Two crystal forms of GL-V9 and their preparation methods

Abstract

The present invention belongs to the field of pharmaceutical chemistry and specifically relates to two crystalline forms of GL-V9 and preparation methods thereof; the two crystalline forms of GL-V9 are respectively Form II and Form III; the two crystalline forms of GL-V9 have good stability, and their solubility and hygroscopicity meet pharmaceutical requirements, and the preparation method is simple and low-cost, which is of great value for the research and development and production of the drug; compared with the crystalline forms in the prior art, the bioavailability is higher.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to two GL-V9 crystal forms and preparation methods thereof. Background Art

[0002] GL-V9 is a derivative of the flavonoid compound wogonin, with a molecular formula of C24H27NO5 and a chemical name of 5-hydroxy-7-(4-pyrrol-1-yl)butoxy-8-methoxyflavone. Its structural formula is shown in formula (I).

[0003]

[0004] Studies have shown that GL-V9 has a wide range of pharmacological activities. Currently, it has been submitted for clinical research approval (IND) in April 2024. It is expected to become a new type of leukemia treatment drug, providing new options for clinical treatment.

[0005] Different crystal forms of the same drug often lead to differences in drug solubility, thereby affecting the drug's dissolution rate and bioavailability, which in turn affects the drug's absorption and utilization in the body, resulting in differences in drug efficacy. Therefore, crystal form is one of the primary issues that must be considered when selecting a dosage form in drug development and is also a key factor in whether the drug can be effectively absorbed. In addition, by studying the characteristics of a drug's crystal form, it is possible to optimize the formulation process, improve the performance of solid drug formulations, and effectively ensure the equivalence of different batches of drugs during the production process. Therefore, screening for the right crystal form is crucial for subsequent drug development.

[0006] The Chinese invention patent application publication number CN115785048A discloses a GL-V9 crystal form and a preparation method thereof. It reports that the crystal form I of GL-V9 has relatively stable properties, but its bioavailability needs to be optimized. Summary of the Invention

[0007] The purpose of the present invention is to address the deficiencies in the prior art and provide two crystal forms of GL-V9 and a method for preparing the same.

[0008] The crystal form of the present invention has good stability, purity, and non-hygroscopicity, and its solubility and hygroscopicity meet pharmaceutical requirements. The preparation method is simple and low-cost, and it is suitable for large-scale industrial production, which is of great value for the research and development and production of the drug. The invention also invented a preparation method for two new crystal solid substances of GL-V9; the invention involves using the two new crystal solid substances to determine the bioavailability, which is higher than the bioavailability of the previously reported crystal form.

[0009] In order to achieve the above object, the present invention is achieved through the following technical solutions:

[0010] In the first aspect, the present invention provides a GL-V9 crystal form, which is crystal form II. In the X-ray powder diffraction spectrum detected by Cu-Kα radiation, 2 θ There are diffraction peaks at: 5.023°, 5.220°, 8.058°, 8.284°, 10.016°, 12.056°, 13.169°, 15.084°, 16.354°, 16.574°, 20.186°, 25.463°, 2 θ The value accuracy is ±0.2°.

[0011] When Form II is heated to 143.8°C, an endothermic peak begins to appear. There is no weight loss before the endothermic peak appears, indicating that it is an anhydrous form and a non-solvate.

[0012] In addition, a preparation method thereof is provided, which is as follows:

[0013] GL-V9 is heated and dissolved in solvent a; under heating, solvent b is slowly added dropwise, and the mixture is kept warm and stirred; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 Form II; wherein solvent a is selected from one or a mixture of two or more of 95% ethanol, DMSO, DMF, NMP or DMA, and solvent b is selected from one or a mixture of two or more of water, isopropyl ether or methyl tert-butyl ether;

[0014] or,

[0015] GL-V9 is heated and dissolved in solvent c, and the mixture is stirred while maintaining the temperature; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 crystal form II; wherein the solvent c is selected from one or a mixture of two or more of 95% ethanol, DMSO, DMF, NMP or DMA.

[0016] Preferably, the volume ratio of solvent a to solvent b is 1:1-10, the mass volume ratio of GL-V9 to solvent a is 5:100-300, unit, g / mL; the heating temperature is 35-100°C, the crystallization temperature is -20-60°C, and the crystallization time is 1-5 hours.

[0017] Preferably, the mass volume ratio of GL-V9 to solvent c is 5:100-300, unit, g / mL; the heating temperature is 35-100°C, the crystallization temperature is -20-60°C, and the crystallization time is 1-5 hours.

[0018] In the second aspect, the present invention provides another GL-V9 crystal form, which is crystal form III. In the X-ray powder diffraction spectrum detected by Cu-Kα radiation, 2 θThere are diffraction peaks at: 5.087°, 6.557°, 8.033°, 8.370°, 10.069°, 11.807°, 12.136°, 13.026°, 13.825°, 15.078°, 16.216°, 16.656°, and 20.126°. θ The value accuracy is ±0.2°.

[0019] When Form III is heated to 143.2°C, an endothermic peak begins to appear. There is no weight loss before the endothermic peak appears, indicating that it is an anhydrous form and a non-solvate.

[0020] In addition, a preparation method thereof is provided, which is as follows:

[0021] GL-V9 is heated and dissolved in solvent d; under heating, solvent e is slowly added dropwise while maintaining the temperature and stirring; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 Form III; wherein solvent d is selected from one or a mixture of two or more of tetrahydrofuran, dioxane, n-butanol or ethyl acetate, and solvent e is selected from one or a mixture of two or more of water, isopropyl ether or methyl tert-butyl ether;

[0022] or,

[0023] GL-V9 is heated and dissolved in solvent f, and the mixture is stirred while maintaining the temperature; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 crystal form III; wherein the solvent f is selected from a mixture of two or more of tetrahydrofuran, dioxane, n-butanol or ethyl acetate.

[0024] Preferably, the volume ratio of solvent d to solvent e is 1:1-10, the mass volume ratio of GL-V9 to solvent d is 5:100-300, unit, g / mL; the heating temperature is 35-100°C, the crystallization temperature is -20-60°C, and the crystallization stirring time is 1-5 hours.

[0025] Preferably, the mass volume ratio of GL-V9 to solvent f is 5:100-300, unit, g / mL; the heating temperature is 35-100° C., the crystallization temperature is -20-60° C., and the crystallization stirring time is 1-5 hours.

[0026] The present invention has the following beneficial effects: (1) The present invention differs from the prior art in that it discovers a new crystalline solid form of GL-V9. Based on the existing state of GL-V9 solid matter and combined with crystal form screening technology, the existence types and state characteristics of different crystal forms of GL-V9 are developed at the raw material level of the active pharmaceutical ingredient. By combining crystal form research with pharmacodynamic research, this provides a basis for developing crystalline solid drugs of GL-V9 with optimal clinical efficacy.

[0027] (2) The crystal form provided by the present invention is highly stable, effectively preventing crystal transformation during drug storage and development, thereby preventing changes in bioavailability and efficacy. The crystal form provided by the present invention is virtually non-hygroscopic, meeting bioavailability and efficacy requirements, and is not demanding on storage conditions, making it convenient for long-term storage. Compared to the reported crystal form I, it has better bioavailability and high market value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : Powder X-ray diffraction pattern of Form II solid sample of GL-V9;

[0029] Figure 2 : DSC spectrum of the solid sample of Form II of GL-V9;

[0030] Figure 3 : TGA spectrum of Form II solid sample of GL-V9;

[0031] Figure 4 : Powder X-ray diffraction pattern of Form III solid sample of GL-V9;

[0032] Figure 5 : DSC spectrum of Form III solid sample of GL-V9;

[0033] Figure 6 : TGA spectrum of the solid sample of Form III of GL-V9;

[0034] Figure 7 : X-ray diffraction overlays of Form II of GL-V9 stored under different conditions;

[0035] Figure 8 : HPLC overlay of Form II of GL-V9 stored under different conditions;

[0036] Figure 9 : X-ray diffraction overlays of Form III of GL-V9 stored under different conditions;

[0037] Figure 10 : HPLC overlay of Form III of GL-V9 stored under different conditions. DETAILED DESCRIPTION

[0038] The technical scheme of the present invention is further illustrated by specific examples below, but the scope of protection of the present invention is not limited thereto. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified.

[0039] The analysis and detection conditions of the present invention are as follows:

[0040] The X-ray powder diffraction patterns of the present invention were collected on a D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters of the present invention are as follows:

[0041] X-ray reflection parameters: Cu, K-α radiation

[0042] Kα11.5406; Kα21.54443

[0043] Kα2 / Kα1 intensity ratio: 0.50

[0044] Voltage: 40 kilovolts (kV)

[0045] Current: 40 milliamperes (mA)

[0046] Scanning range: from 3.0 to 40.0 degrees

[0047] Step size: 0.02°.

[0048] The differential scanning calorimetry (DSC) diagrams of the present invention were collected on a NETZSCH DSC 204. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

[0049] Heating rate: 10℃ / min

[0050] Scanning range: 40.0~350.0℃

[0051] Protective gas: nitrogen.

[0052] The thermogravimetric analysis (TGA) graphs of the present invention were collected on a NETZSCH TG209. The method parameters for the thermogravimetric analysis (TGA) of the present invention are as follows:

[0053] Heating rate: 10℃ / min

[0054] Scanning range: 25.0~350.0℃

[0055] Protective gas: nitrogen.

[0056] Example 1

[0057] The preparation method of GL-V9 crystal form II comprises the following steps:

[0058] Add 5 g of GL-V9 to 150 mL of DMF, heat to 60°C, heat and stir until completely dissolved and clarified, then keep warm for half an hour, slowly cool to 10°C and stir for 5 hours, filter, wash the filter cake with DMF, and dry to obtain GL-V9 crystal form II.

[0059] The GL-V9 crystal form II solid prepared in this example was subjected to X-ray powder diffraction analysis (eg Figure 1As shown), DSC analysis (as Figure 2 As shown) and TGA analysis (as Figure 3 shown).

[0060] The chemical purity and crystal purity of the GL-V9 crystal form II solid described in the present invention are both greater than 95%. When powder X-ray diffraction analysis is performed using CuKα radiation experimental conditions, the diffraction peak position 2-Theta value (dvalue) or peak area value (Intensity) or d value diffraction peak relative intensity peak height value (Intensity%) are shown in Table 1.

[0061] Table 1 Powder X-ray diffraction peak values ​​of GL-V9 crystal form II solid sample

[0062]

[0063] The solid material of GL-V9 crystal form II has an endothermic peak in its DSC spectrum, and its transition value is at 143.8℃ (such as Figure 2 GL-V9 crystal form II solid material, when heated to 143.8 ° C, there is no weight loss (as shown in Figure 3 shown).

[0064] Example 2

[0065] The preparation method of GL-V9 crystal form II comprises the following steps:

[0066] 5 g of GL-V9 was added to 150 mL of DMF and heated to 60 °C until completely dissolved and clarified. 200 mL of water was slowly added dropwise while stirring. After the addition was complete, the temperature was slowly lowered to 20 °C and stirred for 5 hours. The mixture was filtered, the filter cake was washed with water, and dried to obtain GL-V9 Form II.

[0067] Example 3

[0068] The preparation method of GL-V9 crystal form II comprises the following steps:

[0069] 5 g of GL-V9 was added to 150 mL of DMF and heated to 60°C until completely dissolved and clarified. 200 mL of isopropyl ether was slowly added dropwise while stirring. After the addition was complete, the temperature was slowly lowered to 20°C and stirred for 5 hours. The mixture was filtered, the filter cake was washed with isopropyl ether, and dried to obtain GL-V9 Form II.

[0070] Example 4

[0071] The preparation method of GL-V9 crystal form III comprises the following steps:

[0072] Add 5 g of GL-V9 to 150 ml of tetrahydrofuran, heat to 60°C, heat and stir until completely dissolved and clarified, then keep warm for half an hour, slowly cool to 10°C and stir for 5 hours, filter, wash the filter cake with tetrahydrofuran, and dry to obtain GL-V9 crystal form III.

[0073] The GL-V9 crystal form III solid prepared in this example was subjected to X-ray powder diffraction analysis (eg Figure 4 As shown), DSC analysis (as Figure 5 As shown) and TGA analysis (as Figure 6 shown).

[0074] The crystalline form III solid of GL-V9 described in the present invention has a chemical purity and a crystalline purity both greater than 95%. When powder X-ray diffraction analysis is performed using CuKα radiation experimental conditions, the diffraction peak position 2-Theta value (dvalue) or peak area value (Intensity) or d-value diffraction peak relative intensity peak height value (Intensity%) is shown in Table 2.

[0075] Table 2 Powder X-ray diffraction peak values ​​of GL-V9 Form III solid sample

[0076]

[0077] The solid substance of GL-V9 crystal form III has an endothermic peak in its DSC spectrum, and its transition value is at 143.2℃ (such as Figure 5 GL-V9 crystal form III solid material, when heated to 143.2 ° C, there is no weight loss (as shown in Figure 6 shown).

[0078] Example 5

[0079] The preparation method of GL-V9 crystal form III comprises the following steps:

[0080] 5 g of GL-V9 was added to 100 mL of tetrahydrofuran, and the mixture was heated to 60°C until completely dissolved and clarified. 200 mL of water was slowly added dropwise while stirring. After the addition was completed, the mixture was slowly cooled to 20°C and stirred for 5 hours. The mixture was filtered, the filter cake was washed with water, and dried to obtain GL-V9 Form III.

[0081] Example 6

[0082] The preparation method of GL-V9 crystal form III comprises the following steps:

[0083] 5 g of GL-V9 was added to 150 mL of acetone and heated to 60°C until completely dissolved and clarified. 200 mL of isopropyl ether was slowly added dropwise while stirring. After the addition was complete, the temperature was slowly lowered to 20°C and stirred for 5 hours. The mixture was filtered, the filter cake was washed with isopropyl ether, and dried to obtain GL-V9 Form III.

[0084] Experimental Example 1: Hygroscopicity test of GL-V9 crystal form II

[0085] Take a dry, stoppered glass weighing bottle (50 mm outer diameter, 15 mm height) and place it in an artificial climate chamber (set temperature: 25°C ± 1°C, relative humidity: 80% ± 2%) the day before the experiment. Accurately weigh the bottle (20.0105 g). Spread the GL-V9 crystal obtained in Example 1 into the weighing bottle to a thickness of approximately 1 mm and accurately weigh it (20.9979 g). Uncover the weighing bottle and place it, along with the bottle cap, under the above-described constant temperature and humidity conditions for 24 hours. Secure the bottle cap and accurately weigh it (20.9997 g).

[0086] Weight gain percentage = (20.9997g - 20.9979g) / (20.9979g - 20.0105g) × 100% = 0.18%

[0087] Definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition Appendix 9103 Guidelines for Hygroscopicity Test of Drugs, experimental conditions: 25℃±1℃, 80% relative humidity):

[0088] Deliquescent: Absorbs sufficient water to form a liquid.

[0089] Highly hygroscopic: weight gain upon moisture absorption is not less than 15%.

[0090] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.

[0091] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0092] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0093] The results show that the crystal form II of Example 1 of the present invention increases in weight by 0.18% after equilibrium at a relative humidity of 80%, indicating no or almost no hygroscopicity.

[0094] Experimental Example 2: Stability Test of GL-V9 Crystal Form II

[0095] About 200 mg of the GL-V9 crystal sample prepared in Example 1 was placed in an open container at 25°C, 60% RH and 40°C, 75% RH for 30 days. The XRPD and HPLC purity of the Form II sample were measured. The experimental results are shown in Table 3. The XRPD superposition of Form II under different conditions is shown in Table 3. Figure 7 The HPLC superposition diagrams of Form II under different conditions are shown in Figure 8 shown.

[0096] Table 3 Stability of GL-V9 Form II

[0097]

[0098]

[0099] Results showed that GL-V9 Form II remained stable and maintained nearly unchanged purity after 30 days of storage at 25°C, 60% RH, and 40°C, 75% RH. The XRPD spectra are overlaid in Figure 7, and the HPLC overlay is shown in Figure 8. The spectra before and after storage are highly consistent.

[0100] Experimental Example 3: Bioavailability Test of GL-V9 Form II

[0101] Three male and three female Sprague-Dawley rats were provided by the Qinglongshan Animal Breeding Farm in Jiangning District, Nanjing, license number: SCXK(Su)2022-0011. They weighed 180 g to 220 g and were housed in the laboratory of the Experimental Animal Center for three days before use. They were fasted for 12 hours before dosing and had free access to water during the experiment. Oral administration was by gavage at 50 mg / kg, and intravenous administration was by tail vein injection at 5 mg / kg.

[0102] Preparation of dosing solution:

[0103] The solution for oral administration was prepared with 0.5% CMC-Na and mixed evenly before administration; the solution for intravenous administration was prepared with 0.3M hydroxypropyl-β-cyclodextrin / lactic acid (99 / 1, v / v).

[0104] Before and 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after oral administration, approximately 200 μl of blood was collected and placed in an EP tube containing 1% sodium heparin. The blood was centrifuged at 8000 rpm for 5 min to separate the plasma, determine the plasma drug concentration, and calculate the pharmacokinetic parameters.

[0105] Before intravenous administration and 2 min, 15 min, 45 min, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, approximately 100 μl of blood was collected into EP tubes containing 1% sodium heparin. The blood was centrifuged at 8000 rpm for 5 min to separate the plasma, determine the plasma drug concentration, and calculate the pharmacokinetic parameters (PK parameters were calculated using WinNonlin version 6.4).

[0106] The results are shown in Table 4:

[0107] Table 4 Bioavailability data of GL-V9 crystal form II in SD rats

[0108]

[0109] The results showed that the oral bioavailability of GL-V9 crystal form II was high, at 11.00%, which was higher than that of crystal form I reported in patent CN115785048A.

[0110] Experimental Example 4: Hygroscopicity test of GL-V9 crystal form III

[0111] Take a dry, stoppered glass weighing bottle (50 mm outer diameter, 15 mm height) and place it in an artificial climate chamber (set temperature at 25°C ± 1°C, relative humidity at 80% ± 2%) the day before the experiment. Accurately weigh the bottle (20.0102 g). Spread the GL-V9 crystal obtained in Example 4 into the weighing bottle to a thickness of approximately 1 mm and accurately weigh it (20.9981 g). Uncover the weighing bottle and place it, along with the bottle cap, under the above-mentioned constant temperature and humidity conditions for 24 hours. Cover the weighing bottle with the cap and accurately weigh it (20.9996 g).

[0112] Weight gain percentage = (20.9996g - 20.9981g) / (20.9981g - 20.0102g) × 100% = 0.15%

[0113] Definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition Appendix 9103 Guidelines for Hygroscopicity Test of Drugs, experimental conditions: 25℃±1℃, 80% relative humidity):

[0114] Deliquescent: Absorbs sufficient water to form a liquid.

[0115] Highly hygroscopic: weight gain upon moisture absorption is not less than 15%.

[0116] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.

[0117] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0118] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0119] The results show that the crystal form III of Example 4 of the present invention increases in weight by 0.15% after equilibrium at a relative humidity of 80%, indicating no or almost no hygroscopicity.

[0120] Experimental Example 5: Stability Test of GL-V9 Form III

[0121] About 200 mg of the GL-V9 crystal sample prepared in Example 4 was placed in an open container at 25°C, 60% RH and 40°C, 75% RH for 30 days. The XRPD and HPLC purity of the Form III sample were measured. The experimental results are shown in Table 5. The XRPD superposition of Form III under different conditions is shown in Table 5. Figure 9 The HPLC superposition diagrams of Form III under different conditions are shown in Figure 10 shown.

[0122] Table 5 Stability of GL-V9 Form III

[0123]

[0124] The results show that the GL-V9 crystal form III is stable after being placed under the conditions of 25℃, 60% RH and 40℃, 75% RH for 30 days, and the purity is almost unchanged. Figure 9 As shown, the HPLC overlay is as follows Figure 10 As shown, it can be seen that the spectra before and after placement are highly consistent.

[0125] Experimental Example 6: Bioavailability Test of GL-V9 Form III

[0126] Three male and three female Sprague-Dawley rats were provided by the Qinglongshan Animal Breeding Farm in Jiangning District, Nanjing, license number: SCXK(Su)2022-0011. They weighed 180 g to 220 g and were housed in the laboratory of the Experimental Animal Center for three days before use. They were fasted for 12 hours before dosing and had free access to water during the experiment. Oral administration was by gavage at 50 mg / kg, and intravenous administration was by tail vein injection at 5 mg / kg.

[0127] Preparation of dosing solution:

[0128] The solution for oral administration was prepared with 0.5% CMC-Na and mixed evenly before administration; the solution for intravenous administration was prepared with 0.3M hydroxypropyl-β-cyclodextrin / lactic acid (99 / 1, v / v).

[0129] Before and 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after oral administration, approximately 200 μl of blood was collected and placed in an EP tube containing 1% sodium heparin. The blood was centrifuged at 8000 rpm for 5 min to separate the plasma, determine the plasma drug concentration, and calculate the pharmacokinetic parameters.

[0130] Before intravenous administration and 2 min, 15 min, 45 min, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, approximately 100 μl of blood was collected into EP tubes containing 1% sodium heparin. The blood was centrifuged at 8000 rpm for 5 min to separate the plasma, determine the plasma drug concentration, and calculate the pharmacokinetic parameters (PK parameters were calculated using WinNonlin version 6.4).

[0131] The results are shown in Table 6:

[0132] Table 6 Bioavailability data of GL-V9 crystal form III in SD rats

[0133]

[0134] The results showed that the oral bioavailability of GL-V9 crystal form III was high, at 12.06%, which was higher than the oral bioavailability of crystal form I reported in patent CN115785048A.

[0135] The above shows and describes the basic principles, main features, and advantages of the present invention. However, the above is only a specific embodiment of the present invention, and the technical features of the present invention are not limited thereto. Any other implementation methods derived by any person skilled in the art without departing from the technical solution of the present invention should be included in the patent scope of the present invention.

Claims

1. A GL-V9 crystal form, which is crystal form II, has an X-ray powder diffraction spectrum detected by Cu-Kα radiation. θ There are diffraction peaks at: 5.023°, 5.220°, 8.058°, 8.284°, 10.016°, 12.056°, 13.169°, 15.084°, 16.354°, 16.574°, 20.186°, 25.463°, 2 θ The value accuracy is ±0.2°.

2. The GL-V9 crystal form according to claim 1, characterized in that When Form II is heated to 143.8°C, an endothermic peak begins to appear. There is no weight loss before the endothermic peak appears, indicating that it is an anhydrous form and a non-solvate.

3. The method for preparing the GL-V9 crystal form according to claim 1 or 2, characterized in that: The method is as follows: GL-V9 is heated and dissolved in solvent a; under heating, solvent b is slowly added dropwise, and the mixture is kept warm and stirred; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 Form II; wherein solvent a is selected from one or a mixture of two or more of 95% ethanol, DMSO, DMF, NMP or DMA, and solvent b is selected from one or a mixture of two or more of water, isopropyl ether or methyl tert-butyl ether; or, GL-V9 is heated and dissolved in solvent c, and the mixture is stirred while maintaining the temperature; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 crystal form II; wherein the solvent c is selected from one or a mixture of two or more of 95% ethanol, DMSO, DMF, NMP or DMA.

4. The method for preparing the GL-V9 crystal form according to claim 3, wherein: The volume ratio of solvent a to solvent b is 1:1-10, and the mass volume ratio of GL-V9 to solvent a is 5:100-300, unit: g / mL; the heating temperature is 35-100° C., the crystallization temperature is -20-60° C., and the crystallization time is 1-5 hours.

5. The preparation method according to claim 3, characterized in that The mass volume ratio of GL-V9 to solvent c is 5:100-300, unit: g / mL; the heating temperature is 35-100° C., the crystallization temperature is -20-60° C., and the crystallization time is 1-5 hours.

6. A GL-V9 crystal form, which is crystal form III, has an X-ray powder diffraction spectrum detected by Cu-Kα radiation, 2 θ There are diffraction peaks at: 5.087°, 6.557°, 8.033°, 8.370°, 10.069°, 11.807°, 12.136°, 13.026°, 13.825°, 15.078°, 16.216°, 16.656°, and 20.126°. θ The value accuracy is ±0.2°.

7. The GL-V9 crystal form according to claim 6, characterized in that When Form III is heated to 143.2°C, an endothermic peak begins to appear. There is no weight loss before the endothermic peak appears, indicating that it is an anhydrous form and a non-solvate.

8. The method for preparing the GL-V9 crystal form according to claim 6 or 7, characterized in that: The method is as follows: GL-V9 is heated and dissolved in solvent d; under heating, solvent e is slowly added dropwise while maintaining the temperature and stirring; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 Form III; wherein solvent d is selected from one or a mixture of two or more of tetrahydrofuran, dioxane, n-butanol or ethyl acetate, and solvent e is selected from one or a mixture of two or more of water, isopropyl ether or methyl tert-butyl ether; or, GL-V9 is heated and dissolved in solvent f, and the mixture is stirred while maintaining the temperature; the temperature is slowly lowered to precipitate a solid, which is filtered and dried to obtain GL-V9 crystal form III; wherein the solvent f is selected from a mixture of two or more of tetrahydrofuran, dioxane, n-butanol or ethyl acetate.

9. The method for preparing the GL-V9 crystal form according to claim 8, characterized in that: The volume ratio of solvent d to solvent e is 1:1-10, the mass volume ratio of GL-V9 to solvent d is 5:100-300, unit: g / mL; the heating temperature is 35-100° C., the crystallization temperature is -20-60° C., and the crystallization stirring time is 1-5 hours.

10. The method for preparing the GL-V9 crystal form according to claim 8, characterized in that: The mass volume ratio of GL-V9 to solvent f is 5:100-300, unit: g / mL; the heating temperature is 35-100° C., the crystallization temperature is -20-60° C., and the crystallization stirring time is 1-5 hours.

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