Polymorphs of 7,8-dihydroxyflavone and preparation method thereof

Abstract

A polymorph of 7,8-dihydroxyflavone and a preparation method thereof; the polymorph of 7,8-dihydroxyflavone has significantly improved physical and chemical properties, thereby having higher pharmaceutical value.

Description

Technical Field

[0001] The present disclosure relates to polymorphs of 7,8-dihydroxyflavone and a preparation method thereof Background Art

[0002] As a specific agonist of tyrosine receptor kinase B (TrkB), 7,8-dihydroxyflavone can activate TrkB. Numerous in vitro studies have shown that 7,8-dihydroxyflavone has important biological effects, primarily manifesting in its beneficial effects on neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, depression, psychiatric disorders, post-traumatic stress disorder, autism spectrum disorder, stroke, and Rett syndrome.

[0003] Polymorphism, the phenomenon of a substance existing in two or more different crystal structures, is a common phenomenon in solid materials. In the pharmaceutical field, the study of drug polymorphism has become an important frontier. Different crystal structures of the same solid substance often exhibit distinct physical and chemical properties. In the case of drugs, different crystal forms primarily manifest in differences in stability, solubility, and dissolution rate, which can affect the drug's efficacy and even alter its toxic side effects.

[0004] Therefore, it is of great significance to develop a 7,8-dihydroxyflavone crystal form with advantageous properties.

[0005] Overview

[0006] The present disclosure discloses a polymorph of 7,8-dihydroxyflavone and a preparation method thereof. The polymorph of 7,8-dihydroxyflavone provided by the present disclosure has more selective pharmaceutical economic value.

[0007] In one aspect, the present disclosure provides a crystalline form P of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees at approximately 8.3±0.2°, 25.0±0.2°, and 25.9±0.2°.

[0008] 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°.

[0009] In a further embodiment, the X-ray powder diffraction pattern further comprises 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°.

[0010] In a further embodiment, the crystalline form P has substantially Figure 1 The X-ray powder diffraction pattern is shown.

[0011] In a further embodiment, in the thermogravimetric analysis spectrum of the crystalline form P, there is no obvious weight loss.

[0012] In a further embodiment, in the differential scanning calorimetry spectrum of the crystalline form P, there is no endothermic signal corresponding to weight loss.

[0013] In a further embodiment, in the dynamic moisture adsorption diagram of the crystal form P, the weight gain is less than 0.1% in the relative humidity range of 0%-95%, and the "%" is the percentage of the increased mass of the 7,8-dihydroxyflavone crystal form P to the initial mass.

[0014] In a further embodiment, the crystalline form P of 7,8-dihydroxyflavone has substantially Figure 4 Thermogravimetric analysis diagram and / or differential scanning calorimetry diagram shown.

[0015] In a further embodiment, the crystalline form P of 7,8-dihydroxyflavone has substantially Figure 5 The dynamic moisture adsorption diagram is shown.

[0016] In a further embodiment, the 7,8-dihydroxyflavone crystalline form P is an anhydrate.

[0017] In another aspect, the present disclosure provides a crystalline form C of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees at approximately 11.1±0.2°, 15.6±0.2°, 27.0±0.2°, and 28.3±0.2°.

[0018] 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°.

[0019] In a further embodiment, the X-ray powder diffraction pattern further comprises 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°.

[0020] In a further embodiment, the crystalline Form C has substantially Figure 2 The X-ray powder diffraction pattern is shown.

[0021] In a further embodiment, in the thermogravimetric analysis spectrum of the crystalline form C, the mass lost at 110° C. to 150° C. accounts for about 3.7% of the mass before weight loss, where “%” represents mass percentage.

[0022] In a further embodiment, the differential scanning calorimetry of the crystalline form C has an endothermic signal corresponding to weight loss at about 100°C to 160°C.

[0023] In a further embodiment, in the dynamic moisture adsorption diagram of the crystalline form C, the weight gain is less than 0.1% in the relative humidity range of 0%-95%, and the "%" is the percentage of the increased mass of the 7,8-dihydroxyflavone crystalline form C to the initial mass.

[0024] In a further embodiment, the 7,8-dihydroxyflavone crystalline form C has substantially Figure 6 Thermogravimetric analysis diagram and / or differential scanning calorimetry diagram shown.

[0025] In a further embodiment, the 7,8-dihydroxyflavone crystalline form C has substantially Figure 7 The dynamic moisture adsorption diagram is shown.

[0026] In a further embodiment, the 7,8-dihydroxyflavone crystalline form C is a hydrate, such as a monohydrate.

[0027] In another aspect, the present disclosure provides a crystalline form N of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees at approximately 9.3±0.2°, 23.8±0.2°, 24.6±0.2°, and 26.6±0.2°.

[0028] 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°.

[0029] In a further embodiment, the X-ray powder diffraction pattern further comprises 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°.

[0030] In a further embodiment, the 7,8-dihydroxyflavone crystalline form N has substantially Figure 3 The X-ray powder diffraction pattern is shown.

[0031] In a further embodiment, in the thermogravimetric analysis spectrum of the crystal form N, the mass lost at 40°C to 80°C accounts for 6.3% of the mass before weight loss, where "%" refers to mass percentage.

[0032] In a further embodiment, the differential scanning calorimetry of the 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.

[0033] In a further embodiment, in the dynamic moisture adsorption diagram of the crystalline form N, the weight gain is less than 0.1% in the relative humidity range of 0%-95%, and the "%" is the percentage of the increased mass of the 7,8-dihydroxyflavone crystalline form N to the initial mass.

[0034] In a further embodiment, the 7,8-dihydroxyflavone crystalline form N has substantially Figure 8 Thermogravimetric analysis diagram and / or differential scanning calorimetry diagram shown.

[0035] In a further embodiment, the 7,8-dihydroxyflavone crystalline form N has substantially Figure 9 The dynamic moisture adsorption diagram is shown.

[0036] In a further embodiment, the 7,8-dihydroxyflavone crystalline form N is a hydrate, such as a dihydrate.

[0037] In another aspect, the present disclosure provides a method for preparing the crystalline form of 7,8-dihydroxyflavone of the present disclosure, which is one of Methods 1 to 5:

[0038] Method 1: comprising the steps of: dissolving 7,8-dihydroxyflavone in a single solvent, and volatilizing the solvent to obtain a solid;

[0039] Method 2: comprising the following steps: suspending 7,8-dihydroxyflavone in a single solvent or a binary solvent, and then centrifuging to obtain a solid;

[0040] Method 3: comprising the steps of: dissolving 7,8-dihydroxyflavone in a good solvent, adding the obtained solution dropwise into an anti-solvent, precipitating a solid, and separating the solid;

[0041] Method 4: comprising the steps of: dissolving 7,8-dihydroxyflavone in a good solvent, dropwise adding an antisolvent to the obtained solution, precipitating a solid, and then separating the solid;

[0042] Method 5: It comprises the following steps: suspending 7,8-dihydroxyflavone in an anti-solvent, then adding a good solvent dropwise until the solid is dissolved, cooling to precipitate the solid, and then separating the solid.

[0043] In one embodiment, a method for preparing 7,8-dihydroxyflavone crystalline form P is provided, characterized in that, in method 2, the single solvent is n-heptane, and the binary solvent is a combination of one of 4-methyl-2-pentanone, n-propanol, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, and butyl formate, and one of isopropyl acetate, n-heptane, toluene, isopropanol, ethyl acetate, diethyl ether, and cyclohexane;

[0044] And / or, in method 2, the volume ratio of the binary solvents is 1:5-1:10.

[0045] In a further embodiment, a method for preparing 7,8-dihydroxyflavone crystal form P is provided, characterized in that in method 2, the suspension temperature is 20-60°C.

[0046] In one embodiment, provided is a 7,8-dihydroxyflavone prepared according to the method of the present disclosure and having at least one characteristic of the crystalline Form P of the present disclosure.

[0047] In one embodiment, a method for preparing 7,8-dihydroxyflavone crystalline form C is provided, characterized in that, in method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide;

[0048] And / or, in method 1, the volume mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g;

[0049] and / or, in method 1, the solid is precipitated by evaporating the solvent;

[0050] And / or, in method 2, the single solvent is water or diethyl ether; 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;

[0051] 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;

[0052] And / or, in method 2, in the binary solvent, the volume ratio of the organic solvent to water is 1:5-1:10, 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;

[0053] 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 anti-solvent is selected from one or more of water, toluene, dichloromethane, and diethyl ether;

[0054] And / or, in method 3, the volume ratio of the good solvent to the antisolvent is 1:1-1:10;

[0055] And / or, in method 4, the good solvent is one or more of N,N-dimethylformamide and isopropyl alcohol, and / or the anti-solvent is one or more of chloroform, toluene, and water;

[0056] And / or, in method 4, the volume ratio of the good solvent to the antisolvent is 1:1-1:10;

[0057] And / or, in method 5, the anti-solvent is water, and the good solvent is one or more of N,N-dimethylformamide, tetrahydrofuran, ethanol, and ethylene glycol methyl ether;

[0058] And / or, in method 5, the volume ratio of the anti-solvent to the good solvent is 1:0.8-1:1.

[0059] In a further embodiment, a method for preparing 7,8-dihydroxyflavone crystalline form C is provided, characterized in that, in method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide;

[0060] and / or, in method 1, the temperature at which the solid is precipitated is room temperature;

[0061] and / or, in method 2, the suspension temperature is 20-60°C;

[0062] and / or, in method 3, the dropping temperature is 15-50°C;

[0063] and / or, in method 4, the dropping temperature is 15-50°C;

[0064] And / or, in method 5, the cooling temperature is -15°C to 4°C.

[0065] In one embodiment, provided is a 7,8-dihydroxyflavone prepared by the method of the present disclosure and having at least one characteristic of the crystalline Form C of the present disclosure.

[0066] 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;

[0067] And / or, in method 1, the volume mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g;

[0068] and / or, in method 1, the solid is precipitated by evaporating the solvent;

[0069] and / or, in method 2, the single solvent is methanol; the binary solvent is a combination of methanol and water;

[0070] And / or, in method 2, the volume ratio of methanol to water in the binary solvent is 1:5-1:10;

[0071] And / or, in method 3, the good solvent is ethanol, and the anti-solvent is one or more of methyl tert-butyl ether and toluene;

[0072] And / or, in method 3, the volume ratio of the good solvent to the antisolvent is 1:1-1:10;

[0073] And / or, in method 4, the good solvent is ethanol, and the anti-solvent is one or more of cyclohexane, n-heptane and water;

[0074] And / or, in method 4, the volume ratio of the good solvent to the antisolvent is 1:1-1:10;

[0075] And / or, in method 5, the anti-solvent 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;

[0076] And / or, in method 5, the volume ratio of the antisolvent to the good solvent is 1:0.8-1:1;

[0077] 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;

[0078] And / or, in method 1, the temperature of the precipitated solid is room temperature;

[0079] and / or, in method 2, the suspension temperature is 20-60°C;

[0080] And / or, in method 3, the dropping temperature is 15-50°C;

[0081] And / or, in method 4, the dropping temperature is 15-50°C;

[0082] And / or, in method 5, the cooling temperature is -15 to 4°C.

[0083] In one embodiment, provided is a 7,8-dihydroxyflavone prepared by a method of the present disclosure and having at least one characteristic of the crystalline form N of the present disclosure.

[0084] In another aspect, the present disclosure provides a pharmaceutical composition comprising (1) 7,8-dihydroxyflavone crystalline form P, 7,8-dihydroxyflavone crystalline form C and / or 7,8-dihydroxyflavone crystalline form N according to the present disclosure, and (2) at least one pharmaceutically acceptable excipient.

[0085] In another aspect, the present disclosure provides a method for treating diseases related to abnormal TrkB signaling pathway, such as central nervous system damage, peripheral nerve damage, neurodegenerative diseases, psychiatric diseases, hereditary neurological dysfunction, ophthalmic diseases, metabolic diseases, pain, cardiovascular diseases, tumors, or other related diseases, comprising administering to a subject (1) 7,8-dihydroxyflavone crystalline form P, 7,8-dihydroxyflavone crystalline form C, and / or the 7,8-dihydroxyflavone crystalline form N according to the present disclosure, and (2) at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 This is the X-ray powder diffraction pattern of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1.

[0087] Figure 2 This is the X-ray powder diffraction pattern of Form C of 7,8-dihydroxyflavone obtained in Example 2.

[0088] Figure 3 This is the X-ray powder diffraction pattern of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3.

[0089] Figure 4 The thermogravimetric analysis diagram and differential scanning calorimetry diagram of the crystal form P of 7,8-dihydroxyflavone obtained in Example 1.

[0090] Figure 5 This is a dynamic moisture adsorption diagram of the crystal form P of 7,8-dihydroxyflavone obtained in Example 1.

[0091] Figure 6 The thermogravimetric analysis diagram and differential scanning calorimetry diagram of C of the 7,8-dihydroxyflavone obtained in Example 2.

[0092] Figure 7 This is the dynamic moisture adsorption diagram of the crystal form C of 7,8-dihydroxyflavone obtained in Example 2.

[0093] Figure 8 The thermogravimetric analysis diagram and differential scanning calorimetry diagram of the crystal form N of 7,8-dihydroxyflavone obtained in Example 3 are shown.

[0094] Figure 9 This is the dynamic moisture adsorption diagram of the crystal form N of 7,8-dihydroxyflavone obtained in Example 3.

[0095] Figure 10 The X-ray powder diffraction patterns of the crystal form P of 7,8-dihydroxyflavone obtained in Example 1 before and after the dynamic moisture adsorption experiment.

[0096] Figure 11 This is a polarizing microscope analysis image of the crystal form P of 7,8-dihydroxyflavone obtained in Example 1.

[0097] Figure 12 This is the H NMR spectrum of the crystalline form P of 7,8-dihydroxyflavone obtained in Example 1.

[0098] Figure 13 The X-ray powder diffraction patterns of the crystalline form C of 7,8-dihydroxyflavone obtained in Example 2 before and after the dynamic moisture adsorption experiment.

[0099] Figure 14 This is a polarizing microscope analysis image of the crystal form C of 7,8-dihydroxyflavone obtained in Example 2.

[0100] Figure 15 This is the H NMR spectrum of Form C of 7,8-dihydroxyflavone obtained in Example 2.

[0101] Figure 16 The X-ray powder diffraction patterns of the crystal form N of 7,8-dihydroxyflavone obtained in Example 3 before and after the dynamic moisture adsorption experiment.

[0102] Figure 17 This is a polarizing microscope analysis image of the crystal form N of 7,8-dihydroxyflavone obtained in Example 3.

[0103] Figure 18 This is the H NMR spectrum of the crystalline form N of 7,8-dihydroxyflavone obtained in Example 3.

[0104] Figure 19 The X-ray powder diffraction pattern of the crystalline form A of the 7,8-dihydroxyflavone was obtained for comparison with Example 1.

[0105] Figure 20 The X-ray powder diffraction pattern of the crystalline form B of the 7,8-dihydroxyflavone was obtained for comparison with Example 2.

[0106] Figure 21 The X-ray powder diffraction pattern of the crystalline form E of 7,8-dihydroxyflavone was obtained for comparison with Example 3.

[0107] Figure 22 The X-ray powder diffraction pattern of the crystalline form F of 7,8-dihydroxyflavone was obtained for comparison with Example 4.

[0108] Figure 23The X-ray powder diffraction pattern of the crystalline form G of 7,8-dihydroxyflavone was obtained for comparison with Example 5.

[0109] Figure 24 The X-ray powder diffraction pattern of the crystalline form H of the 7,8-dihydroxyflavone was obtained for comparison with Example 6.

[0110] Figure 25 The X-ray powder diffraction pattern of the crystalline form I of the 7,8-dihydroxyflavone was obtained for comparison with Example 7.

[0111] Figure 26 The X-ray powder diffraction pattern of the crystalline form J of 7,8-dihydroxyflavone was obtained for comparison with Example 8.

[0112] Figure 27 The X-ray powder diffraction pattern of the crystal form K of the 7,8-dihydroxyflavone was obtained for comparison with Example 9.

[0113] Figure 28 The X-ray powder diffraction pattern of the crystalline form L of the 7,8-dihydroxyflavone was obtained for comparison with Example 10.

[0114] Figure 29 The X-ray powder diffraction pattern of the crystalline form M of the 7,8-dihydroxyflavone was obtained for comparison with Example 11.

[0115] Figure 30 The X-ray powder diffraction pattern of the crystalline form O of the 7,8-dihydroxyflavone was obtained for comparison with Example 12.

[0116] Figure 31 The X-ray powder diffraction pattern of the crystal form Q of the 7,8-dihydroxyflavone obtained in Comparative Example 13 was obtained.

[0117] Figure 32 The X-ray powder diffraction pattern of the crystalline form R of the 7,8-dihydroxyflavone was obtained for comparison with Example 14.

[0118] Figure 33 The X-ray powder diffraction pattern of the crystalline form S of the 7,8-dihydroxyflavone was obtained for comparison with Example 15.

[0119] Figure 34 The X-ray powder diffraction pattern of the crystalline form T of the 7,8-dihydroxyflavone was obtained for comparison with Example 16.

[0120] Figure 35 The X-ray powder diffraction pattern of the crystal form P of 7,8-dihydroxyflavone obtained in Example 1 is shown.

[0121] Figure 36The X-ray powder diffraction pattern of the crystal form C of the 7,8-dihydroxyflavone obtained in Example 1 was obtained.

[0122] Figure 37 The X-ray powder diffraction pattern of the crystal form N of the 7,8-dihydroxyflavone obtained in Example 1 was obtained.

[0123] Figure 38 The X-ray powder diffraction pattern of the crystal form P of 7,8-dihydroxyflavone obtained in Example 2 was obtained.

[0124] Figure 39 The X-ray powder diffraction pattern of the crystal form C of the 7,8-dihydroxyflavone obtained in Example 2 was obtained.

[0125] Figure 40 The X-ray powder diffraction pattern of the crystalline form N of the 7,8-dihydroxyflavone obtained in Example 2 was obtained.

[0126] Details

[0127] In the present disclosure, the structural formula of the 7,8-dihydroxyflavone is:

[0128]

[0129] 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 as well as any crystalline form.

[0130] In one embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one P crystalline form, wherein the crystalline form P is characterized by an X-ray diffraction pattern thereof, 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 the 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, the crystalline form P is an anhydrate. In a further embodiment, the X-ray diffraction pattern of the crystalline form P is as follows Figure 1 In a further embodiment, the positions of the characteristic X-ray diffraction peaks of Form P are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0131] In one embodiment, the present disclosure relates to a crystalline form P of 7,8-dihydroxyflavone that is stable against crystal transformation.

[0132] In one embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline Form C, wherein Form C is characterized by an X-ray diffraction pattern thereof, 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, Form C is a hydrate, such as a monohydrate. In a further embodiment, the X-ray diffraction pattern of Form C is as follows: Figure 2 In a further embodiment, the positions of the characteristic X-ray diffraction peaks of Form C are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0133] In one embodiment, the present disclosure relates to a crystalline Form C of 7,8-dihydroxyflavone that is stable against crystal transformation.

[0134] In one embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one N crystalline form, wherein the crystalline form N is characterized by its X-ray diffraction pattern, characterized in that X-ray diffraction peaks are present 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 the 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, the crystalline form N is a hydrate, such as a dihydrate. In a further embodiment, the X-ray diffraction pattern of the crystalline form N is as follows: Figure 3 In a further embodiment, the positions of the characteristic X-ray diffraction peaks of Form N are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0135] In one embodiment, the present disclosure relates to a crystalline form N of 7,8-dihydroxyflavone that is stable against crystal transformation.

[0136] The present disclosure relates to a method for preparing a crystalline form of 7,8-dihydroxyflavone, including method 1 to method 5:

[0137] Method 1: comprising the following steps: dissolving 7,8-dihydroxyflavone in a single solvent until the solvent is completely evaporated to obtain a solid;

[0138] Method 2: comprising the following steps: suspending 7,8-dihydroxyflavone in a single solvent or a binary solvent, and then centrifuging to obtain a solid;

[0139] Method 3: comprising the following steps: dissolving 7,8-dihydroxyflavone in a good solvent, adding the mixture dropwise to an anti-solvent, precipitating a solid, and centrifuging to obtain a solid;

[0140] Method 4: It comprises the following steps: dissolving 7,8-dihydroxyflavone in a good solvent, adding an anti-solvent dropwise, precipitating a solid and centrifuging to obtain a solid

[0141] Method 5: It comprises the following steps: suspending 7,8-dihydroxyflavone in an anti-solvent, adding a good solvent dropwise until the solid is dissolved, cooling to precipitate the solid, and then centrifuging to obtain a solid.

[0142] In one embodiment, the present disclosure relates to a method for preparing 7,8-dihydroxyflavone having at least one crystalline form P, especially pure crystalline form P. The method can be, for example:

[0143] In method 2, the single solvent is n-heptane, and the binary solvent is a combination of one of 4-methyl-2-pentanone, n-propanol, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, and butyl formate, and one of isopropyl acetate, n-heptane, toluene, isopropanol, 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;

[0144] And / or, in method 2, the volume ratio of the binary solvent is 1:5-1:10; more preferably, the volume ratio of the binary solvent is 1:10;

[0145] In method 2, the suspension temperature is 20-60°C; more preferably, the suspension temperature is 50°C.

[0146] In one embodiment, the present disclosure relates to a method for preparing 7,8-dihydroxyflavone having at least one crystalline form C, especially pure crystalline form C. The method can be, for example:

[0147] In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; more preferably, the single solvent is N,N-dimethylformamide;

[0148] And / or, in method 1, the volume mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g; further preferably, the volume mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 mL / g;

[0149] And / or, in method 1, the solid is precipitated by volatilizing the solvent;

[0150] 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;

[0151] 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;

[0152] And / or, in method 2, in the binary solvent, the volume ratio of the organic solvent to water is 1:5-1:10, 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; further preferably, in the binary solvent, the volume ratio of the organic solvent to water is 1:5;

[0153] 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, dichloromethane, and diethyl ether; more preferably, the good solvent is N,N-dimethylformamide, and the anti-solvent is water;

[0154] And / or, in method 3, the volume ratio of the good solvent to the anti-solvent is 1:1-1:10; more preferably, the volume ratio of the good solvent to the anti-solvent is 1:1;

[0155] 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;

[0156] And / or, in method 4, the volume ratio of the good solvent to the anti-solvent is 1:1-1:10; more preferably, the volume ratio of the good solvent to the anti-solvent is 1:1;

[0157] And / or, in method 5, the anti-solvent is water, and the good solvent is one of N,N-dimethylformamide, tetrahydrofuran, ethanol, and ethylene glycol methyl ether; more preferably, the anti-solvent is water, and the good solvent is N,N-dimethylformamide;

[0158] 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;

[0159] In method 1, the single solvent is one of isopropyl acetate and N,N-dimethylformamide; more preferably, the single solvent is N,N-dimethylformamide;

[0160] And / or, in method 1, the temperature of the precipitated solid is room temperature;

[0161] And / or, in method 2, the suspension temperature is 20-60°C; more preferably, the suspension temperature is 25°C;

[0162] And / or, in method 3, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0163] And / or, in method 4, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0164] And / or, in method 5, the cooling temperature is -15-4°C.

[0165] The present disclosure relates to a method for preparing 7,8-dihydroxyflavone characterized by at least one crystalline form N, especially pure crystalline form N. The method can be, for example:

[0166] In method 1, the single solvent is methanol;

[0167] And / or, in method 1, the volume mass ratio of the single solvent to 7,8-dihydroxyflavone is 5-500 mL / g; more preferably, the volume mass ratio of the single solvent to 7,8-dihydroxyflavone is 5 mL / g

[0168] And / or, in method 1, the solid is precipitated by volatilizing the solvent;

[0169] and / or, in method 2, the single solvent is methanol; the binary solvent is a combination of methanol and water;

[0170] And / or, in method 2, the volume ratio of methanol to water in the binary solvent is 1:5-1:10; more preferably, the volume ratio of methanol to water in the binary solvent is 1:5;

[0171] And / or, in method 3, the good solvent is ethanol, and the anti-solvent is one of methyl tert-butyl ether and toluene; more preferably, the anti-solvent is methyl tert-butyl ether;

[0172] And / or, in method 3, the volume ratio of the good solvent to the anti-solvent is 1:1-1:10; more preferably, the volume ratio of the good solvent to the anti-solvent is 1:1;

[0173] 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;

[0174] And / or, in method 4, the volume ratio of the good solvent to the anti-solvent is 1:1-1:10; more preferably, the volume ratio of the good solvent to the anti-solvent is 1:1;

[0175] And / or, in method 5, the anti-solvent 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 anti-solvent is toluene and the good solvent is ethanol;

[0176] 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;

[0177] and / or, in method 1, the single solvent is methanol;

[0178] And / or, in method 1, the temperature of the precipitated solid is room temperature;

[0179] And / or, in method 2, the suspension temperature is 20-60°C; more preferably, the suspension temperature is 50°C;

[0180] And / or, in method 3, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0181] And / or, in method 4, the dropping temperature is 15-50°C; more preferably, the dropping temperature is 25°C;

[0182] And / or, in method 5, the cooling temperature is -15-4°C; more preferably, the cooling temperature is 0°C.

[0183] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form A, wherein the crystalline form A is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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°; the crystalline form A is a hydrate. The X-ray diffraction pattern of the crystalline form A is as follows: Figure 19 The positions of the characteristic X-ray diffraction peaks of Form A are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0184] On the one hand, Form A will transform into Form N when fully dried, making it unable to exist for a long time under dry conditions; on the other hand, Form A will transform into mixed crystals with Form F when heated to 130°C, and will transform into mixed crystals with Form F and Form J when heated to 160°C.

[0185] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form B, wherein the crystalline form B is characterized by its X-ray diffraction pattern, characterized by the presence of 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°; the crystalline form B is an anhydrous form containing a small amount of adsorbed solvent. The X-ray diffraction pattern of the crystalline form B is as follows: Figure 20 The positions of the characteristic X-ray diffraction peaks of Form B are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0186] On the one hand, Form B will transform into Form C at room temperature, making it unable to exist for a long time at room temperature; on the other hand, when Form B is heated to 110°C, a small amount of characteristic peaks of Form J appear, and at 180°C it will transform into a mixed crystal containing Form F and Form J.

[0187] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form E, wherein the crystalline form E is characterized by its X-ray diffraction pattern, characterized by the presence of 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°; the crystalline form E is a hydrate or a dimethyl sulfoxide solvate. The X-ray diffraction pattern of the crystalline form E is as follows: Figure 21 The positions of the characteristic X-ray diffraction peaks of Form E are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0188] Form E will transform into Form N at room temperature.

[0189] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form F, wherein the crystalline form F is characterized by its X-ray diffraction pattern, characterized by the presence of 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°; the crystalline form F is an anhydrate containing a small amount of adsorbed solvent. The X-ray diffraction pattern of the crystalline form F is as follows: Figure 22The positions of the characteristic X-ray diffraction peaks of Form F are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0190] On the one hand, Form F will transform into Form B at room temperature, making it unable to exist for a long time at room temperature; on the other hand, Form F will transform into a mixed crystal of Form J and Form P when heated to 220°C.

[0191] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one Form G, wherein Form G is characterized by an X-ray diffraction pattern thereof, characterized by the presence of X-ray diffraction peaks at 2θ values ​​of about 11.6±0.2°, 18.5±0.2°, and 35.4±0.2°; Form G is a hydrate. The X-ray diffraction pattern of Form G is as follows: Figure 23 The positions of the characteristic X-ray diffraction peaks of Form G are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0192] Form G will transform into Form T with a small amount of Form J when heated to 140°C.

[0193] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one H crystalline form, wherein the crystalline form H is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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 the crystalline form H is as follows: Figure 24 The positions of the characteristic X-ray diffraction peaks of Form H are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0194] Crystal form H will transform into other crystal forms at room temperature and cannot exist at room temperature for a long time.

[0195] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form I, wherein the crystalline form I is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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 the crystalline form I is as follows: Figure 25 The positions of the characteristic X-ray diffraction peaks of Form I are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0196] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one Form J, wherein Form J is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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°; Form J is an anhydrate. The X-ray diffraction pattern of Form J is as follows: Figure 26 The positions of the characteristic X-ray diffraction peaks of Form J are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0197] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one K crystalline form, wherein the crystalline form K is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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°; the crystalline form K is a 1:1 dioxane solvate. The X-ray diffraction pattern of the crystalline form K is as follows: Figure 27 The positions of the characteristic X-ray diffraction peaks of Form K are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0198] Form K will transform into a mixed crystal of Form F and Form J when heated to 150°C and then cooled to room temperature.

[0199] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one L crystalline form, wherein the crystalline form L is characterized by its X-ray diffraction pattern, characterized by the presence of 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 the crystalline form L is as follows: Figure 28 The positions of the characteristic X-ray diffraction peaks of Form L are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0200] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form M, wherein the crystalline form M is characterized by its X-ray diffraction pattern, characterized by the presence of 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°; the crystalline form M is an acetone solvate. The X-ray diffraction pattern of the crystalline form M is as follows: Figure 29The positions of the characteristic X-ray diffraction peaks of Form M are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0201] Crystal form M will transform into crystal form C at room temperature and cannot exist at room temperature for a long time.

[0202] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one crystalline form O, wherein the crystalline form O is characterized by its X-ray diffraction pattern, characterized by the presence of 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°; the crystalline form O is an anhydrate or a chloroform solvate with a small amount of residual solvent. The X-ray diffraction pattern of the crystalline form O is as follows: Figure 30 The positions of the characteristic X-ray diffraction peaks of Form O are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0203] Crystal form O will transform into crystal form C at room temperature and cannot exist at room temperature for a long time.

[0204] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one Q crystalline form, wherein the crystalline form Q is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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 the crystalline form Q is as follows: Figure 31 The positions of the characteristic X-ray diffraction peaks of Form Q are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0205] Crystal form Q will transform into crystal form C at room temperature and cannot exist at room temperature for a long time.

[0206] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one R crystalline form, wherein the crystalline form R is characterized by an X-ray diffraction pattern thereof, characterized by the presence of an X-ray diffraction peak at a 2θ value of about ; the X-ray diffraction pattern of the crystalline form R is as follows Figure 32 The positions of the characteristic X-ray diffraction peaks of Form R are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0207] Form R can only be obtained by heating Form N to 100°C and cannot exist at room temperature for a long time.

[0208] In a comparative embodiment, the present disclosure provides 7,8-dihydroxyflavone having at least one S crystalline form, wherein the crystalline form S is characterized by an X-ray diffraction pattern thereof, characterized by the presence of 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 the crystalline form S is as follows: Figure 33 The positions of the characteristic X-ray diffraction peaks of Form S are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0209] Crystal form S will transform into crystal form C at room temperature and cannot exist at room temperature for a long time.

[0210] In a comparative embodiment, the present disclosure further provides 7,8-dihydroxyflavone having at least one T crystalline form, wherein the crystalline form T is 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°, 13.0±0.2°, 15.4±0.2°, and 23.8±0.2°; the X-ray diffraction pattern of the crystalline form T is as follows: Figure 34 The positions of the characteristic X-ray diffraction peaks of Form T are shown in Table 1 together with the positions of the characteristic X-ray diffraction peaks of other 7,8-dihydroxyflavone crystal forms.

[0211] Form T can only be obtained by heating Form G to 140°C and cannot exist at room temperature for a long time.

[0212] Table 1

[0213]

[0214] In one embodiment, the present 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.

[0215] In one embodiment, tablets were prepared according to a standard formulation method and found to be stable for six months under harsh conditions such as light, high temperature, and high humidity. The stability of Form P in tablets is not limited by the specific dosage form.

[0216] In one embodiment, tablets are prepared according to a standard formulation method, and it is found that Form P has better dissolution in the tablets.

[0217] In one embodiment, the present disclosure further provides a pharmaceutical composition comprising 7,8-dihydroxyflavone crystalline form C and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0218] In one embodiment, tablets were prepared according to a standard formulation method, and it was found that Form C in the tablets could be stable for 6 months under harsh conditions such as light, high temperature, and high humidity. The stability of Form C of 7,8-dihydroxyflavone in tablets is not limited by the specific dosage form.

[0219] In one embodiment, the present disclosure further provides a pharmaceutical composition comprising 7,8-dihydroxyflavone crystalline form N and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral solid dosage form.

[0220] In one embodiment, the present disclosure provides pharmaceutical compositions containing one or more polymorphs of 7,8-dihydroxyflavone described herein. In addition to the active ingredient, the pharmaceutical compositions of the present disclosure may also contain one or more excipients. Various excipients may be added to the composition to achieve different purposes.

[0221] Fillers add bulk to solid pharmaceutical compositions and can make pharmaceutical dosage forms containing the compositions easier for patients and caregivers to use. Fillers used in solid compositions include, for example, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrin, glucose, dibasic calcium phosphate dihydrate, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0222] Solid pharmaceutical compositions compressed into dosage forms such as tablets may include excipients, which function, among other things, to help bind the active ingredient to other excipients after compression. Binders for solid pharmaceutical compositions include povidone, gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, and starch.

[0223] The dissolution rate of a compressed solid pharmaceutical composition in a patient's stomach can be increased by adding a disintegrant. Disintegrants include sodium carboxymethyl starch, alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polycrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, and starch.

[0224] When a fractionated composition is compressed into a dosage form such as a tablet, the composition is subjected to pressure from the die and punch. Certain excipients and active ingredients have a tendency to adsorb to the punch and die surfaces, which can cause depressions and other surface irregularities in the product. Lubricants can be added to the composition to reduce adsorption and facilitate separation from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, palmitostearin, hydrogenated castor oil, hydrogenated vegetable oils, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0225] The solid dosage form of the pharmaceutical composition provided by the present disclosure can be, for example, tablets, powders, capsules, suppositories, sachets, tablets, lozenges, liquid syrups, suspensions, etc. In one embodiment, the dosage form of the present disclosure is a tablet.

[0226] In one aspect, the present disclosure also provides a method for treating diseases associated with abnormal tyrosine kinase receptor B (TrkB) signaling pathways, such as central nervous system damage, peripheral nerve damage, neurodegenerative diseases, psychiatric diseases, hereditary neurological dysfunction, ophthalmic diseases, metabolic diseases, pain, cardiovascular diseases, tumors, or other related diseases, comprising administering to a subject a crystalline form of 7,8-dihydroxyflavone disclosed herein and at least one pharmaceutically acceptable excipient. In one embodiment, the disease associated with abnormal TrkB signaling pathways is a disease caused by low expression or insufficient activation of TrkB. It is known in the art that 7,8-dihydroxyflavone can be used as a specific small molecule agonist of TrkB to activate the signaling pathway downstream of TrkB.

[0227] In one aspect, the disclosure provides a method for treating or preventing traumatic brain injury or aging-related cognitive decline, comprising administering the crystalline form of 7,8-dihydroxyflavone to a subject.

[0228] In one aspect, the present invention discloses 7,8-dihydroxyflavone crystalline form P, 7,8-dihydroxyflavone crystalline form C, or 7,8-dihydroxyflavone crystalline form N for use in treating or preventing traumatic brain injury or aging-related cognitive decline.

[0229] In one aspect, the present invention discloses 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 traumatic brain injury or aging-related cognitive decline. Those skilled in the art will appreciate that the peak intensity and / or peak conditions of X-ray powder diffraction may vary due to different experimental conditions. At the same time, due to the varying precision of the instruments, the measured 2θ values ​​may have an error of approximately ±0.2 degrees. The relative intensity of the peaks depends more on certain properties of the sample being measured, such as the size and purity of the crystals, than the position of the peaks. Therefore, the measured peak intensity may have a deviation of approximately ±20%. Despite experimental errors, instrument errors, and orientation preferences, those skilled in the art can still obtain sufficient information to identify each crystalline form from the X-ray powder diffraction data provided herein.

[0230] In the present disclosure, the expression "at least has one '#' crystal form" (wherein '#' is a letter) means that 7,8-dihydroxyflavone has at least a characteristic X-ray peak of the crystal form '#'.

[0231] In the present disclosure, "solvent volatilization method" refers to a crystallization method commonly used in the field of crystal formation, which is to continuously volatilize the solution so that the solution changes from an unsaturated state to a supersaturated state, thereby causing crystals to precipitate.

[0232] The above-mentioned preferred conditions can be arbitrarily combined without violating common knowledge in the art.

[0233] Unless otherwise stated, reagents and starting materials used in this disclosure are commercially available. Example

[0234] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0235] Test Method

[0236] Nuclear magnetic analysis (1H NMR)

[0237] 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, Germany).

[0238] X-ray powder diffraction (XRPD)

[0239] The solid samples obtained in the experiment were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 seconds. The tube voltage and current were 40 kV and 40 mA, respectively, and the sample pan was a zero-background sample pan.

[0240] Thermogravimetric analysis (TGA)

[0241] The thermogravimetric analyzer (TA Discovery 55, TA, US) was used. A 2-5 mg sample was placed in a equilibrated 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. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0242] Differential Scanning Calorimetry (DSC)

[0243] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0244] Dynamic Water Sorption Analysis (DVS)

[0245] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient mode with humidity changes from 50% to 95% to 0% to 50%, with each gradient increasing by 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes. After the test, the sample was subjected to XRPD analysis to confirm any changes in the solid form. The criteria are shown in Table 2:

[0246] Table 2

[0247]

[0248] Polarized light microscopy (PLM)

[0249] The polarizing microscope model is Nikon Ci-POL (Nikon, JPN). A small amount of sample is placed on a glass slide and the sample morphology is observed using a suitable lens.

[0250] Example 1 Preparation of Crystalline Form P of 7,8-Dihydroxyflavone

[0251] 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 suspension and stirring at 50°C for 7 days, the suspension was centrifuged and the solid was dried in vacuum at room temperature;

[0252] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°, There are diffraction peaks at 18.4±0.2°, 18.7±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°. Its XRPD pattern is as follows: Figure 1 shown.

[0253] By 1H NMR detection, no obvious residual solvent peak was found, indicating that the crystal form P of 7,8-dihydroxyflavone is not a solvate. Its 1H NMR spectrum is as follows Figure 12 shown.

[0254] The TGA test showed that the crystal form P of 7,8-dihydroxyflavone had no obvious weight loss, and its TGA spectrum was as follows: Figure 4 shown.

[0255] The DSC test showed that the crystal form P of 7,8-dihydroxyflavone had no endothermic signal corresponding to weight loss. Its DSC spectrum was as follows: Figure 4 shown.

[0256] According to DVS test, the dynamic moisture adsorption diagram of the crystal form P of 7,8-dihydroxyflavone shows that the weight gain is less than 0.1% in the relative humidity range of 0%-95%. Figure 5 shown.

[0257] PLM detection shows that the crystal form P of 7,8-dihydroxyflavone is fine particles with a particle size generally less than 20 μm. Its PLM spectrum is as follows: Figure 11 shown.

[0258] Example 2 Preparation of Crystalline Form C of 7,8-Dihydroxyflavone

[0259] Weigh approximately 20 mg of the starting material into an EP tube. Add a certain amount of solvent gradually at room temperature (~25°C). Stir and sonicate the solution until the solid is completely dissolved. Allow the resulting clear solution to stand open at room temperature until the solvent has completely or mostly evaporated, yielding a solid.

[0260] The XRPD detection showed that the X-ray powder diffraction patterns expressed in 2θ angles were 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°, 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°, 2 There are diffraction peaks at 7.0±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°. Its XRPD spectrum is as follows: Figure 2 shown.

[0261] By 1H NMR detection, no obvious residual solvent peak was found, indicating that the crystal form C of 7,8-dihydroxyflavone is not a solvate. Its 1H NMR spectrum is as follows Figure 15 shown.

[0262] According to TGA test, the weight loss of crystalline form C of 7,8-dihydroxyflavone at 150°C accounts for 3.7% of the weight before weight loss. The weight loss here is the weight of water in the hydrate crystal form. Its TGA spectrum is as follows: Figure 6 shown.

[0263] According to DSC detection, the crystal form C of 7,8-dihydroxyflavone has an endothermic signal corresponding to weight loss at 100℃ to 160℃ and a melting endothermic peak at 247℃. Its DSC spectrum is as follows: Figure 6shown.

[0264] According to DVS test, the dynamic moisture adsorption diagram of crystalline form C of 7,8-dihydroxyflavone shows a weight increase of less than 0.1% in the relative humidity range of 0%-95%. Figure 7 shown.

[0265] PLM detection showed that the crystal form C of 7,8-dihydroxyflavone was small particles with a particle size generally less than 5 μm. Its PLM spectrum is as follows: Figure 14 shown.

[0266] Example 3 Preparation of Crystalline Form N of 7,8-Dihydroxyflavone

[0267] 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of methanol until a suspension was formed. After suspension and stirring at 50°C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0268] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°. , 17.7±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. There are diffraction peaks at 2°, 32.4±0.2°, 35.0±0.2°, 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°. Its XRPD pattern is as follows: Figure 3 shown.

[0269] By 1H NMR detection, no obvious residual solvent peak was found, indicating that the crystal form N of 7,8-dihydroxyflavone is not a solvate. Its 1H NMR spectrum is as follows Figure 18 shown.

[0270] According to TGA test, the weight loss of crystalline form N of 7,8-dihydroxyflavone at 40℃ to 80℃ accounts for 6.3% of the weight before weight loss. The weight loss here is the weight of water in the hydrate crystal form. Its TGA spectrum is as follows: Figure 8 shown.

[0271] According to DSC detection, the crystal form N of 7,8-dihydroxyflavone has an endothermic peak corresponding to weight loss at 100℃, and exothermic signals at 136℃ and 169℃ respectively. Its DSC spectrum is as follows Figure 8 shown.

[0272] According to DVS test, the dynamic moisture adsorption diagram of the crystal form N of 7,8-dihydroxyflavone shows that the weight gain is less than 0.1% in the relative humidity range of 0%-95%. Figure 9 shown.

[0273] PLM detection showed that the crystal form N of 7,8-dihydroxyflavone was fine particles with a particle size generally less than 20 μm. Its PLM spectrum is as follows: Figure 17 shown.

[0274] Comparative Example 1 Preparation of Crystalline Form A of 7,8-Dihydroxyflavone

[0275] 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 dried under vacuum at room temperature;

[0276] XRPD detection shows that its X-ray powder diffraction, expressed in 2θ angles, has 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°. Its XRPD pattern is as follows: Figure 19 shown.

[0277] Comparative Example 2 Preparation of Crystal Form B of 7,8-Dihydroxyflavone

[0278] 40.0 mg of 7,8-dihydroxyflavone was added to 9.0 mL of ethyl formate until a suspension was formed. After suspension and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0279] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°, 1 0.3±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± There are diffraction peaks at 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°. Its XRPD pattern is as follows: Figure 20 shown.

[0280] Comparative Example 3 Preparation of Crystal Form E of 7,8-Dihydroxyflavone

[0281] Weigh approximately 20 mg of the starting material into 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. Allow the resulting clear solution to stand open at room temperature until the solvent is completely or mostly evaporated, yielding a solid.

[0282] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°. .2°, 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°, There are diffraction peaks at 30.7±0.2°, 31.8±0.2°, 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°. Its XRPD pattern is as follows: Figure 21 shown.

[0283] Comparative Example 4 Preparation of Crystal Form F of 7,8-Dihydroxyflavone

[0284] 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of acetonitrile until a suspension was formed. After suspending and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0285] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°. °, 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 22 shown.

[0286] Comparative Example 5 Preparation of Crystal Form G of 7,8-Dihydroxyflavone

[0287] Weigh 160 mg of 7,8-dihydroxyflavone and add 11 mL of ethylene glycol dimethyl ether dropwise at room temperature until the sample is completely dissolved. Take 1.3 mL of the solution and add it dropwise to 6.5 mL of water. Stir for 15 minutes to 1 hour, then centrifuge the precipitated solid and dry it in a vacuum oven at room temperature.

[0288] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles 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°, 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 23 shown.

[0289] Comparative Example 6 Preparation of Crystalline Form H of 7,8-Dihydroxyflavone

[0290] Weigh 160 mg of 7,8-dihydroxyflavone and add 11 mL of ethylene glycol dimethyl ether dropwise at room temperature until the sample is completely dissolved. Add 1.3 mL of the solution dropwise to 1.0 mL of n-heptane. Stir at room temperature for 15 minutes to 1 hour, centrifuge the precipitated solid, and dry it in a vacuum oven at room temperature.

[0291] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°, 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°, 31.0±0.2° have diffraction peaks, and its XRPD spectrum is as follows Figure 24 shown.

[0292] Comparative Example 7 Preparation of Crystalline Form I of 7,8-Dihydroxyflavone

[0293] Weigh 160 mg of 7,8-dihydroxyflavone and add 11 mL of ethylene glycol dimethyl ether dropwise at room temperature until the sample is completely dissolved. Add 5.0 mL of water dropwise to 1.3 mL of the solution. Stir at room temperature for 15 minutes to 1 hour, centrifuge the precipitated solid, and dry it in a vacuum oven at room temperature.

[0294] XRPD analysis showed that the X-ray powder diffraction pattern expressed in 2θ angles 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°. The XRPD pattern was as shown in FIG. Figure 25 shown.

[0295] Comparative Example 8 Preparation of Crystal Form J of 7,8-Dihydroxyflavone

[0296] 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of toluene until a suspension was formed. After suspending and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0297] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°, 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 26 shown.

[0298] Comparative Example 9 Preparation of Crystal Form K of 7,8-Dihydroxyflavone

[0299] 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 dried under vacuum at room temperature;

[0300] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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. There are diffraction peaks at 3±0.2°, 27.4±0.2°, 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°. Its XRPD spectrum is as follows: Figure 27 shown.

[0301] Comparative Example 10 Preparation of Crystal Form L of 7,8-Dihydroxyflavone

[0302] 20.0 mg of 7,8-dihydroxyflavone was added to 10.0 mL of methyl formate until a suspension was formed. After suspending and stirring at room temperature for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature;

[0303] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 28 shown.

[0304] Comparative Example 11 Preparation of Crystalline Form M of 7,8-Dihydroxyflavone

[0305] 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 dried under vacuum at room temperature;

[0306] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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 °, 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 29 shown.

[0307] Comparative Example 12 Preparation of Crystal Form O of 7,8-Dihydroxyflavone

[0308] 20.0 mg of 7,8-dihydroxyflavone was added to 1.0 mL of chloroform until a suspension was formed. After suspension and stirring at 50°C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0309] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles 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°, There are diffraction peaks at 20.4±0.2°, 20.7±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°. Its XRPD spectrum is as follows: Figure 30 shown.

[0310] Comparative Example 13 Preparation of Crystal Form Q of 7,8-Dihydroxyflavone

[0311] 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 suspension and stirring at 50°C for 7 days, the suspension was centrifuged and the solid was dried under vacuum at room temperature.

[0312] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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±0.2°, 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 31 shown.

[0313] Comparative Example 14 Preparation of Crystalline Form R of 7,8-Dihydroxyflavone

[0314] Form N was heated to 100°C in in-situ variable temperature XRPD to obtain

[0315] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles was 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°. °, 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°, 44.3±0.2° have diffraction peaks, and its XRPD spectrum is as follows Figure 32shown.

[0316] Comparative Example 15 Preparation of Crystal Form S of 7,8-Dihydroxyflavone

[0317] Weigh 160 mg of 7,8-dihydroxyflavone and add 11 mL of ethylene glycol dimethyl ether dropwise at room temperature until the sample is completely dissolved. Add 8.0 mL of butyl formate dropwise to 1.3 mL of the solution. Stir at room temperature for 15 minutes to 1 hour, centrifuge the precipitated solid, and dry it in a vacuum oven at room temperature.

[0318] XRPD detection shows that its X-ray powder diffraction, expressed in 2θ angles, has 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°. Its XRPD pattern is as follows: Figure 33 shown.

[0319] Comparative Example 16 Preparation of Crystal Form T of 7,8-Dihydroxyflavone

[0320] Form G was obtained by heating to 140°C in situ temperature-variable XRPD.

[0321] The XRPD detection showed that the X-ray powder diffraction pattern expressed in 2θ angles 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°, 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° have diffraction peaks, and their XRPD patterns are as follows: Figure 34 shown.

[0322] Tablet Preparation Example 1 Preparation of 7,8-dihydroxyflavone tablet dosage form

[0323] 80g of the API (the dihydroxyflavone crystalline form prepared in the present 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. 40g to 50g of purified water was added and wet granulated. The mixture was stirred for 8-10 minutes. After drying and granulation, 7g of sodium carboxymethyl starch and 1g of magnesium stearate were added. The materials were mixed, tableted, and demolded to obtain the desired tablets.

[0324] Effect Example 1 Stability of different crystalline forms of 7,8-dihydroxyflavone

[0325] The stability of different crystalline forms of 7,8-dihydroxyflavone was studied under high temperature (60°C), high humidity (25°C / 92.5%RH), light (25°C / 4500Lux), and accelerated (40°C / 75%RH) conditions. Samples were taken for XRPD characterization at 7 days and 15 days, respectively. The results are shown in Table 3. The XPRD test results are shown in Table 3. Figures 35-37 shown.

[0326] Table 3

[0327]

[0328]

[0329] Effect Example 2 Dynamic solubility of different crystalline forms of 7,8-dihydroxyflavone in three biological media (FaSSIF, FeSSIF and FaSSGF) and water.

[0330] Take 20 mg of different crystalline forms of 7,8-dihydroxyflavone and add them to 4.0 mL of biological medium or water, shake at a constant temperature of 37 ° C for 24 hours, take samples at 0.5 hours, 2 hours and 24 hours respectively, filter the sampled solution with a 0.22 μm water filter membrane, measure the signal peak area of ​​the solution by HPLC, and finally calculate the concentration of the compound in the solution based on the peak area, the HPLC standard curve of the raw material and the dilution multiple. In addition, take the 24-hour supernatant to test its pH value, and perform XRPD test on the remaining solid. The configuration of the biological medium is shown in Table 4. The experimental results are shown in Table 5, and the XPRD test results are shown in Table 5. Figures 38-40 shown.

[0331] Table 4

[0332]

[0333] Table 5

[0334]

[0335] Effect Example 3 Study on the Stability of 7,8-Dihydroxyflavone Crystalline Form P Tablets

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

[0337] Table 6

[0338]

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

[0340] The stability of 7,8-dihydroxyflavone Form C tablets was studied under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated (40°C / 75% RH) conditions. Samples were taken for XRPD characterization at 3 months and 6 months, respectively. The results are shown in Table 7.

[0341] Table 7

[0342]

[0343] Effect Example 5 Study on the Dissolution of 7,8-Dihydroxyflavone P Crystalline Tablets

[0344] The dissolution of 7,8-dihydroxyflavone P crystalline tablets was studied under different pH conditions. The results are shown in Table 8.

[0345] Table 8

[0346]

[0347] Effect Example 6 Study on the Dissolution of 7,8-Dihydroxyflavone C Crystalline Tablets

[0348] The dissolution of 7,8-dihydroxyflavone C crystalline tablets was studied under different pH conditions. The results are shown in Table 9.

[0349] Table 9

[0350]

[0351] Effect Example 7 Study on the Dissolution of 7,8-Dihydroxyflavone A Crystalline Tablets

[0352] The dissolution of 7,8-dihydroxyflavone A crystalline tablets was studied under different pH conditions. The results are shown in Table 10.

[0353] Table 10

[0354]

[0355] In summary, the present disclosure provides polymorphs of 7,8-dihydroxyflavone and a preparation method thereof. The polymorphs of 7,8-dihydroxyflavone provided by the present disclosure have more selective pharmaceutical economic value.

Claims

1. A crystalline form of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern substantially as shown in FIG1 .

2. A crystalline form of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern comprising characteristic peaks expressed in 2θ degrees at approximately 5.6±0.2°, 9.5±0.2°, 15.5±0.2°, 11.1±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°.

3. The crystalline form of 7,8-dihydroxyflavone according to claim 2, wherein The 7,8-dihydroxyflavone crystal form is a hydrate.

4. The crystalline form of 7,8-dihydroxyflavone according to claim 3, wherein the hydrate is a monohydrate.

5. A crystalline form of 7,8-dihydroxyflavone having an X-ray powder diffraction pattern substantially as shown in Figure 3.

6. The crystalline form of 7,8-dihydroxyflavone according to claim 5, wherein The 7,8-dihydroxyflavone crystal form is a hydrate.

7. The crystalline form of 7,8-dihydroxyflavone according to claim 6, wherein The hydrate is a dihydrate.

8. A pharmaceutical composition comprising (1) the crystalline form of 7,8-dihydroxyflavone according to claim 1, the crystalline form of 7,8-dihydroxyflavone according to any one of claims 2 to 4, and / or the crystalline form of 7,8-dihydroxyflavone according to any one of claims 5 to 7, and (2) at least one pharmaceutically acceptable excipient.

9. Use of the crystalline form of 7,8-dihydroxyflavone according to claim 1, the crystalline form of 7,8-dihydroxyflavone according to any one of claims 2-4 and / or the crystalline form of 7,8-dihydroxyflavone according to any one of claims 5-7, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating diseases associated with abnormal TrkB signaling pathway, wherein the diseases associated with abnormal TrkB signaling pathway are selected from the group consisting of central nervous system damage, peripheral nervous system damage, neurodegenerative diseases, psychiatric diseases, hereditary neurological dysfunction, ophthalmic diseases, metabolic diseases, pain, cardiovascular diseases and tumors.

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