Crystal form of a heterocyclic compound with cell necrosis inhibitory activity, its preparation method and uses

Abstract

This invention provides a heterocyclic compound with cell necrosis inhibitory activity, its crystal form, preparation method, and uses. The structure of this heterocyclic compound is shown in Formula 1, and its crystal forms include four salt forms and two co-crystal forms. The salt forms are hydrochloride crystal form B, hydrochloride crystal form D, hydrochloride crystal form K, and p-toluenesulfonate crystal form B, and its co-crystal forms are maleic acid co-crystal form C and gentian acid co-crystal form B. The heterocyclic compound provided by this invention has low hygroscopicity, good solubility, and good stability in its salt or co-crystal forms, making it suitable for preparing drugs for the prevention and / or treatment of diseases and / or symptoms related to cell necrosis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystal chemistry technology, specifically relating to the crystal form (especially the salt form and co-crystal form) of a heterocyclic compound with cell necrosis inhibitory activity, its preparation method and uses. Background Technology

[0002] Chinese invention patent application CN109111464A discloses a series of heterocyclic compounds with cell necrosis inhibitory activity, which can be used to treat and prevent systemic inflammatory diseases, tumors, metabolic diseases, and neurodegenerative diseases such as cerebral ischemia and stroke associated with cell necrosis. As one of the aforementioned heterocyclic compounds with cell necrosis inhibitory activity, compound 1 has the following structure.

[0003]

[0004] Although CN109111464A discloses compound 1 and its preparation technology, it does not provide a detailed description of its appearance or microstructure.

[0005] It is known that the polymorphism of a drug has significant implications for its physicochemical properties, bioavailability, and the quality and manufacturing process of the formulation. For example, the differences in physicochemical properties between different polymorphs of a drug can affect its stability, and different polymorphs of the same drug may have significantly different bioavailability. Therefore, comprehensive and systematic polymorphism screening in drug development to select the most suitable polymorph is an important and indispensable research aspect. Currently, no reports have been found regarding the polymorphism of compound 1 (including free base, salt, and cocrystal).

[0006] Therefore, it is necessary to study and screen the crystal forms of compound 1, and develop crystal forms that have good stability, high water solubility, low hygroscopicity, and are suitable for industrial production, so as to provide more and better options for the subsequent development of the drug. Summary of the Invention

[0007] The problem the invention aims to solve

[0008] In subsequent research, the inventors discovered that compound 1 exhibited poor metastable crystal stability and low water solubility, which negatively impacted the formulation process. To address these technical problems, this invention provides four salt forms and two eutectic forms of compound 1.

[0009] Solution for solving the problem

[0010] In a first aspect, the present invention provides a salt or co-crystal of compound 1 with an acid.

[0011]

[0012] The acid is selected from at least one of the following: hydrogen chloride, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, preferably hydrogen chloride, sulfuric acid, benzenesulfonic acid, and p-toluenesulfonic acid, more preferably hydrogen chloride and p-toluenesulfonic acid; or,

[0013] The acid is selected from at least one of the following: phosphoric acid, maleic acid, fumaric acid, malonic acid, citric acid, gentian acid, malic acid, tartaric acid, salicylic acid, and methanesulfonic acid, preferably phosphoric acid, maleic acid, fumaric acid, gentian acid, and tartaric acid, and more preferably maleic acid and gentian acid.

[0014] In a second aspect, the present invention provides a salt of compound 1 and an acid, wherein the salt is a salt of compound 1 and hydrogen chloride; preferably, the molar ratio of compound 1 to hydrogen chloride in the salt is 1:1; more preferably, the salt has crystal form B.

[0015] Furthermore, the X-ray powder diffraction (XRPD) pattern of crystal form B under Cu Kα radiation contains peaks at the following 2θ values: 5.6±0.2°, 17.0±0.2°, 17.2±0.2°, and 22.4±0.2°.

[0016] Preferably, the XRPD spectrum of crystal form B also includes peaks at the following 2θ values: 12.8±0.2°, 13.1±0.2°, 17.9±0.2° and 25.0±0.2°.

[0017] More preferably, the XRPD spectrum of the crystal form B also includes peaks at the following 2θ values: 22.0±0.2°, 22.7±0.2°, 23.5±0.2°, 24.8±0.2° and 27.5±0.2°.

[0018] More preferably, the XRPD spectrum of crystal form B is substantially the same as... Figure 2 Consistent.

[0019] Furthermore, the TGA spectrum of crystal form B shows a weight loss of 3%-4% before reaching 150±1℃.

[0020] Preferably, the TGA spectrum of crystal form B is substantially the same as... Figure 3 Consistent.

[0021] Furthermore, the DSC spectrum of crystal form B shows endothermic peaks at 56±1℃, 240±1℃, 252±1℃ and 277±1℃.

[0022] Preferably, the DSC spectrum of crystal form B is substantially the same as... Figure 3 Consistent.

[0023] Preferably, the crystal form B is amorphous.

[0024] Thirdly, the present invention provides a method for preparing the salt (particularly hydrochloride salt having crystal form B) described in the second aspect, which is selected from evaporation crystallization, gas-solid diffusion, gas-liquid diffusion, dissolution crystallization, suspension crystallization, cooling crystallization and polymer-induced crystallization.

[0025] Preferably, the solvent used in the evaporation crystallization method is an alkyl alcohol; more preferably, the alkyl alcohol is methanol.

[0026] Preferably, the temperature of the evaporation crystallization method is room temperature.

[0027] Preferably, the solvent used in the gas-solid diffusion method is an ether; more preferably, the ether is methyl tert-butyl ether.

[0028] Preferably, the temperature of the gas-solid diffusion method is room temperature.

[0029] Preferably, the good solvent used in the gas-liquid diffusion method is sulfoxide or a combination of chloroalkanes and alkyl alcohols, and the antisolvent used is an alkane, alkyl ketone, alkyl ester, or nitrile; more preferably, for the good solvent, the sulfoxide is dimethyl sulfoxide, and the combination of chloroalkanes and alkyl alcohols is a combination of dichloromethane and methanol; for the antisolvent, the alkane is n-heptane, the alkyl ketone is acetone, the alkyl ester is ethyl acetate, and the nitrile is acetonitrile.

[0030] Preferably, the temperature of the gas-liquid diffusion method is room temperature.

[0031] Preferably, the good solvent used in the solution-crystallization method is an alkyl alcohol, an amide, or a sulfoxide, and the antisolvent is an alkyl alcohol, an alkyl ketone, an alkyl ester, or an ether; more preferably, for the good solvent, the alkyl alcohol is methanol, the amide is N,N-dimethylformamide, and the sulfoxide is dimethyl sulfoxide; for the antisolvent, the alkyl alcohol is ethanol or isopropanol, the alkyl ketone is methyl isobutyl ketone, the alkyl ester is ethyl acetate or isopropyl acetate, and the ether is tetrahydrofuran or methyl tert-butyl ether; even more preferably, the volume ratio of the good solvent to the antisolvent used in the solution-crystallization method is 1:1 to 1:6 (e.g., 1:1, 1:3.2, 1:4, 1:6, etc.).

[0032] Preferably, the solvent used in the suspension crystallization method is an alkyl alcohol or a nitrile; more preferably, the alkyl alcohol is ethanol or isopropanol, and the nitrile is acetonitrile.

[0033] Preferably, the temperature of the suspension crystallization method is 25°C or 50°C.

[0034] Preferably, the solvent used in the cooling crystallization method is an alkyl alcohol; more preferably, the alkyl alcohol is ethanol.

[0035] Preferably, the starting temperature of the cooling crystallization method is 50°C, the ending temperature is 0°C, the cooling rate is 0.1°C / min, and the temperature is kept constant for 16 hours after the target temperature is reached.

[0036] Preferably, the polymer-induced crystallization method involves first dissolving the hydrochloride and a certain amount of polymer in a solvent, and then stirring to induce crystallization.

[0037] Preferably, the solvent used in the polymer-induced crystallization method is an alkyl alcohol, and more preferably, the alkyl alcohol is ethanol.

[0038] Preferably, the polymer used in the polymer-induced crystallization method is a polymer composed of polyvinylpyrrolidone-polyethylene glycol-hydroxypropyl methylcellulose (PVP K30:PEG4000:HPMC-EF) in a mass ratio of 1:1:1, and the content of the polymer used in the polymer-induced crystallization method is 10%.

[0039] Preferably, the temperature for the polymer-induced crystallization method is room temperature.

[0040] Fourthly, the present invention provides a salt of compound 1 and an acid, wherein the salt is a salt of compound 1 and hydrogen chloride; preferably, the molar ratio of compound 1 to hydrogen chloride in the salt is 1:1; more preferably, the salt has crystal form D.

[0041] Furthermore, the XRPD spectrum of the crystal form D under Cu Kα radiation contains peaks at the following 2θ values: 5.9±0.2°, 10.5±0.2°, and 15.5±0.2°.

[0042] Preferably, the XRPD spectrum of the crystal form D further includes peaks at the following 2θ values: 16.8±0.2°, 19.9±0.2°, and 21.2±0.2°.

[0043] More preferably, the XRPD spectrum of the crystal form D also includes peaks at the following 2θ values: 13.7±0.2°, 16.4±0.2°, 20.5±0.2° and 22.1±0.2°.

[0044] More preferably, the XRPD spectrum of the crystal form D is substantially the same as... Figure 15 Consistent.

[0045] Furthermore, the TGA spectrum of the crystal form D shows a weight loss of 3%-4% before reaching 140±1℃.

[0046] Preferably, the TGA spectrum of crystal form D is substantially the same as... Figure 16 Consistent.

[0047] Furthermore, the DSC spectrum of the crystal form D shows endothermic peaks at 143±1℃ and 191±1℃.

[0048] Preferably, the DSC spectrum of the crystal form D is substantially the same as... Figure 16 Consistent.

[0049] Preferably, the crystal form D is a monohydrate.

[0050] Fifthly, the present invention provides a method for preparing the salt (particularly hydrochloride salt having crystal form D) described in the fourth aspect, which is selected from evaporation crystallization, gas-solid diffusion, dissolution crystallization, suspension crystallization and cooling crystallization.

[0051] Preferably, the solvent used in the evaporation crystallization method is an alkyl alcohol or a combination of alkyl alcohol and water; more preferably, the alkyl alcohol is ethanol, and the combination of alkyl alcohol and water is a combination of ethanol and water.

[0052] Preferably, the temperature of the evaporation crystallization method is room temperature.

[0053] Preferably, the solvent used in the gas-solid diffusion method is water.

[0054] Preferably, the temperature of the gas-solid diffusion method is room temperature.

[0055] Preferably, the good solvent used in the solution-crystallization method is an alkyl alcohol, water, amide, or sulfoxide, and the antisolvent is an alkane, alkyl alcohol, alkyl ketone, or nitrile; more preferably, for the good solvent, the alkyl alcohol is methanol, the amide is N,N-dimethylformamide, and the sulfoxide is dimethyl sulfoxide; for the antisolvent, the alkane is n-heptane, the alkyl alcohol is ethanol or isopropanol, the alkyl ketone is acetone or butanone, and the nitrile is acetonitrile; even more preferably, the volume ratio of the good solvent to the antisolvent used in the solution-crystallization method is 1:3 to 1:6 (e.g., 1:3, 1:4, 1:6, etc.).

[0056] Preferably, the solvent used in the suspension crystallization method is a combination of chlorinated hydrocarbons, alkanes, alkyl ketones, alkyl esters, ethers, alkyl alcohols and water, alkyl ketones and water, ethers and water, nitriles and water, sulfoxides and alkyl esters, or sulfoxides and alkyl ketones; more preferably, the chlorinated hydrocarbon is dichloromethane, the alkane is n-heptane, the alkyl ketone is acetone or methyl isobutyl ketone, the alkyl ester is ethyl acetate or isopropyl acetate, the ether is 2-methyltetrahydrofuran or methyl tert-butyl ether, the combination of alkyl alcohol and water is ethanol and water, the combination of alkyl ketone and water is acetone and water, the combination of ether and water is tetrahydrofuran or 2-methyltetrahydrofuran and water, the combination of nitriles and water is acetonitrile and water, the combination of sulfoxides and alkyl esters is dimethyl sulfoxide and ethyl acetate, and the combination of sulfoxides and alkyl ketones is dimethyl sulfoxide and acetone.

[0057] Preferably, the temperature of the suspension crystallization method is 25°C or 50°C.

[0058] Preferably, the solvent used in the cooling crystallization method is a combination of nitrile and water; more preferably, the combination of nitrile and water is a combination of acetonitrile and water.

[0059] Preferably, the starting temperature of the cooling crystallization method is 50°C, the ending temperature is 0°C, the cooling rate is 0.1°C / min, and the temperature is kept constant for 16 hours after the target temperature is reached.

[0060] In a sixth aspect, the present invention provides a salt of compound 1 and an acid, wherein the salt is a salt of compound 1 and hydrogen chloride; preferably, the molar ratio of compound 1 to hydrogen chloride in the salt is 1:1; more preferably, the salt has crystal form K.

[0061] Furthermore, the XRPD spectrum of the crystal form K under Cu Kα radiation contains peaks at the following 2θ values: 18.2±0.2°, 18.9±0.2°, and 23.2±0.2°.

[0062] Preferably, the XRPD spectrum of the crystal form K also includes peaks at the following 2θ values: 11.2±0.2°, 28.6±0.2°, and 32.6±0.2°.

[0063] More preferably, the XRPD spectrum of the crystal form K also includes peaks at the following 2θ values: 14.3±0.2°, 20.2±0.2° and 27.9±0.2°.

[0064] More preferably, the XRPD spectrum of the crystal form K is substantially the same as... Figure 18 Consistent.

[0065] Furthermore, the TGA spectrum of the crystal form K showed no significant weight loss before 150±1℃.

[0066] Preferably, the TGA spectrum of the crystal form K is substantially the same as... Figure 19 Consistent.

[0067] Furthermore, the DSC spectrum of the crystal form K shows an endothermic peak at 251±1℃.

[0068] Preferably, the DSC spectrum of the crystal form K is substantially the same as... Figure 19 Consistent.

[0069] Preferably, the crystal form K is amorphous.

[0070] In a seventh aspect, the present invention provides a method for preparing the salt (particularly hydrochloride having crystal form K) described in the sixth aspect, which is selected from the solution-crystallization method.

[0071] Preferably, the good solvent used in the solution-crystallization method is sulfoxide, and the antisolvent is an alkyl ketone; more preferably, for the good solvent, the sulfoxide is dimethyl sulfoxide; for the antisolvent, the alkyl ketone is acetone; even more preferably, the volume ratio of the good solvent to the antisolvent used in the solution-crystallization method is 1:4.

[0072] In an eighth aspect, the present invention provides a salt of compound 1 and an acid, wherein the salt is a salt of compound 1 and p-toluenesulfonic acid; preferably, the molar ratio of compound 1 to p-toluenesulfonic acid in the salt is 1:1; more preferably, the salt has crystal form B.

[0073] Furthermore, the XRPD spectrum of crystal form B under Cu Kα radiation contains peaks at the following 2θ values: 5.3±0.2°, 16.3±0.2°, and 21.5±0.2°.

[0074] Preferably, the XRPD spectrum of crystal form B also includes peaks at the following 2θ values: 5.5±0.2°, 8.4±0.2°, 11.3±0.2° and 24.2±0.2°.

[0075] More preferably, the XRPD spectrum of crystal form B also includes peaks at the following 2θ values: 13.0±0.2°, 18.1±0.2°, 18.6±0.2°, 23.9±0.2° and 24.9±0.2°.

[0076] More preferably, the XRPD spectrum of crystal form B is substantially the same as... Figure 25 Consistent.

[0077] Furthermore, the TGA spectrum of crystal form B showed no significant weight loss before 200±1℃.

[0078] Preferably, the TGA spectrum of crystal form B is substantially the same as... Figure 26 Consistent.

[0079] Furthermore, the DSC spectrum of crystal form B shows an endothermic peak at 252±1℃.

[0080] Preferably, the DSC spectrum of crystal form B is substantially the same as... Figure 26 Consistent.

[0081] Preferably, the crystal form B is amorphous.

[0082] In a ninth aspect, the present invention provides a method for preparing the salt described in the eighth aspect (particularly p-toluenesulfonate having crystal form B), which is selected from the solution-crystallization method, comprising the following steps: suspending compound 1 in a solvent, adding p-toluenesulfonic acid and stirring to react, and then adding an antisolvent and continuing to stir to obtain the product.

[0083] Preferably, the ratio of compound 1 to solvent is 30-60 mg: 1 mL, and the temperature of the stirring reaction is 50°C.

[0084] Preferably, the volume ratio of the antisolvent to the solvent is 2 to 4:1, and more preferably 3:1.

[0085] Preferably, the solvent is a mixed solvent of chlorinated hydrocarbons and alkyl alcohols, more preferably a mixed solvent of dichloromethane and methanol, and even more preferably a mixed solvent of dichloromethane and methanol with a volume ratio of 5:1.

[0086] Preferably, the antisolvent is an alkyl ester; preferably, the alkyl ester is ethyl acetate.

[0087] In a tenth aspect, the present invention provides a cocrystal of compound 1 and an acid, wherein the cocrystal is a cocrystal of compound 1 and maleic acid; preferably, the molar ratio of compound 1 and maleic acid in the cocrystal is 1:1; more preferably, the cocrystal has crystal form C.

[0088] Furthermore, the XRPD spectrum of the crystal form C under Cu Kα radiation contains peaks at the following 2θ values: 6.6±0.2°, 13.3±0.2°, and 20.1±0.2°.

[0089] Preferably, the XRPD spectrum of crystal form C further includes peaks at the following 2θ values: 22.5±0.2°, 22.7±0.2°, and 25.5±0.2°.

[0090] More preferably, the XRPD spectrum of the crystal form C also includes peaks at the following 2θ values: 13.6±0.2°, 17.7±0.2°, 26.6±0.2° and 28.5±0.2°.

[0091] More preferably, the XRPD spectrum of crystal form C is substantially the same as... Figure 28 Consistent.

[0092] Furthermore, the TGA spectrum of the crystal form C showed no significant weight loss before 150±1℃.

[0093] Preferably, the TGA spectrum of crystal form C is substantially the same as... Figure 29 Consistent.

[0094] Furthermore, the DSC spectrum of the crystal form C shows an endothermic peak at 198±1℃.

[0095] Preferably, the DSC spectrum of the crystal form C is substantially the same as... Figure 29 Consistent.

[0096] Preferably, the crystal form C is the amorphous form.

[0097] In the eleventh aspect, the present invention provides a method for preparing the eutectic described in the tenth aspect (particularly a maleic acid eutectic with crystal form C), which is selected from the solution crystallization method, comprising the following steps: suspending compound 1 in a solvent, adding maleic acid and stirring to react, and then adding an antisolvent and continuing to stir to obtain the product.

[0098] Preferably, the ratio of compound 1 to solvent is 30-60 mg: 1 mL, and the temperature of the stirring reaction is 50°C.

[0099] Preferably, the volume ratio of the antisolvent to the solvent is 2 to 4:1, and more preferably 3:1.

[0100] Preferably, the solvent is a mixed solvent of chlorinated hydrocarbons and alkyl alcohols, more preferably a mixed solvent of dichloromethane and methanol, and even more preferably a mixed solvent of dichloromethane and methanol with a volume ratio of 5:1.

[0101] Preferably, the antisolvent is an alkyl ester; preferably, the alkyl ester is ethyl acetate.

[0102] In a twelfth aspect, the present invention provides a cocrystal of compound 1 and an acid, wherein the cocrystal is a cocrystal of compound 1 and gentic acid; preferably, the molar ratio of compound 1 and gentic acid in the cocrystal is 1:1; more preferably, the cocrystal has crystal form B.

[0103] Furthermore, the XRPD spectrum of crystal form B under Cu Kα radiation contains peaks at the following 2θ values: 7.0±0.2°, 17.6±0.2°, and 26.1±0.2°.

[0104] Preferably, the XRPD spectrum of crystal form B also includes peaks at the following 2θ values: 10.7±0.2°, 17.0±0.2°, and 18.7±0.2°.

[0105] More preferably, the XRPD spectrum of the crystal form B also includes peaks at the following 2θ values: 12.8±0.2°, 21.4±0.2°, 21.6±0.2° and 24.0±0.2°.

[0106] More preferably, the XRPD spectrum of crystal form B is substantially the same as... Figure 31 Consistent.

[0107] Furthermore, the TGA spectrum of crystal form B showed no significant weight loss before 200±1℃.

[0108] Preferably, the TGA spectrum of crystal form B is substantially the same as... Figure 32 Consistent.

[0109] Furthermore, the DSC spectrum of crystal form B shows an endothermic peak at 261±1℃.

[0110] Preferably, the DSC spectrum of crystal form B is substantially the same as... Figure 32 Consistent.

[0111] Preferably, the crystal form B is amorphous.

[0112] In a thirteenth aspect, the present invention provides a method for preparing the cocrystal described in the twelfth aspect (particularly a gentic acid cocrystal having crystal form B), which is selected from the suspension crystallization method and includes the following steps: suspending compound 1 in a solvent and adding gentic acid to stir and react.

[0113] Preferably, the ratio of compound 1 to solvent is 30-60 mg: 1 mL, and the temperature of the stirring reaction is 50°C.

[0114] Preferably, the solvent is a mixed solvent of chlorinated hydrocarbons and alkyl alcohols, more preferably a mixed solvent of dichloromethane and methanol, and even more preferably a mixed solvent of dichloromethane and methanol with a volume ratio of 5:1.

[0115] In a fourteenth aspect, the present invention provides a pharmaceutical composition comprising the above-described salt or cocrystal.

[0116] Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0117] Preferably, the pharmaceutically acceptable excipients include (but are not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odor-correcting agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, opacifiers, etc.

[0118] In a fifteenth aspect, the present invention provides the use of the above-described salt or cocrystal or pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of diseases and / or conditions associated with cell necrosis.

[0119] Preferably, the disease and / or condition includes systemic inflammatory diseases, tumors, metabolic diseases, and neurodegenerative diseases (such as cerebral ischemia, stroke, etc.).

[0120] The effects of the invention

[0121] The preparation process of the salt or cocrystal of compound 1 provided by this invention is simple and inexpensive. Moreover, its salt or cocrystal form has good stability under high temperature, high humidity and strong light conditions, and good solubility in pure water and biological media. It is of great value for the future optimization and development of this drug and has good prospects for drug development. Attached Figure Description

[0122] Figure 1 The SCXRD spectrum of the hydrochloride salt of compound 1 is shown.

[0123] Figure 2 The XRPD spectrum of crystal form B of the hydrochloride salt of compound 1 is shown.

[0124] Figure 3 TGA / DSC spectrum of crystal form B of the hydrochloride salt of compound 1;

[0125] Figure 4 Crystal form B of the hydrochloride salt of compound 1 1 H-NMR spectrum;

[0126] Figure 5 The XRPD spectrum of crystal form C of the hydrochloride salt of compound 1 is shown.

[0127] Figure 6 The XRPD spectrum of crystal form E of the hydrochloride salt of compound 1 is shown.

[0128] Figure 7 The XRPD spectrum of crystal form F of the hydrochloride salt of compound 1 is shown.

[0129] Figure 8 The XRPD spectrum of crystal form A of the hydrochloride salt of compound 1 is shown.

[0130] Figure 9The XRPD spectrum of crystal form G of the hydrochloride salt of compound 1 is shown.

[0131] Figure 10 The XRPD spectrum of crystal form I of the hydrochloride salt of compound 1 is shown.

[0132] Figure 11 The XRPD spectrum of the hydrochloride salt of compound 1, crystal form H;

[0133] Figure 12 This is a superimposed image of the XRPD spectra from the grinding and crystallization experiment.

[0134] Figure 13 The XRPD spectrum of crystal form J of the hydrochloride salt of compound 1 is shown.

[0135] Figure 14 The XRPD spectrum of crystal form L of the hydrochloride salt of compound 1 is shown.

[0136] Figure 15 The XRPD spectrum of crystal form D of the hydrochloride salt of compound 1 is shown.

[0137] Figure 16 TGA / DSC spectrum of crystal form D of the hydrochloride salt of compound 1;

[0138] Figure 17 Crystal form D of the hydrochloride salt of compound 1 1 H-NMR spectrum;

[0139] Figure 18 The XRPD spectrum of crystal form K of the hydrochloride salt of compound 1 is shown.

[0140] Figure 19 TGA / DSC spectrum of crystal form K of the hydrochloride salt of compound 1;

[0141] Figure 20 The crystal form K of the hydrochloride salt of compound 1 1 H-NMR spectrum;

[0142] Figure 21 The XRPD spectrum of the crystal form of compound 1 is shown.

[0143] Figure 22 The TGA spectrum of the crystal form of compound 1 is shown.

[0144] Figure 23 The DSC spectrum of the crystal form of compound 1 is shown.

[0145] Figure 24 The crystal form of compound 1 1 H-NMR spectrum;

[0146] Figure 25The XRPD spectrum of crystal form B of p-toluenesulfonate of compound 1 is shown.

[0147] Figure 26 The TGA / DSC spectrum of crystal form B of p-toluenesulfonate of compound 1 is shown.

[0148] Figure 27 The crystal form B of p-toluenesulfonate of compound 1 1 H-NMR spectrum;

[0149] Figure 28 The XRPD spectrum of maleic acid eutectic of compound 1 in crystal form C is shown.

[0150] Figure 29 The TGA / DSC spectrum of maleic acid eutectic of compound 1 in crystal form C is shown.

[0151] Figure 30 The maleic acid eutectic of compound 1 has crystal form C. 1 H-NMR spectrum;

[0152] Figure 31 The XRPD spectrum of gentianic acid cocrystal B of compound 1 is shown.

[0153] Figure 32 The TGA / DSC spectrum of gentianic acid cocrystal B of compound 1 is shown.

[0154] Figure 33 The crystal form B of the gentianic acid eutectic of compound 1 1 H-NMR spectrum;

[0155] Figure 34 The DVS spectrum of crystal form B of the hydrochloride salt of compound 1 is shown.

[0156] Figure 35 XRPD spectra of crystal form B of the hydrochloride salt of compound 1 before and after the DVS experiment;

[0157] Figure 36 The DVS spectrum of crystal form D of the hydrochloride salt of compound 1;

[0158] Figure 37 XRPD spectra of crystal form D of the hydrochloride salt of compound 1 before and after the DVS experiment;

[0159] Figure 38 The DVS spectrum of crystal form K of the hydrochloride salt of compound 1 is shown.

[0160] Figure 39 XRPD spectra of crystal form K of the hydrochloride salt of compound 1 before and after DVS experiment;

[0161] Figure 40The DVS spectrum of crystal form B of p-toluenesulfonate of compound 1 is shown.

[0162] Figure 41 XRPD spectra of p-toluenesulfonate B of compound 1 before and after DVS experiment;

[0163] Figure 42 The DVS spectrum of maleic acid eutectic of compound 1 in crystal form C;

[0164] Figure 43 XRPD spectra of maleic acid eutectic form C before and after DVS experiment for compound 1;

[0165] Figure 44 The DVS spectrum of gentianic acid cocrystal B of compound 1 is shown.

[0166] Figure 45 XRPD spectra of gentianic acid cocrystal B of compound 1 before and after DVS experiment. Detailed Implementation

[0167] Terminology Definition

[0168] As used herein, the term "substantially consistent with Figure…" for XRPD spectra means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the given XRPD spectrum of a certain crystal of Formula 1 are displayed. Variations in representative peak positions (2θ) and relative peak intensities are also taken into account. Peak positions may vary between different instruments and different samples, typically by up to 0.1° to 0.2°. Furthermore, relative peak intensities may also vary due to differences between instruments, as well as the degree of crystallinity, preferred orientation, the prepared sample, and other factors known to those skilled in the art.

[0169] As used herein, the phrase "substantially consistent with the figure…" for DSC or TGA spectra is also intended to cover variations known to those skilled in the art related to these analytical techniques. For well-defined peaks in DSC spectra, variations are typically as high as ±0.2 °C, and even greater (up to ±1 °C, or up to ±5 °C) for broad peaks. For mass loss in TGA spectra, depending on many factors such as sample preparation and instrumentation, the detected mass loss varies slightly between different instruments and different samples, typically by up to ±1%, or up to ±2%.

[0170] As used in this article, the terms “room temperature” or “normal temperature” refer to 10–30°C.

[0171] X-ray powder diffraction (XRPD)

[0172] XRPD spectra were acquired using a Bruker X-ray diffractometer, and the scanning parameters are shown in Table 1. During sample preparation, an appropriate amount of sample was placed on the sample tray and flattened using a spoon or glass slide to ensure a smooth and flat surface.

[0173] Table 1. XRPD Test Parameters

[0174]

[0175] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0176] TGA and DSC spectra were acquired on a TGA550 thermogravimetric analyzer and a DSC25 differential scanning calorimeter, respectively. The data were analyzed using the TRIOS software. Table 2 lists the test parameters.

[0177] Table 2. Test parameters for TGA and DSC

[0178] parameter TGA DSC model TA, Discovery TGA 550 TA, Discovery DSC 25 Sample tray Aluminum tray, open Aluminum disc, hanging holes Temperature range Ambient temperature -300℃ 25℃-300℃ Heating rate (°C / min) 10 10 Protective gas Nitrogen Nitrogen Flow rate (mL / min) 60 50

[0179] Dynamic moisture adsorption analysis (DVS)

[0180] The instrument used for dynamic moisture adsorption analysis was the Intrinsic DVS (Surface Measurement Systems, UK). The sample size was approximately 15–30 mg. The temperature of the test chamber was controlled between 25 ± 1 °C, and the relative humidity was increased from 0% to 90% and then decreased to 0% at a rate of 10% / h, with mass data recorded every 20 seconds. Table 3 lists the test parameters.

[0181] Table 3. DVS Test Parameters

[0182] instrument DVS Intrinsic temperature 25℃ Protective gas and flow rate N2, 200 mL / min dm / dt 0.002% / min Minimum dm / dt equilibrium time 10min Maximum balancing time 120min RH range 0%RH-90%RH-0%RH RH gradient 10% (0%RH-90%RH-0%RH)

[0183] Scanning electron microscope (SEM)

[0184] The samples were analyzed using Phenom Pure+. After gold sputtering, the samples were placed in the instrument for testing. Different magnifications were adjusted to obtain the sample crystal structure.

[0185] Polarizing microscope (PLM)

[0186] The sample was analyzed using a polarizing microscope, and the morphology of the crystal was obtained by adjusting different magnifications.

[0187] Hygroscopicity evaluation is classified as follows:

[0188] Hygroscopic classification ΔW% deliquescence Absorbs sufficient water to form a liquid Extremely hygroscopic ΔW% ≥ 15% Hygroscopic 15% > ΔW% ≥ 2% Slightly hygroscopic 2% > ΔW% ≥ 0.2% None or almost none hygroscopic ΔW% < 0.2%

[0189] Note: ΔW% represents the moisture gain of the test sample at 25±1℃ and 80±2%RH.

[0190] 1H NMR spectrum ( 1 H-NMR)

[0191] 1 H-NMR was performed using a Varian 400MHz instrument. Unless otherwise specified, samples were dissolved in DMSO-d6 and tested according to the parameters in Table 4. Data were analyzed using the MestReNova software.

[0192] Table 4. 1 H-NMR test parameters

[0193] instrument Varian frequency 400MHz Number of scans 4 temperature 295K Relaxation delay 1s

[0194] High-performance liquid chromatography (HPLC)

[0195] The solubility and stability tests in the experiment were conducted using an Agilent 1260 high-performance liquid chromatograph, and the analytical conditions are shown in Table 5.

[0196] Table 5. HPLC test conditions

[0197]

[0198] A list of Chinese names for solvent abbreviations

[0199] The solvent abbreviations and their corresponding Chinese names used in this article are shown in Table 6 below.

[0200] Table 6. Comparison of English Abbreviations and Chinese Names for Solvents

[0201] English abbreviations Chinese English abbreviations Chinese MeOH methanol Ethyl formate Ethyl formate EtOH ethanol EA Ethyl acetate NPA n-Propanol IPAC Isopropyl acetate IPA Isopropanol n-Hexane n-Hexane ACN Acetonitrile Heptane n-Heptane Acetone acetone THF Tetrahydrofuran MEK Butanone 2-MeTHF 2-Methyltetrahydrofuran MIBK Methyl isobutyl ketone 1,4-Dioxane 1,4-Dioxane DCM dichloromethane MTBE Methyl tert-butyl ether Toluene Toluene DMF N,N-Dimethylformamide AcOH Acetic acid DMSO Dimethyl sulfoxide <![CDATA[H2O]]> water

[0202] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0203] Example 1: Preparation and structural identification of the hydrochloride salt of compound 1

[0204] Compound 1 used in this invention is self-made and has the appearance of a white solid. The preparation method and structural confirmation data can be found in Example 19 and Table 1 of Chinese Invention Patent Application CN109111464A.

[0205] The preparation method of the hydrochloride salt of compound 1 used in this invention is as follows: 100g of compound 1 is added to dichloromethane (1.8L) and ethanol (0.9L), stirred until dissolved, and the temperature is controlled at 20-30℃. Concentrated hydrochloric acid (about 160g) is added dropwise to adjust the pH to 1-2. The mixture is stirred for 1 hour, concentrated under reduced pressure at 40℃ to 300-500mL, and ethanol (1L) is added to replace and concentrate twice to 300-500mL. The mixture is cooled to room temperature, filtered, and dried under reduced pressure at 40℃ to obtain crude hydrochloride salt of compound 1 (90g). The crude hydrochloride was added to dichloromethane (800 mL) and ethanol (450 mL), stirred until dissolved, heated to 35–40 °C, and ethanol (900 mL) was added dropwise. The temperature was then raised to 45–55 °C, stirred for 15–30 min, and ethanol (1.8 L) was added dropwise. The temperature was gradually lowered to 0–10 °C in stages, and stirred for 1–1.5 h. The mixture was filtered and dried under reduced pressure at 40 °C until the ethanol content was ≤3.0%, yielding 60 g of blocky crystals. The single crystal X-ray diffraction (SCXRD) spectrum is shown below. Figure 1 As shown. By Figure 1 It can be seen that the molar ratio of compound 1 and hydrogen chloride in hydrochloride is 1:1.

[0206] In addition, XRPD testing was performed on the hydrochloride salt of compound 1. The crystal form corresponding to the hydrochloride salt of compound 1 obtained in this embodiment was named hydrochloride crystal form B. The XRPD data for this crystal form are shown in Table 7, and the XRPD spectrum is shown in... Figure 2 As shown, the DSC / TGA spectrum is as follows: Figure 3 As shown, 1 H-NMR spectrum as follows Figure 4 As shown.

[0207] Table 7. XRPD data of hydrochloride crystal form B

[0208]

[0209] Depend on Figure 3 It can be seen that when heated to about 150°C, the sample loses 3.862% of its weight, and there are four melting endothermic peaks at about 56°C, 240°C, 252°C and 277°C (peak temperature).

[0210] Depend on Figure 4 It can be seen that there is residual ethanol in hydrochloride crystal form B.

[0211] Example 2: Crystal form screening of the hydrochloride salt of compound 1 (prepared according to the salt formation process in Example 1)

[0212] All hydrochloride crystal form screenings used 1:1 molar ratio hydrochloride as the initial raw material, and no further molar ratio characterization was performed on the new hydrochloride crystal forms during the screening process.

[0213] 1. Solubility Experiment

[0214] Before crystal form screening, the solubility of the hydrochloride sample of compound 1 was determined using 22 single solvents as shown in Table 8 at room temperature. Approximately 5 mg of the hydrochloride sample was weighed into a 4 mL sample vial, and the corresponding solvent was gradually added at room temperature (5 μL of solvent added each time) until the solid was completely dissolved. If the sample was not completely dissolved after adding 4 mL of solvent, no more solvent was added, and the solubility was recorded as <1.2 mg / mL. The approximate solubility range in the corresponding solvents was calculated based on the sample mass and the volume of solvent added, as shown in Table 8. This data served as the basis for solvent selection in the hydrochloride crystal form screening experiment.

[0215] Table 8. Preliminary results of hydrochloride solubility measurement (room temperature)

[0216] serial number solvent Solubility (mg / mL) serial number solvent Solubility (mg / mL) 1 MeOH 6 12 MTBE ＜1.2 2 EtOH ＜1.2 13 MIBK ＜1.2 3 NPA ＜1.2 14 MEK ＜1.2 4 IPA ＜1.2 15 Heptane ＜1.2 5 THF ＜1.2 16 Toluene ＜1.2 6 Acetone ＜1.2 17 DCM ＜1.2 7 EA ＜1.2 18 1,4-Dioxane ＜1.2 8 ACN ＜1.2 19 Ethyl formate ＜1.2 9 <![CDATA[H2O]]> ＞20 20 n-Hexane ＜1.2 10 2-MeTHF ＜1.2 21 DMF 7.98 11 IPAC ＜1.2 22 DMSO 78.23

[0217] "<1.2mg / mL" indicates that the sample was not completely dissolved.

[0218] As shown in Table 8, the solubility of hydrochloride in various solvents is less than 1.2 mg / mL.

[0219] 2. Preparation of the crystal form of hydrochloride

[0220] 2.1 Evaporation Crystallization Method

[0221] Specific procedures: Eight different solvents (methanol, ethanol, water, ethanol / water, acetone / water, acetonitrile / water, tetrahydrofuran / water, and dichloromethane / ethanol) were used to conduct different evaporation crystallization experiments. Approximately 5 mg of the hydrochloride sample of compound 1 was taken, and 0.5–4 mL of solvent was added. The resulting clear solution was allowed to evaporate slowly at room temperature. When the sample became turbid, it was filtered. The filtrate was allowed to evaporate slowly at room temperature, and the solid was collected and subjected to XRPD testing.

[0222] The results showed that under the above experimental conditions, a total of five hydrochloride crystal forms were prepared, namely crystal form B, crystal form C, and crystal form C. Figure 5 Crystal form D, crystal form E Figure 6 ) and crystal form F( Figure 7 ); whereby, at room temperature and with methanol as the solvent, hydrochloride crystal form B can be prepared; in ethanol, ethanol / water (V 乙醇 :V 水 Under the condition of using a solvent of 5:1, hydrochloride crystal form D can be prepared.

[0223] 2.2 Humidity Induction Method

[0224] Specific procedure: Take about 10 mg of the hydrochloride sample of compound 1, place it in 60% RH and 80% RH environments for 7 days respectively, collect the solid, and perform XRPD test.

[0225] The results showed that, under the above experimental conditions, two hydrochloride crystal forms were prepared, namely crystal form A (…). Figure 8 ) and crystal form G ( Figure 9 The hydrochloride sample can be prepared into hydrochloride crystal form G by placing it in a 60% RH environment for 7 days; and into hydrochloride crystal form A by placing it in an 80% RH environment for 7 days.

[0226] 2.3 Gas-solid diffusion method

[0227] Specific procedure: Take about 10 mg of the hydrochloride sample of compound 1, place it openly in a 30 mL bottle containing solvent, seal the bottle, and leave it at room temperature for 7 days. Collect the solid and perform XRPD test.

[0228] The results showed that under experimental conditions with seven different solvents (methanol, acetone, ethyl acetate, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, and water), four hydrochloride crystal forms were prepared, namely crystal form A, crystal form B, crystal form D, and crystal form I. Figure 10 ); wherein, at room temperature, hydrochloride crystal form B can be prepared with methyl tert-butyl ether as a solvent; and hydrochloride crystal form D can be prepared with water as a solvent.

[0229] 2.4 Gas-Liquid Diffusion Method

[0230] Specific procedure: Take a certain amount of the hydrochloride sample of compound 1 into a liquid chromatography vial, add a good solvent to dissolve it, place the vial open in a 30mL bottle containing the antisolvent, seal the bottle, and leave it at room temperature for 7 days. If solid precipitates, collect the solid and perform XRPD testing.

[0231] The results showed that under the experimental conditions of 6 different solvent combinations, a total of 1 hydrochloride crystal form, namely crystal form B, was prepared. Among them, dimethyl sulfoxide as a good solvent, in combination with acetone, ethyl acetate or acetonitrile as antisolvents, or dichloromethane / methanol as a good solvent, in combination with n-heptane as an antisolvent, could also prepare hydrochloride crystal form B.

[0232] 2.5 Dissolution Crystallization Method

[0233] Specific procedure: Take a certain amount of the hydrochloride sample of compound 1 in a glass bottle, add an appropriate amount of solvent to dissolve it, then slowly add the antisolvent, stir overnight, add ice to cool, and filter. If no solid precipitates, evaporate the solution at room temperature to obtain the solid, collect the solid, and perform XRPD testing.

[0234] The results showed that under experimental conditions of 25 different solvent combinations, a total of 5 hydrochloride crystal forms were prepared, namely crystal form A, crystal form B, crystal form C, crystal form D and crystal form H (see Figure 11 Hydrochloride crystal form B can be prepared by using methanol as a solvent in combination with tetrahydrofuran, methyl tert-butyl ether, or ethyl acetate as an antisolvent; or by using N,N-dimethylformamide as a solvent in combination with ethyl acetate as an antisolvent; or by using dimethyl sulfoxide as a solvent in combination with ethanol, isopropanol, methyl isobutyl ketone, or isopropyl acetate as an antisolvent. Hydrochloride crystal form D can also be prepared by using methanol as a solvent in combination with acetonitrile as an antisolvent; or by using water as a solvent in combination with ethanol, isopropanol, acetone, butanone, or acetonitrile as an antisolvent; or by using N,N-dimethylformamide as a solvent in combination with n-heptane as an antisolvent; or by using dimethyl sulfoxide as a solvent in combination with acetone as an antisolvent.

[0235] 2.6 Grinding and Crystallization Method

[0236] Specific procedure: Take a certain amount of the hydrochloride crystal form B of compound 1 into a mortar, add 0.01 mL of solvent, grind for 5 min, and then perform XRPD testing (see Table 9). Figure 12 .

[0237] Table 9. Results of grinding and crystal transformation experiments

[0238] solvent XRPD Results Reference (API) Crystal form B N / A amorphous <![CDATA[H2O]]> Crystallization of crystal form B deteriorates EtOH Crystallization of crystal form B deteriorates

[0239] "N / A" refers to grinding without the addition of any solvent.

[0240] 2.7 Suspension Crystallization Method

[0241] Specific procedure: Take about 30 mg of the hydrochloride sample of compound 1 in a glass bottle, add solvent to make a suspension, place it in a 25°C environment and stir for 3 days, filter, collect the solid and perform XRPD test.

[0242] The results showed that, under experimental conditions with 14 single solvents and 7 mixed solvents, a total of 5 hydrochloride crystal forms were prepared, namely crystal form B, crystal form D, crystal form G, crystal form I and crystal form J. Figure 13 ); Hydrochloride crystal form B can be prepared at 25℃ using ethanol, isopropanol, or acetonitrile as solvents; acetone, methyl isobutyl ketone, isopropyl acetate, methyl tert-butyl ether, 2-methyltetrahydrofuran, dichloromethane, and ethanol / water (V... 乙醇 :V 水 =10:1), acetone / water (V 丙酮 :V水 =10:1), acetonitrile / water (V 乙腈 :V 水 =10:1), tetrahydrofuran / water (V 四氢呋喃 :V 水 =10:1), 2-methyltetrahydrofuran / water (V 2-甲基四氢呋喃 :V 水 =10:1), ethyl acetate / dimethyl sulfoxide (V 乙酸乙酯 :V 二甲基亚砜 =10:1) or acetone / dimethyl sulfoxide (V 丙酮 :V 二甲基亚砜 Under the condition of using ethyl acetate or n-hexane as solvent, hydrochloride crystal form D can be prepared; under the condition of using ethyl acetate or n-hexane as solvent, hydrochloride crystal form G can be prepared; under the condition of using 1,4-dioxane as solvent, hydrochloride crystal form I can be prepared; under the condition of using tetrahydrofuran as solvent, hydrochloride crystal form J can be prepared.

[0243] The present invention further investigates the crystal form obtained by suspension crystallization at an ambient temperature of 50°C.

[0244] The results showed that under experimental conditions with 14 single solvents and 7 mixed solvents, a total of 5 hydrochloride crystal forms were prepared, namely crystal form B, crystal form D, crystal form G, crystal form I, and crystal form J. Among them, crystal form B could be prepared at 50℃ with ethanol, isopropanol, or acetonitrile as solvents. 乙醇 :V 水 =10:1), acetone / water (V 丙酮 :V 水 =10:1), acetonitrile / water (V 乙腈 :V 水 =10:1), tetrahydrofuran / water (V 四氢呋喃 :V 水 =10:1), 2-methyltetrahydrofuran / water (V 2-甲基四氢呋喃 :V 水 =10:1) or ethyl acetate / dimethyl sulfoxide (V 乙酸乙酯 :V 二甲基亚砜 Under conditions where acetone / dimethyl sulfoxide (V 10:1) is used as a solvent, hydrochloride crystal form D can be prepared; under conditions where n-hexane is used as a solvent, hydrochloride crystal form G can be prepared; under conditions where tetrahydrofuran or 1,4-dioxane is used as a solvent, hydrochloride crystal form I can be prepared; under ... I can be prepared; under conditions where acetone / dimethyl sulfoxide (V 10:1) is used as a solvent, hydrochloride crystal form D can be prepared 丙酮 :V 二甲基亚砜 Under the condition of using a solvent of 10:1, hydrochloride crystal form J can be prepared.

[0245] 2.8 Cooling Crystallization Method

[0246] Specific procedure: Add excess hydrochloride sample to the selected 1.5 mL solvent, dissolve it at 50 °C, filter any undissolved sample, then slowly cool to 0 °C at a rate of 0.1 °C / min, and maintain at 0 °C for 16 h. Observe whether any solid precipitates, collect the solid, and perform XRPD testing.

[0247] The results showed that under the experimental conditions of six different solvents (methanol, ethanol, tetrahydrofuran, dichloromethane / methanol, dichloromethane / ethanol, and acetonitrile / water), three hydrochloride crystal forms were prepared, namely crystal form A, crystal form B, and crystal form D. Among them, crystal form B could be prepared when ethanol was used as the solvent, and crystal form D could be prepared when acetonitrile / water was used as the solvent.

[0248] 2.9 Polymer-induced crystallization method

[0249] Specific procedures: Take about 30 mg of hydrochloride sample and a certain amount of polymer in a glass bottle, add 0.5 mL of solvent, stir at room temperature for 24 h, filter, collect the solid, dry at 50 °C, and perform XRPD test, see Table 10.

[0250] Table 10. Results of Polymer-Induced Crystallization Experiment

[0251]

[0252] Polymer A: PVP K30: PEG4000: HPMC-EF = 1:1:1 (equal mass)

[0253] Polymer B:MC:CC-Na:MCC = 1:1:1 (equal mass)

[0254] 2.10 Magnified Crystal Transformation Method

[0255] Specific procedure: Take about 2g of hydrochloride sample, add 40mL of DMSO, sonicate until the solid is completely dissolved, prepare a solution with a concentration of 50mg / mL, take 10mL of the solution into a 100mL round-bottom flask, slowly add 40mL of Acetone, stir for 0.5h to form a precipitate, continue stirring overnight to transform into mixed crystals, continue stirring overnight at 40℃ or room temperature to transform into crystal form K.

[0256] Weigh approximately 2g of the hydrochloride sample, add 40mL of DMSO, and sonicate until the solid is completely dissolved to prepare a 50mg / mL solution. Take 10mL of this solution and transfer it to a 100mL round-bottom flask. Slowly add 40mL of 2-MeTHF, stir for 0.5h until a precipitate forms, and stir overnight at 40℃ to obtain crystal form C. Then, dry the crystal in a 50℃ vacuum oven for one day. Subsequent testing revealed a change in XRPD, transforming it into crystal form L. Figure 14 ).

[0257] The crystal forms of the hydrochloride salt of compound 1 are summarized in Table 11.

[0258] Table 11. Summary of crystal forms of the hydrochloride salt of compound 1

[0259]

[0260] Example 3: Preparation of hydrochloride crystal form D

[0261] Take 400 mg of hydrochloride sample (prepared according to the salt formation process in Example 1), add it to 8 mL of DMSO, stir until dissolved, then add 40 mL of Acetone, stir for 5 min, add 2 mL of water, continue stirring at room temperature for 20 h, filter, rinse the filter cake with an appropriate amount of Acetone and water, and then dry in a vacuum drying oven at 30 °C for about 20 h to obtain the product. Perform XRPD testing, which is the hydrochloride crystal form D. The XRPD data of this crystal form is shown in Table 12, and the XRPD spectrum is shown in... Figure 15 As shown, the DSC / TGA spectrum is as follows: Figure 16 As shown, 1 H-NMR spectrum as follows Figure 17 As shown.

[0262] Table 12. XRPD data of hydrochloride crystal form D

[0263]

[0264] Depend on Figure 16 It can be seen that the sample lost 3.569% of its weight at RT-140℃ and 3.823% of its weight at 140-200℃, with two melting endothermic peaks at approximately 143℃ and 191℃ (peak temperatures). The moisture content test results showed a water content of 3.30%, which is basically consistent with the weight loss in the first stage of TGA. Therefore, it can be concluded that the hydrochloride crystal form D is a monohydrate.

[0265] Depend on Figure 17 It can be seen that there is no solvent residue in hydrochloride crystal form D.

[0266] Example 4: Preparation of hydrochloride crystal form K

[0267] Take 200 mg of hydrochloride sample (prepared according to the salt formation process in Example 1), add it to 4 mL of DMSO, stir until dissolved, then add 12 mL of Acetone, stir overnight at room temperature to obtain the product, perform XRPD testing, which is the hydrochloride crystal form K. The XRPD data of this crystal form are shown in Table 13, and the XRPD spectrum is as follows. Figure 18 As shown, the DSC / TGA spectrum is as follows: Figure 19 As shown, 1 H-NMR spectrum as follows Figure 20 As shown.

[0268] Table 13. XRPD data of hydrochloride crystal form K

[0269]

[0270] Depend on Figure 19 It can be seen that when heated to approximately 150°C, the sample shows no significant weight loss, and there is a melting endothermic peak at approximately 242°C (initial temperature) (peak temperature approximately 251°C). Based on the above data, the hydrochloride crystal form K is amorphous.

[0271] Depend on Figure 20 It can be seen that the residual acetone in the hydrochloride crystal form K is 0.17% and the residual DMSO is 0.49%, which are lower than the limit value for residual solvent.

[0272] Example 5: Competitive Pulping Experiment

[0273] Mix hydrochloride crystal forms A, B, C, H, K, and L in equal proportions, then add 1 mL of water or DMSO / Acetone (1:4) to each crystal form. Suspend and stir at room temperature for 0.5 h, 2 h, and 24 h, and then take samples to measure XRPD.

[0274] The results showed that after 24 hours of suspension and stirring in pure water, the above crystal forms almost completely transformed into crystal form D and a small amount of crystal form G; after 24 hours of suspension and stirring in anhydrous DMSO / Acetone (1:4), all crystal forms transformed into crystal form K; and after adding 0.1 mL of water to the DMSO / Acetone (1:4) system, all crystal forms eventually transformed into crystal form D after 3 days. Therefore, crystal form K is relatively stable in anhydrous systems, while crystal form D is relatively stable in aqueous systems.

[0275] Example 6: Water Activity Experiment

[0276] Weigh approximately 5 mg of hydrochloride crystal form D and crystal form K respectively, add 1 mL of water / acetone solution with different water activities to make the solution supersaturated, stir at 25℃, filter, and determine the XRPD of the solid. The results are shown in Table 14.

[0277] The results showed that after stirring in an aqueous system for 20 hours, all crystals had transformed into crystal form D; after stirring in acetone for 24 hours, the crystals were a mixture of crystal form D and crystal form K, but after 3 days, they transformed into crystal form K.

[0278] Table 14. Results of water activity test

[0279] serial number solvent Water / acetone (%), v / v Water activity Volume (mL) XRPD Results 1 Water / Acetone 0 0 1 Crystal form K 2 Water / Acetone 1 0.131 1 Crystal form D 3 Water / Acetone 3 0.323 1 Crystal form D 4 Water / Acetone 6 0.503 1 Crystal form D 5 Water / Acetone 15 0.720 1 Crystal form D

[0280] Example 7: Screening of different salt types or eutectic

[0281] 1. Preparation and characterization of free base

[0282] The hydrochloride salt was prepared into a free base for subsequent salt or eutectic screening experiments.

[0283] Approximately 6 g of the hydrochloride obtained in Example 1 was weighed into a 500 mL round-bottom flask and dissolved in 150 mL of a 1:1 ACN:H₂O mixed solvent. Under magnetic stirring, 15 mL of sodium bicarbonate solution (1.779 g NaHCO₃ dissolved in 15 mL of water, approximately 1.2 eq) was slowly added dropwise. A white solid precipitated during the addition. After the addition was complete, the mixture was reacted at room temperature under magnetic stirring for approximately 3 hours, followed by filtration to obtain 5.13 g of free alkali (yield 92%). The obtained solid was subjected to XRPD, TGA, DSC, and other tests. 1 HNMR characterization. XRPD results ( Figure 21 The results showed that the obtained solid crystal form differed from that of the raw material hydrochloride, exhibiting higher crystallinity; TGA results ( Figure 22 The results showed that the obtained solid had a weight loss of 0.177% before reaching 150±1℃; DSC results ( Figure 23 The obtained solid showed two endothermic peaks. The first endothermic peak had a melting point of 216.86℃, a peak temperature of 227.06℃, and an enthalpy of 15.512 J / g. The second endothermic peak had a melting point of 282.98℃, a peak temperature of 283.89℃, and an enthalpy of 111.09 J / g. 1 H-NMR results ( Figure 24 The results show that the obtained solid has a chemical shift compared to the hydrochloride salt, and there is no solvent residue, indicating that the obtained solid is a free alkali.

[0284] 2. Solubility Experiment

[0285] Before the salt form or co-crystal form screening, solubility experiments were conducted on the free base. Twenty single solvents and eleven mixed solvents shown in Table 15 were selected to roughly determine the solubility of the free base at room temperature. Approximately 5 mg of the free base sample was weighed into a 4 mL sample vial, and then the corresponding solvent was gradually added (10 μL of solvent was added each time) until the solid was completely dissolved; if the sample was still not completely dissolved after adding 4 mL of solvent, no more solvent was added, and the solubility was recorded as <1.2 mg / mL. The approximate solubility range in the corresponding solvent was calculated based on the mass of the sample and the volume of the added solvent, as shown in Table 15, and based on this data, the solvent selection in the salt form or co-crystal screening experiment was guided.

[0286] Table 15. Rough results of free base solubility (room temperature)

[0287] serial number solvent Solubility (mg / mL) serial number solvent Solubility (mg / mL) 1 MeOH <1.3 17 DCM 15.5<s<23.3 2 EtOH <1.2 18 1,4-Dioxane 1.2<s<1.6 3 NPA <1.2 19 Ethyl formate <1.2 4 IPA <1.4 20 DMF 12.6<s<16.9 5 THF <1.2 21 DCM:MeOH(5:1) 37.6<s<45.1 6 Acetone <1.2 22 DCM:MeOH(10:1) 30.9<s<34.4 7 EA <1.4 23 DCM:EtOH(5:1) 41<s<49.2 8 ACN <1.2 24 DCM:EtOH(10:1) 41.9<s<48.8 9 <![CDATA[H2O]]> <1.4 25 <![CDATA[THF:H2O(3:1)]]> 12.9<s<17.2 10 2-MeTHF <1.2 26 <![CDATA[THF:H2O(5:1)]]> 14.3<s<21.5 11 IPAC <1.2 27 <![CDATA[ACN:H2O(3:1)]]> 5.3<s<5.8 12 MTBE <1.3 28 <![CDATA[ACN:H2O(5:1)]]> 7.4<s<10.2 13 MIBK <1.2 29 <![CDATA[Acetone:H2O(3:1)]]> 6.6<s<7.3 14 MEK <1.3 30 <![CDATA[Acetone:H2O(5:1)]]> 2.4<s<5.6 15 Heptane <1.2 31 <![CDATA[AcOH:H2O(1:1)]]> 60<s<72 16 Toluene <1.2

[0288] "<1.2 mg / mL" indicates that the sample was not completely dissolved.

[0289] As can be seen from Table 15, the solubility of the free base in many single solvents was less than 1.2 mg / mL, while the solubility in the single solvent DCM was relatively moderate (15.5 < s < 23.3) and it was easy to dry; the solubility in anhydrous mixed solvents was good and basically the same, and DCM / MeOH was the most commonly used solvent combination; the solubility in water-containing mixed solvents (including organic solvent / water combinations (such as THF / H2O), organic acid / water combinations (AcOH / H₂O)) was good; therefore, finally, four solvents, DCM and the mixed solvents THF:H₂O (5:1), DCM:MeOH (5:1), and AcOH:H₂O (1:1), were selected as the solvents for the ligand reaction.

[0290] 3. Salt form or co-crystal form screening

[0291] Based on the solubility of the free base, it was selected to conduct salt / co-crystal screening with 13 ligands in a system of 4 solvents (DCM, THF:H₂O (5:1), DCM:MeOH (5:1), and AcOH:H₂O (1:1)). The specific operation steps are as follows:

[0292] Approximately 30 mg of the free base was weighed and added to the corresponding solvent, and then an appropriate amount of acid ligand was added at 0 °C. The molar ratio of the free base to the acid ligand was 1:1.2. The reaction was carried out overnight at 50 °C under magnetic stirring, the phenomenon was observed, and then it was cooled to room temperature and kept for 3 h, followed by filtration, centrifugation, and drying to obtain a solid, and the solid was characterized by XRPD, DSC, TGA, and 1 ¹H-NMR, and the specific results are shown in Table 16.

[0293] Table 16. Experimental conditions and results of salt or co-crystal screening

[0294]

[0295]

[0296]

[0297] Here, "with / without displacement" is relative to free alkali. 1 In terms of chemical shift in H-NMR.

[0298] The results in Table 16 show that the free base can be prepared with the above acid ligands in different solvent systems to obtain: sulfate, phosphate cocrystal, maleic acid cocrystal, fumaric acid cocrystal, malonic acid cocrystal, citric acid cocrystal, gentian acid cocrystal, malic acid cocrystal, tartaric acid cocrystal, salicylic acid cocrystal, methanesulfonate, methanesulfonic acid cocrystal, benzenesulfonate, and p-toluenesulfonate. Among them, maleic acid cocrystal type B, gentian acid cocrystal type B, and p-toluenesulfonate crystal type B contain one endothermic peak and are crystal-free. Therefore, these three crystal types are selected as the dominant salt type or cocrystal type of the free base.

[0299] 4. Scale-up experiments of dominant salt forms or eutectic forms

[0300] Based on the characterization results, scale-up experiments were conducted on maleic acid eutectic form B, gentianic acid eutectic form B, and p-toluenesulfonate crystalline form B. Approximately 400 mg of free base was weighed into a 50 mL round-bottom flask, and a DCM:MeOH (5:1) mixed solvent was added. 1.2 equivalents of acid ligand were weighed and added at 0 °C. The mixture was reacted overnight at 50 °C with magnetic stirring, then cooled to room temperature for 3 hours before filtration. The resulting solid samples were dried overnight at 50 °C and then characterized. The results are shown in Table 17.

[0301] Table 17. Scale-up experimental results of dominant salt type or eutectic type

[0302] ligands Solvent volume (mL) Phenomenon XRPD Results Maleic acid 10 Clarify, add 30mL EA, and it becomes white and cloudy. Maleic acid eutectic C Gentian acid 10 It was clear at first, but turned white and cloudy after stirring for about 1 hour. Gentian acid eutectic B p-Toluenesulfonic acid 10 Clarify, add 30mL EA, and it becomes white and cloudy. p-Toluenesulfonate crystal form B

[0303] Example 8: Preparation of p-toluenesulfonate crystal form B

[0304] Take 400 mg of compound 1, add 10 mL of DCM / MeOH (v / v = 5:1) mixed solution, disperse evenly, add 1.2 equivalents of p-toluenesulfonic acid ligand at 0 °C, react overnight at 50 °C with magnetic stirring, then cool to room temperature and maintain for 3 h, add 30 mL of EA, white turbidity is formed, filter, collect the filter cake, dry at 50 °C overnight to obtain the product, perform XRPD test, which is p-toluenesulfonate crystal form B. The XRPD data of this crystal form are shown in Table 18, and the XRPD spectrum is shown in... Figure 25 As shown, the DSC / TGA spectrum is as follows: Figure 26As shown, 1 H-NMR spectrum as follows Figure 27 As shown.

[0305] Table 18. XRPD data for p-toluenesulfonate crystal form B

[0306]

[0307] Depend on Figure 26 It can be seen that when heated to 200℃, the sample does not show significant weight loss, and there is a sharp melting endothermic peak at approximately 249℃ (initial temperature) (peak temperature approximately 252℃). Based on the above data, it can be concluded that p-toluenesulfonate crystal form B is the amorphous form.

[0308] Depend on Figure 27 It can be seen that the molar ratio of compound 1 and p-toluenesulfonic acid in p-toluenesulfonate crystal form B is 1:1.

[0309] Example 9: Preparation method of maleic acid eutectic C

[0310] Take 400 mg of compound 1, add 10 mL of DCM / MeOH (v / v = 5:1) mixed solution, disperse evenly, add 1.2 equivalents of maleic acid ligand, react overnight at 50 °C with magnetic stirring, then cool to room temperature and maintain for 3 h, add 30 mL of EA, the mixture becomes white and turbid, filter, collect the filter cake, dry at 50 °C overnight to obtain the product, and proceed with... 1 H-NMR testing revealed that this is the maleic acid eutectic form C. The XRPD data for this crystal form are shown in Table 19, and the XRPD spectrum is as follows: Figure 28 As shown, the DSC / TGA spectrum is as follows: Figure 29 As shown, 1 H-NMR spectrum as follows Figure 30 As shown.

[0311] Table 19. XRPD data of maleic acid eutectic C

[0312]

[0313] Depend on Figure 29 It can be seen that when heated to approximately 150℃, the sample shows no significant weight loss, and there is a melting endothermic peak at approximately 193℃ (initial temperature) (peak temperature approximately 198℃). Based on the above data, maleic acid eutectic form C is amorphous.

[0314] Depend on Figure 30 It can be seen that the molar ratio of compound 1 and maleic acid in maleic acid eutectic C is 1:1.

[0315] Example 10: Preparation of gentianic acid eutectic form B

[0316] Take 400 mg of compound 1, add 10 mL of DCM / MeOH (v / v = 5:1) mixed solution, disperse evenly, add 1.2 equivalents of gentic acid ligand, react overnight at 50 °C with magnetic stirring, then cool to room temperature and maintain for 3 h. The mixture becomes white and turbid, filter, collect the filter cake, dry at 50 °C overnight to obtain the product, and perform XRPD testing, which identifies it as gentic acid eutectic form B. The XRPD data for this crystal form are shown in Table 20, and the XRPD spectrum is shown below. Figure 31 As shown, the DSC / TGA spectrum is as follows: Figure 32 As shown, 1 H-NMR spectrum as follows Figure 33 As shown.

[0317] Table 20. XRPD data of gentianic acid eutectic B

[0318]

[0319] Depend on Figure 32 It can be seen that when heated to approximately 200℃, the sample showed no significant weight loss, and there was a melting endothermic peak at approximately 259℃ (initial temperature) (peak temperature approximately 261℃). Based on the above data, gentianic acid eutectic B is an amorphous form.

[0320] Depend on Figure 33 It can be seen that the molar ratio of compound 1 and gentic acid in gentic acid eutectic B is 1:1.

[0321] Example 11: Hygroscopicity Test

[0322] The hygroscopicity of the samples was determined using a dynamic moisture adsorption (DVS) instrument. The weight gain due to moisture absorption was measured within the range of 0% RH (relative humidity) to 80% RH. XRPD tests were performed on the crystalline samples before and after the DVS experiment. The experimental results are shown in [Figure number missing]. Figures 34-45 The test results are shown in Table 21.

[0323] Table 21. Results of Hygroscopicity Test

[0324] sample Moisture absorption and weight gain / % Hygroscopic solid crystal form Hydrochloride crystal form B 5.604 Hygroscopic Crystal form change Hydrochloride crystal form D 0.3427 Slightly hygroscopic Crystal form unchanged Hydrochloride crystal form K 1.073 Slightly hygroscopic Crystal form unchanged p-Toluenesulfonate crystal form B 0.765 Slightly hygroscopic Crystal form unchanged Maleic acid eutectic C 0.6135 Slightly hygroscopic Crystal form unchanged Gentian acid eutectic B 0.945 Slightly hygroscopic Crystal form unchanged

[0325] As shown in Table 21, according to the definition criteria for hygroscopic weight gain, hydrochloride crystal form B is hygroscopic under the test conditions, while hydrochloride crystal forms D, K, p-toluenesulfonate crystal form B, maleic acid eutectic form C, and gentic acid eutectic form B are slightly hygroscopic under the test conditions. This indicates that hydrochloride crystal forms D, K, p-toluenesulfonate crystal form B, maleic acid eutectic form C, and gentic acid eutectic form B are not only not easily deliquescent due to high humidity, but also do not undergo crystal transformation.

[0326] Example 12: Stability Test

[0327] Take appropriate amounts of samples and place them for 7 days under the following conditions: 60℃ (closed), 25℃ / 60%RH (open), and 40℃ / 75%RH (open), respectively, with a light intensity of 1.2×10⁻⁶. 6 lux . The samples were placed under closed-cell conditions for 10 days, and then samples were taken on the 7th or 10th day. The purity of the samples was detected by HPLC, and the crystal form of the samples was detected by XRPD. The test conditions and test results are shown in Table 22.

[0328] Table 22. Stability Test Results

[0329]

[0330] Table 22 shows that under high temperature of 60℃ (closed), 25℃ / 60%RH (open), 40℃ / 75%RH (open) and light intensity of 1.2×10⁻⁶, the following conditions were observed: 6 lux . After being placed under h (closed) conditions for 7 or 10 days, the purity and crystal form of hydrochloride crystal form D, hydrochloride crystal form K, p-toluenesulfonate crystal form B, maleic acid co-crystal form C, and gentic acid co-crystal form B showed no significant changes. Moreover, compared with hydrochloride crystal form B, hydrochloride crystal form D, hydrochloride crystal form K, p-toluenesulfonate crystal form B, maleic acid co-crystal form C, and gentic acid co-crystal form B exhibited relatively better physicochemical stability and were suitable for pharmaceutical use.

[0331] Example 13: Solubility Test

[0332] Add 10–20 mg of sample to a sample vial, and add 1–2 mL of water or biological solvent (SGF, FaSSIF, and FeSSIF) to make the solution supersaturated. Shake in a constant temperature bath at 37°C for 24 h at a shaking speed of 1000 rpm. Take samples at 0.5 h, 2 h, and 24 h. Filter an appropriate amount of suspension each time, determine the pH value of the filtrate, determine its solubility by HPLC, and perform XRPD testing on the solid sample. The test results are shown in Table 23.

[0333] Table 23. Solubility Test Results

[0334]

[0335] Note: FaSSIF represents fasting simulated intestinal fluid, FeSSIF represents satiated simulated intestinal fluid, and SGF represents simulated gastric fluid.

[0336] As shown in Table 23, compared with gentianic acid eutectic form B, hydrochloride crystal forms B, D, and K, p-toluenesulfonate crystal form B, and maleic acid eutectic form C have relatively better water solubility. Gentianic acid eutectic form B maintains its crystal form unchanged in FaSSIF, FeSSIF, SGF, and water. The solubility difference between hydrochloride crystal forms B and K in SGF and water is small, but in SGF, the crystal form will transform into hydrochloride crystal form D within 2 hours. Hydrochloride crystal form D has a lower solubility than hydrochloride crystal forms B and K only in SGF within 2 hours, but the solubility difference between these three hydrochloride crystal forms in FaSSIF and FeSSIF is small, and the crystal form of hydrochloride crystal form D remains unchanged in SGF.

[0337] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. Salts or eutectic forms of compound 1 with an acid, The acid is selected from at least one of the following: hydrogen chloride, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, preferably hydrogen chloride, sulfuric acid, benzenesulfonic acid, and p-toluenesulfonic acid, more preferably hydrogen chloride and p-toluenesulfonic acid; or, The acid is selected from at least one of the following: phosphoric acid, maleic acid, fumaric acid, malonic acid, citric acid, gentian acid, malic acid, tartaric acid, salicylic acid, and methanesulfonic acid, preferably phosphoric acid, maleic acid, fumaric acid, gentian acid, and tartaric acid, and more preferably maleic acid and gentian acid.

2. The salt or eutectic according to claim 1, characterized in that, The salt is a salt of compound 1 and hydrogen chloride; Preferably, the molar ratio of compound 1 in the salt to hydrogen chloride is 1:1; More preferably, the salt has crystal form B, which meets at least one of the following conditions: 1) The X-ray powder diffraction (XRPD) pattern of crystal form B under Cu Kα radiation contains peaks at the following 2θ values: 5.6±0.2°, 17.0±0.2°, 17.2±0.2° and 22.4±0.2°; Preferably, the XRPD spectrum of crystal form B further includes peaks located at the following 2θ values: 12.8±0.2°, 13.1±0.2°, 17.9±0.2°, and 25.0±0.2°; More preferably, the XRPD spectrum of the crystal form B also includes peaks located at the following 2θ values: 22.0±0.2°, 22.7±0.2°, 23.5±0.2°, 24.8±0.2° and 27.5±0.2°; More preferably, the XRPD spectrum of crystal form B is substantially consistent with that in Figure 2; 2) The TGA spectrum of crystal form B shows a weight loss of 3%-4% before reaching 150±1℃; Preferably, the TGA spectrum of crystal form B is substantially consistent with that in Figure 3; 3) The DSC spectrum of the crystal form B shows endothermic peaks at 56±1℃, 240±1℃, 252±1℃ and 277±1℃; Preferably, the DSC spectrum of crystal form B is substantially consistent with that in Figure 3.

3. The salt or eutectic according to claim 2, characterized in that, The salt has a crystal form D, which meets at least one of the following conditions: 1) The XRPD spectrum of the crystal form D under Cu Kα radiation contains peaks at the following 2θ values: 5.9±0.2°, 10.5±0.2° and 15.5±0.2°; Preferably, the XRPD spectrum of the crystal form D further includes peaks located at the following 2θ values: 16.8±0.2°, 19.9±0.2°, and 21.2±0.2°; More preferably, the XRPD spectrum of the crystal form D also includes peaks located at the following 2θ values: 13.7±0.2°, 16.4±0.2°, 20.5±0.2° and 22.1±0.2°; More preferably, the XRPD spectrum of the crystal form D is substantially consistent with that in Figure 15; 2) The TGA spectrum of crystal form D shows a weight loss of 3%-4% before reaching 140±1℃; Preferably, the TGA spectrum of the crystal form D is substantially consistent with that in Figure 16; 3) The DSC spectrum of the crystal form D shows endothermic peaks at 143±1℃ and 191±1℃; Preferably, the DSC spectrum of the crystal form D is substantially consistent with that in Figure 16.

4. The salt or eutectic according to claim 2, characterized in that, The salt has a crystal form K, which meets at least one of the following conditions: 1) The XRPD spectrum of the crystal form K under Cu Kα radiation contains peaks at the following 2θ values: 18.2±0.2°, 18.9±0.2° and 23.2±0.2°; Preferably, the XRPD spectrum of the crystal form K further includes peaks located at the following 2θ values: 11.2±0.2°, 28.6±0.2°, and 32.6±0.2°; More preferably, the XRPD spectrum of the crystal form K also includes peaks located at the following 2θ values: 14.3±0.2°, 20.2±0.2° and 27.9±0.2°; More preferably, the XRPD spectrum of the crystal form K is substantially consistent with that in Figure 18; 2) The TGA spectrum of the crystal form K shows no significant weight loss before 150±1℃; Preferably, the TGA spectrum of the crystal form K is substantially consistent with that in Figure 19; 3) The DSC spectrum of the crystal form K shows an endothermic peak at 251±1℃; Preferably, the DSC spectrum of the crystal form K is substantially consistent with that in Figure 19.

5. The salt or eutectic according to claim 1, characterized in that, The salt is a salt of compound 1 and p-toluenesulfonic acid; Preferably, the molar ratio of compound 1 in the salt to p-toluenesulfonic acid is 1:1; More preferably, the salt has crystal form B, which meets at least one of the following conditions: 1) The XRPD spectrum of crystal form B under Cu Kα radiation contains peaks at the following 2θ values: 5.3±0.2°, 16.3±0.2° and 21.5±0.2°; Preferably, the XRPD spectrum of crystal form B further includes peaks located at the following 2θ values: 5.5±0.2°, 8.4±0.2°, 11.3±0.2°, and 24.2±0.2°; More preferably, the XRPD spectrum of the crystal form B also includes peaks located at the following 2θ values: 13.0±0.2°, 18.1±0.2°, 18.6±0.2°, 23.9±0.2° and 24.9±0.2°; More preferably, the XRPD spectrum of crystal form B is substantially consistent with that in Figure 25; 2) The TGA spectrum of crystal form B shows no significant weight loss before 200±1℃; Preferably, the TGA spectrum of crystal form B is substantially consistent with that in Figure 26; 3) The DSC spectrum of crystal form B shows an endothermic peak at 252±1℃; Preferably, the DSC spectrum of crystal form B is substantially consistent with that in Figure 26.

6. The salt or eutectic according to claim 1, characterized in that, The co-crystal is a co-crystal of compound 1 and maleic acid; Preferably, the molar ratio of compound 1 to maleic acid in the eutectic is 1:1; More preferably, the eutectic has crystal form C, which meets at least one of the following conditions: 1) The XRPD spectrum of the crystal form C under Cu Kα radiation contains peaks at the following 2θ values: 6.6±0.2°, 13.3±0.2° and 20.1±0.2°; Preferably, the XRPD spectrum of crystal form C further includes peaks located at the following 2θ values: 22.5±0.2°, 22.7±0.2°, and 25.5±0.2°; More preferably, the XRPD spectrum of the crystal form C also includes peaks located at the following 2θ values: 13.6±0.2°, 17.7±0.2°, 26.6±0.2° and 28.5±0.2°; More preferably, the XRPD spectrum of crystal form C is substantially consistent with that in Figure 28; 2) The TGA spectrum of the crystal form C shows no significant weight loss before 150±1℃; Preferably, the TGA spectrum of crystal form C is substantially consistent with that in Figure 29; 3) The DSC spectrum of the crystal form C shows an endothermic peak at 198±1℃; Preferably, the DSC spectrum of the crystal form C is substantially consistent with that in Figure 29.

7. The salt or eutectic according to claim 1, characterized in that, The co-crystal is a co-crystal of compound 1 and gentianic acid; Preferably, the molar ratio of compound 1 to gentic acid in the eutectic is 1:1; More preferably, the eutectic has crystal form B, which meets at least one of the following conditions: 1) The XRPD spectrum of crystal form B under Cu Kα radiation contains peaks at the following 2θ values: 7.0±0.2°, 17.6±0.2° and 26.1±0.2°; Preferably, the XRPD spectrum of crystal form B further includes peaks located at the following 2θ values: 10.7±0.2°, 17.0±0.2°, and 18.7±0.2°; More preferably, the XRPD spectrum of the crystal form B also includes peaks located at the following 2θ values: 12.8±0.2°, 21.4±0.2°, 21.6±0.2° and 24.0±0.2°; More preferably, the XRPD spectrum of crystal form B is substantially consistent with that in Figure 31; 2) The TGA spectrum of crystal form B shows no significant weight loss before 200±1℃; Preferably, the TGA spectrum of crystal form B is substantially consistent with that in Figure 32; 3) The DSC spectrum of crystal form B shows an endothermic peak at 261±1℃; Preferably, the DSC spectrum of crystal form B is substantially consistent with that in Figure 32.

8. A pharmaceutical composition comprising a salt or cocrystal of compound 1 according to any one of claims 1-7; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

9. A method for preparing a salt or eutectic according to claim 2, wherein the method is selected from evaporation crystallization, gas-solid diffusion, gas-liquid diffusion, dissolution crystallization, suspension crystallization, cooling crystallization, and polymer-induced crystallization.

10. A method for preparing a salt or eutectic according to claim 3, wherein the method is selected from evaporation crystallization, gas-solid diffusion, dissolution crystallization, suspension crystallization, and cooling crystallization.

11. A method for preparing a salt or eutectic according to claim 4, wherein the salt is selected from the solution-crystallization method.

12. A method for preparing a salt or eutectic according to claim 5, wherein the method is selected from the solution-crystallization method.

13. A method for preparing a salt or eutectic according to claim 6, wherein the salt is selected from the solution-crystallization method.

14. A method for preparing a salt or eutectic according to claim 7, wherein the salt is selected from suspension crystallization.

15. Use of the salt or cocrystal according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for the prevention and / or treatment of diseases and / or conditions associated with cell necrosis; Preferably, the disease and / or condition includes systemic inflammatory diseases, tumors, metabolic diseases, and neurodegenerative diseases.

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