Polymorph of 7,8-dihydroxyflavone, and preparation method therefor

Abstract

The invention relates to a polymorphic substance of 7, 8-dihydroxyflavone and a preparation method of the polymorphic substance. The 7, 8-dihydroxyflavone polymorphic substance provided by the invention has obviously improved physicochemical properties, so that the 7, 8-dihydroxyflavone polymorphic substance has higher medicinal value.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511184492.9 (22) Application Date 2023.04.11 (66) Domestic Priority Data 202210383296.4 2022.04.12 CN (62) Divisional Application Data 202380011365.1 2023.04.11 (71) Applicant Suzhou Granco Pharmaceutical Technology Co., Ltd. Address 215127, Unit 303A-303B, Building A4, BioNano Park, No. 218 Xinghu Street, Suzhou Industrial Park, Suzhou City, Jiangsu Province Applicant Huiankai (Xiamen) Pharmaceutical Technology Co., Ltd. Quanzhou Haichuang Pharmaceutical Technology Co., Ltd. (72) Inventor Chen Jinhui (74) Patent Agency Beijing Shangzhuan Yongxin Intellectual Property Agency (General Partnership) 11400 Patent Attorney Zhang Han (51) Int.Cl. C07D 311 / 30(2006.01) A61K 9 / 20(2006.01) C07D 311 / 40(2006.01) A61K 31 / 352(2006.01) A61P 25 / 00(2006.01) A61P 25 / 02(2006.01) A61P 25 / 28(2006.01) A61P 25 / 18(2006.01) A61P 27 / 02(2006.01) A61P 3 / 00(2006.01) A61P 29 / 00(2006.01) A61P 9 / 00(2006.01) A61P 35 / 00 (2006.01) (54) Invention Title: Polymorphs of 7,8-dihydroxyflavone and Preparation Method Thereof (57) Abstract: This application relates to polymorphs of 7,8-dihydroxyflavone and preparation methods thereof. The 7,8-dihydroxyflavone polymorphs provided in this disclosure have significantly improved physicochemical properties, thereby having higher pharmaceutical value. Claims: 1 page Description: 24 pages Drawings: 10 pages CN 121064139 A 2025.12.05 CN 1 21 06 41 39 A 1. A 7,8-dihydroxyflavone polymorph having an X-ray powder diffraction pattern comprising characteristic peaks represented at approximately 8.3±0.2°, 25.0±0.2°, and 25.9±0.2° at 2θ angles. 2. The 7,8-dihydroxyflavone crystalline form according to claim 1, wherein the X-ray powder diffraction pattern further includes characteristic peaks at approximately 27.4 ± 0.2° and / or 31.4 ± 0.2°. 3. A 7,8-dihydroxyflavone crystalline form having characteristic peaks represented by 2θ angles at approximately 11.1 ± 0.2°, 15.6 ± 0.2°, and...4. The 7,8-dihydroxyflavone crystalline form according to claim 3, wherein the X-ray powder diffraction pattern further includes characteristic peaks at about 5.6±0.2°, 9.5±0.2°, 15.5±0.2°, 21.0±0.2°, 24.3±0.2° and / or 25.5±0.2°. 5. The 7,8-dihydroxyflavone crystalline form according to any one of claims 3-4, which is a hydrate, such as a monohydrate. 6. A 7,8-dihydroxyflavone crystalline form having an X-ray powder diffraction pattern comprising characteristic peaks represented at 2θ angles at about 9.3±0.2°, 23.8±0.2°, 24.6±0.2° and 26.6±0.2°. 7. The 7,8-dihydroxyflavone crystal form according to claim 6, wherein the X-ray powder diffraction pattern further includes characteristic peaks at about 12.3 ± 0.2° and / or 21.1 ± 0.2°. 8. The 7,8-dihydroxyflavone crystal form according to any one of claims 6-7, wherein it is a hydrate, for example a dihydrate. 9. A pharmaceutical composition comprising (1) the 7,8-dihydroxyflavone crystal form according to any one of claims 1-2, the 7,8-dihydroxyflavone crystal form according to any one of claims 3-5, and / or the 7,8-dihydroxyflavone crystal form according to any one of claims 6-8, and (2) at least one pharmaceutically acceptable excipient. 10. A method for treating diseases associated with abnormal TrkB signaling pathways, such as central nervous system injury, peripheral nerve injury, neurodegenerative diseases, mental disorders, hereditary neurological dysfunctions, ophthalmic diseases, metabolic diseases, pain, cardiovascular diseases, tumors, or other related diseases, comprising administering to a subject (1) the 7,8-dihydroxyflavone crystalline form according to any one of claims 1-2, 7,8-dihydroxyflavone crystalline form according to any one of claims 3-5, and / or 7,8-dihydroxyflavone crystalline form according to any one of claims 6-8, and (2) at least one pharmaceutically acceptable excipient. 11. Use of the 7,8-dihydroxyflavone crystalline form according to claim 1 or 2, the 7,8-dihydroxyflavone crystalline form according to any one of claims 3-5, and / or the 7,8-dihydroxyflavone crystalline form according to any one of claims 6-8 in the preparation of a medicament for the treatment or prevention of traumatic brain injury or age-related cognitive decline. 12. A crystalline form of 7,8-dihydroxyflavone having X-ray diffraction peaks at 2θ values ​​of approximately 9.1 ± 0.2°, 17.2 ± 0.2°, 20.5 ± 0.2°, and 27.3 ± 0.2°. 13. A crystalline form of 7,8-dihydroxyflavone having X-ray diffraction peaks at 2θ values ​​of approximately 11.6 ± 0.2°, 18.5 ± 0.2°, and 18.5 ± 0.2°.14. A 7,8-dihydroxyflavonoid crystal form having X-ray diffraction peaks at 2θ values ​​of approximately 10.8±0.2°, 19.5±0.2°, 22.1±0.2°, 22.4±0.2°, 24.7±0.2°, and 28.2±0.2°, expressed in 2θ angles. 15. A method for preparing 7,8-dihydroxyflavone tablets, comprising the following steps: mixing 80g of raw material, 80g of lactose, 13g of microcrystalline cellulose, 12g of povidone, and 7g of sodium carboxymethyl starch, pouring the mixture into a 1L granulation pot, stirring and mixing for 6 minutes, adding 40g to 50g of purified water, wet granulation, stirring, drying, granulating, adding 7g of sodium carboxymethyl starch and 1g of magnesium stearate, and then compressing and demolding the mixture to obtain 7,8-dihydroxyflavone tablets. Claims 1 / 1 Page 2 CN 121064139 A Polymorphs of 7,8-Dihydroxyflavonoids and Preparation Method Thereof

[0001] This application is a divisional application of the original application number CN202380011365.1 (PCT / CN2023 / 087608), entitled "Polymorphs of 7,8-Dihydroxyflavonoids and Preparation Method Thereof", filed on April 11, 2023.

[0002] This disclosure claims priority to Chinese patent application CN202210383296.4, filed on April 12, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to polymorphs of 7,8-dihydroxyflavonoids and preparation methods thereof. Background Art

[0004] As a specific agonist of tyrosine receptor kinase B (TrkB), 7,8-dihydroxyflavonoids can activate TrkB. Numerous in vitro studies have shown that 7,8-dihydroxyflavonoids have important biological effects, mainly manifested in their good efficacy in treating neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, depression, psychiatric disorders, post-traumatic stress disorder, autism spectrum disorder, stroke, and Ritter syndrome.

[0005] Polymorphism refers to the phenomenon that a substance exists with two or more different crystal structures, which is a common phenomenon in solid substances. In the pharmaceutical field, the study of drug polymorphism has become an important cutting-edge topic. Different crystal structures of the same solid substance often exhibit different physicochemical properties. In terms of drugs, different crystal forms mainly manifest in differences in stability, solubility, and dissolution rate, thereby affecting the efficacy of the drug and even changing its toxic side effects.

[0006] Therefore, developing a 7,8-dihydroxyflavonoid crystal form with superior properties is of great significance.

[0007] Overview

[0008] This disclosure discloses polymorphs of 7,8-dihydroxyflavone and methods for preparing the same. The polymorphs of 7,8-dihydroxyflavone provided by this disclosure offer greater pharmaceutical economic value through selection.

[0009] In one aspect, this disclosure provides a 7,8-dihydroxyflavone polymorph P having an X-ray powder diffraction pattern comprising characteristic peaks at approximately 8.3 ± 0.2°, 25.0 ± 0.2°, and 25.9 ± 0.2°, expressed at 2θ angles.

[0010] In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at approximately 27.4 ± 0.2° and / or 31.4 ± 0.2°.

[0011] In a further embodiment, the X-ray powder diffraction pattern also includes characteristic peaks at approximately 12.5 ± 0.2°, 15.8 ± 0.2°, 18.4 ± 0.2°, 18.7 ± 0.2°, 19.4 ± 0.2°, and / or 33.7 ± 0.2°.

[0012] In a further embodiment, the crystal form P has an X-ray powder diffraction pattern substantially as shown in FIG1. ​​

[0013] In a further embodiment, no significant weight loss is observed in the thermogravimetric analysis spectrum of the crystal form P.

[0014] In a further embodiment, no endothermic signal corresponding to weight loss is observed in the differential scanning calorimetry (DSC) thermogram of the crystal form P.

[0015] In a further embodiment, in the dynamic moisture adsorption map of the crystalline form P, the weight gain is less than 0.1% in the range of 0%-95% relative humidity, where "%" is the percentage of the increased mass of the 7,8-dihydroxyflavone crystalline form P relative to the initial mass.

[0016] In a further embodiment, the 7,8-dihydroxyflavone crystalline form P has a thermogravimetric analysis map and / or differential scanning calorimetry map substantially as shown in FIG4.

[0017] In a further embodiment, the 7,8-dihydroxyflavone crystalline form P has a dynamic moisture adsorption map substantially as shown in FIG5.

[0018] In a further embodiment, the 7,8-dihydroxyflavone crystalline form P is anhydrous.

[0019] In another aspect, this disclosure provides a 7,8-dihydroxyflavone crystal form C having an X-ray powder diffraction pattern comprising characteristic peaks represented at 2θ angles at approximately 11.1 ± 0.2°, 15.6 ± 0.2°, 27.0 ± 0.2°, and 28.3 ± 0.2°.

[0020] In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at approximately 5.6 ± 0.2°, 9.5 ± 0.2°, 15.5 ± 0.2°, 21.0 ± 0.2°, 24.3 ± 0.2°, and / or 25.5 ± 0.2°.

[0021] In a further embodiment, the X-ray powder diffraction pattern also includes characteristic peaks at approximately 12.7 ± 0.2°, 13.7 ± 0.2°, 18.3 ± 0.2°, 20.4 ± 0.2°, 21.9 ± 0.2°, 23.2 ± 0.2°, 25.2 ± 0.2°, and / or 29.7 ± 0.2°.

[0022] In a further embodiment, the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG2.

[0023] In a further embodiment, in the thermogravimetric analysis spectrum of the crystalline form C, the mass lost at 110°C to 150°C is approximately 3.7% of the mass before weight loss, where “%” is a mass percentage.

[0024] In a further embodiment, in the differential scanning calorimetry spectrum of the crystalline form C, there is an endothermic signal corresponding to the weight loss at approximately 100°C to 160°C.

[0025] In a further embodiment, in the dynamic moisture adsorption map of the crystal form C, the weight gain is less than 0.1% in the range of 0%–95% relative humidity, where “%” is the percentage of the increased mass of the 7,8-dihydroxyflavone crystal form C relative to its initial mass.

[0026] In a further embodiment, the 7,8-dihydroxyflavone crystal form C has a thermogravimetric analysis map and / or differential scanning calorimetry map substantially as shown in FIG. 6.

[0027] In a further embodiment, the 7,8-dihydroxyflavone crystal form C has a dynamic moisture adsorption map substantially as shown in FIG. 7.

[0028] In a further embodiment, the 7,8-dihydroxyflavone crystal form C is a hydrate, such as a monohydrate.

[0029] In another aspect, this disclosure provides a 7,8-dihydroxyflavone crystal form N having an X-ray powder diffraction pattern comprising characteristic peaks represented at 2θ angles at approximately 9.3 ± 0.2°, 23.8 ± 0.2°, 24.6 ± 0.2°, and 26.6 ± 0.2°.

[0030] In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at approximately 12.3 ± 0.2° and / or 21.1 ± 0.2°.

[0031] In a further embodiment, the X-ray powder diffraction pattern also includes characteristic peaks at approximately 5.7 ± 0.2°, 11.9 ± 0.2°, 13.1 ± 0.2°, 14.2 ± 0.2°, 15.9 ± 0.2°, 16.8 ± 0.2°, 18.9 ± 0.2°, 20.7 ± 0.2°, and / or 30.3 ± 0.2°.

[0032] In a further embodiment, the 7,8-dihydroxyflavone crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 3.

[0033] In a further embodiment, in the thermogravimetric analysis spectrum of the crystalline form N, the weight loss at 40°C to 80°C is specified in the specification 2 / 24 pages 4 CN 121064139 AThe mass of the 7,8-dihydroxyflavone crystalline N is 6.3% of the mass before weight loss, where “%” is a mass percentage.

[0034] In a further embodiment, in the differential scanning spectroscopy of the crystalline N, there is an endothermic peak corresponding to weight loss at approximately 100°C, and exothermic signals at approximately 136°C and 169°C, respectively.

[0035] In a further embodiment, in the dynamic moisture adsorption map of the crystalline N, the weight gain is less than 0.1% in the range of 0%-95% relative humidity, where “%” is the percentage of the increased mass of the 7,8-dihydroxyflavone crystalline N relative to the initial mass.

[0036] In a further embodiment, the 7,8-dihydroxyflavone crystalline N has a thermogravimetric analysis map and / or differential scanning spectroscopy map substantially as shown in FIG8.

[0037] In a further embodiment, the 7,8-dihydroxyflavone crystalline N has a dynamic moisture adsorption map substantially as shown in FIG9.

[0038] In a further embodiment, the 7,8-dihydroxyflavone crystal form N is a hydrate, such as a dihydrate.

[0039] In another aspect, this disclosure provides a method for preparing the 7,8-dihydroxyflavone crystal form of this disclosure, which is one of methods 1 to 5:

[0040] Method 1: comprising the steps of dissolving 7,8-dihydroxyflavone in a single solvent and evaporating the solvent to obtain a solid;

[0041] Method 2: comprising the steps of suspending 7,8-dihydroxyflavone in a single solvent or a binary solvent and then centrifuging to obtain a solid;

[0042] Method 3: comprising the steps of dissolving 7,8-dihydroxyflavone in a good solvent and adding the obtained solution dropwise to an antisolvent, precipitating a solid and then separating the solid;

[0043] Method 4: comprising the steps of dissolving 7,8-dihydroxyflavone in a good solvent, adding an antisolvent dropwise to the obtained solution, precipitating a solid and then separating the solid;

[0044] Method 5: comprising the steps of dissolving 7,8-dihydroxyflavone in a good solvent, adding an antisolvent dropwise to the obtained solution, precipitating a solid and then separating the solid;

[0044] Method 5: comprising the steps of dissolving 7,8-dihydroxyflavone in a single solvent and then centrifuging to obtain a solid; 7,8-Dihydroxyflavonoids are suspended in an antisolvent, and then a good solvent is added dropwise until the solid dissolves. After cooling and precipitation, the solid is separated.

[0045] In one embodiment, a method for preparing 7,8-dihydroxyflavonoid crystalline form P is provided, characterized in that, in method 2, the single solvent is n-heptane, and the binary solvent is one of 4-methyl-2-pentanone, n-propanol, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, butyl formate, and a combination with one of isopropyl acetate, n-heptane, toluene, isopropanol, ethyl acetate, diethyl ether, cyclohexane;

[0046] and / or, in method 2, the volume ratio of the binary solvent is 1:5 to 1:10.

[0047] In a further embodiment, a method for preparing 7,8-dihydroxyflavonoid crystalline form P is provided, characterized in that...In method 2, the suspension temperature is 20-60°C.

[0048] In one embodiment, a 7,8-dihydroxyflavone having at least one characteristic of the crystal form P of the present disclosure is provided, prepared according to the method of the present disclosure.

[0049] In one embodiment, a method for preparing 7,8-dihydroxyflavone crystal form C is provided, characterized in that, in method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide;

[0050] and / or, in method 1, the volume-to-mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g;

[0051] and / or, in method 1, the solid is precipitated by solvent evaporation;

[0052] and / or, in method 2, the single solvent is water or diethyl ether; the binary solvent is selected from a combination of organic solvent and water, a combination of butyl formate and n-heptane, a combination of ethylene glycol methyl ether and chloroform, and a combination of acetonitrile and toluene; Specification 3 / 24 pages 5 CN 121064139 A

[0053] And / or, in method 2, the organic solvent is selected from one or more of tetrahydrofuran, isopropanol, acetonitrile, methanol, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, and ethylene glycol dimethyl ether;

[0054] And / or, in method 2, in the binary solvent, the volume ratio of the organic solvent to water is 1:5 to 1:10, the volume ratio of butyl formate to n-heptane is 1:1, the volume ratio of ethylene glycol methyl ether to chloroform is 1:5, and / or the volume ratio of acetonitrile to toluene is 1:1;

[0055] And / or, in method 3, the good solvent is selected from one or more of N,N-dimethylformamide, tetrahydrofuran, and ethylene glycol dimethyl ether, and / or the antisolvent is selected from one or more of water, toluene, dichloromethane, and diethyl ether;

[0056] And / or, in method 3, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10;

[0057] And / or, in method 4, the good solvent is one or more of N,N-dimethylformamide and isopropanol, and / or the antisolvent is one or more of chloroform, toluene, and water;

[0058] And / or, in method 4, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10;

[0059] And / or, in method 5, the antisolvent is water, and the good solvent is one or more of N,N-dimethylformamide, tetrahydrofuran, ethanol, and ethylene glycol methyl ether;

[0060] And / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8 to 1:1.

[0061] In a further embodiment, a method for preparing 7,8-dihydroxyflavone crystal form C is provided, characterized in that, in method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide;

[0062] And / or, in method 1, the solid precipitation temperature is room temperature;

[0063] And / or, in method 2, the suspension temperature is 20-60°C;

[0064] and / or, in method 3, the dropping temperature is 15-50°C;

[0065] and / or, in method 4, the dropping temperature is 15-50°C;

[0066] and / or, in method 5, the cooling temperature is -15°C to 4°C.

[0067] In one embodiment, a 7,8-dihydroxyflavone having at least one characteristic of the crystal form C of the present disclosure is provided by the method of the present disclosure.

[0068] In one embodiment, a method for preparing 7,8-dihydroxyflavone crystal form N is provided, characterized in that, in method 1, the single solvent is methanol;

[0069] and / or, in method 1, the volume-to-mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g;

[0070] and / or, in method 1, the solid is precipitated by solvent evaporation;

[0071] and / or, in method 2, the single solvent is methanol; the binary solvent is a combination of methanol and water;

[0072] and / or, in method 2, the volume ratio of methanol to water in the binary solvent is 1:5-1:10;

[0073] and / or, in method 3, the good solvent is ethanol, and the antisolvent is one or more of methyl tert-butyl ether and toluene;

[0074] and / or, in method 3, the volume ratio of the good solvent to the antisolvent is 1:1-1:10;

[0075] And / or, in method 4, the good solvent is ethanol, and the antisolvent is one or more of cyclohexane, n-heptane, and water;

[0076] And / or, in method 4, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10;

[0077] And / or, in method 5, the antisolvent is one or more of toluene, isopropyl acetate, 4-methyl-2-pentanone, water, and acetonitrile, and the good solvent is one or more of ethanol and methanol;

[0078] And / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8 to 1:1;

[0079] In a further embodiment, a method for preparing 7,8-dihydroxyflavone crystal form N is provided, characterized in that, in method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide;

[0080] And / or, in method 1, the temperature at which the precipitated solid is at room temperature;

[0081] and / or, in method 2, the suspension temperature is 20-60°C;

[0082] and / or, in method 3, the dropping temperature is 15-50°C;

[0083] and / or, in method 4, the dropping temperature is 15-50°C;

[0084] and / or, in method 5, the cooling temperature is -15 to 4°C.

[0085] In one embodiment, a 7,8-dihydroxyflavone having at least one characteristic of crystal form N of the present disclosure is provided, prepared by the method of the present disclosure.

[0086] In another aspect, the present disclosure provides a pharmaceutical composition comprising (1) 7,8-dihydroxyflavone crystal form P, 7,8-dihydroxyflavone crystal form C and / or 7,8-dihydroxyflavone crystal form N according to the present disclosure, and (2) at least one pharmaceutically acceptable excipient.

[0087] In another aspect, the present disclosure provides a method for treating diseases associated with abnormal TrkB signaling pathways, such as central nervous system injury, peripheral nerve injury, neurodegenerative diseases, mental illnesses, hereditary neurological disorders, ophthalmic diseases, metabolic diseases, pain, cardiovascular diseases, tumors, or other related diseases, comprising administering to a subject (1) 7,8-dihydroxyflavone crystal form P, 7,8-dihydroxyflavone crystal form C and / or said 7,8-dihydroxyflavone crystal form N according to the present disclosure, and (2) at least one pharmaceutically acceptable excipient.

[0088] Figure 1 is an X-ray powder diffraction pattern of crystal form P of the 7,8-dihydroxyflavone obtained in Example 1.

[0089] Figure 2 is an X-ray powder diffraction pattern of crystal form C of the 7,8-dihydroxyflavone obtained in Example 2.

[0090] Figure 3 is an X-ray powder diffraction pattern of crystal form N of the 7,8-dihydroxyflavone obtained in Example 3.

[0091] Figure 4 is a thermogravimetric analysis diagram and differential scanning spectroscopy (DSS) diagram of crystal form P of the 7,8-dihydroxyflavone obtained in Example 1.

[0092] Figure 5 is a dynamic moisture adsorption diagram of crystal form P of the 7,8-dihydroxyflavone obtained in Example 1.

[0093] Figure 6 is a thermogravimetric analysis diagram and DSS diagram of crystal form C of the 7,8-dihydroxyflavone obtained in Example 2.

[0094] Figure 7 is a dynamic moisture adsorption diagram of crystal form C of the 7,8-dihydroxyflavone obtained in Example 2.

[0095] Figure 8 is a thermogravimetric analysis diagram and differential scanning spectroscopy (DSS) diagram of crystal form N of the 7,8-dihydroxyflavone obtained in Example 3.

[0096] Figure 9 is a dynamic moisture adsorption diagram of crystal form N of the 7,8-dihydroxyflavone obtained in Example 3.

[0097] Figure 10 is an X-ray powder diffraction pattern of crystal form P of the 7,8-dihydroxyflavone obtained in Example 1 before and after the dynamic moisture adsorption experiment.

[0098] Figure 11 is a polarized light microscope analysis diagram of crystal form P of the 7,8-dihydroxyflavone obtained in Example 1.

[0099] Figure 12 is a 1H NMR spectrum of crystal form P of the 7,8-dihydroxyflavone obtained in Example 1.

[0100] Figure 13 is an X-ray powder diffraction pattern of crystal form C of the 7,8-dihydroxyflavone obtained in Example 2 before and after the dynamic moisture adsorption experiment.

[0101] Figure 14 is a polarized light microscope analysis of the crystal form C of the 7,8-dihydroxyflavone obtained in Example 2.

[0102] Figure 15 is the 1H NMR spectrum of crystal form C of the 7,8-dihydroxyflavone obtained in Example 2.

[0103] Figure 16 is the X-ray powder diffraction pattern of crystal form N of the 7,8-dihydroxyflavone obtained in Example 3 before and after the dynamic water adsorption experiment.

[0104] Figure 17 is the polarized light microscope analysis diagram of crystal form N of the 7,8-dihydroxyflavone obtained in Example 3.

[0105] Figure 18 is the 1H NMR spectrum of crystal form N of the 7,8-dihydroxyflavone obtained in Example 3. Specification 5 / 24 pages 7 CN 121064139 A

[0106] Figure 19 is the X-ray powder diffraction pattern of crystal form A of the 7,8-dihydroxyflavone obtained in Comparative Example 1.

[0107] Figure 20 is the X-ray powder diffraction pattern of crystal form B of the 7,8-dihydroxyflavone obtained in Comparative Example 2.

[0108] Figure 21 is an X-ray powder diffraction pattern of crystal form E of the 7,8-dihydroxyflavone obtained in Comparative Example 3.

[0109] Figure 22 is an X-ray powder diffraction pattern of crystal form F of the 7,8-dihydroxyflavone obtained in Comparative Example 4.

[0110] Figure 23 is an X-ray powder diffraction pattern of crystal form G of the 7,8-dihydroxyflavone obtained in Comparative Example 5.

[0111] Figure 24 is an X-ray powder diffraction pattern of crystal form H of the 7,8-dihydroxyflavone obtained in Comparative Example 6.

[0112] Figure 25 is an X-ray powder diffraction pattern of crystal form I of the 7,8-dihydroxyflavone obtained in Comparative Example 7.

[0113] Figure 26 is an X-ray powder diffraction pattern of crystal form J of the 7,8-dihydroxyflavone obtained in Comparative Example 8.

[0114] Figure 27 is an X-ray powder diffraction pattern of crystal form K of the 7,8-dihydroxyflavone obtained in Comparative Example 9.

[0115] Figure 28 is an X-ray powder diffraction pattern of crystal form L of the 7,8-dihydroxyflavone obtained in Comparative Example 10.

[0116] Figure 29 is an X-ray powder diffraction pattern of crystal form M of the 7,8-dihydroxyflavone obtained in Comparative Example 11.

[0117] Figure 30 is an X-ray powder diffraction pattern of crystal form O of the 7,8-dihydroxyflavone obtained in Comparative Example 12.

[0118] Figure 31 is an X-ray powder diffraction pattern of crystal form Q of the 7,8-dihydroxyflavone obtained in Comparative Example 13.

[0119] Figure 32 is an X-ray powder diffraction pattern of crystal form R of the 7,8-dihydroxyflavone obtained in Comparative Example 14.

[0120] Figure 33 is an X-ray powder diffraction pattern of crystal form S of the 7,8-dihydroxyflavone obtained in Comparative Example 15.

[0121] Figure 34 is an X-ray powder diffraction pattern of crystal form T of the 7,8-dihydroxyflavone obtained in Comparative Example 16.

[0122] Figure 35 is an X-ray powder diffraction pattern of crystal form P of the 7,8-dihydroxyflavone obtained in Effective Example 1.

[0123] Figure 36 is an X-ray powder diffraction pattern of crystal form C of the 7,8-dihydroxyflavone obtained in Effect Example 1.

[0124] Figure 37 is an X-ray powder diffraction pattern of crystal form N of the 7,8-dihydroxyflavone obtained in Effect Example 1.

[0125] Figure 38 is an X-ray powder diffraction pattern of crystal form P of the 7,8-dihydroxyflavone obtained in Effect Example 2.

[0126] Figure 39 is an X-ray powder diffraction pattern of crystal form C of the 7,8-dihydroxyflavone obtained in Effect Example 2.

[0127] Figure 40 is an X-ray powder diffraction pattern of crystal form N of the 7,8-dihydroxyflavone obtained in Effect Example 2.

[0128] Detailed Description

[0129] In this disclosure, the structural formula of the 7,8-dihydroxyflavone is:

[0130]

[0131] Unless explicitly stated otherwise, the term 7,8-dihydroxyflavone as used in this disclosure does not require any particular physical state, but may be amorphous and of any crystalline form.

[0132] In one embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one P crystalline form, characterized by its X-ray diffraction pattern, characterized by the presence of X-ray diffraction peaks at 2θ values ​​of about 8.3 ± 0.2°, 25.0 ± 0.2°, and 25.9 ± 0.2°. In a further embodiment, the X-ray diffraction pattern of crystalline form P also has X-ray diffraction peaks at 2θ values ​​of about 27.4 ± 0.2° and / or 31.4 ± 0.2°. In a further embodiment, crystalline form P is anhydrous. In a further embodiment, the X-ray diffraction pattern of crystal form P is shown in Figure 1. In a further embodiment, the positions of the characteristic X-ray diffraction peaks of crystal form P and the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown together in Table 1.

[0133] In an effective embodiment, this disclosure relates to a stable 7,8-dihydroxyflavone crystal form P that does not undergo transmorphism. Specification 6 / 24 pages 8 CN 121064139 A

[0134] In one embodiment, the present disclosure provides a 7,8-dihydroxyflavone having at least one C crystal form, characterized by its X-ray diffraction pattern, characterized by the presence of X-ray diffraction peaks at 2θ values ​​of about 5.6±0.2°, 9.5±0.2°, 11.1±0.2°, 15.5±0.2°, 15.6±0.2°, 21.0±0.2°, 24.3±0.2°, 25.5±0.2°, 27.0±0.2°, and 28.3±0.2°. In a further embodiment, crystal form C is a hydrate, such as a monohydrate. In a further embodiment, the X-ray diffraction pattern of crystal form C is shown in Figure 2. In a further embodiment, crystal form C is characterized by...The positions of the X-ray diffraction peaks and the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown together in Table 1.

[0135] In one effective embodiment, this disclosure relates to a stable 7,8-dihydroxyflavone crystal form C that does not undergo transmorphism.

[0136] In one embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one N crystal form, characterized by its X-ray diffraction pattern, characterized by the presence of X-ray diffraction peaks at 2θ values ​​of about 9.3 ± 0.2°, 23.8 ± 0.2°, 24.6 ± 0.2°, and 26.6 ± 0.2°; in a further embodiment, the X-ray diffraction pattern of crystal form N also has X-ray diffraction peaks at 2θ values ​​of about 12.3 ± 0.2° and / or 21.1 ± 0.2°. In a further embodiment, crystal form N is a hydrate, such as a dihydrate. In a further embodiment, the X-ray diffraction pattern of crystal form N is shown in Figure 3. In a further embodiment, the positions of the characteristic X-ray diffraction peaks of crystal form N and the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown together in Table 1.

[0137] In an effective embodiment, this disclosure relates to 7,8-dihydroxyflavone crystal form N which is stable and does not undergo transmorphism.

[0138] This disclosure relates to methods for preparing 7,8-dihydroxyflavone crystals, including methods 1 to 5:

[0139] Method 1: includes the following steps: dissolving 7,8-dihydroxyflavone in a single solvent until the solvent is completely evaporated to obtain a solid;

[0140] Method 2: includes the following steps: suspending 7,8-dihydroxyflavone in a single solvent or a binary solvent, and then centrifuging to obtain a solid;

[0141] Method 3: includes the following steps: dissolving 7,8-dihydroxyflavone in a good solvent, adding it dropwise to an antisolvent, precipitating a solid, and then centrifuging to obtain a solid;

[0142] Method 4: includes the following steps: dissolving 7,8-dihydroxyflavone in a good solvent, adding it dropwise to an antisolvent, precipitating a solid, and then centrifuging to obtain a solid;

[0143] Method 5: includes the following steps: suspending 7,8-dihydroxyflavone in an antisolvent, adding a good solvent dropwise until the solid dissolves, cooling to precipitate the solid, and then centrifuging to obtain a solid.

[0144] In one embodiment, this disclosure relates to a method for preparing 7,8-dihydroxyflavonoids having at least one crystalline form P, particularly pure crystalline form P. The method may be, for example:

[0145] In method 2, the single solvent is n-heptane, and the binary solvent is one of 4-methyl-2-pentanone, n-propanol, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, butyl formate, in combination with one of isopropyl acetate, n-heptane, toluene, isopropanol, ethyl acetate, diethyl ether, cyclohexane; more preferably, the single solvent is n-heptane.The binary solvent is a combination of ethanol and ethyl acetate;

[0146] and / or, in method 2, the volume ratio of the binary solvent is 1:5 to 1:10; more preferably, the volume ratio of the binary solvent is 1:10;

[0147] In method 2, the suspension temperature is 20-60°C; more preferably, the suspension temperature is 50°C.

[0148] In one embodiment, this disclosure relates to a method for preparing 7,8-dihydroxyflavone having at least one crystalline form C, especially pure crystalline form C. (Specification 7 / 24 pages 9 CN 121064139 A) The method may be, for example:

[0149] In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; more preferably, the single solvent is N,N-dimethylformamide;

[0150] and / or, in method 1, the volume-to-mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g; more preferably, the volume-to-mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 mL / g;

[0151] and / or, in method 1, the solid is precipitated by solvent evaporation;

[0152] and / or, in method 2, the single solvent is water or diethyl ether; more preferably, the single solvent is water; the binary solvent is a combination of an organic solvent and water, a combination of butyl formate and n-heptane, a combination of ethylene glycol methyl ether and chloroform, or a combination of acetonitrile and toluene; more preferably, the binary solvent is a combination of an organic solvent and water;

[0153] And / or, in method 2, the organic solvent is one of tetrahydrofuran, isopropanol, acetonitrile, methanol, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, and ethylene glycol dimethyl ether; more preferably, the organic solvent is tetrahydrofuran;

[0154] And / or, in method 2, in the binary solvent, the volume ratio of the organic solvent to water is 1:5 to 1:10, the volume ratio of butyl formate to n-heptane is 1:1, the volume ratio of ethylene glycol methyl ether to chloroform is 1:5, and the volume ratio of acetonitrile to toluene is 1:1; more preferably, in the binary solvent, the volume ratio of the organic solvent to water is 1:5;

[0155] And / or, in method 3, the good solvent is one of N,N-dimethylformamide, tetrahydrofuran, and ethylene glycol dimethyl ether, and the antisolvent is one of water, toluene, dichloromethane, and diethyl ether; more preferably, the good solvent is N,N-dimethylformamide, and the antisolvent is water;

[0156] And / or, in method 3, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; more preferably, the volume ratio of the good solvent to the antisolvent is 1:1;

[0157] And / or, in method 4, the good solvent is one of N,N-dimethylformamide and isopropanol, and the antisolvent is one of water, toluene, dichloromethane, and diethyl ether;The solvent is one of chloroform, toluene, and water; more preferably, the good solvent is N,N-dimethylformamide, and the antisolvent is chloroform;

[0158] and / or, in method 4, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; more preferably, the volume ratio of the good solvent to the antisolvent is 1:1;

[0159] and / or, in method 5, the antisolvent is water, and the good solvent is one of N,N-dimethylformamide, tetrahydrofuran, ethanol, and ethylene glycol methyl ether; more preferably, the antisolvent is water, and the good solvent is N,N-dimethylformamide;

[0160] and / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8 to 1:1; more preferably, the volume ratio of the antisolvent to the good solvent is 1:0.8;

[0161] In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; more preferably, the single solvent is N,N-dimethylformamide;

[0162] and / or, in method 1, the temperature at which the precipitated solid is formed is room temperature;

[0163] and / or, in method 2, the suspension temperature is 20-60°C; more preferably, the suspension temperature is 25°C;

[0164] and / or, in method 3, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0165] and / or, in method 4, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0166] and / or, in method 5, the cooling temperature is -15-4°C.

[0167] This disclosure relates to a method for preparing 7,8-dihydroxyflavonoids having at least one crystalline N, especially pure crystalline N. The method may be, for example:

[0168] In method 1, the single solvent is methanol;

[0169] and / or, in method 1, the volume-to-mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g; Further preferably, the volume-to-mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 mL / g and / or, in method 1, the solid is precipitated by solvent evaporation;

[0170] and / or, in method 2, the single solvent is methanol; the binary solvent is a combination of methanol and water;

[0171] and / or, in method 2, the volume ratio of methanol to water in the binary solvent is 1:5-1:10; further preferably, the volume ratio of methanol to water in the binary solvent is 1:5;

[0172] And / or, in method 3, the good solvent is ethanol, and the antisolvent is one of methyl tert-butyl ether and toluene; more preferably, the antisolvent is methyl tert-butyl ether;

[0173] And / or, in method 3, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; more preferably, the volume ratio of the good solvent to the antisolvent is 1:1;

[0174] And / or, in method 4, the good solvent is ethanol, and the antisolvent is one of cyclohexane, n-heptane, and water; more preferably, the antisolvent is cyclohexane;

[0175] And / or, in method 4, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; more preferably, the volume ratio of the good solvent to the antisolvent is 1:1;

[0176] And / or, in method 5, the antisolvent is one of toluene, isopropyl acetate, 4-methyl-2-pentanone, water, and acetonitrile, and the good solvent is one of ethanol and methanol; more preferably, the antisolvent is toluene, and the good solvent is ethanol;

[0177] And / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8-1:1; more preferably, the volume ratio of the antisolvent to the good solvent is 1:0.8;

[0178] And / or, in method 1, the single solvent is methanol;

[0179] And / or, in method 1, the temperature at which the precipitated solid is formed is room temperature;

[0180] And / or, in method 2, the suspension temperature is 20-60°C; more preferably, the suspension temperature is 50°C;

[0181] And / or, in method 3, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0182] And / or, in method 4, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0183] And / or, in method 5, the cooling temperature is -15-4°C; more preferably, the cooling temperature is 0°C.

[0184] In one comparative embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one crystal form A, characterized by its X-ray diffraction pattern, which features X-ray diffraction peaks at 2θ values ​​of approximately 9.1 ± 0.2°, 17.2 ± 0.2°, 20.5 ± 0.2°, and 27.3 ± 0.2°; crystal form A is a hydrate. The X-ray diffraction pattern of crystal form A is shown in Figure 19. The positions of the characteristic X-ray diffraction peaks of crystal form A and the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown together in Table 1.

[0185] On the one hand, crystal form A transforms into crystal form N under sufficient drying, making it impossible for it to exist for a long time under drying conditions; on the other hand, crystal form A transforms into a mixed crystal containing crystal form F when heated to 130°C, and into a mixed crystal containing crystal forms F and J when heated to 160°C.

[0186] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavonoids having at least one crystal form B, characterized by its X-ray diffraction pattern at approximately 6.4 ± 0.2°, 9.4 ± 0.2°, 10.9 ± 0.2°, and 12°.X-ray diffraction peaks exist at 2θ values ​​of 0.8±0.2°, 13.9±0.2°, 17.2±0.2°, 18.8±0.2°, 20.4±0.2°, and 20.7±0.2°; crystal form B is an anhydrous substance containing a small amount of adsorbed solvent. The X-ray diffraction pattern of crystal form B is shown in Figure 20. The positions of the characteristic X-ray diffraction peaks of crystal form B and the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown in Table 1.

[0187] On the one hand, crystal form B will transform into crystal form C at room temperature, making it unable to exist at room temperature for a long time; on the other hand, when crystal form B is heated to 110°C, a small amount of characteristic peaks of crystal form J appear, and at 180°C it will transform into a mixed crystal containing crystal form F and crystal form J. (See page 9 / 24 of the specification, CN 121064139 A)

[0188] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one crystal form E, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 14.2 ± 0.2°, 16.3 ± 0.2°, 20.3 ± 0.2°, 23.3 ± 0.2°, 24.2 ± 0.2°, and 27.3 ± 0.2°; crystal form E is a hydrate or a dimethyl sulfoxide solvate. The X-ray diffraction pattern of crystal form E is shown in Figure 21. The positions of the characteristic X-ray diffraction peaks of crystal form E, together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0189] Crystal form E transforms into crystal form N at room temperature.

[0190] In one comparative embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one F crystal form, characterized by its X-ray diffraction pattern, characterized by the presence of X-ray diffraction peaks at 2θ values ​​of approximately 6.0 ± 0.2°, 15.9 ± 0.2°, 17.2 ± 0.2°, 19.2 ± 0.2°, and 26.9 ± 0.2°; crystal form F is an anhydrous form containing a small amount of adsorbed solvent. The X-ray diffraction pattern of crystal form F is shown in Figure 22. The positions of the characteristic X-ray diffraction peaks of crystal form F and the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown together in Table 1.

[0191] On the one hand, crystal form F transforms into crystal form B at room temperature, making it impossible for it to exist at room temperature for a long time; on the other hand, crystal form F transforms into a mixed crystal of crystal forms J and P when heated to 220°C.

[0192] In one comparative embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one G crystal form, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 11.6 ± 0.2°, 18.5 ± 0.2°, and 35.4 ± 0.2°; crystal form G is a hydrate. The X-ray diffraction pattern of crystal form G is shown in Figure 23. The positions of the characteristic X-ray diffraction peaks of crystal form G and other 7The positions of the characteristic X-ray diffraction peaks of the 7,8-dihydroxyflavone crystal form are shown together in Table 1.

[0193] Crystal form G will transform into crystal form T, which has a small amount of crystal form J, when heated to 140°C.

[0194] In a comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one crystal form H, characterized by its X-ray diffraction pattern, which features X-ray diffraction peaks at 2θ values ​​of approximately 8.3 ± 0.2°, 11.2 ± 0.2°, 11.6 ± 0.2°, 16.7 ± 0.2°, and 21.5 ± 0.2°. The X-ray diffraction pattern of crystal form H is shown in Figure 24. The positions of the characteristic X-ray diffraction peaks of crystal form H and the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown together in Table 1.

[0195] Crystal form H will transform into other crystal forms at room temperature and cannot exist at room temperature for a long time.

[0196] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one crystal form I, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 10.5 ± 0.2°, 17.0 ± 0.2°, and 20.5 ± 0.2°. The X-ray diffraction pattern of crystal form I is shown in Figure 25. The positions of the characteristic X-ray diffraction peaks of crystal form I, along with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0197] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one J crystal form, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 4.3 ± 0.2°, 5.7 ± 0.2°, 6.8 ± 0.2°, 8.3 ± 0.2°, 12.4 ± 0.2°, 12.8 ± 0.2°, 17.2 ± 0.2°, and 18.0 ± 0.2°; crystal form J is anhydrous. The X-ray diffraction pattern of crystal form J is shown in Figure 26. The positions of the characteristic X-ray diffraction peaks of crystal form J, along with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0198] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one K crystal form, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 10.8 ± 0.2°, 19.5 ± 0.2°, 22.1 ± 0.2°, 22.4 ± 0.2°, 24.7 ± 0.2°, and 28.2 ± 0.2°; crystal form K is a 1:1 dioxane solvate. The X-ray diffraction pattern of crystal form K is shown in Figure 27. The positions of the characteristic X-ray diffraction peaks of crystal form K, along with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0199] Crystal form K, when heated to 150°C and then cooled to room temperature, transforms into a mixed crystal of crystal forms F and J.

[0200] In a comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one L crystal form, characterized by its X-ray diffraction pattern, which features X-ray diffraction peaks at 2θ values ​​of approximately 10.6 ± 0.2°, 11.3 ± 0.2°, 12.0 ± 0.2°, 15.5 ± 0.2°, 17.7 ± 0.2°, 19.5 ± 0.2°, and 22.6 ± 0.2°; the X-ray diffraction pattern of crystal form L is shown in Figure 28. The positions of the characteristic X-ray diffraction peaks of crystal form L, together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0201] In one comparative embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one crystal form M, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 8.5 ± 0.2°, 14.8 ± 0.2°, 16.5 ± 0.2°, and 19.0 ± 0.2°; crystal form M is an acetone solvate. The X-ray diffraction pattern of crystal form M is shown in Figure 29. The positions of the characteristic X-ray diffraction peaks of crystal form M, together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0202] Crystal form M transforms into crystal form C at room temperature and cannot persist at room temperature for extended periods.

[0203] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one O crystal form, characterized by its X-ray diffraction pattern, featuring X-ray diffraction peaks at 2θ values ​​of approximately 3.4 ± 0.2°, 5.9 ± 0.2°, 8.9 ± 0.2°, 10.9 ± 0.2°, 11.7 ± 0.2°, 13.6 ± 0.2°, 14.1 ± 0.2°, 15.2 ± 0.2°, 20.4 ± 0.2°, and 20.7 ± 0.2°; crystal form O is an anhydrous form or a chloroform solvate with a small amount of solvent residue. The X-ray diffraction pattern of crystal form O is shown in Figure 30. The positions of the characteristic X-ray diffraction peaks of crystal form O, along with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0204] Crystal form O will transform into crystal form C at room temperature and cannot exist at room temperature for a long time.

[0205] In a comparative embodiment, this disclosure provides a 7,8-dihydroxyflavone having at least one crystal form Q, characterized by its X-ray diffraction pattern, which is characterized by the presence of X-ray diffraction peaks at 2θ values ​​of approximately 3.6 ± 0.2°, 7.7 ± 0.2°, 12.1 ± 0.2°, 13.0 ± 0.2°, 16.6 ± 0.2°, and 20.2 ± 0.2°; the X-ray diffraction pattern of crystal form Q is shown in Figure 31.The positions of the characteristic X-ray diffraction peaks of crystal form Q and the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown in Table 1.

[0206] Crystal form Q will transform into crystal form C at room temperature and cannot exist at room temperature for a long time.

[0207] In a comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one crystal form R, characterized by its X-ray diffraction pattern, characterized by the presence of an X-ray diffraction peak at approximately 2θ; the X-ray diffraction pattern of crystal form R is shown in Figure 32. The positions of the characteristic X-ray diffraction peaks of crystal form R and the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms are shown in Table 1.

[0208] Crystal form R can only be obtained by heating crystal form N to 100°C and cannot exist at room temperature for a long time.

[0209] In one comparative embodiment, this disclosure provides 7,8-dihydroxyflavone having at least one S crystal form, characterized by its X-ray diffraction pattern, which features X-ray diffraction peaks at 2θ values ​​of approximately 8.6 ± 0.2°, 17.3 ± 0.2°, and 22.6 ± 0.2°; the X-ray diffraction pattern of crystal form S is shown in Figure 33. The positions of the characteristic X-ray diffraction peaks of crystal form S, together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown in Table 1.

[0210] Crystal form S transforms into crystal form C at room temperature and cannot persist at room temperature for extended periods.

[0211] In one comparative embodiment, this disclosure also provides 7,8-dihydroxyflavone having at least one T crystal form, characterized by its X-ray diffraction pattern, characterized by the presence of X-ray diffraction peaks at 2θ values ​​of approximately 9.3 ± 0.2°, 13.0 ± 0.2°, 15.4 ± 0.2°, and 23.8 ± 0.2°; the X-ray diffraction pattern of crystal form T is shown in Figure 34. The positions of the characteristic X-ray diffraction peaks of crystal form T, as well as the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms, are shown together in Table 1.

[0212] Crystal form T can only be obtained by heating crystal form G to 140°C and cannot exist at room temperature for a long period of time.

[0213] Table 1

[0214]

[0215] In one embodiment, this disclosure provides a pharmaceutical composition comprising 7,8-dihydroxyflavone crystalline form P and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0216] In one embodiment, tablets were prepared according to a standard formulation method, and it was found that crystalline form P in the tablets remained stable for 6 months under harsh conditions such as light, high temperature, and high humidity. The stability of 7,8-dihydroxyflavone crystalline form P in the tablets is not limited by the specific dosage form.

[0217] In one embodiment, tablets were prepared according to a standard formulation method, and it was found that crystal form P in the tablets had better dissolution.

[0218] In one embodiment, this disclosure also provides a pharmaceutical composition comprising 7,8-dihydroxyflavone crystal form C and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0219] In one embodiment, tablets were prepared according to a standard formulation method, and it was found that crystal form C in the tablets was stable for 6 months under harsh conditions such as light, high temperature, and high humidity. The stability of 7,8-dihydroxyflavone crystal form C in the tablets is not limited by the specific dosage form.

[0220] In one embodiment, this disclosure also provides a pharmaceutical composition comprising 7,8-dihydroxyflavone crystal form N and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0221] In one embodiment, the pharmaceutical composition provided by this disclosure contains one or more polymorphs of the 7,8-dihydroxyflavone described herein. In addition to the active ingredient, the pharmaceutical composition disclosed herein may also include one or more excipients. Various excipients may be added to the composition to achieve different purposes.

[0222] Fillers increase the volume of the solid pharmaceutical composition and make it easier for patients and caregivers to use the pharmaceutical dosage form containing the composition. Fillers used for solid compositions include, for example, microcrystalline cellulose, ultrafine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, glucose binder, dextrin, glucose, calcium hydrogen phosphate dihydrate, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethyl methacrylate, potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0223] Solid pharmaceutical compositions compressed into dosage forms such as tablets may include excipients that help the active ingredient bind together with other excipients after compression. The binders of the solid pharmaceutical composition include povidone, gum arabic, alginate, carbomer, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polymethyl methacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, and starch.

[0224] The dissolution rate of the compressed solid pharmaceutical composition in the patient's stomach can be increased by adding disintegrants. Disintegrants include sodium carboxymethyl starch, alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, colloidal silica, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, potassium polycrylamide, powdered cellulose, pregelatinized starch, sodium alginate, sodium glycolate starch, and starch.

[0225] When a fractional composition is compressed into a dosage form such as a tablet, the composition is subjected to pressure from a die and a punch. Certain excipients and active ingredients tend to adhere to the surfaces of the punch and die, a tendency that can lead to indentations and other surface irregularities in the product. A lubricant can be added to the composition to reduce adhesion and facilitate product release from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, palmitoyl stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc, and zinc stearate.

[0226] The pharmaceutical compositions provided in this disclosure can be in solid dosage forms, for example, tablets, powders, capsules, suppositories, small capsules, tablets, lozenges, liquid syrups, suspensions, etc. In one embodiment, the dosage form of this disclosure is a tablet.

[0227] In one aspect, this disclosure also provides a method for treating diseases associated with abnormalities in the Tyrosine Kinase Receptor B (TrkB) signaling pathway, such as central nervous system injury, peripheral nerve injury, neurodegenerative diseases, mental illnesses, hereditary neurological disorders, ophthalmic diseases, metabolic diseases, pain, cardiovascular diseases, tumors, or other related diseases, comprising administering to a subject the 7,8-dihydroxyflavone crystal form of this disclosure and at least one pharmaceutically acceptable excipient. In one embodiment, the disease associated with abnormalities in the TrkB signaling pathway is a disease caused by low expression or insufficient activation of TrkB. 7,8-dihydroxyflavone is known in the art as a specific small molecule agonist of TrkB, activating downstream signaling pathways of TrkB.

[0228] In one aspect, this disclosure provides a method for treating or preventing traumatic brain injury or age-related cognitive decline, comprising administering to a subject the 7,8-dihydroxyflavone crystal form described herein.

[0229] In one aspect, 7,8-dihydroxyflavone crystal form P, 7,8-dihydroxyflavone crystal form C, or 7,8-dihydroxyflavone crystal form N are disclosed for use in treating or preventing traumatic brain injury or age-related cognitive decline.

[0230] In one aspect, the use of 7,8-dihydroxyflavone crystal form P, 7,8-dihydroxyflavone crystal form C, and / or 7,8-dihydroxyflavone crystal form N in the preparation of a medicament for treating or preventing traumatic brain injury or age-related cognitive decline is disclosed. Those skilled in the art will understand that the peak intensity and / or peak characteristics of X-ray powder diffraction may vary depending on experimental conditions. Furthermore, due to varying instrument precision, the measured 2θ value may have an error of approximately ±0.2 degrees. The relative intensity value of the peak (see page 13 / 24 of CN 121064139 A) depends more on certain properties of the sample being measured, such as crystal size and purity, than on the peak position.The measured peak intensity may deviate by approximately ±20%. Despite experimental errors, instrumental errors, and orientation preferences, those skilled in the art can obtain sufficient information to identify each crystal form from the X-ray powder diffraction data provided in this disclosure.

[0231] In this disclosure, the expression "having at least one '#' crystal form" (where '#' is a letter) means that 7,8-dihydroxyflavone has at least one crystal form '#' X-ray characteristic peak.

[0232] In this disclosure, "solvent evaporation method" refers to a crystallization method commonly used in the field of crystal forms, which involves the continuous evaporation of the solution, causing the solution to go from unsaturated to supersaturated, resulting in crystal precipitation.

[0233] Without violating common sense in the art, the above preferred conditions can be combined arbitrarily.

[0234] Unless otherwise stated, the reagents and raw materials used in this disclosure are commercially available. Examples

[0235] The present invention will be further illustrated below by way of examples, but the invention is not limited to the scope of the examples described. Unless otherwise specified, experimental methods in the following examples were performed using conventional methods and conditions, or according to the product instructions.

[0236] Test Methods

[0237] Nuclear Magnetic Resonance Analysis (1H NMR)

[0238] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE NEO 400 (Bruker, GER).

[0239] X-ray Powder Diffraction (XRPD)

[0240] The obtained solid sample was analyzed using a Bruker D8 Advance (Bruker, GER) X-ray powder diffractometer. The 2θ scanning angle ranged from 3° to 45°, the scanning step size was 0.02°, and the exposure time was 0.08 seconds. The phototube voltage and current for the test sample were 40 kV and 40 mA, respectively, and the sample disk was a zero-background sample disk.

[0241] Thermogravimetric Analysis (TGA)

[0242] The thermogravimetric analyzer was a TADiscovery 55 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with a nitrogen purging rate of 60 mL / min at the sample and 40 mL / min at the balance.

[0243] Differential Scanning Calorimetry (DSC)

[0244] The differential scanning calorimeter was a TADiscovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan, heated to the final temperature at a rate of 10 °C / min, with a nitrogen purging rate of 50 mL / min in the furnace.

[0245] Dynamic Moisture Adsorption Analysis (DVS)

[0246] Dynamic moisture adsorption-desorption analysis was performed using DVS.Measurements were performed using an Intrinsic (SMS, UK) instrument. The test employed a gradient mode with humidity variations ranging from 50% to 95% to 0% to 50%. Within the 0% to 90% range, each gradient represented a 10% change in humidity. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the endpoint. After the test, XRPD analysis was performed on the samples to confirm whether the solid morphology had changed. The judgment criteria are shown in Table 2:

[0247] Table 2

[0248] Hygroscopicity Classification Hygroscopic Weight Gain Deliquescence Absorbs Sufficient Moisture to Form Liquid Instruction Manual 14 / 24 Page 16 CN 121064139 A Extremely Hygroscopic Hygroscopic Weight Gain Not Less Than 15% Hygroscopic Hygroscopic Weight Gain Less Than 15% But Not Less Than 2% Slightly Hygroscopic Hygroscopic Weight Gain Less Than 2% But Not Less Than 0.2% Out of Stock Almost No Hygroscopic Hygroscopic Weight Gain Less Than 0.2%

[0249] Polarizing Microscope Analysis (PLM)

[0250] The polarizing microscope model is Nikon Ci-POL (Nikon, JPN). A small amount of sample is placed on a glass slide, and a suitable lens is selected to observe the sample morphology.

[0251] Example 1 Preparation of crystal form P of 7,8-dihydroxyflavone

[0252] 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of ethanol and 1.0 mL of ethyl acetate until a suspension was formed. After stirring at 50 °C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0253] XRPD analysis showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 4.1±0.2°, 6.2±0.2°, 7.0±0.2°, 7.3±0.2°, 7.9±0.2°, 8.3±0.2°, 11.0±0.2°, 12.5±0.2°, 13.6±0.2°, and 14.0±0.2°. Diffraction peaks were observed at 15.8±0.2o, 16.6±0.2o, 17.2±0.2o, 18.4±0.2o, 18.7±0.2o, 19.4±0.2o, 20.8±0.2o, 21.4±0.2o, 22.8±0.2o, 24.1±0.2o, 25.0±0.2o, 25.9±0.2o, 27.0±0.2o, 27.4±0.2o, 31.2±0.2o, 31.4±0.2o, and 33.7±0.2o, and their XRPD spectra are shown in Figure 1.

[0254] 1H NMR analysis revealed no obvious solvent residue peaks, indicating that the crystal form P of 7,8-dihydroxyflavone is not a solvate, and its 1H NMR spectrum is shown in Figure 12.

[0255] TGA analysis showed that the crystalline form P of 7,8-dihydroxyflavone did not exhibit significant weight loss, as shown in Figure 4.

[0256] DSC analysis showed that crystal form P of 7,8-dihydroxyflavone had no corresponding endothermic signal for weight loss, and its DSC spectrum is shown in Figure 4.

[0257] DVS analysis showed that the weight gain of crystal form P of 7,8-dihydroxyflavone was less than 0.1% in the dynamic moisture adsorption spectrum within the range of 0%-95% relative humidity, and its DVS spectrum is shown in Figure 5.

[0258] PLM analysis showed that crystal form P of 7,8-dihydroxyflavone was composed of fine particles with a particle size generally less than 20 μm, and its PLM spectrum is shown in Figure 11.

[0259] Example 2 Preparation of crystal form C of 7,8-dihydroxyflavone

[0260] Approximately 20 mg of raw material was weighed and added to an EP tube. A certain amount of solvent was added gradually at room temperature (~25℃), and the solution was stirred and sonicated until the solid was completely dissolved. The resulting clear solution was left to stand open at room temperature until the solvent completely or mostly evaporated to obtain a solid;

[0261] XRPD analysis showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 5.6±0.2o, 9.5±0.2o, 11.1±0.2o, 12.7±0.2o, 13.5±0.2o, 13.7±0.2o, 15.5±0.2o, 16.0±0.2o, 16.3±0.2o, 16.6±0.2o, 16.9±0.2o, 17.4±0.2o, 18.3±0.2o, 18.9±0.2o, 19.2±0.2o, 19.4±0.2o, 20.4±0.2o, 20.8±0.2o, 21.0±0.2o, 21 .9±0.2o, 22.2±0.2o, 23.2±0.2o, 23.4±0.2o, 24.1± 0.2o, 24.3±0.2o, 25.0±0.2o, 25.2±0.2o, 25.5±0.2o, 25.8±0.2o, 27.0±0.2o, 27.3± 0.2o, 27.6±0.2o, 27.9±0.2o, 28.3±0.2o, 28.6±0.2o, 28.9±0.2o, 29.7±0.2o, 30.4±0.2o, 30.7±0.2o, 31 Diffraction peaks were observed at 0.7±0.2o, 33.2±0.2o, 33.6±0.2o, 34.3±0.2o, 34.5±0.2o, 34.6±0.2o, 35.1±0.2o, 35.7±0.2o, 36.3±0.2o, 37.7±0.2o, 39.8±0.2o, 42.6±0.2o, and 44.5±0.2o. The XRPD spectrum is shown in Figure 2.

[0262] 1H NMR analysis revealed no obvious solvent residue peaks, indicating that crystal form C of 7,8-dihydroxyflavone is not a solvate. The 1H NMR spectrum is shown in Figure 15.

[0263] TGA analysis showed that 7...The weight loss of 7,8-dihydroxyflavone crystal form C at 150℃ is 3.7% of its original weight. This weight loss refers to the weight of water in the hydrate crystal form. Its TGA spectrum is shown in Figure 6.

[0264] DSC detection shows that 7,8-dihydroxyflavone crystal form C has an endothermic signal corresponding to weight loss at 100℃ to 160℃ and a melting endothermic peak at 247℃. Its DSC spectrum is shown in Figure 6.

[0265] DVS detection shows that the weight gain of 7,8-dihydroxyflavone crystal form C in the dynamic water adsorption diagram is less than 0.1% in the range of 0%-95% relative humidity. Its DVS spectrum is shown in Figure 7.

[0266] PLM detection shows that 7,8-dihydroxyflavone crystal form C consists of fine particles with a particle size generally less than 5μm. Its PLM spectrum is shown in Figure 14.

[0267] Example 3 Preparation of Crystal Form N of 7,8-Dihydroxyflavone

[0268] 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of methanol until a suspension was formed. After stirring at 50 °C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0269] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, was at 5.7±0.2°, 9.3±0.2°, 11.1±0.2°, 11.4±0.2°, 11.9±0.2°, 12.3±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 15.9±0.2°. 0.2o, 16.8±0.2o, 17.1±0.2o, 17.7±0.2o, 18.7±0.2o, 18.9±0.2o, 19.2±0.2o, 20.2± 0.2o, 20.7±0.2o, 21 .1±0.2o, 22.1±0.2o, 22.4±0.2o, 23.1±0.2o, 23.2±0.2o, 23.4± 0.2o, 23.8±0.2o, 24.6±0.2o, 25.2±0.2o, 25.7±0.2o, 26.3±0.2o, 26.6±0.2o, 26.9± 0.2o, 27.3±0.2o, 28.9±0.2o, 28.0±0.2o, 29.0±0.2o, 29.4±0.2o, 29.6±0.2o, 30.4±0.2o, 31.3±0.2o, 31 .9±0.2o, 32.1±0.2o, 32.4±0.2o, 35.0±0.2o, 35.4±0.2o, 36.2±0.2o, 36.8±0.2o, 38.2±0.2o, 38.4±0.2o, 38.6±0.2o, 38.9±0.2o, 41 .0±0.2o, 41.4± Diffraction peaks are observed at 0.2°, 42.0±0.2°, and 43.9±0.2°, and its XRPD pattern is shown in Figure 3.

[0270] After 1HNMR detection showed no obvious solvent residue peaks, indicating that crystalline form N of 7,8-dihydroxyflavone is not a solvate. Its 1H NMR spectrum is shown in Figure 18.

[0271] TGA detection showed that the mass loss of crystalline form N of 7,8-dihydroxyflavone at 40℃ to 80℃ accounted for 6.3% of the mass before weight loss. This weight loss is the weight of water in the hydrate crystal form. Its TGA spectrum is shown in Figure 8.

[0272] DSC detection showed that crystalline form N of 7,8-dihydroxyflavone had an endothermic peak corresponding to weight loss at 100℃, and exothermic signals at 136℃ and 169℃, respectively. Its DSC spectrum is shown in Figure 8.

[0273] DVS detection showed that the weight gain of crystalline form N of 7,8-dihydroxyflavone was less than 0.1% in the dynamic water adsorption pattern within the relative humidity range of 0%-95%. Its DVS spectrum is shown in Figure 9.

[0274] PLM analysis showed that the crystal form N of 7,8-dihydroxyflavone was a fine particle with a particle size generally less than 20 μm, and its PLM spectrum is shown in Figure 17.

[0275] Comparative Example 17,8-Dihydroxyflavone Crystal Form A Preparation

[0276] 20.0 mg of 7,8-dihydroxyflavone was added to 2.0 mL of ethanol until a suspension was formed. After suspending and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was vacuum dried at room temperature;

[0277] XRPD detection showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 5.6±0.2°, 9.1±0.2°, 11.7±0.2°, 12.0±0.2°, 12.2±0.2°, 16.4±0.2°, 17.2±0.2°, 18.2±0.2°, 18.5±0.2°, 20.4±0.2°, 20.5±0.2°, 21°. Diffraction peaks are observed at 0±0.2°, 23.5±0.2°, 26.1±0.2°, 27.3±0.2°, 27.8±0.2°, 35.3±0.2°, and 41.1±0.2°, and its XRPD pattern is shown in Figure 19.

[0278] Comparative Example 2: Preparation of Crystal Form B of 7,8-Dihydroxyflavone

[0279] 40.0 mg of 7,8-dihydroxyflavone was added to 9.0 mL of ethyl formate until a suspension was formed. After stirring for 7 days at room temperature, the suspension was centrifuged and the solid was vacuum dried at room temperature;

[0280] XRPD analysis showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 3.1±0.2°, 3.4±0.2°, 3.7±0.2°, 5.5±0.2°, 5.9±0.2°, 6.4±0.2°, 7.3±0.2°, 8.2±0.2°, 8.5±0.2°, 9.4±0.2°, 9.8±0.2°. 0.2o, 10.3±0.2o, 10.9±0.2o, 11.2±0.2o, 11.8±0.2o, 12.8±0.2o, 13.4±0.2o, 13.9± 0.2o, 14.2±0.2o, 14.8±0.2o, 15.2±0.2o, 15.7±0.2o, 16.3±0.2o, 16.7±0.2o, 17.2± 0.2o, 17.9±0.2o, 18.8±0.2o, 19.3±0.2o, 19.8±0.2o, 20.4±0.2o, 20.7±0.2o, 22.1± Diffraction peaks are observed at 0.2°, 22.2±0.2°, 22.5±0.2°, 23.7±0.2°, 24.2±0.2°, 24.9±0.2°, 25.3±0.2°, 26.0±0.2°, 26.7±0.2°, 27.8±0.2°, 28.1±0.2°, 28.3±0.2°, 29.0±0.2°, 30.2±0.2°, 32.5±0.2°, 34.7±0.2°, and 41.46±0.2°, and their XRPD patterns are shown in Figure 20.

[0281] Comparative Example 3 Preparation of Crystal Form E of 7,8-Dihydroxyflavone

[0282] Weigh about 20 mg of raw material and add it to an EP tube. Add 2 mL of ethylene glycol dimethyl ether at room temperature (~25°C), stir and sonicate the solution until the solid is completely dissolved. The resulting clear solution was left to stand open at room temperature until the solvent completely or mostly evaporated to obtain a solid;

[0283] XRPD analysis showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 5.6±0.2°, 8.9±0.2°, 11.1±0.2°, 11.6±0.2°, 11.9±0.2°, 12.1±0.2°, 13.5±0.2°, 14.0±0.2°, 14.2±0.2°, 15.8±0.2°, 16.3±0.2°, 16.6±0.2°, 17.0±0.2°, 17.3±0.2°, 17.9±0.2°, 18.3±0.2°, 18.6±0.2°. 0.2o, 18.8±0.2o, 19.0±0.2o, 19.3±0.2o, 20.3±0.2o, 21.2±0.2o, 21.7±0.2o, 22.0± 0.2o, 22.3±0.2o, 22.6±0.2o, 23.3±0.2o, 23.8±0.2o, 24.2±0.2o, 25.0±0.2o, 25.4± 0.2o, 25.8±0.2o, 26.5±0.2o, 26.9±0.2o, 27.3±0.2o, 27.8±0.2o, 28.1±0.2o, 28.6± 0.2o, 29.2±0.2o, 29.7±0.2o, 30.7±0.2o, 31.8±0.2o, 31.9±0.2o, 34.0±0.2o, 34.8±Diffraction peaks are observed at 0.2°, 34.9±0.2°, 35.5±0.2°, 36.2±0.2°, 37.6±0.2°, 39.5±0.2°, 40.6±0.2°, 42.6±0.2°, and 43.2±0.2°, and its XRPD pattern is shown in Figure 21.

[0284] Comparative Example 4: Preparation of Crystal Form F of 7,8-Dihydroxyflavone

[0285] 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of acetonitrile until a suspension was formed. After stirring at room temperature for 7 days, the suspension was centrifuged and the solid was vacuum dried at room temperature;

[0286] XRPD analysis showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 6.0±0.2°, 10.3±0.2°, 12.0±0.2°, 12.3±0.2°, 13.7±0.2°, 15.0±0.2°, 15.9±0.2°, 17.2±0.2°, 18.2±0.2°, 19.2±0.2°, 20.9±0.2°, 21°. The XRPD pattern of the diffraction peaks at 0.9±0.2o, 22.7±0.2o, 24.2±0.2o, 24.7±0.2o, 25.5±0.2o, 26.2±0.2o, 26.9±0.2o, 27.6±0.2o, 28.2±0.2o, 29.5±0.2o, 30.1±0.2o, 31.0±0.2o, 32.0±0.2o, 33.3±0.2o, 33.7±0.2o, 35.5±0.2o, 36.4±0.2o, 36.9±0.2o, 38.0±0.2o, and 38.5±0.2o is shown in Figure 22.

[0287] Comparative Example 5: Preparation of Crystal Form G of 7,8-Dihydroxyflavone

[0288] 160 mg of 7,8-dihydroxyflavone was weighed and 11 mL of ethylene glycol dimethyl ether was added dropwise at room temperature to completely dissolve the sample; 1.3 mL of the solution was taken and added dropwise to 6.5 mL of water. After stirring for 15 min to 1 h, the precipitated solid was centrifuged and then dried under vacuum at room temperature.

[0289] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, occurred at 11.6±0.2°, 12.1±0.2°, 13.1±0.2°, 13.5±0.2°, 16.8±0.2°, 18.5±0.2°, 20.3±0.2°, 21.3±0.2°, 21.7±0.2°, 22.9±0.2°, 23.4±0.2°, 24.2±0.2°, 24.7±0.2°, 26.5±0.2°, 26.8±0.2°, 28.2±0.2°, and 30.0±0.2°. Diffraction peaks are observed at 0.2°, 31.9±0.2°, 34.2±0.2°, 35.4±0.2°, 38.9±0.2°, and 42.0±0.2°. (See XRPD spectrum description 17 / 24)Page 19 CN 121064139 A As shown in Figure 23.

[0290] Comparative Example 6 Preparation of Crystal Form H of 7,8-Dihydroxyflavone

[0291] Weigh 160 mg of 7,8-dihydroxyflavone, and add 11 mL of ethylene glycol dimethyl ether at room temperature to completely dissolve the sample; take 1.3 mL of the solution and add 1.0 mL of n-heptane. After stirring at room temperature for 15 min to 1 h, centrifuge the precipitated solid and dry it under vacuum at room temperature.

[0292] XRPD analysis showed that the X-ray powder diffraction, expressed as a 2θ angle, occurred at 7.2±0.2°, 8.3±0.2°, 8.8±0.2°, 9.5±0.2°, 10.2±0.2°, 11.2±0.2°, 11.6±0.2°, 12.2±0.2°, 12.4±0.2°, 13.4±0.2°, 13.7±0.2°, 14.5±0.2°, 14.9±0.2°, 15.5±0.2°, 16.2±0.2°, 16.7±0.2°, and 18.4±0.2°. Diffraction peaks are observed at 0.2°, 19.1±0.2°, 19.2±0.2°, 19.9±0.2°, 20.3±0.2°, 20.9±0.2°, 21.5±0.2°, 21.9±0.2°, 23.1±0.2°, 23.9±0.2°, 25.5±0.2°, 25.8±0.2°, 27.6±0.2°, 27.7±0.2°, 28.0±0.2°, 28.9±0.2°, and 31.0±0.2°, and their XRPD patterns are shown in Figure 24.

[0293] Comparative Example 7 Preparation of Crystal Form I of 7,8-Dihydroxyflavone

[0294] 160 mg of 7,8-dihydroxyflavone was weighed and 11 mL of ethylene glycol dimethyl ether was added dropwise at room temperature to completely dissolve the sample; 1.3 mL of the solution was taken and 5.0 mL of water was added dropwise. After stirring at room temperature for 15 min to 1 h, the precipitated solid was centrifuged and then dried under vacuum at room temperature.

[0295] XRPD analysis showed that the X-ray powder diffraction, expressed as an angle of 2θ, had diffraction peaks at 7.0±0.2°, 8.3±0.2°, 10.5±0.2°, 12.3±0.2°, 13.0±0.2°, 14.0±0.2°, 14.8±0.2°, 16.7±0.2°, 17.0±0.2°, 20.5±0.2°, 21.8±0.2°, 22.0±0.2°, 22.1±0.2°, 23.8±0.2°, 25.9±0.2°, 27.1±0.2°, 27.6±0.2°, and 33.7±0.2°. The XRPD pattern is shown in Figure 25.

[0296] Comparative Example 8: Preparation of Crystal Form J of 7,8-Dihydroxyflavone

[0297] 20.0 mg of [unspecified substance] was added to 10.0 mL of toluene.7,8-Dihydroxyflavonoids were added until a suspension was formed. After stirring at room temperature for 7 days, the suspension was centrifuged and the solid was vacuum dried at room temperature.

[0298] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, was at 4.3±0.2°, 5.7±0.2°, 6.8±0.2°, 8.3±0.2°, 10.6±0.2°, 10.8±0.2°, 11.4±0.2°, 12.4±0.2°, 12.8±0.2°, 13.9±0.2°, 15.1±0.2°, 16.0±0.2°, 16.7±0.2°, 17.1±0.2°, 18.0±0.2°, 19.2±0.2°, 20.1±0.2°. Diffraction peaks are observed at 0.2°, 20.5±0.2°, 21.2±0.2°, 21.7±0.2°, 22.9±0.2°, 24.0±0.2°, 24.2±0.2°, 25.1±0.2°, 26.3±0.2°, 26.9±0.2°, 28.0±0.2°, 28.6±0.2°, and 32.1±0.2°, and their XRPD patterns are shown in Figure 26.

[0299] Comparative Example 9: Preparation of Crystal Form K of 7,8-Dihydroxyflavone

[0300] 20.0 mg of 7,8-dihydroxyflavone was added to 2.0 mL of dioxane until a suspension was formed. After suspending and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was vacuum dried at room temperature;

[0301] XRPD detection showed that its X-ray powder diffraction, expressed as a 2θ angle, was at 9.9±0.2°, 10.8±0.2°, 12.0±0.2°, 12.4±0.2°, 13.4±0.2°, 14.3±0.2°, 14.7±0.2°, 15.7±0.2°, 17.5±0.2°, 17.9± 0.2o, 19.5±0.2o, 20.4±0.2o, 20.7±0.2o, 20.9±0.2o, 22.1±0.2o, 22.4±0.2o, 23.4± 0.2o,23.9±0.2o,24.7±0.2o,25.8±0.2o,26.3±0.2o,27.3±0.2o,27.4±0.2o,28.1±0.2o,28.7±0.2o,29.6±0.2o,30.4±0.2o,31 .0±0.2o, 31.4±0.2o, 31.9±0.2o, 32.4± 0.2o, 33.1±0.2o, 33.7±0.2o, 34.2±0.2o, 34.8±0.2o, 35.4±0.2o, 36.2±0.2o, 37.0±Diffraction peaks are observed at 0.2°, 37.8±0.2°, 38.8±0.2°, 39.6±0.2°, 40.9±0.2°, 43.8±0.2°, and 44.8±0.2°. The XRPD pattern is shown in Figure 27. Instruction manual, pages 18 / 24, 20 CN 121064139 A

[0302] Comparative Example 10 Preparation of crystal form L of 7,8-dihydroxyflavone

[0303] 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of methyl formate until a suspension was formed. After stirring at room temperature for 7 days, the suspension was centrifuged and the solid was vacuum dried at room temperature;

[0304] XRPD detection showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 7.7±0.2°, 10.6±0.2°, 11.3±0.2°, 12.0±0.2°, 12.4±0.2°, 15.5±0.2°, 16.9±0.2°, 17.7±0.2°, 18.9±0.2°, 19.5±0.2°, 20.0±0.2°, 21 The XRPD patterns of the following peaks are shown in Figure 28: 0.0±0.2o, 21.3±0.2o, 22.0±0.2o, 22.2±0.2o, 22.6±0.2o, 23.3±0.2o, 23.7±0.2o, 25.5±0.2o, 25.6±0.2o, 26.3±0.2o, 27.3±0.2o, 27.8±0.2o, 28.9±0.2o, 29.3±0.2o, 30.4±0.2o, 31.6±0.2o, 32.1±0.2o, 32.3±0.2o, 32.4±0.2o, 34.2±0.2o, 34.9±0.2o, and 37.9±0.2o.

[0305] Comparative Example 11: Preparation of Crystal Form M of 7,8-Dihydroxyflavone

[0306] 20.0 mg of 7,8-dihydroxyflavone was added to 2.0 mL of acetone until a suspension was formed. After suspending and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was vacuum dried at room temperature;

[0307] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, was at 8.5 ± 0.2°, 11.1 ± 0.2°, 14.5 ± 0.2°, 14.8 ± 0.2°, 16.5 ± 0.2°, 18.1 ± 0.2°, 18.3 ± 0.2°, 19.0 ± 0.2°, 20.8 ± 0.2°, and 22.0 ± 0.2°. 0.2o, 22.3±0.2o, 22.8±0.2o, 14.2±0.2o, 24.4±0.2o, 25.4±0.2o, 25.9±0.2o, 26.4± 0.2o, 26.6±0.2o, 27.7±0.2o, 28.3±0.2o, 29.0±0.2o, 30.5±0.2o, 30.9±0.2o, 32.5±Diffraction peaks were observed at 0.2° and 33.3±0.2°, and its XRPD pattern is shown in Figure 29.

[0308] Comparative Example 12 Preparation of Crystal Form O of 7,8-Dihydroxyflavone

[0309] 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of chloroform until a suspension was formed. After suspending and stirring at 50°C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0310] XRPD detection showed that its X-ray powder diffraction, expressed as an angle of 2θ, was at 3.4±0.2°, 5.9±0.2°, 7.0±0.2°, 8.5±0.2°, 8.9±0.2°, 10.3±0.2°, 10.9±0.2°, 11.7±0.2°, 12.8±0.2°, and 13.6±0.2°. 14.1±0.2o, 14.7±0.2o, 15.2±0.2o, 16.0±0.2o, 17.0±0.2o, 17.3±0.2o, 17.9±0.2o, 18.6±0.2o, 19.3±0.2o, 19.8±0.2o, 20.4±0.2o, 20.7±0.2o, 22.1±0.2o, 22.6±0.2o, 23.9±0.2o, 25.1±0.2o, 25.5±0.2o, 25.7±0.2o, 27.1±0.2o, 27.3±0.2o, 27.5±0.2o, Diffraction peaks are observed at 28.3±0.2o, 28.9±0.2o, 29.5±0.2o, 29.7±0.2o, 29.8±0.2o, 32.6±0.2o, 32.7±0.2o, 36.2±0.2o, 41.3±0.2o, and 41.4±0.2o, and their XRPD patterns are shown in Figure 30.

[0311] Comparative Example 13: Preparation of Crystal Form Q of 7,8-Dihydroxyflavone

[0312] 20.0 mg of 7,8-dihydroxyflavone was added to 0.2 mL of dioxane and 1.0 mL of chloroform until a suspension was formed. After suspending and stirring at 50 °C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0313] XRPD analysis showed that its X-ray powder diffraction, expressed at 2θ angles, was at 3.2±0.2°, 3.6±0.2°, 4.5±0.2°, 5.6±0.2°, 6.1±0.2°, 7.3±0.2°, 7.7±0.2°, 8.8±0.2°, 9.4±0.2°, 9.7±0.2°, 10.9°. ±0.2o, 11.2±0.2o, 12.1±0.2o, 13.0±0.2o, 13.9±0.2o, 14.5±0.2o, 15.3±0.2o, 15.5± 0.2o, 16.2±0.2o, 16.6±0.2o, 17.3±0.2o, 17.7±0.2o, 18.1±0.2o, 18.5±0.2o, 19.2±Diffraction peaks are observed at 0.2°, 19.6±0.2°, 19.9±0.2°, 20.2±0.2°, 20.6±0.2°, 21.2±0.2°, 21.9±0.2°, 22.7±0.2°, 23.9±0.2°, 24.2±0.2°, 25.9±0.2°, 26.9±0.2°, 27.6±0.2°, 29.6±0.2°, 33.2±0.2°, 35.2±0.2°, and 40.8±0.2°, and their XRPD patterns are shown in Figure 31.

[0314] Comparative Example 14 Preparation of Crystal Form R of 7,8-Dihydroxyflavone

[0315] Crystal form N was heated to 100°C in situ using variable-temperature XRPD to obtain the product described in the specification, page 19 / 24, CN 121064139 A.

[0316] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, was at 9.7±0.2°, 10.8±0.2°, 11.1±0.2°, 11.7±0.2°, 12.4±0.2°, 12.6±0.2°, 12.8±0.2°, 13.4±0.2°, 13.9±0.2°, and 14.1±0.2°. 0.2o, 14.3±0.2o, 14.5±0.2o, 15.6±0.2o, 16.1±0.2o, 16.4±0.2o, 17.5±0.2o, 19.2± 0.2o, 19.7±0.2o, 21 .4±0.2o, 22.2±0.2o, 23.0±0.2o, 23.2±0.2o, 23.4±0.2o, 24.2± 0.2o, 24.4±0.2o, 24.7±0.2o, 25.1±0.2o, 25.4±0.2o, 25.9±0.2o, 26.5±0.2o, 27.9± Diffraction peaks were observed at 0.2°, 28.5±0.2°, 28.7±0.2°, 29.9±0.2°, 31.5±0.2°, 32.2±0.2°, and 44.3±0.2°. The XRPD pattern is shown in Figure 32.

[0317] Comparative Example 15: Preparation of Crystal Form S of 7,8-Dihydroxyflavone

[0318] 160 mg of 7,8-dihydroxyflavone was weighed, and 11 mL of ethylene glycol dimethyl ether was added dropwise at room temperature to completely dissolve the sample. 1.3 mL of the solution was taken, and 8.0 mL of butyl formate was added dropwise. After stirring at room temperature for 15 min to 1 h, the precipitated solid was centrifuged and then dried under vacuum at room temperature.

[0319] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, occurred at 8.6±0.2°, 12.6±0.2°, 17.3±0.2°, 18.4±0.2°, 22.6±0.2°, 26.9±0.2°, 29.1±0.2°, 31.3±0.2°, 33.2±0.2°, and 35.1±0.2°.Diffraction peaks are observed at 0.2°, 35.7±0.2°, 41.8±0.2°, and 44.8±0.2°, and its XRPD pattern is shown in Figure 33.

[0320] Comparative Example 16: Preparation of Crystal Form T of 7,8-Dihydroxyflavone

[0321] Crystal form G was heated to 140°C in situ using variable-temperature XRPD to obtain

[0322] XRPD analysis showed that its X-ray powder diffraction, expressed as a 2θ angle, was at 8.3±0.2°, 9.3±0.2°, 10.4±0.2°, 10.9±0.2°, 11.4±0.2°, 12.4±0.2°, 13.0±0.2°, 14.0±0.2°, 15.4±0.2°, 16.2±0.2°, 16.7±0.2°, 17.5±0.2°, 18.5±0.2°, 19.7±0.2°, 20.5±0.2°, 22.0±0.2°, 22.9±0.2°. 0.2o, 23.8±0.2o, 25.2±0.2o, 26.0±0.2o, 26.5±0.2o, 27.5±0.2o, 28.0±0.2o, 29.5± 0.2o, 30.0±0.2o, 31.1±0.2o, 31.3±0.2o, 31 .5±0.2o, 31.7±0.2o, 32.7±0.2o, 34.0± 0.2o, 34.7±0.2o, 34.9±0.2o, 35.8±0.2o, 36.1±0.2o, 38.0±0.2o, 38.2±0.2o, 42.1± Diffraction peaks were observed at 0.2°, 43.5±0.2°, 43.7±0.2°, and 44.1±0.2°, and its XRPD pattern is shown in Figure 34.

[0323] Tablet Preparation Example 1 Preparation of 7,8-Dihydroxyflavone Tablet Formulation

[0324] 80g of raw material (the dihydroxyflavone crystal form prepared in this disclosure), 80g of lactose, 13g of microcrystalline cellulose, 12g of povidone, and 7g of sodium carboxymethyl starch were mixed and poured into a 1L granulation pot. The mixture was stirred for 6 minutes, and 40g to 50g of purified water was added. Wet granulation was performed and stirred for 8-10 minutes. After drying and granulation, 7g of sodium carboxymethyl starch and 1g of magnesium stearate were added. After total mixing of materials, the tablets were compressed and demolded to obtain the target tablets.

[0325] Effect Example 1: Stability of different 7,8-dihydroxyflavonoid crystal forms

[0326] The stability of different 7,8-dihydroxyflavonoid crystal forms under high temperature (60℃), high humidity (25℃ / 92.5%RH), light (25℃ / 4500Lux), and accelerated (40℃ / 75%RH) conditions was studied. Samples were taken at 7 days and 15 days for XRPD characterization. The results are shown in Table 3, and the XRPD detection results are shown in Figures 35-37.

[0327] Table 3

[0328] Specification 20 / 24 pages 22 CN 121064139 A

[0329]

[0330] Effect Example 2: Dynamic solubility of different 7,8-dihydroxyflavone crystal forms in three biological media (FaSSIF, FeSSIF, and FaSSGF) and water.

[0331] 20 mg of different 7,8-dihydroxyflavone crystal forms were added to 4.0 mL of biological media or water, and the mixture was kept at 37°C and shaken for 24 h. Samples were taken at 0.5 h, 2 h, and 24 h. The sampled solutions were filtered through a 0.22 μm aqueous filter membrane. The signal peak area of ​​the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. In addition, the pH value of the supernatant after 24 h was tested, and the remaining solid was tested by XRPD. The preparation of the biological media is shown in Table 4. The experimental results are shown in Table 5, and the XRPD detection results are shown in Figures 38-40.

[0332] Table 4 Table 5 Instruction manual 21 / 24 pages 23 CN 121064139 A

[0333]

[0334]

[0335] Effect Example 3 Stability study of 7,8-dihydroxyflavone crystal form P tablets

[0336] The stability of 7,8-dihydroxyflavone crystal form P tablets was studied under high temperature (60℃), high humidity (25℃ / 92.5%RH), light (25℃ / 4500Lux), and accelerated (40℃ / 75%RH) conditions. Samples were taken at 3 months and 6 months for XRPD characterization. The results are shown in Table 6.

[0337] Table 6

[0338]

[0339] Effect Example 4 Stability Study of 7,8-Dihydroxyflavone Crystal Form C Tablets

[0340] The stability of 7,8-dihydroxyflavone crystal form C tablets was studied under high temperature (60℃), high humidity (25℃ / 92.5%RH), light (25℃ / 4500Lux), and accelerated (40℃ / 75%RH) conditions. Samples were taken at 3 months and 6 months for XRPD characterization, as per the instructions on page 22 / 24 of the manual, CN 121064139 A. The results are shown in Table 7.

[0341] Table 7

[0342]

[0343]

[0344] Effect Example 5 Dissolution Study of 7,8-Dihydroxyflavone P Crystal Form Tablets

[0345] The dissolution of 7,8-dihydroxyflavone P crystal form tablets was studied under different pH conditions, and the results are shown in Table 8.

[0346] Table 8

[0347] Time (minutes) pH=4.5 medium pH=6.8 medium 15 67.9% 68.2% 30 81.5% 82.0% 45 87.4% 85.6% 60 89.9% 90.7% 90 93.7% 92.5% 120 94.7% 96.6%

[0348] Effect Example 67,8-Dihydroxyflavone C Crystal Tablet Dissolution Study

[0349] Dissolution studies of 7,8-dihydroxyflavone C crystal tablets under different pH conditions were conducted, and the results are shown in Table 9.

[0350] Table 9

[0351] Time (minutes) pH=4.5 medium pH=6.8 medium 15 47.7% 47.5% 30 55.1% 58.2% 45 58.8% 64.1% 60 60.8% 67.6% 90 63.6% 71.6% 120 64.8% 73.6%

[0352] Effect Example 7 Dissolution study of 7,8-dihydroxyflavone A crystal tablets Instructions for use 23 / 24 pages 25 CN 121064139 A

[0353] Dissolution studies of 7,8-dihydroxyflavone A crystal tablets under different pH conditions were conducted, and the results are shown in Table 10.

[0354] Table 10

[0355] Time (minutes) pH=4.5 medium pH=6.8 medium 15 33.9% 33.2% 30 58.8% 57.9% 45 68.9% 68.2% 60 76.1% 75.1% 90 84.2% 82.7% 120 89.6% 89.0%

[0356] In summary, this disclosure provides polymorphs of 7,8-dihydroxyflavone and their preparation methods. The polymorphs of 7,8-dihydroxyflavone provided in this disclosure have more selective pharmaceutical economic value. Instruction Manual 24 / 24 Page 26 CN 121064139 A Figure 1 Figure 2 Figure 3 Figure 4 Instruction Manual Appendix 1 / 10 Page 27 CN 121064139 A Figure 5 Figure 6 Figure 7 Figure 8 Instruction Manual Appendix 2 / 10 Page 28 CN 121064139 A Figure 9 Figure 10 Figure 11 Figure 12 Instruction Manual Appendix 3 / 10 Page 29 CN 121064139 A Figure 13 Figure 14 Figure 15 Figure 16 Instruction Manual Appendix 4 / 10 Page 30 CN 121064139 A Figure 17 Figure 18 Figure 19 Figure 20 Instruction Manual Appendix 5 / 10 Page 31 CN 121064139 A Figure 21 Figure 22 Figure 23 Figure 24 Instruction Manual Appendix 6 / 10 Page 32 CN 121064139 A Figure 25 Figure 26 Figure 27 Figure 28 Instruction Manual Appendix 7 / 10 Page 33 CN 121064139 A Figure 29 Figure 30 Figure 31 Figure 32 Figure 33 Instruction Manual Drawings 8 / 10 Page 34 CN 121064139 A Figure 34 Figure 35 Figure 36 Figure 37 Instruction Manual Drawings 9 / 10 Page 35 CN 121064139 A Figure 38 Figure 39 Figure 40 Instruction Manual AppendixPage 36 of 10 / 10, CN 121064139 A, Title of Invention: POLYMORPH OF 7,8-DIHYDROXYFLAVONE, AND PREPARATION METHOD THEREFOR, ABSTRACT: A polymorph of 7,8-dihydroxyflavone, and a preparation method therefor. The polymorph of 7,8-dihydroxyflavone has significantly improved physicochemical properties, and thus has a higher medicinal value.

Claims

1. A crystalline form of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks, expressed in terms of 2 theta (°) at about 8.3 ± 0.2°, 25.0 ± 0.2°, and 25.9 ± 0.2°.

2. The crystalline form of 7,8-dihydroxyflavone according to claim 1, wherein the X-ray powder diffraction pattern further comprises characteristic peaks at about 27.4 ± 0.2° and / or 31.4 ± 0.2°.

3. A crystalline form of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks, expressed in terms of 2 theta (°) at about 11.1 ± 0.2°, 15.6 ± 0.2°, 27.0 ± 0.2°, and 28.3 ± 0.2°.

4. The crystalline form of 7,8-dihydroxyflavone according to claim 3, wherein the X-ray powder diffraction pattern further comprises characteristic peaks at about 5.6 ± 0.2°, 9.5 ± 0.2°, 15.5 ± 0.2°, 21.0 ± 0.2°, 24.3 ± 0.2°, and / or 25.5 ± 0.2°.

5. The crystalline form of 7,8-dihydroxyflavone according to any one of claims 3-4, which is a hydrate, for example a monohydrate.

6. A crystalline form of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks, expressed in terms of 2 theta (°) at about 9.3 ± 0.2°, 23.8 ± 0.2°, 24.6 ± 0.2°, and 26.6 ± 0.2°.

7. The crystalline form of 7,8-dihydroxyflavone according to claim 6, wherein the X-ray powder diffraction pattern further comprises characteristic peaks at about 12.3 ± 0.2° and / or 21.1 ± 0.2°.

8. The crystalline form of 7,8-dihydroxyflavone according to any one of claims 6-7, which is a hydrate, for example a dihydrate.

9. A pharmaceutical composition comprising (1) the crystalline form of 7,8-dihydroxyflavone according to any one of claims 1-2, the crystalline form of 7,8-dihydroxyflavone according to any one of claims 3-5, and / or the crystalline form of 7,8-dihydroxyflavone according to any one of claims 6-8, and (2) at least one pharmaceutically acceptable excipient.

10. A method of treating a disease associated with abnormality of TrkB signaling pathway, for example, central nervous injury, peripheral nerve injury, neurodegenerative disease, mental disease, hereditary neurological disorder, ophthalmic disease, metabolic disease, pain, cardiovascular disease, tumor, or other related disease, comprising administering to a subject (1) the crystalline form of 7,8-dihydroxyflavone according to any one of claims 1-2, the crystalline form of 7,8-dihydroxyflavone according to any one of claims 3-5, and / or the crystalline form of 7,8-dihydroxyflavone according to any one of claims 6-8, and (2) at least one pharmaceutically acceptable excipient.

11. Use of the 7,8-dihydroxyflavone crystalline form according to claim 1 or 2, the 7,8-dihydroxyflavone crystalline form according to any one of claims 3-5, and / or the 7,8-dihydroxyflavone crystalline form according to any one of claims 6-8 in the manufacture of a medicament for the treatment or prevention of traumatic brain injury or age-related cognitive decline.

12. A 7,8-dihydroxyflavone crystalline form having an X-ray diffraction pattern comprising peaks expressed in terms of 2 theta (2Q) angles at approximately 9.1 ± 0.2°, 17.2 ± 0.2°, 20.5 ± 0.2°, 27.3 ± 0.2°.

13. A 7,8-dihydroxyflavone crystalline form having an X-ray diffraction pattern comprising peaks expressed in terms of 2 theta (2Q) angles at approximately 11.6 ± 0.2°, 18.5 ± 0.2°, 35.4 ± 0.2°.

14. A 7,8-dihydroxyflavone crystalline form having an X-ray diffraction pattern comprising peaks expressed in terms of 2 theta (2Q) angles at approximately 10.8 ± 0.2°, 19.5 ± 0.2°, 22.1 ± 0.2°, 22.4 ± 0.2°, 24.7 ± 0.2°, 28.2 ± 0.2°.

15. A method for preparing a 7,8-dihydroxyflavone tablet, comprising the following steps: Mixing 80 g of raw material, 80 g of lactose, 13 g of microcrystalline cellulose, 12 g of povidone, and 7 g of sodium carboxymethyl starch, pouring into a 1 L granulator, stirring and mixing for 6 minutes, adding 40-50 g of pure water, wet granulation, stirring, and after drying and granulating, adding 7 g of sodium carboxymethyl starch and 1 g of magnesium stearate, and then total mixing of the materials, tabletting, and demolding to obtain a 7,8-dihydroxyflavone tablet.

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