent trapping mechanism or crystal defects. Analysis of thermal transition characteristics revealed that all samples exhibited typical dual endothermic behavior.

[0061] The results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of tripterygium wilfordii solvate are shown in Figure 2. Figure 3-Figure 6 As shown. Figure 3-Figure 6 As can be seen, the TGA curve shows a multi-step mass loss in the range of 20-150°C, corresponding to the gradual release of solvent; the accompanying endothermic transition in the DSC spectrum confirms the energy changes of these desolvation processes, as shown below: The thermogravimetric analysis curve of the ethanol solvate shows a weight loss of 5.15% when heated to 161.57°C; The thermogravimetric analysis curve of 1-propanol solvate shows a weight loss of 6.34% when heated to 168.71°C; The thermogravimetric analysis curve of the isopropanol solvate shows a weight loss of 6.28% when heated to 120.21°C; The thermogravimetric analysis curve of 1-butanol solvate shows a weight loss of 7.09% when heated to 104.25°C; The thermogravimetric analysis curve of the isobutanol solvate shows a weight loss of 8.05% when heated to 145.49°C; The thermogravimetric analysis curve of methyl acetate solvate shows a weight loss of 7.47% when heated to 124.24°C; The thermogravimetric analysis curve of ethyl acetate solvate shows a weight loss of 8.36% when heated to 156.35°C; The thermogravimetric analysis curve of propyl acetate solvate shows a weight loss of 5.21% when heated to 153.31°C; The thermogravimetric analysis curve of isopropyl acetate solvate shows a weight loss of 10.84% ​​when heated to 141.01°C; The thermogravimetric analysis curve of ethyl formate solvate shows a weight loss of 8.23% when heated to 126.46°C; The thermogravimetric analysis curve of dioxane solvate shows a weight loss of 10.47% when heated to 171.91°C; The thermogravimetric analysis curve of acetonitrile solvate shows a weight loss of 5.05% when heated to 170.54 °C; The thermogravimetric analysis curve of acetone solvate I shows a weight loss of 7.68% when heated to 142.83°C; The thermogravimetric analysis curve of acetone solvate II shows a weight loss of 6.25% when heated to 123.81°C; The thermogravimetric analysis curve of methyl tert-butyl ether solvate shows a weight loss of 16.42% when heated to 118.30°C; The thermogravimetric analysis curve of n-octane solvate shows a weight loss of 14.79% when heated to 124.31°C; The thermogravimetric analysis curve of the isopropyl ether solvate shows a weight loss of 13.71% when heated to 102.54°C; The thermogravimetric analysis curve of cyclohexanone solvate shows a weight loss of 23.83% when heated to 129.28°C; The thermogravimetric analysis curve of vinyl acetate solvate I shows a weight loss of 11.60% when heated to 198.96°C; The thermogravimetric analysis curve of dimethyl carbonate solvate shows a weight loss of 8.74% when heated to 154.65°C.

[0062] The differential scanning calorimetry (DSC) curve of the ethanol solvate showed an endothermic peak at 161.57°C and an exothermic peak at 216.50°C. The differential scanning calorimetry (DSC) curve of 1-propanol solvate showed an endothermic peak at 168.71°C and an exothermic peak at 228.83°C. The differential scanning calorimetry (DSC) curve of the isopropanol solvate showed an endothermic peak at 161.23°C and an exothermic peak at 205.07°C. The differential scanning calorimetry (DSC) curve of 1-butanol solvate showed an endothermic peak at 104.25°C and an exothermic peak at 221.32°C; The differential scanning calorimetry (DSC) curve of the isobutanol solvate showed an endothermic peak at 145.49°C and an exothermic peak at 220.50°C. The differential scanning calorimetry (DSC) curve of methyl acetate solvate showed an endothermic peak at 124.24°C and an exothermic peak at 206.55°C. The differential scanning calorimetry (DSC) curve of ethyl acetate solvate showed an endothermic peak at 156.35°C and an exothermic peak at 208.08°C. The differential scanning calorimetry (DSC) curve of propyl acetate solvate showed an endothermic peak at 153.31°C and an exothermic peak at 225.15°C. The differential scanning calorimetry (DSC) curve of isopropyl acetate solvate showed an endothermic peak at 141.01°C and an exothermic peak at 225.31°C. The differential scanning calorimetry (DSC) curve of dioxane solvate showed an endothermic peak at 171.91°C and an exothermic peak at 215.75°C. The differential scanning calorimetry (DSC) curve of the acetonitrile solvate showed an endothermic peak at 191.87°C and an exothermic peak at 220.74°C. The differential scanning calorimetry (DSC) curve of acetone solvate I showed an endothermic peak at 142.83°C and an exothermic peak at 214.96°C. The differential scanning calorimetry (DSC) curve of acetone solvate II showed an endothermic peak at 123.81°C and an exothermic peak at 198.39°C. The differential scanning calorimetry (DSC) curve of methyl tert-butyl ether solvate showed an endothermic peak at 118.30°C and an exothermic peak at 198.17°C. The differential scanning calorimetry (DSC) curve of the n-octane solvate showed an endothermic peak at 124.31°C and an exothermic peak at 217.51°C. The differential scanning calorimetry (DSC) curve of cyclohexanone solvate showed an endothermic peak at 129.28°C and an exothermic peak at 206.38°C.

[0063] The differential scanning calorimetry (DSC) curve of the n-octane solvate showed an endothermic peak at 124.31°C and an exothermic peak at 217.51°C. The differential scanning calorimetry (DSC) curve of cyclohexanone solvate showed an endothermic peak at 129.28°C and an exothermic peak at 206.38°C.

[0064] Thermal analysis results showed that the TGA weight loss curves of most solvates were highly consistent with the solvent content predicted by the crystal structure. CYC ) exhibits unusual weight loss behavior, suggesting the possible existence of cocrystal structures with different stoichiometric ratios. The thermal transition mechanism warrants further investigation. It is noteworthy that solvent polarity has a key influence on thermal stability: polar solvents (such as ethanol) form stable complexes through strong hydrogen bonds, while non-polar solvents (such as heptane) rely primarily on weaker van der Waals forces.

[0065] Representative solvates of Celastrol include ethanol solvate (S ETOH ) is shown in the 1H NMR spectrum. Figure 7 As shown. Figure 7 It can be seen that ethanol solvate (S ETOH ) formed a new crystal structure.

[0066] Figure 8The crystal structure diagram of triptolide crystal form II, including (a) the asymmetric unit of type II crystal, (b) the schematic diagram of hydrogen bond connection of the asymmetric unit, (c) the two-dimensional chain structure observed along the b axis, and (d) the three-dimensional chain structure observed along the c axis. Figure 8 It is not difficult to see that single crystal X-ray diffraction confirms the formation of a new crystal structure of Form II.

[0067] In summary, the present invention successfully developed 23 novel solid forms of tripterygium wilfordii, including one solvent-free polymorph and 22 solvates. Of these, 22 crystal structures (20 solvates and two solvent-free crystalline forms) were resolved by single crystal X-ray diffraction. Structural analysis showed that all 20 solvates exhibited significant intermolecular hydrogen bonding network characteristics, with solubility 2-10 times higher than that of tripterygium wilfordii. The solvent molecules are specifically encapsulated in a three-dimensional framework constructed by the API molecules. This unique spatial arrangement effectively maintains the stability of the crystal structure.

[0068] Through thermal analysis of tripterygium wilfordii and its solvates, the stability grade system of tripterygium wilfordii solvates was clarified, among which the stability of alcohol solvates was ranked as follows: S 1-PrOH >S EtOH >S IPA >S 1-BuOH ; The stability of ester solvates is ranked as follows: S PA >S IPAc >S EA ; The stability of non-polar solvates is ranked as follows: S Dioxane >S Octane >S MTBE .

[0069] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A crystal form of a tripterygium wilfordii solvate, characterized in that: The crystal form is a co-crystal of tripterygium wilfordii and a solvent, wherein the ratio of tripterygium wilfordii to the solvent is (45-200) mg: (1-30) mL; The solvent is selected from one of C1-C4 alcohol solvents, C3-C5 ester solvents, dioxane, acetonitrile, acetone, methyl tert-butyl ether, petroleum ether, n-octane, n-hexane, isopropyl ether, cyclohexanone, vinyl acetate, and dimethyl carbonate.

2. The crystal form of the tripterygium wilfordii solvate according to claim 1, characterized in that The C1-C4 alcohol solvents include ethanol, 1-propanol, isopropanol, 1-butanol and isobutanol; Or, the C3-C5 ester solvent includes methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and ethyl formate; Alternatively, the crystalline form includes ethanol solvate, 1-propanol solvate, isopropanol solvate, 1-butanol solvate, isobutanol solvate, methyl acetate solvate, ethyl acetate solvate, propyl acetate solvate, isopropyl acetate solvate, ethyl formate solvate, dioxane solvate, acetonitrile solvate, acetone solvate, methyl tert-butyl ether solvate, petroleum ether solvate, n-octane solvate, n-hexane solvate, isopropyl ether solvate, cyclohexanone solvate, vinyl acetate solvate and dimethyl carbonate solvate.

3. The crystal form of the tripterygium wilfordii solvate according to claim 2, characterized in that When using Cu-Kα radiation, the X-ray powder diffraction pattern of ethyl acetate solvate has characteristic peaks at 2θ values ​​of 12.5°±0.2°, 13.1°±0.2°, 14.5°±0.2°, 17.3°±0.2°, 18.0°±0.2°, and 22.5°±0.2°; or, the X-ray powder diffraction pattern of the methyl acetate solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 16.2°±0.2°, 18.0°±0.2°, 20.5°±0.2°, and 23.1°±0.2°; or, the X-ray powder diffraction pattern of the isobutanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 16.2°±0.2°, 17.1°±0.2°, 18.0°±0.2°, and 22.1°±0.2°; or, the X-ray powder diffraction pattern of the 1-butanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 14.3°±0.2°, 15.5°±0.2°, 16.1°±0.2°, and 22.1°±0.2°; or, the X-ray powder diffraction pattern of the isopropanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 16.1°±0.2°, 18.3°±0.2°, 20.2°±0.2°, and 22.0°±0.2°; or, the X-ray powder diffraction pattern of the 1-propanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 13.2°±0.2°, 16.1°±0.2°, 19.2°±0.2°, 21.0°±0.2°, and 22.5°±0.2°; or, the X-ray powder diffraction pattern of the ethanol solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 11.0°±0.2°, 13.1°±0.2°, 16.5°±0.2°, 19.0°±0.2°, and 21.1°±0.2°; or, the X-ray powder diffraction pattern of methyl tert-butyl ether solvate has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 7.2°±0.2°, 11.0°±0.2°, 13.1°±0.2°, 15.0°±0.2°, 17.5°±0.2°, and 18.5°±0.2°; Alternatively, the X-ray powder diffraction pattern of acetone solvate II has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 13.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.5°±0.2°, and 21.1°±0.2°; Or, the X-ray powder diffraction pattern of acetone solvate I has characteristic peaks at 2θ values ​​of 8.5°±0.2°, 11.0°±0.2°, 14.1°±0.2°, 16.2°±0.2°, 17.1°±0.2°, and 19.0°±0.2°; Or, the X-ray powder diffraction pattern of the dioxane solvate has characteristic peaks at 2θ values ​​of 9.1°±0.2°, 12.5°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 16.1°±0.2°, and 24.0°±0.2°; or, the X-ray powder diffraction pattern of the ethyl formate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 24.0°±0.2°; or, the X-ray powder diffraction pattern of isopropyl acetate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 15.0°±0.2°, 16.0°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 26.1°±0.2°; Or, the X-ray powder diffraction pattern of propyl acetate solvate has characteristic peaks at 2θ values ​​of 9.5°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 18.0°±0.2°, 20.5°±0.2°, and 23.0°±0.2°; or, the X-ray powder diffraction pattern of the dimethyl carbonate solvate has characteristic peaks at 2θ values ​​of 12.1°±0.2°, 13.0°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 17.0°±0.2°, and 19.1°±0.2°; Alternatively, the X-ray powder diffraction pattern of vinyl acetate solvate I has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 17.0°±0.2°, and 25.0°±0.2°; Alternatively, the X-ray powder diffraction pattern of vinyl acetate solvate II has characteristic peaks at 2θ values ​​of 10.0°±0.2°, 13.1°±0.2°, and 16.0°±0.2°; or, the X-ray powder diffraction pattern of the isopropyl ether solvate has characteristic peaks at 2θ values ​​of 7.0°±0.2°, 8.1°±0.2°, 12.0°±0.2, 13.0°±0.2°, 16.1°±0.2°, and 17.1°±0.2°; Or, the X-ray powder diffraction pattern of the n-hexane solvate has characteristic peaks at 2θ values ​​of 5.1°±0.2°, 9.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, 17.0°±0.2°, and 18.0°±0.2°; the X-ray powder diffraction pattern of the n-octane solvate has characteristic peaks at 2θ values ​​of 5.0°±0.2°, 9.0°±0.2°, 11.2°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 18.0°±0.2°; Alternatively, the X-ray powder diffraction pattern of the petroleum ether solvate has characteristic peaks at 2θ values ​​of 6.0°±0.2°, 7.1°±0.2°, 11.0°±0.2°, 13.0°±0.2°, 16.1°±0.2°, and 18.1°±0.2°.

4. The crystal form of the tripterygium wilfordii solvate according to claim 2, characterized in that The thermogravimetric analysis curve of the ethanol solvate shows a weight loss of 5.15% when heated to 161.57°C; Alternatively, the 1-propanol solvate loses 6.34% of its weight when heated to 168.71°C according to the thermogravimetric analysis curve; Alternatively, the isopropanol solvate loses 6.28% of its weight when heated to 120.21°C according to the thermogravimetric analysis curve; Alternatively, the 1-butanol solvate loses 7.09% of its weight when heated to 104.25°C according to the thermogravimetric analysis curve; Alternatively, the isobutanol solvate loses 8.05% of its weight when heated to 145.49°C according to the thermogravimetric analysis curve; Alternatively, the thermogravimetric analysis curve of methyl acetate solvate shows a weight loss of 7.47% when heated to 124.24°C; Alternatively, the ethyl acetate solvate loses 8.36% of its weight when heated to 156.35°C according to the thermogravimetric analysis curve; Alternatively, the thermogravimetric analysis curve of propyl acetate solvate shows a weight loss of 5.21% when heated to 153.31°C; Alternatively, the thermogravimetric analysis curve of isopropyl acetate solvate shows a weight loss of 10.84% ​​when heated to 141.01°C; Alternatively, the thermogravimetric analysis curve of ethyl formate solvate shows a weight loss of 8.23% when heated to 126.46 °C; Alternatively, the thermogravimetric analysis curve of the dioxane solvate shows a weight loss of 10.47% when heated to 171.91°C; Alternatively, the acetonitrile solvate loses 3.45% of its weight when heated to 170.54°C in the thermogravimetric analysis curve; Alternatively, the thermogravimetric analysis curve of acetone solvate I shows a weight loss of 7.68% when heated to 142.83°C; Alternatively, the thermogravimetric analysis curve of acetone solvate II shows a weight loss of 6.25% when heated to 123.81°C; Alternatively, the thermogravimetric analysis curve of methyl tert-butyl ether solvate shows a weight loss of 16.42% when heated to 118.30°C; Alternatively, the thermogravimetric analysis curve of n-octane solvate shows a weight loss of 14.79% when heated to 124.31°C; Alternatively, the thermogravimetric analysis curve of the isopropyl ether solvate shows a weight loss of 13.71% when heated to 102.54°C; Alternatively, the thermogravimetric analysis curve of cyclohexanone solvate shows a weight loss of 23.83% when heated to 129.28°C; Alternatively, the thermogravimetric analysis curve of vinyl acetate solvate I shows a weight loss of 11.60% when heated to 198.96°C; Alternatively, the dimethyl carbonate solvate loses 8.74% of its weight when heated to 154.65° C. according to a thermogravimetric analysis curve.

5. The crystal form of the tripterygium wilfordii solvate according to claim 2, characterized in that The differential scanning calorimetry (DSC) curve of the ethanol solvate showed an endothermic peak at 161.57°C and an exothermic peak at 216.50°C. Alternatively, the differential scanning calorimetry (DSC) curve of the 1-propanol solvate exhibits an endothermic peak at 168.71°C and an exothermic peak at 228.83°C; Alternatively, the differential scanning calorimetry (DSC) curve of the isopropanol solvate exhibits an endothermic peak at 161.23°C and an exothermic peak at 205.07°C; Alternatively, the differential scanning calorimetry (DSC) curve of the 1-butanol solvate exhibits an endothermic peak at 104.25°C and an exothermic peak at 221.32°C; Alternatively, the differential scanning calorimetry (DSC) curve of the isobutanol solvate exhibits an endothermic peak at 145.49°C and an exothermic peak at 220.50°C; Alternatively, the differential scanning calorimetry (DSC) curve of methyl acetate solvate exhibits an endothermic peak at 124.24°C and an exothermic peak at 206.55°C; Alternatively, the differential scanning calorimetry (DSC) curve of the ethyl acetate solvate exhibits an endothermic peak at 156.35°C and an exothermic peak at 208.08°C; Alternatively, the differential scanning calorimetry (DSC) curve of propyl acetate solvate exhibits an endothermic peak at 153.31°C and an exothermic peak at 225.15°C; Alternatively, the differential scanning calorimetry (DSC) curve of isopropyl acetate solvate exhibits an endothermic peak at 141.01°C and an exothermic peak at 225.31°C; Alternatively, the differential scanning calorimetry (DSC) curve of the dioxane solvate exhibits an endothermic peak at 171.91°C and an exothermic peak at 215.75°C; Alternatively, the differential scanning calorimetry (DSC) curve of the acetonitrile solvate exhibits an endothermic peak at 191.87°C and an exothermic peak at 220.74°C; Alternatively, the differential scanning calorimetry (DSC) curve of acetone solvate I shows an endothermic peak at 142.83°C and an exothermic peak at 214.96°C; Alternatively, the differential scanning calorimetry (DSC) curve of acetone solvate II shows an endothermic peak at 123.81°C and an exothermic peak at 198.39°C; Alternatively, the differential scanning calorimetry (DSC) curve of methyl tert-butyl ether solvate exhibits an endothermic peak at 118.30°C and an exothermic peak at 198.17°C; Alternatively, the differential scanning calorimetry (DSC) curve of the n-octane solvate exhibits an endothermic peak at 124.31°C and an exothermic peak at 217.51°C in the thermogravimetric analysis curve; Alternatively, the differential scanning calorimetry (DSC) curve of the cyclohexanone solvate shows an endothermic peak at 129.28°C and an exothermic peak at 206.38°C.

6. A method for preparing the crystal form of the tripterygium wilfordii solvate according to any one of claims 1 to 5, characterized in that: The following steps are involved: Add triptolide to the solvent, stir and mix evenly, filter out the solvent, and let it stand to obtain the product; Among them, the ratio of tripterygium wilfordii to solvent is (45-200) mg: (1-30) mL; The solvent is selected from one of C1-C4 alcohol solvents, C3-C5 ester solvents, dioxane, acetonitrile, acetone, methyl tert-butyl ether, petroleum ether, n-octane, n-hexane, isopropyl ether, cyclohexanone, vinyl acetate, and dimethyl carbonate; The stirring time is 4 hours to 5 days, the stirring temperature is 5-80° C., the stirring speed is 300-500 rpm; and the standing time is 1-50 days.

7. The method for preparing the crystal form of the tripterygium wilfordii solvate according to claim 6, wherein: The ethanol solvate was prepared as follows: 101.3 mg of triptolide was added to 8 mL of ethanol and stirred at 400 rpm at room temperature for 12 hours. After stirring, the solution was filtered and then slowly evaporated. After 6 days, red square single crystals began to form. Alternatively, the 1-propanol solvate was prepared as follows: 100.4 mg of triptolide was added to 10 mL of 1-propanol, stirred at 400 rpm at room temperature for 24 hours, filtered and the solvent was slowly evaporated, and red square single crystals appeared after 10 days; Alternatively, the isopropanol solvate was prepared as follows: 50 mg of tripterygium wilfordii was added to 8 mL of isobutanol, stirred at 80°C for 4 hours, and then filtered. The solvent was then slowly evaporated, and single crystals began to form after 25 days; Alternatively, the 1-butanol solvate was prepared as follows: 100.1 mg of triptolide was dissolved in 10 mL of 1-butanol, stirred at 400 rpm at room temperature for 24 hours, filtered, and the solvent was slowly evaporated, and red square single crystals were precipitated after 30 days; Alternatively, the isobutanol solvate was prepared as follows: 200 mg of tripterygium wilfordii was mixed with 20 mL of isobutanol, stirred at 400 rpm at room temperature for 48 hours, and then filtered. 10 mL of the filtrate was slowly evaporated, and red single crystals began to form after 15 days. Alternatively, the methyl acetate solvate was prepared as follows: 100.7 mg of tripterygium wilfordii was added to 10 mL of methyl acetate, stirred at 400 rpm at room temperature for 12 hours, filtered, and slowly evaporated, and red square single crystals appeared after 2 days; Alternatively, the ethyl acetate solvate is prepared as follows: 50 mg of tripterygium wilfordii is dissolved in 5 mL of ethyl acetate, filtered, and the solvent is slowly evaporated to precipitate red single crystals after 5 days; Alternatively, the propyl acetate solvate is prepared as follows: 100 mg of tripterygium wilfordii is added to 8 mL of propyl acetate, filtered, and slowly evaporated to form red crystals after 5 days; Alternatively, the preparation method of isopropyl acetate solvate is as follows: 50 mg of tripterygium wilfordii is dissolved in 1 mL of isopropyl acetate, placed in a 20°C environment for 5 days to slowly evaporate, and crystals are precipitated after 2 days; Alternatively, the ethyl formate solvate was prepared as follows: 49.9 mg of tripterygium wilfordii was added to 8 mL of ethyl formate, stirred at 400 rpm at room temperature for 5 days, filtered and slowly evaporated, and single crystals appeared after 2 days; Alternatively, the dioxane solvate is prepared as follows: 100 mg of tripterygium wilfordii is dissolved in 20 mL of 1,4-dioxane, stirred at 400 rpm for 5 days, allowed to stand for 24 hours, filtered, and slowly evaporated. Single crystals were formed after 20 days; Alternatively, the acetonitrile solvate was prepared as follows: 100 mg of tripterygium wilfordii was added to 30 mL of acetonitrile, stirred at 400 rpm at 80°C for 4 hours, filtered, and slowly evaporated at room temperature, and single crystals were precipitated after 2 days; Alternatively, acetone solvates I and II were prepared as follows: 100.6 mg of triptolide was dissolved in 20 mL of acetone, stirred at 400 rpm at room temperature for 5 days, filtered, and slowly evaporated. Two crystalline forms were observed after approximately 48 hours: red square single crystals of acetone solvate I and rhombohedral single crystal aggregates of acetone solvate II. Alternatively, the preparation method of methyl tert-butyl ether solvate is as follows: 50 mg of tripterygium wilfordii is dissolved in 10 mL of methyl tert-butyl ether, filtered, and slowly evaporated at room temperature to form bulk single crystals within 24 hours; Alternatively, the petroleum ether solvate was prepared as follows: 100 mg of triptolide was suspended in 20 mL of petroleum ether, stirred at 400 rpm at room temperature for 5 days, allowed to stand for 24 hours, filtered, and the solvent was slowly evaporated, and crystals formed after 5 days; Alternatively, the n-octane solvate was prepared as follows: 100.7 mg of triptolide was dissolved in 20 mL of n-octane, stirred continuously at 400 rpm at room temperature for 5 days, filtered, and the solvent was slowly evaporated to obtain a single crystal after 10 days; Alternatively, the n-hexane solvate was prepared as follows: 101.9 mg of tripterygium wilfordii was suspended in 20 mL of n-hexane, stirred continuously at 400 rpm at room temperature for 5 days, filtered, and the solvent was slowly evaporated, and single crystals were precipitated after 50 days; Alternatively, the preparation method of the isopropyl ether solvate is as follows: 100 mg of tripterygium wilfordii is added to 20 mL of isopropyl ether, stirred at 400 rpm at 80°C for 4 hours, filtered, and slowly evaporated at room temperature, and a crystalline product is formed after 6 days; or, the preparation method of the cyclohexanone solvate is as follows: 100 mg of tripterygium wilfordii is added to 20 mL of cyclohexanone, stirred at 400 rpm at room temperature for 5 days, allowed to stand for 24 hours, filtered, and the solvent was slowly evaporated, and crystals began to form after 15 days; Alternatively, vinyl acetate solvates I and II were prepared as follows: 0.05 g of tripterygium wilfordii was added to 8 mL of vinyl acetate, heated at 80°C and stirred at 400 rpm for 4 hours, filtered, and the solvent was slowly evaporated. After 35 days, two different vinyl acetate solvate crystal forms I and II appeared; Alternatively, the preparation method of dimethyl carbonate solvate is as follows: 0.05 g of triptolide is dissolved in 8 mL of dimethyl carbonate, stirred at 400 rpm at 80° C. for 4 hours, filtered, and then the solvent is slowly evaporated to form single crystals after 30 days.

8. A solvent-free crystal form II of tripterygium wilfordii, characterized in that: When using Cu-Kα radiation, the X-ray powder diffraction pattern of the solvent-free crystalline form II of tripterygium wilfordii has characteristic peaks at 2θ values ​​of 9.4°±0.2°, 13.5°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 17.0°±0.2°, 18.2°±0.2°, 18.9°±0.2°, and 19.2°±0.2°; In the thermogravimetric analysis curve, weight loss begins when heated at 317-300°C; The differential scanning calorimetry (DSC) curve showed an endothermic peak at 191.8°C; The method for preparing the solvent-free crystal form II of tripterygium wilfordii comprises the following steps: 0.10 g of triptolide was dissolved in 20 mL of cyclohexanone and heated and cooled in a cycle of 5-50°C for 24 hours at a heating and cooling rate of 11-11.5°C / h. After filtration, the solvent was slowly evaporated to form single crystals after 10 days.

9. Use of the crystalline form of the tripterygium wilfordii solvate according to any one of claims 1 to 5 or the solvent-free crystalline form II of tripterygium wilfordii according to claim 8 in the preparation of anti-inflammatory, anti-tumor, diabetes-improving, anti-obesity, neuroprotective, and antiviral products.

10. A pharmaceutical preparation, characterized in that It comprises the crystal form of the tripterygium wilfordii solvate according to any one of claims 1 to 5 or the solvent-free crystal form II of tripterygium wilfordii according to claim 8 and a pharmaceutically acceptable carrier.

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