Crystal polymorphs of 7,8-dihydroxyflavone and preparation method thereof

Abstract

Crystal polymorphs of 7,8-dihydroxyflavone and their preparation methods. [Means for Solving the Problems] The 7,8-dihydroxyflavone crystalline polymorphs have significantly improved physicochemical properties, and thus have higher medicinal value.

Description

[Technical field]

[0001] The present disclosure relates to crystalline polymorphs of 7,8-dihydroxyflavone and methods for their preparation. [Background technology]

[0002] As a specific agonist of tyrosine receptor kinase B (TrkB), 7,8-dihydroxyflavone can activate TrkB. Many in vitro studies have shown that 7,8-dihydroxyflavone has important biological effects and has good therapeutic effects in terms of neurodegenerative diseases, mainly including Parkinson's disease, Alzheimer's disease, depression, psychotic disorders, post-traumatic stress disorder, autism spectrum disorder, stroke, Reiter's syndrome and other diseases.

[0003] Polymorphism refers to the phenomenon that a substance has two or more different crystal structures, which is a common phenomenon in solid substances. In the pharmaceutical field, research into polymorphism of drugs has become an important frontier issue. Different crystal structures in the same solid substance often show different physicochemical properties. For drugs, different crystal forms mainly show differences in stability, solubility, dissolution rate, etc., which affect the efficacy of the drug and even change the toxic side effects of the drug.

[0004] Therefore, the development of a crystalline form of 7,8-dihydroxyflavone with superior properties is of great significance. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure discloses a crystalline polymorph of 7,8-dihydroxyflavone and a method for preparing the same. The crystalline polymorph of 7,8-dihydroxyflavone disclosed in the present disclosure has more selectable pharmaceutical economic value. [Means for solving the problem]

[0006] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: having an X-ray powder diffraction pattern containing characteristic peaks at 2θ angles of about 8.3±0.2°, 25.0±0.2°, and 25.9±0.2°; Crystalline form P of 7,8-dihydroxyflavone is provided.

[0007] In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at about 27.4±0.2° and / or 31.4±0.2°.

[0008] In a further embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at about 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°.

[0009] In a further embodiment, the crystalline form P has an X-ray powder diffraction pattern essentially as shown in FIG.

[0010] In a further embodiment, the thermogravimetric analysis spectrum of crystalline form P has no apparent weight loss.

[0011] In a further embodiment, the differential scanning calorimetry spectrum of crystalline form P has no endothermic signal corresponding to weight loss.

[0012] In a further embodiment, the dynamic moisture sorption profile of the crystalline form P shows a weight increase of less than 0.1% within the range of 0% to 95% relative humidity, where the "%" is the percentage of the increased mass of the crystalline form P of 7,8-dihydroxyflavone relative to its initial mass.

[0013] In a further embodiment, the crystalline form P of 7,8-dihydroxyflavone has a thermogravimetric and / or differential scanning calorimetry spectrum essentially as shown in FIG.

[0014] In a further embodiment, the crystalline form P of 7,8-dihydroxyflavone has a dynamic moisture sorption graph essentially as shown in FIG.

[0015] In a further embodiment, the crystalline form P of 7,8-dihydroxyflavone is anhydrous.

[0016] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: having an X-ray powder diffraction pattern containing characteristic peaks at 2θ angles of about 11.1±0.2°, 15.6±0.2°, 27.0±0.2° and 28.3±0.2°, Crystalline form C of 7,8-dihydroxyflavone is provided.

[0017] In one embodiment, 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°.

[0018] In a further embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at 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°.

[0019] In a further embodiment, the crystalline form C has an X-ray powder diffraction pattern essentially as shown in FIG.

[0020] In a further embodiment, the thermogravimetric analysis spectrum of the crystalline form C shows that the mass loss at 110° C. to 150° C. accounts for about 3.7% of the mass before the loss, where "%" is mass percentage.

[0021] In a further embodiment, the differential scanning calorimetry spectrum of crystalline form C has an endothermic signal corresponding to weight loss at about 100°C to 160°C.

[0022] In a further embodiment, the dynamic moisture sorption profile of the crystalline form C shows a weight increase of less than 0.1% within the range of 0% to 95% relative humidity, where "%" is the percentage of the increased mass of the crystalline form C of 7,8-dihydroxyflavone relative to its initial mass.

[0023] In a further embodiment, the crystalline form C of 7,8-dihydroxyflavone has a thermogravimetric spectrum and / or a differential scanning calorimetry spectrum essentially as shown in FIG.

[0024] In a further embodiment, the crystalline form C of 7,8-dihydroxyflavone has a dynamic moisture sorption graph essentially as shown in FIG.

[0025] In a further embodiment, the crystalline form C of 7,8-dihydroxyflavone is a hydrate, such as a monohydrate.

[0026] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: having an X-ray powder diffraction pattern containing characteristic peaks at 2θ angles of about 9.3±0.2°, 23.8±0.2°, 24.6±0.2° and 26.6±0.2°, The crystalline form N of 7,8-dihydroxyflavone is provided.

[0027] In one embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at about 12.3±0.2° and / or 21.1±0.2°.

[0028] In a further embodiment, the X-ray powder diffraction pattern further comprises characteristic peaks at about 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°.

[0029] In a further embodiment, the crystalline form N of 7,8-dihydroxyflavone has an X-ray powder diffraction pattern essentially as shown in FIG.

[0030] In a further embodiment, in the thermogravimetric analysis spectrum of the crystalline form N, the mass loss at 40° C. to 80° C. accounts for 6.3% of the mass before the loss, where "%" is mass percentage.

[0031] In a further embodiment, the differential scanning calorimetry spectrum of crystalline form N has an endothermic peak corresponding to weight loss at about 100° C. and exothermic signals at about 136° C. and 169° C., respectively.

[0032] In a further embodiment, the dynamic moisture sorption profile of the crystalline form N shows a weight increase of less than 0.1% within the range of 0% to 95% relative humidity, where the "%" is the percentage of the increased mass of the crystalline form N of 7,8-dihydroxyflavone relative to the initial mass.

[0033] In a further embodiment, the crystalline form N of 7,8-dihydroxyflavone has a thermogravimetric spectrum and / or a differential scanning calorimetry spectrum essentially as shown in FIG.

[0034] In a further embodiment, the crystalline form N of 7,8-dihydroxyflavone has a dynamic moisture sorption graph essentially as shown in FIG.

[0035] In a further embodiment, the crystalline form N of 7,8-dihydroxyflavone is a hydrate, such as a dihydrate.

[0036] In another aspect, the present disclosure provides a method for preparing a crystalline form of 7,8-dihydroxyflavone of the present disclosure, which is one of Methods 1 to 5.

[0037] Method 1: The method includes dissolving 7,8-dihydroxyflavone in a single solvent and evaporating the solvent to obtain a solid.

[0038] Method 2: suspending 7,8-dihydroxyflavone in a single solvent or a binary solvent, and then centrifuging to obtain a solid.

[0039] Method 3: Dissolving 7,8-dihydroxyflavone in a good solvent, dropping the obtained solution into an antisolvent to precipitate a solid, and then isolating the solid.

[0040] Method 4: Dissolving 7,8-dihydroxyflavone in a good solvent, dropping an antisolvent into the obtained solution to precipitate a solid, and then isolating the solid.

[0041] Method 5: suspending 7,8-dihydroxyflavone in an antisolvent, then adding a good solvent dropwise until the solid is dissolved, cooling to precipitate a solid, and then isolating the solid.

[0042] In one embodiment, In method 2, the single solvent is n-heptane and the binary solvent is one of 4-methyl-2-pentanone, n-propyl alcohol, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, and butyl formate in combination with one of isopropyl acetate, n-heptane, toluene, isopropyl alcohol, ethyl acetate, diethyl ether, and cyclohexane; And / or, in method 2, the volume ratio of the binary solvents is 1:5 to 1:10; The present invention provides a method for preparing crystalline form P of 7,8-dihydroxyflavone, characterized in that

[0043] In a further embodiment, In method 2, the temperature of the suspension is 20 to 60°C. The present invention provides a method for preparing crystalline form P of 7,8-dihydroxyflavone, characterized in that

[0044] In one embodiment, there is provided 7,8-dihydroxyflavone having at least one characteristic of crystalline form P of the present disclosure prepared by the method of the present disclosure.

[0045] In one embodiment, In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; and / or in method 1, the volumetric mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g; And / or, in method 1, a solid is precipitated by volatilizing a solvent; and / or in method 2, the single solvent is water or diethyl ether, and the binary solvent is selected from 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, and a combination of acetonitrile and toluene; and / or in method 2, the organic solvent is one or more selected from tetrahydrofuran, isopropyl alcohol, acetonitrile, methanol, ethanol, dimethyl sulfoxide, N,N-dimethylformamide, and ethylene glycol dimethyl ether; and / or in method 2, the binary solvent includes an organic solvent and water in a volume ratio of 1:5 to 1:10, a butyl formate and n-heptane in a volume ratio of 1:1, an ethylene glycol methyl ether and chloroform in a volume ratio of 1:5, and / or an acetonitrile and toluene in a volume ratio of 1:1; and / or in method 3, the good solvent is one or more selected from N,N-dimethylformamide, tetrahydrofuran, and ethylene glycol dimethyl ether, and / or the anti-solvent is one or more selected from water, toluene, methylene chloride, and diethyl ether; and / or in method 3, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; and / or in method 4, the good solvent is one or more of N,N-dimethylformamide, isopropyl alcohol, and / or the anti-solvent is one or more of chloroform, toluene, water; and / or in method 4, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; and / or in method 5, the antisolvent is water and the good solvent is one or more of N,N-dimethylformamide, tetrahydrofuran, ethanol, ethylene glycol methyl ether; and / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8 to 1:1; The present invention provides a method for preparing crystalline form C of 7,8-dihydroxyflavone, characterized in that

[0046] In a further embodiment, In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; and / or, in method 1, the temperature of solid precipitation is room temperature; and / or, in method 2, the suspension temperature is 20 to 60°C; And / or, in method 3, the dropping temperature is 15 to 50°C; And / or, in method 4, the dropping temperature is 15 to 50°C; And / or, in method 5, the cooling temperature is -15°C to 4°C; The present invention provides a method for preparing crystalline form C of 7,8-dihydroxyflavone, characterized in that

[0047] In one embodiment, there is provided 7,8-dihydroxyflavone having at least one characteristic of crystalline form C of the present disclosure prepared by the method of the present disclosure.

[0048] In one embodiment, In method 1, the single solvent is methanol; and / or in method 1, the volumetric mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g; And / or, in method 1, a solid is precipitated by evaporating a solvent; and / or, in method 2, the single solvent is methanol and the binary solvent is a combination of methanol and water; and / or in method 2, the binary solvent has a volume ratio of methanol to water of 1:5 to 1:10; and / or in method 3, the good solvent is ethanol and the anti-solvent is one or more of methyl t-butyl ether, toluene; and / or in method 3, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; and / or in method 4, the good solvent is ethanol and the antisolvent is one or more of cyclohexane, n-heptane and water; and / or in method 4, the volume ratio of the good solvent to the antisolvent is 1:1 to 1:10; 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, methanol; and / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8 to 1:1; The present invention provides a method for preparing crystalline form N of 7,8-dihydroxyflavone, characterized in that

[0049] In a further embodiment, In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; and / or, in method 1, the temperature at which the solid is precipitated is room temperature; and / or, in method 2, the temperature of the suspension is 20 to 60°C; And / or, in method 3, the temperature of the dropping is 15 to 50°C; And / or, in method 4, the temperature of the dropwise addition is 15 to 50°C; And / or, in method 5, the cooling temperature is -15 to 4°C; The present invention provides a method for preparing crystalline form N of 7,8-dihydroxyflavone, characterized in that

[0050] In one embodiment, there is provided 7,8-dihydroxyflavone having at least one characteristic of crystalline form N of the present disclosure prepared by the method of the present disclosure.

[0051] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: (1) crystalline form P of 7,8-dihydroxyflavone, crystalline form C of 7,8-dihydroxyflavone and / or crystalline form N of 7,8-dihydroxyflavone according to the present disclosure, and (2) at least one pharma- ceutically acceptable excipient; Pharmaceutical compositions are provided.

[0052] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising: 1. A method for treating a disease associated with abnormalities in the TrkB signaling pathway, such as central nervous system injury, peripheral nervous system injury, neurodegenerative lesions, psychiatric disorders, inherited neurological dysfunction, ophthalmological disorders, metabolic disorders, pain, cardiovascular diseases, tumors, or other related diseases, comprising: (1) administering to a subject crystalline form P of 7,8-dihydroxyflavone, crystalline form C of 7,8-dihydroxyflavone, and / or crystalline form N of 7,8-dihydroxyflavone according to the present disclosure, and (2) at least one pharma- ceutically acceptable excipient; A method is provided. [Brief description of the drawings]

[0053] [Figure 1] 1 is the X-ray powder diffraction pattern of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1. [Diagram 2] 1 is the X-ray powder diffraction pattern of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2. [Diagram 3]1 is the X-ray powder diffraction pattern of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3. [Figure 4] 1 shows the thermogravimetric spectrum and differential scanning calorimetry spectrum of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1. [Diagram 5] 2 is a dynamic moisture adsorption graph of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1. [Figure 6] 2 shows the thermogravimetric spectrum and differential scanning calorimetry spectrum of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2. [Figure 7] 2 is a dynamic moisture adsorption graph of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2. [Figure 8] 2 shows the thermogravimetric spectrum and differential scanning calorimetry spectrum of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3. [Figure 9] 2 is a dynamic moisture adsorption graph of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3. [Figure 10] 1 shows the X-ray powder diffraction patterns of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1 before and after dynamic water adsorption experiments. [Figure 11] FIG. 2 is a polarizing microscope analysis diagram of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1. [Figure 12] 1 is the nuclear magnetic hydrogen spectrum of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1. [Figure 13] 4 shows the X-ray powder diffraction patterns of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2 before and after dynamic water adsorption experiments. [Figure 14] FIG. 2 is a polarizing microscope analysis diagram of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2. [Figure 15] 1 is the nuclear magnetic hydrogen spectrum of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2. [Figure 16]4 shows the X-ray powder diffraction patterns of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3 before and after dynamic water adsorption experiments. [Figure 17] FIG. 2 is a polarizing microscope analysis diagram of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3. [Figure 18] 4 is the nuclear magnetic hydrogen spectrum of the crystal form N of 7,8-dihydroxyflavone obtained in Example 3. [Figure 19] 1 is the X-ray powder diffraction pattern of the crystalline form A of 7,8-dihydroxyflavone obtained in Comparative Example 1. [Figure 20] 1 is the X-ray powder diffraction pattern of the crystalline form B of 7,8-dihydroxyflavone obtained in Comparative Example 2. [Figure 21] 1 is the X-ray powder diffraction pattern of the crystalline form E of 7,8-dihydroxyflavone obtained in Comparative Example 3. [Figure 22] 1 is an X-ray powder diffraction pattern of the crystalline form F of 7,8-dihydroxyflavone obtained in Comparative Example 4. [Figure 23] 1 is the X-ray powder diffraction pattern of the crystalline form G of 7,8-dihydroxyflavone obtained in Comparative Example 5. [Figure 24] 1 is the X-ray powder diffraction pattern of the crystalline form H of 7,8-dihydroxyflavone obtained in Comparative Example 6. [Diagram 25] 1 is the X-ray powder diffraction pattern of the crystalline form I of 7,8-dihydroxyflavone obtained in Comparative Example 7. [Figure 26] 1 is an X-ray powder diffraction pattern of the crystalline form J of 7,8-dihydroxyflavone obtained in Comparative Example 8. [Figure 27] 1 is the X-ray powder diffraction pattern of the crystalline form K of 7,8-dihydroxyflavone obtained in Comparative Example 9. [Figure 28] 1 is the X-ray powder diffraction pattern of the crystalline form L of 7,8-dihydroxyflavone obtained in Comparative Example 10. [Figure 29] 1 is the X-ray powder diffraction pattern of the crystalline form M of 7,8-dihydroxyflavone obtained in Comparative Example 11. [Diagram 30] 1 is the X-ray powder diffraction pattern of the crystalline form O of 7,8-dihydroxyflavone obtained in Comparative Example 12. [Diagram 31] 1 is the X-ray powder diffraction pattern of the crystalline form Q of 7,8-dihydroxyflavone obtained in Comparative Example 13. [Diagram 32] 1 is the X-ray powder diffraction pattern of the crystalline form R of 7,8-dihydroxyflavone obtained in Comparative Example 14. [Diagram 33] 1 is an X-ray powder diffraction pattern of the crystalline form S of 7,8-dihydroxyflavone obtained in Comparative Example 15. [Diagram 34] 1 is the X-ray powder diffraction pattern of the crystalline form T of 7,8-dihydroxyflavone obtained in Comparative Example 16. [Diagram 35] 1 is the X-ray powder diffraction pattern of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1. [Diagram 36] 1 is the X-ray powder diffraction pattern of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 1. [Figure 37] 1 is the X-ray powder diffraction pattern of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 1. [Figure 38] 1 is the X-ray powder diffraction pattern of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 2. [Figure 39] 1 is the X-ray powder diffraction pattern of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2. [Diagram 40] 1 is the X-ray powder diffraction pattern of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] In the present disclosure, the structural formula of said 7,8-dihydroxyflavone is as follows: [ka]

[0055] Unless expressly stated otherwise, the term 7,8-dihydroxyflavone as used in this disclosure is not required to have any particular physical state and may be amorphous and in any crystalline form.

[0056] In one embodiment, the disclosure provides 7,8-dihydroxyflavone having at least one crystalline form P, crystalline form P being characterized by its X-ray diffraction pattern characterized by X-ray diffraction peaks at 2θ values ​​of about 8.3±0.2°, 25.0±0.2°, and 25.9±0.2°. In one 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 one further embodiment, crystalline form P is anhydrous. In one further embodiment, the X-ray diffraction pattern of crystalline form P is as shown in FIG. 1. In one further embodiment, the positions of the characteristic X-ray diffraction peaks of crystalline form P are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0057] In one advantageous embodiment, the present disclosure relates to crystalline form P of 7,8-dihydroxyflavone, which is stable and does not undergo crystalline transitions.

[0058] In one embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form C, characterized by its X-ray diffraction pattern with 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, crystalline form C is a hydrate, e.g., a monohydrate. In a further embodiment, the X-ray diffraction pattern of crystalline form C is as shown in FIG. 2. In a further embodiment, the positions of the characteristic X-ray diffraction peaks of crystalline form C are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0059] In one advantageous embodiment, the present disclosure relates to crystalline form C of 7,8-dihydroxyflavone, which is stable and does not undergo crystalline transition.

[0060] In one embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form N, crystalline form N being characterized by its X-ray diffraction pattern characterized by 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 crystalline 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, crystalline form N is a hydrate, e.g., a dihydrate. In a further embodiment, the X-ray diffraction pattern of crystalline form N is as shown in FIG. 3. In a further embodiment, the positions of the characteristic X-ray diffraction peaks of crystalline form N are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0061] In one advantageous embodiment, the present disclosure relates to crystalline form N of 7,8-dihydroxyflavone, which is stable and does not undergo crystalline transition.

[0062] The present disclosure relates to methods for preparing crystalline forms of 7,8-dihydroxyflavone, including Method 1 to Method 5.

[0063] Method 1: Dissolving 7,8-dihydroxyflavone in a single solvent to obtain a solid until the solvent is completely evaporated.

[0064] Method 2: suspending 7,8-dihydroxyflavone in a single solvent or a binary solvent, and then centrifuging to obtain a solid.

[0065] Method 3: Dissolve 7,8-dihydroxyflavone in a good solvent, add dropwise to an antisolvent, precipitate a solid, and then separate by centrifugation to obtain the solid.

[0066] Method 4: Dissolving 7,8-dihydroxyflavone in a good solvent, dropping an antisolvent therein, precipitating a solid, and then centrifuging to obtain the solid.

[0067] Method 5: suspending 7,8-dihydroxyflavone in an antisolvent, adding a good solvent dropwise until the solid is dissolved, cooling to precipitate the solid, and then centrifuging to obtain the solid.

[0068] In one embodiment, the present disclosure relates to a method for preparing 7,8-dihydroxyflavone having at least one crystalline form P, in particular the pure crystalline form P. The method may, for example, be as follows:

[0069] In method 2, the single solvent is n-heptane, and the binary solvent is a combination of one of 4-methyl-2-pentanone, n-propyl alcohol, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, and butyl formate with one of isopropyl acetate, n-heptane, toluene, isopropyl alcohol, ethyl acetate, diethyl ether, and cyclohexane; more preferably, the single solvent is n-heptane, and the binary solvent is a combination of ethanol and ethyl acetate; 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; In method 2, the temperature of the suspension is 20 to 60°C, and more preferably, the temperature of the suspension is 50°C.

[0070] In one embodiment, the present disclosure relates to a method for preparing 7,8-dihydroxyflavone having at least one crystalline form C, in particular pure crystalline form C. The method may, for example, be as follows:

[0071] In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide, more preferably, the single solvent is N,N-dimethylformamide; and / or, in method 1, the volumetric mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 to 500 mL / g, more preferably, the volumetric mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 mL / g; And / or, in the method 1, the solid is precipitated by volatilizing a solvent; and / or in method 2, the single solvent is water, diethyl ether, more preferably the single solvent is water, and 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, a combination of acetonitrile and toluene, more preferably the binary solvent is a combination of an organic solvent and water; and / or in method 2, the organic solvent is one of tetrahydrofuran, isopropyl alcohol, acetonitrile, methanol, ethanol, dimethylsulfoxide, N,N-dimethylformamide, ethylene glycol dimethyl ether, more preferably the organic solvent is tetrahydrofuran; and / or in method 2, the binary solvent has a volume ratio of organic solvent to water of 1:5 to 1:10, a volume ratio of butyl formate to n-heptane of 1:1, a volume ratio of ethylene glycol methyl ether to chloroform of 1:5, and a volume ratio of acetonitrile to toluene of 1:1; more preferably, the binary solvent has a volume ratio of organic solvent to water of 1:5; and / or in method 3, the good solvent is one of N,N-dimethylformamide, tetrahydrofuran, and ethylene glycol dimethyl ether, and the anti-solvent is one of water, toluene, methylene chloride, and diethyl ether, more preferably, the good solvent is N,N-dimethylformamide, and the anti-solvent is water; 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; and / or in method 4, the good solvent is one of N,N-dimethylformamide and isopropyl alcohol, and the anti-solvent is one of chloroform, toluene and water, more preferably, the good solvent is N,N-dimethylformamide and the anti-solvent is chloroform; 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; 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;

[0072] 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; In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide, more preferably, the single solvent is N,N-dimethylformamide; and / or, in method 1, the temperature at which the solid is precipitated is room temperature; and / or, in method 2, the temperature of the suspension is 20 to 60°C, more preferably the temperature of the suspension is 25°C; and / or, in method 3, the temperature of the dropping is 15 to 50°C, more preferably, the temperature of the dropping is 25°C; and / or, in method 4, the temperature of the dropping is 15 to 50°C, more preferably, the temperature of the dropping is 25°C; And / or, in method 5, the cooling temperature is -15 to 4°C.

[0073] The present disclosure relates to a method for preparing 7,8-dihydroxyflavone having at least one characteristic of crystalline form N, in particular pure crystalline form N. The method may, for example, be as follows:

[0074] In method 1, the single solvent is methanol; and / or, in method 1, the volumetric mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g, more preferably, the volumetric mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 mL / g; And / or, in the method 1, the solid is precipitated by volatilizing a solvent; and / or, in method 2, the single solvent is methanol and the binary solvent is a combination of methanol and water; and / or in method 2, the binary solvent has a volume ratio of methanol to water of 1:5 to 1:10, more preferably the binary solvent has a volume ratio of methanol to water of 1:5; and / or in method 3, the good solvent is ethanol and the anti-solvent is one of methyl t-butyl ether and toluene, more preferably, the anti-solvent is methyl t-butyl ether; 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; and / or in method 4, the good solvent is ethanol and the anti-solvent is one of cyclohexane, n-heptane, and water, more preferably the anti-solvent is cyclohexane; 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; 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; 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; and / or, in method 1, the single solvent is methanol; and / or, in method 1, the temperature at which the solid is precipitated is room temperature; and / or, in method 2, the suspension temperature is 20 to 60°C, more preferably, the suspension temperature is 50°C; and / or, in method 3, the temperature of the dropping is 15 to 50°C, more preferably, the temperature of the dropping is 25°C; and / or, in method 4, the temperature of the dropping is 15 to 50°C, more preferably, the temperature of the dropping is 25°C; And / or, in method 5, the cooling temperature is -15 to 4°C, and more preferably the cooling temperature is 0°C.

[0075] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form A, which is characterized by its X-ray diffraction pattern having X-ray diffraction peaks at 2θ values ​​of about 9.1±0.2°, 17.2±0.2°, 20.5±0.2°, and 27.3±0.2°. Crystalline form A is a hydrate. The X-ray diffraction pattern of crystal form A is shown in FIG. 19. The positions of the characteristic X-ray diffraction peaks of crystal form A are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0076] On the other hand, when crystalline form A is sufficiently dried, it cannot exist for a long time under dry conditions because it converts to crystalline form N. On the other hand, when crystalline form A is heated to 130°C, it converts to a mixed crystal having crystalline form F, and when heated to 160°C, it converts to a mixed crystal having crystalline form F and crystalline form J.

[0077] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form B, characterized by its X-ray diffraction pattern with X-ray diffraction peaks at 2θ values ​​of about 6.4±0.2°, 9.4±0.2°, 10.9±0.2°, 12.8±0.2°, 13.9±0.2°, 17.2±0.2°, 18.8±0.2°, 20.4±0.2°, and 20.7±0.2°. Crystalline form B is an anhydrous form containing a small amount of adsorbed solvent. The X-ray diffraction pattern of crystalline form B is shown in FIG. 20. The positions of the characteristic X-ray diffraction peaks of crystalline form B are listed in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0078] On the other hand, crystalline form B cannot exist for a long time at room temperature because it converts to crystalline form C at room temperature and humidity. On the other hand, when crystalline form B is further heated to 110°C, a small amount of the characteristic peak of crystalline form J appears, and at 180°C, it converts to a mixed crystal having crystalline forms F and J.

[0079] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form E, which is characterized by its X-ray diffraction pattern having X-ray diffraction peaks at 2θ values ​​of about 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°. Crystalline form E is a hydrate or dimethylsulfoxide solvate. The X-ray diffraction pattern of crystal form E is shown in FIG. 21. The positions of the characteristic X-ray diffraction peaks of crystal form E are listed in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0080] Form E transforms into form N at room temperature.

[0081] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form F, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 6.0±0.2°, 15.9±0.2°, 17.2±0.2°, 19.2±0.2°, and 26.9±0.2°. Crystalline form F is an anhydrate containing a small amount of adsorbed solvent. The X-ray diffraction pattern of crystal form F is shown in FIG. 22. The positions of the characteristic X-ray diffraction peaks of crystal form F are listed in Table 1, together with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0082] On the other hand, crystalline form F cannot exist for a long period of time at room temperature because it converts to crystalline form B at room temperature, whereas crystalline form F converts to a mixed crystal of crystalline forms J and P when heated to 220°C.

[0083] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form G, which is characterized by its X-ray diffraction pattern having X-ray diffraction peaks at 2θ values ​​of about 11.6±0.2°, 18.5±0.2°, and 35.4±0.2°. Crystalline form G is a hydrate. The X-ray diffraction pattern of crystalline form G is shown in FIG. 23. The positions of the characteristic X-ray diffraction peaks of crystalline form G are listed in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0084] Form G transforms to form T with a small amount of form J when heated to 140°C.

[0085] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form H, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 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 crystalline form H is shown in Figure 24. The positions of the characteristic X-ray diffraction peaks of crystalline form H are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0086] Crystalline form H converts to other crystal forms at room temperature and cannot exist at room temperature for extended periods of time.

[0087] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form I, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 10.5±0.2°, 17.0±0.2°, and 20.5±0.2°. The X-ray diffraction pattern of crystalline form I is shown in Figure 25. The positions of the characteristic X-ray diffraction peaks of crystalline form I are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0088] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form J, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 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°. Crystalline form J is anhydrous. The X-ray diffraction pattern of crystal form J is shown in FIG. 26. The positions of the characteristic X-ray diffraction peaks of crystal form J are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0089] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form K, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 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°. Crystalline form K is a 1:1 dioxane solvate. The X-ray diffraction pattern of crystal form K is shown in FIG. 27. The positions of the characteristic X-ray diffraction peaks of crystal form K are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0090] When the crystal form K is heated to 150° C. and then cooled to room temperature, it transforms into a mixed crystal of the crystal forms F and J.

[0091] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form L, which is characterized by its X-ray diffraction pattern having X-ray diffraction peaks at 2θ values ​​of about 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 crystalline form L is shown in Figure 28. The positions of the characteristic X-ray diffraction peaks of crystalline form L are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0092] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form M, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 8.5±0.2°, 14.8±0.2°, 16.5±0.2°, and 19.0±0.2°. Crystalline form M is an acetone solvate. The X-ray diffraction pattern of crystal form M is shown in FIG. 29. The positions of the characteristic X-ray diffraction peaks of crystal form M are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0093] Crystalline form M converts to crystal form C at room temperature and cannot exist at room temperature for extended periods of time.

[0094] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form O, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 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°. Crystalline form O is an anhydrate or chloroform solvate with a small amount of solvent remaining. The X-ray diffraction pattern of crystal form O is shown in FIG. 30. The positions of the characteristic X-ray diffraction peaks of crystal form O are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystal forms of 7,8-dihydroxyflavone.

[0095] Crystal form O converts to crystal form C at room temperature and cannot exist at room temperature for extended periods.

[0096] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form Q, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 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 crystalline form Q is shown in Figure 31. The positions of the characteristic X-ray diffraction peaks of crystalline form Q are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0097] Crystalline form Q converts to crystal form C at room temperature and cannot exist at room temperature for extended periods of time.

[0098] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form R, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at about 2θ values. The X-ray diffraction pattern of crystalline form R is shown in Figure 32. The positions of the characteristic X-ray diffraction peaks of crystalline form R are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0099] Form R can only be obtained by heating form N to 100° C. and cannot exist for long periods at room temperature.

[0100] In one comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form S, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 8.6±0.2°, 17.3±0.2°, and 22.6±0.2°. The X-ray diffraction pattern of crystalline form S is shown in Figure 33. The positions of the characteristic X-ray diffraction peaks of crystalline form S are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0101] Crystal form S converts to crystal form C at room temperature and cannot exist at room temperature for extended periods of time.

[0102] In one comparative embodiment, the present disclosure further provides 7,8-dihydroxyflavone having at least one crystalline form T, which is characterized by its X-ray diffraction pattern, characterized by X-ray diffraction peaks at 2θ values ​​of about 9.3±0.2°, 13.0±0.2°, 15.4±0.2°, and 23.8±0.2°. The X-ray diffraction pattern of crystalline form T is shown in Figure 34. The positions of the characteristic X-ray diffraction peaks of crystalline form T are listed in Table 1, along with the positions of the characteristic X-ray diffraction peaks of other crystalline forms of 7,8-dihydroxyflavone.

[0103] Crystalline form T can only be obtained by heating crystal form G to 140° C. and cannot exist for long periods at room temperature.

[0104] [Table 1]

[0105] In one embodiment, the present disclosure provides a pharmaceutical composition, comprising crystalline form P of 7,8-dihydroxyflavone and at least one pharma- ceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0106] In one embodiment, a tablet is prepared by a standard compounding method, and it is found that the crystalline form P in the tablet can be stable for 6 months under harsh conditions such as light exposure, high temperature, high humidity, etc. The stability of the crystalline form P of 7,8-dihydroxyflavone in the tablet is not limited by the specific dosage form.

[0107] In one embodiment, tablets are prepared using standard compounding methods and crystalline form P in the tablets is found to have better dissolution.

[0108] In one embodiment, the present disclosure further provides a pharmaceutical composition, comprising crystalline form C of 7,8-dihydroxyflavone and at least one pharma- ceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0109] In one embodiment, a tablet is prepared by a standard compounding method, and it is found that the crystalline form C in the tablet can be stable for 6 months under harsh conditions such as light exposure, high temperature, high humidity, etc. The stability of the crystalline form C of 7,8-dihydroxyflavone in the tablet is not limited by the specific dosage form.

[0110] In one embodiment, the present disclosure further provides a pharmaceutical composition, comprising crystalline form N of 7,8-dihydroxyflavone and at least one pharma- ceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0111] In one embodiment, the pharmaceutical composition of the present disclosure comprises one or more crystalline polymorphs of 7,8-dihydroxyflavone described in the present invention. In addition to the active ingredient, the pharmaceutical composition of the present disclosure may have one or more excipients. Different excipients can be added to the composition to achieve different purposes.

[0112] Fillers can increase the volume of a solid pharmaceutical composition and make it easier for patients and caregivers to use a pharmaceutical dosage form containing the composition. Fillers used in solid compositions include, for example, microcrystalline cellulose, microfine 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, polymethacrylate, potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc powder.

[0113] Solid pharmaceutical compositions pressed into dosage forms such as tablets may contain excipients whose function includes helping to bind the active ingredient with other excipients after pressing. Binders for solid pharmaceutical compositions include povidone, gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, and starch.

[0114] Disintegrants can be added to increase the dissolution rate of the pressed solid pharmaceutical composition in the patient's stomach, including sodium carboxymethyl starch, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, colloidal silica, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, and starch.

[0115] When a powder composition is pressed into a dosage form such as a tablet, the composition is subjected to pressure from dies and punches. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punches and dies, which can result in pitting and other surface irregularities in the product. Adding a lubricant to the composition can reduce adhesion and facilitate the release of the product from the dies. Lubricants include magnesium stearate, calcium stearate, glycerin monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc powder, and zinc stearate.

[0116] The solid dosage form of the pharmaceutical composition of the present disclosure may be, for example, a tablet, a powder, a capsule, a suppository, a sachet, a pill, a tablet, a liquid syrup, a suspension, etc. In one embodiment, the dosage form of the present disclosure is a tablet.

[0117] In one aspect, the present disclosure further provides a method for treating a disease associated with abnormalities in the signal pathway of Tyrosine Kinase receptor B (TrkB), such as central nerve injury, peripheral nerve injury, neurodegenerative lesion, psychiatric disease, inherited neurological dysfunction, ophthalmological disease, metabolic disease, pain, cardiovascular disease, tumor, or other related disease, comprising administering to a subject the crystalline form of 7,8-dihydroxyflavone of the present disclosure and at least one pharma- ceutically acceptable excipient. In one embodiment, the disease associated with abnormalities in the signal pathway of TrkB is a disease caused by low expression or insufficient activation of TrkB. It is known in the art that 7,8-dihydroxyflavone can activate the signal pathway downstream of TrkB as a specific small molecule agonist of TrkB.

[0118] In one aspect, the disclosure provides a method of treating or preventing cognitive decline associated with traumatic brain injury or aging, the method comprising administering to a subject a crystalline form of 7,8-dihydroxyflavone.

[0119] In one aspect, the present disclosure provides crystalline form P of 7,8-dihydroxyflavone, crystalline form C of 7,8-dihydroxyflavone, or crystalline form N of 7,8-dihydroxyflavone for treating or preventing cognitive decline associated with traumatic brain injury or aging.

[0120] In one embodiment, the present disclosure provides the use of 7,8-dihydroxyflavone crystalline form P, 7,8-dihydroxyflavone crystalline form C, and / or 7,8-dihydroxyflavone crystalline form N in the preparation of a medicament for treating or preventing cognitive decline associated with traumatic brain injury or aging. Those skilled in the art know that the peak intensity and / or peak profile of X-ray powder diffraction may vary depending on experimental conditions. In addition, due to different precision of instruments, the measured 2θ value may have an error of about ±0.2 degrees. Meanwhile, the relative intensity value of the peak depends on certain properties of the measured sample, such as the size of the crystal, high or low purity, rather than the position of the peak, so the measured peak intensity may have a deviation of about ±20%. Even with test error, instrument error, and orientation preference, etc., those skilled in the art can still obtain enough information to authenticate each crystal form from the X-ray powder diffraction data according to the present disclosure.

[0121] In this disclosure, the phrase "having at least one crystal form "#"" (where "#" is an alphabet) means that 7,8-dihydroxyflavone has at least the X-ray characteristic peaks of crystal form "#".

[0122] In this disclosure, the term "solvent evaporation method" refers to a commonly used crystallization method in the field of crystallization, in which the solution is continuously evaporated to change from an unsaturated state to a supersaturated state, thereby precipitating crystals.

[0123] Within the scope of the common knowledge in this field, the above-mentioned preferable conditions can be combined in any manner.

[0124] Unless otherwise noted, all reagents and materials used in this disclosure are commercially available. EXAMPLES

[0125] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the above examples. In the following examples, the experimental methods without specific conditions are selected according to the usual methods and conditions or according to the product specifications.

[0126] Test Method Nuclear magnetic analysis (1H NMR) A few milligrams of the solid sample were dissolved in dimethyl sulfoxide-d 6 The sample was dissolved in a solvent and subjected to nuclear magnetic analysis using a Bruker AVANCE NEO 400 (Bruker, GER).

[0127] X-ray powder diffraction (XRPD) The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle was 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds. When the samples were tested, the tube voltage and current were 40 kV and 40 mA, respectively, and the sample plate was a zero-background sample plate.

[0128] Thermogravimetric analysis (TGA) The model number of the thermogravimetric analyzer was TA Discovery 55 (TA, US). 2–5 mg of sample was placed on a balanced open aluminum sample plate and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, and the nitrogen purge rate at the sample was 60 mL / min and at the balance was 40 mL / min.

[0129] Differential Scanning Calorimetry (DSC) The model number of the differential scanning calorimeter was TA Discovery 2500 (TA, US). After accurately weighing 1–2 mg of sample, it was placed on a perforated DSC Tzero sample plate and heated to the final temperature at a rate of 10 °C / min, and the nitrogen purge rate in the furnace was 50 mL / min.

[0130] Dynamic moisture sorption analysis (DVS) Dynamic moisture sorption analysis was measured using DVS Intrinsic (SMS, UK). The test was performed in gradient mode, with humidity change of 50%-95%-0%-50%, with the humidity change of each gradient being 10% within the range of 0% to 90%, and the gradient end point was determined by the method of dm / dt, where dm / dt was less than 0.002% and maintained for 10 minutes. After the test, XRPD analysis was performed on the sample to confirm whether the solid form had changed. The criteria were as shown in Table 2.

[0131] [Table 2]

[0132] Polarized Light Microscopy (PLM) The model number of the polarizing microscope was Nikon Ci-POL (Nikon, JPN). A small amount of sample was placed on a glass slide, and the morphology of the sample was observed by selecting an appropriate lens.

[0133] Example 1 Preparation of crystalline form P of 7,8-dihydroxyflavone 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, and the mixture was suspended and stirred at 50° C. for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0134] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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°, 14.0±0.2°, 15.8±0.2°, 16.6±0.2°, 17.2±0.2°, 18.4±0.2°, and 19.7±0.2°. Diffraction peaks were observed at 8.7±0.2°, 19.4±0.2°, 20.8±0.2°, 21.4±0.2°, 22.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.9±0.2°, 27.0±0.2°, 27.4±0.2°, 31.2±0.2°, 31.4±0.2°, and 33.7±0.2°, and the XRPD spectrum was as shown in Figure 1.

[0135] 1H NMR detection showed no obvious solvent residual peaks, indicating that the crystalline form P of 7,8-dihydroxyflavone was not a solvate, and its 1H NMR spectrum was as shown in FIG. 12.

[0136] TGA detection showed that there was no obvious weight loss in the crystalline form P of 7,8-dihydroxyflavone, and its TGA spectrum was as shown in FIG.

[0137] According to DSC detection, the crystalline form P of 7,8-dihydroxyflavone had no endothermic signal corresponding to weight loss, and its DSC spectrum was as shown in FIG.

[0138] According to the DVS detection, the dynamic moisture sorption graph of the crystalline form P of 7,8-dihydroxyflavone showed a weight increase of less than 0.1% within the range of relative humidity of 0% to 95%, and its DVS spectrum was as shown in FIG.

[0139] PLM detection showed that the crystalline form P of 7,8-dihydroxyflavone was fine particles, with particle size generally less than 20 μm, and its PLM spectrum was as shown in FIG.

[0140] Example 2 Preparation of crystalline form C of 7,8-dihydroxyflavone Approximately 20 mg of raw material was weighed out and placed in an EP tube, and a certain amount of solvent was gradually added at room temperature (approximately 25°C), and the solution was stirred and ultrasonicated until the solid was completely dissolved. The resulting clear solution was left open and still at room temperature until the solvent was completely evaporated or most of it was evaporated to obtain a solid.

[0141] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, are 5.6±0.2°, 9.5±0.2°, 11.1±0.2°, 12.7±0.2°, 13.5±0.2°, 13.7±0.2°, 15.5±0.2°, 16.0±0.2°, 16.3±0.2°, 16.6±0.2°, 16.9±0.2°, and 17.4±0.2°. , 18.3±0.2°, 18.9±0.2°, 19.2±0.2°, 19.4±0.2°, 20.4±0.2°, 20.8±0.2°, 21.0±0.2°, 21.9±0.2°, 22.2±0.2°, 23.2±0.2°, 23.4±0.2°, 24.1±0.2°, 24.3±0.2°, 25.0±0.2°, 25.2 ±0.2°, 25.5±0.2°, 25.8±0.2°, 27.0±0.2°, 27.3±0.2°, 27.6±0.2°, 27.9±0.2°, 28.3±0.2°, 28.6±0.2°, 28.9±0.2°, 29.7±0.2°, 30.4±0.2°, 30.7±0.2°, 31.7±0.2°, 33.2±0.2° , 33.6±0.2°, 34.3±0.2°, 34.5±0.2°, 34.6±0.2°, 35.1±0.2°, 35.7±0.2°, 36.3±0.2°, 37.7±0.2°, 39.8±0.2°, 42.6±0.2°, and 44.5±0.2°, and the XRPD spectrum was as shown in Figure 2.

[0142] 1H NMR detection showed no obvious solvent residual peaks, indicating that the crystalline form C of 7,8-dihydroxyflavone was not a solvate, and its 1H NMR spectrum was as shown in FIG. 15.

[0143] According to TGA detection, the mass loss of the crystalline form C of 7,8-dihydroxyflavone at 150°C was 3.7% of the mass before the loss, and the weight loss here was the weight of water in the hydrate crystalline form, and the TGA spectrum was as shown in Figure 6.

[0144] According to DSC detection, the crystalline form C of 7,8-dihydroxyflavone had an endothermic signal corresponding to weight loss at 100°C to 160°C, and a melting endothermic peak at 247°C. The DSC spectrum was as shown in FIG.

[0145] According to the DVS detection, the dynamic moisture sorption graph of the crystalline form C of 7,8-dihydroxyflavone showed a weight increase of less than 0.1% within the range of relative humidity of 0% to 95%, and its DVS spectrum was as shown in FIG.

[0146] PLM detection showed that the crystalline form C of 7,8-dihydroxyflavone was fine particles, with a particle size generally less than 5 μm, and its PLM spectrum was as shown in FIG.

[0147] Example 3 Preparation of crystalline form N of 7,8-dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of methanol until a suspension was formed, and the mixture was suspended and stirred at 50°C for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0148] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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°, 16.8±0.2°, 17.1±0.2°, and 17.7±0.2°. ±0.2°, 18.7±0.2°, 18.9±0.2°, 19.2±0.2°, 20.2±0.2°, 20.7±0.2°, 21.1±0.2°, 22.1±0.2°, 22.4±0.2°, 23.1±0.2°, 23.2±0.2°, 23.4±0.2°, 23.8±0.2°, 24.6±0.2°, 25.2±0.2°, 25.7 ±0.2°, 26.3±0.2°, 26.6±0.2°, 26.9±0.2°, 27.3±0.2°, 28.9±0.2°, 28.0±0.2°, 29.0±0.2°, 29.4±0.2°, 29.6±0.2°, 30.4±0.2°, 31.3±0.2°, 31.9±0.2°, 32.1±0.2°, 32.4±0.2°, 35.0 The diffraction peaks were at 35.4±0.2°, 36.2±0.2°, 36.8±0.2°, 38.2±0.2°, 38.4±0.2°, 38.6±0.2°, 38.9±0.2°, 41.0±0.2°, 41.4±0.2°, 42.0±0.2°, and 43.9±0.2°, and the XRPD spectrum was as shown in Figure 3.

[0149] 1H NMR detection showed no obvious solvent residual peaks, indicating that the crystalline form N of 7,8-dihydroxyflavone was not a solvate, and its 1H NMR spectrum was as shown in FIG. 18.

[0150] According to TGA detection, the mass loss of the crystal form N of 7,8-dihydroxyflavone at 40°C to 80°C was 6.3% of the mass before the loss, and the weight loss here was the weight of water in the hydrate crystal form. The TGA spectrum was as shown in Figure 8.

[0151] According to DSC detection, the crystal form N of 7,8-dihydroxyflavone had an endothermic peak corresponding to weight loss at 100° C., and exothermic signals at 136° C. and 169° C., respectively, and its DSC spectrum was as shown in FIG.

[0152] According to the DVS detection, the dynamic moisture sorption graph of the crystal form N of 7,8-dihydroxyflavone showed a weight increase of less than 0.1% within the range of relative humidity of 0% to 95%, and its DVS spectrum was as shown in FIG.

[0153] PLM detection showed that the crystalline form N of 7,8-dihydroxyflavone was fine particles, with particle size generally less than 20 μm, and its PLM spectrum was as shown in FIG.

[0154] Comparative Example 1 Preparation of Crystalline Form A of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 2.0 mL of ethanol until a suspension was formed, and the mixture was suspended and stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0155] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection showed diffraction peaks 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°, 21.0±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 the XRPD spectrum was as shown in FIG. 19.

[0156] Comparative Example 2 Preparation of Crystalline Form B of 7,8-Dihydroxyflavone 40.0 mg of 7,8-dihydroxyflavone was added to 9.0 mL of ethyl formate until a suspension was formed, and the mixture was suspended and stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0157] X-ray powder diffraction expressed in 2θ angles by XRPD detection were 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°, 10.3±0.2°, 11.7±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.7±0.2°, 16.7±0.2°, 17.7±0.2°, 18.7±0.2°, 19.7±0.2°, 20.7±0.2°, 21.7±0 2°, 10.9±0.2°, 11.2±0.2°, 11.8±0.2°, 12.8±0.2°, 13.4±0.2°, 13.9±0.2°, 14.2±0.2°, 14.8±0.2°, 15.2±0.2°, 15.7±0.2°, 16.3±0.2°, 16.7±0.2°, 17.2±0.2°, 17.9±0.2°, 18.8±0.2°, 19.3±0.2°, 19.8±0.2°, 20.4±0.2°, 20.7±0.2°, 22.1±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. There were diffraction peaks at 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 the XRPD spectrum was as shown in Figure 20.

[0158] Comparative Example 3 Preparation of Crystal Form E of 7,8-Dihydroxyflavone Approximately 20 mg of the raw material was weighed out and placed in an EP tube, and 2 mL of ethylene glycol dimethyl ether was added at room temperature (approximately 25°C). The solution was stirred and sonicated until the solid was completely dissolved. The resulting clear solution was left open at room temperature until the solvent was completely evaporated or most of it was evaporated to give a solid.

[0159] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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°, and 17. .0±0.2°, 17.3±0.2°, 17.9±0.2°, 18.3±0.2°, 18.6±0.2°, 18.8±0.2°, 19.0±0.2°, 19.3±0.2°, 20.3±0.2°, 21.2±0.2°, 21.7±0.2°, 22.0±0.2°, 22.3±0.2°, 22.6±0.2°, 23.3±0.2°, 23.8±0.2°, 24.2±0.2°, 25.0±0.2°, 25.4±0.2°, 25.8±0.2°, 26.5±0.2°, 26.9±0.2°, 27.3±0.2°, 27.8±0.2°, 28.1±0.2°, 28.6±0.2°, 29.2±0.2°, 29.7±0.2°, 30.7±0.2°, 31.8±0.2°. 2°, 31.9±0.2°, 34.0±0.2°, 34.8±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 the XRPD spectrum is shown in Figure 21.

[0160] Comparative Example 4 Preparation of Crystalline Form F of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of acetonitrile until a suspension was formed, and the mixture was suspended and stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0161] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, are 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°, 21.9±0.2°, 22.7±0.2°, 24.2±0.2°, 24.7±0.2°, and 25.5±0.2°. , 26.2±0.2°, 26.9±0.2°, 27.6±0.2°, 28.2±0.2°, 29.5±0.2°, 30.1±0.2°, 31.0±0.2°, 32.0±0.2°, 33.3±0.2°, 33.7±0.2°, 35.5±0.2°, 36.4±0.2°, 36.9±0.2°, 38.0±0.2°, and 38.5±0.2°, and the XRPD spectrum is as shown in FIG. 22.

[0162] Comparative Example 5 Preparation of Crystal Form G of 7,8-Dihydroxyflavone Weigh out 160 mg of 7,8-dihydroxyflavone, dropwise add 11 mL of ethylene glycol dimethyl ether at room temperature to completely dissolve the sample, take 1.3 mL of the solution, and dropwise add the solution to 6.5 mL of water. After stirring for 15 min to 1 h, the precipitated solid was centrifuged, and then the solid was vacuum dried at room temperature.

[0163] X-ray powder diffraction, expressed in 2θ angles by XRPD detection, was 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°, 25.0±0.2°, 26.0±0.2°, 27.0±0.2°, 28.0±0.2°, 29.0±0.2°, 30.0±0.2°, 31.0±0.2°, 32.0±0.2°, 33.0±0.2°, 34.0±0.2°, 35.0±0.2°, 36.0±0.2°, 37.0±0.2°, 38.0±0.2°, 39.0±0.2°, 40.0±0.2°, 41.0±0.2°, 42.0±0.2°, 43.0±0.2°, 44.0±0.2°, 45.0±0.2°, 46.0±0.2°, 47.0±0.2°, 48.0±0.2°, 49.0±0.2°, 50.0±0.2°, 51.0±0.2°, 52.0±0.2°, 53.0±0.2°, 54.0±0.2°, 55.0±0.2°, 56.0±0.2°, 57.0±0. The diffraction peaks were at 24.7±0.2°, 26.5±0.2°, 26.8±0.2°, 28.2±0.2°, 30.0±0.2°, 31.9±0.2°, 34.2±0.2°, 35.4±0.2°, 38.9±0.2°, and 42.0±0.2°, and the XRPD spectrum was as shown in Figure 23.

[0164] Comparative Example 6 Preparation of Crystalline Form H of 7,8-Dihydroxyflavone Weigh out 160 mg of 7,8-dihydroxyflavone, drop 11 mL of ethylene glycol dimethyl ether at room temperature to completely dissolve the sample, take 1.3 mL of the solution, and drop 1.0 mL of n-heptane. After stirring at room temperature for 15 min to 1 h, the precipitated solid was centrifuged, and then the solid was vacuum dried at room temperature.

[0165] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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°, 18.4±0.2°, and 19. Diffraction peaks were observed at 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 the XRPD spectrum was as shown in FIG. 24.

[0166] Comparative Example 7 Preparation of Crystal Form I of 7,8-Dihydroxyflavone Weigh out 160 mg of 7,8-dihydroxyflavone, drop 11 mL of ethylene glycol dimethyl ether at room temperature to completely dissolve the sample, take 1.3 mL of the solution, and drop 5.0 mL of water. After stirring at room temperature for 15 min to 1 h, the precipitated solid was centrifuged, and then the solid was vacuum dried at room temperature.

[0167] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection showed 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°, and the XRPD spectrum was as shown in FIG. 25.

[0168] Comparative Example 8 Preparation of Crystalline Form J of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of toluene until a suspension was formed, and the mixture was suspended and stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0169] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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°, and 19. Diffraction peaks were present at 9.2±0.2°, 20.1±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 the XRPD spectrum was as shown in Figure 26.

[0170] Comparative Example 9 Preparation of Crystal Form K of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 2.0 mL of dioxane until a suspension was formed, and the suspension was stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0171] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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±0.2°, 19.5±0.2°, 20.4±0.2°, 20.7±0.2°, 20.9±0.2°, 22.1±0.2°, 22.4±0.2°, 23.4±0.2°, 23.9±0.2°, 24.7±0.2°, 25.8±0.2°, 26.3±0.2°, 27.3±0.2°, 27.4±0.2°, 28.4±0.2°, 29.4±0.2°, 30.4±0.2°, 31.4±0.2°, 32.4±0.2°, 33.2±0.2°, 34.4±0.2°, 35.6±0.2°, 36.2±0.2°, 37.2±0.2°, 38.2±0.2°, 39.2±0.2°, 40.2±0.2°, 41.2±0.2°, 42.2±0.2°, 43.2±0.2°, 44.2±0.2°, 45.2±0.2°, 46.2±0.2°, 47.2±0.2°, 48.2±0.2°, 49.2±0. Diffraction peaks were observed at 28.1±0.2°, 28.7±0.2°, 29.6±0.2°, 30.4±0.2°, 31.0±0.2°, 31.4±0.2°, 31.9±0.2°, 32.4±0.2°, 33.1±0.2°, 33.7±0.2°, 34.2±0.2°, 34.8±0.2°, 35.4±0.2°, 36.2±0.2°, 37.0±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°, and the XRPD spectrum was as shown in FIG. 27.

[0172] Comparative Example 10 Preparation of Crystalline Form L of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of methyl formate until a suspension was formed, and the mixture was suspended and stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0173] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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°, 21.0±0.2°, 21.3±0.2°, 22.0±0.2°, 22.2±0.2°, 22.6±0.2°, 23.3±0.2°. , 23.7±0.2°, 25.5±0.2°, 25.6±0.2°, 26.3±0.2°, 27.3±0.2°, 27.8±0.2°, 28.9±0.2°, 29.3±0.2°, 30.4±0.2°, 31.6±0.2°, 32.1±0.2°, 32.3±0.2°, 32.4±0.2°, 34.2±0.2°, 34.9±0.2°, and 37.9±0.2°, and the XRPD spectrum is as shown in FIG. 28.

[0174] Comparative Example 11 Preparation of Crystalline Form M of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 2.0 mL of acetone until a suspension was formed, and the mixture was suspended and stirred at room temperature for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0175] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, are 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°, 22.0±0.2°, 22.3±0.2°, 22.8±0.2°, and 14.2±0.2°. , 24.4±0.2°, 25.4±0.2°, 25.9±0.2°, 26.4±0.2°, 26.6±0.2°, 27.7±0.2°, 28.3±0.2°, 29.0±0.2°, 30.5±0.2°, 30.9±0.2°, 32.5±0.2°, and 33.3±0.2°, and the XRPD spectrum is shown in Figure 29.

[0176] Comparative Example 12 Preparation of Crystal Form O of 7,8-Dihydroxyflavone 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of chloroform until a suspension was formed, and the mixture was suspended and stirred at 50°C for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0177] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, was 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°, 13.6±0.2°, 14.1±0.2°, 14.7±0.2°, 15.2±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.9±0.2°, 18.6±0.2°, 19.3±0.2°, 19.8±0.2°, 20.4±0.2°, and 21.0±0.2°. Diffraction peaks were observed at 0.7±0.2°, 22.1±0.2°, 22.6±0.2°, 23.9±0.2°, 25.1±0.2°, 25.5±0.2°, 25.7±0.2°, 27.1±0.2°, 27.3±0.2°, 27.5±0.2°, 28.3±0.2°, 28.9±0.2°, 29.5±0.2°, 29.7±0.2°, 29.8±0.2°, 32.6±0.2°, 32.7±0.2°, 36.2±0.2°, 41.3±0.2°, and 41.4±0.2°, and the XRPD spectrum was as shown in FIG. 30.

[0178] Comparative Example 13 Preparation of Crystalline Form Q of 7,8-Dihydroxyflavone 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, and the mixture was suspended and stirred at 50° C. for 7 days, after which the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0179] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, were 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±0.2°, 11.2±0.2°, 12.1±0.2°, 13.0±0.2°, 13.9±0.2°, 14.5±0.2°, 15.3±0.2°, 15.5±0.2°, 16.2±0.2°, 16.6±0.2°, 17.3±0.2°, 17.7 ... Diffraction peaks were observed at 18.1±0.2°, 18.5±0.2°, 19.2±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 the XRPD spectrum was as shown in FIG. 31.

[0180] Comparative Example 14 Preparation of Crystal Form R of 7,8-Dihydroxyflavone Crystalline form N was obtained by heating to 100° C. with in situ variable temperature XRPD.

[0181] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, are 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°, 14.1±0.2°, 14.3±0.2°, 14.5±0.2°, 15.6±0.2°, 16.1±0.2°, 16.4±0.2°, 17.5±0.2°, 19.2±0.2°, 19.7±0.2°, and 21.4±0.2°. , 22.2±0.2°, 23.0±0.2°, 23.2±0.2°, 23.4±0.2°, 24.2±0.2°, 24.4±0.2°, 24.7±0.2°, 25.1±0.2°, 25.4±0.2°, 25.9±0.2°, 26.5±0.2°, 27.9±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°, and the XRPD spectrum was as shown in FIG. 32.

[0182] Comparative Example 15 Preparation of Crystalline Form S of 7,8-Dihydroxyflavone Weigh out 160 mg of 7,8-dihydroxyflavone, drop 11 mL of ethylene glycol dimethyl ether at room temperature to completely dissolve the sample, take 1.3 mL of the solution, drop 8.0 mL of butyl formate, and after stirring at room temperature for 15 min to 1 h, the precipitated solid was centrifuged, and then vacuum dried at room temperature.

[0183] XRPD detection showed that the X-ray powder diffraction expressed in 2θ angles had diffraction peaks 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°, 35.1±0.2°, 35.7±0.2°, 41.8±0.2°, and 44.8±0.2°, and the XRPD spectrum was as shown in FIG. 33.

[0184] Comparative Example 16 Preparation of Crystal Form T of 7,8-Dihydroxyflavone Crystalline form G was obtained by heating to 140° C. with in situ variable temperature XRPD.

[0185] X-ray powder diffraction, expressed in 2θ angles, by XRPD detection, was 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°, 23.8±0.2°, 25.2±0.2°, 26.0±0.2°, 26.5±0.2°, Diffraction peaks were observed at 27.5±0.2°, 28.0±0.2°, 29.5±0.2°, 30.0±0.2°, 31.1±0.2°, 31.3±0.2°, 31.5±0.2°, 31.7±0.2°, 32.7±0.2°, 34.0±0.2°, 34.7±0.2°, 34.9±0.2°, 35.8±0.2°, 36.1±0.2°, 38.0±0.2°, 38.2±0.2°, 42.1±0.2°, 43.5±0.2°, 43.7±0.2°, and 44.1±0.2°, and the XRPD spectrum was as shown in FIG. 34.

[0186] Tablet Preparation Example 1 Preparation of a tablet dosage form of 7,8-dihydroxyflavone 80g of raw drug (crystal form of dihydroxyflavone prepared in this disclosure), 80g of lactose, 13g of microcrystalline cellulose, 12g of povidone, and 7g of sodium carboxymethyl starch were mixed and placed in a 1L granulation pan, stirred for 6 minutes, and 40g-50g of pure water was added, and wet granulation was adopted and stirred for 8-10 minutes. After drying and granulation, 7g of sodium carboxymethyl starch and 1g of magnesium stearate were added, and the materials were thoroughly mixed, and then compressed and demolded to obtain the target tablets.

[0187] Example 1: Stability of different crystal forms of 7,8-dihydroxyflavone Stability studies were conducted on different crystalline forms of 7,8-dihydroxyflavone under conditions of high temperature (60°C), high humidity (25°C / 92.5%RH), light exposure (25°C / 4500Lux), and accelerated (40°C / 75%RH). Samples were taken on the 7th and 15th days for XRPD analysis. The results are shown in Table 3, and the results of XPRD detection are shown in Figures 35 to 37.

[0188] [Table 3]

[0189] Efficacy Example 2 Dynamic solubility of different crystalline forms of 7,8-dihydroxyflavone in three biological media (FaSSIF, FeSSIF and FaSSGF) and in water 20 mg of different crystalline forms of 7,8-dihydroxyflavone were placed in 4.0 mL of biological medium or water, respectively, and shaken at 37 ° C for 24 h. Samples were taken at 0.5 h, 2 h and 24 h, respectively, and the sampled solutions were filtered through a 0.22 μm aqueous filter membrane, and the peak area of ​​the signal 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 calibration curve of the raw material and the dilution factor. In addition, the supernatant of 24 h was taken to test its pH, and the remaining solid was subjected to XRPD testing. The formulation of the biological medium is shown in Table 4. The experimental results are shown in Table 5, and the XPRD detection results are shown in Figures 38 to 40.

[0190] [Table 4]

[0191] [Table 5]

[0192] Efficacy Example 3: Stability study of tablets of 7,8-dihydroxyflavone crystalline form P Stability studies were conducted on tablets of 7,8-dihydroxyflavone crystalline form P under high temperature (60°C), high humidity (25°C / 92.5%RH), light exposure (25°C / 4500Lux) and accelerated (40°C / 75%RH) conditions, and samples were taken at 3 and 6 months for XRPD analysis, with the results shown in Table 6.

[0193] [Table 6]

[0194] Efficacy Example 4: Stability study of tablets of 7,8-dihydroxyflavone crystalline form C Stability studies were conducted on tablets of 7,8-dihydroxyflavone crystalline form C under high temperature (60°C), high humidity (25°C / 92.5%RH), light exposure (25°C / 4500Lux) and accelerated (40°C / 75%RH) conditions, and samples were taken at 3 and 6 months for XRPD analysis, with the results shown in Table 7.

[0195] [Table 7]

[0196] Efficacy Example 5: Dissolution study of tablets of 7,8-dihydroxyflavone crystalline form P Dissolution studies were carried out on tablets of crystalline form P of 7,8-dihydroxyflavone under different pH conditions, and the results are shown in Table 8.

[0197] [Table 8]

[0198] Efficacy Example 6: Dissolution study of tablets of 7,8-dihydroxyflavone crystalline form C Dissolution studies were carried out on tablets of crystalline form C of 7,8-dihydroxyflavone under different pH conditions, and the results are shown in Table 9.

[0199] [Table 9]

[0200] Efficacy Example 7: Dissolution study of tablets of 7,8-dihydroxyflavone crystalline form A Dissolution studies were carried out on tablets of crystalline form A of 7,8-dihydroxyflavone under different pH conditions, and the results are shown in Table 10.

[0201] [Table 10]

[0202] In summary, the present disclosure provides 7,8-dihydroxyflavone crystalline polymorphs and their preparation methods. The 7,8-dihydroxyflavone crystalline polymorphs disclosed herein have more selectable pharmaceutical economic value.

Claims

1. having an X-ray powder diffraction pattern including characteristic peaks at 2θ angles of about 8.3±0.2°, 25.0±0.2°, and 25.9±0.2°; Crystalline form P of 7,8-dihydroxyflavone.

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

3. having an X-ray powder diffraction pattern including characteristic peaks at 2θ angles of about 11.1±0.2°, 15.6±0.2°, 27.0±0.2°, and 28.3±0.2°; Crystalline form C of 7,8-dihydroxyflavone.

4. 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°. The crystalline form C of 7,8-dihydroxyflavone according to claim 3.

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

6. having an X-ray powder diffraction pattern including characteristic peaks at 2θ angles of about 9.3±0.2°, 23.8±0.2°, 24.6±0.2°, and 26.6±0.2°; Crystalline form N of 7,8-dihydroxyflavone.

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

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

9. (1) crystalline form P of 7,8-dihydroxyflavone according to any one of claims 1 to 2, crystalline form C of 7,8-dihydroxyflavone according to any one of claims 3 to 5, and / or crystalline form N of 7,8-dihydroxyflavone according to any one of claims 6 to 8, and (2) at least one pharma- ceutically acceptable excipient. Pharmaceutical compositions.

10. 1. A method for treating a disease associated with abnormalities in the TrkB signaling pathway, such as central nervous system injury, peripheral nervous system injury, neurodegenerative lesions, psychiatric disorders, inherited neurological dysfunction, ophthalmological disorders, metabolic disorders, pain, cardiovascular diseases, tumors, or other related diseases, comprising: (1) administering to a subject a crystalline form P of 7,8-dihydroxyflavone as claimed in any one of claims 1 to 2, a crystalline form C of 7,8-dihydroxyflavone as claimed in any one of claims 3 to 5, and / or a crystalline form N of 7,8-dihydroxyflavone as claimed in any one of claims 6 to 8, and (2) at least one pharma- ceutically acceptable excipient. method.

Images