Salt form and co-crystal of pyridine-n-oxide, preparation method therefor and use thereof

Abstract

Provided in the present invention are a salt form or co-crystal of a pharmaceutically acceptable salt of a compound as represented by formula (I) and a preparation method therefor. The salt form or co-crystal has a good effect of inhibiting a voltage-gated sodium channel, has good stability, can meet the requirement of developing clinical pharmaceutical preparations, and has a very important clinical application value.

Description

Salt form, eutectic of pyridine nitrogen oxide, preparation method and application thereof

[0001] This application claims the benefit of priority to a prior application filed by the applicant with the State Intellectual Property Office of China on June 14, 2023, with patent application number 202310705174.7, entitled “Salt forms, cocrystals, preparation methods, and applications of pyridine nitrogen oxide compounds.” The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a salt form, a cocrystal, a preparation method and an application of a pyridine nitrogen oxide compound. Background Art

[0003] Pain is one of the most common clinical symptoms and the fifth vital sign after respiration, pulse, blood pressure, and body temperature, seriously affecting patients' quality of life. According to statistics, the global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute, moderate, and severe pain mainly relies on opioids, accounting for about two-thirds of the analgesic market share and will grow steadily at a compound annual growth rate of 2.5% in the future. The number of patients with chronic pain, mainly neuropathic pain and arthritis pain, is increasing year by year, and the market is expected to show a compound annual growth rate of approximately 18%, which will be the main driving force for the continued growth of the global pain market in the next decade.

[0004] Research results in recent years have gradually revealed that sodium channel subtype 1.8 (NaV1.8) plays an important role in the occurrence and transmission of pain. NaV1.8 is a voltage-gated sodium channel that is mainly expressed on afferent neurons, including sensory neurons. By controlling the flow of sodium ions into and out of cells, it plays an important role in maintaining the excitability of nociceptive sensory neurons, the firing and persistence of action potentials, and the regulation of pain sensitivity. Patients with activating mutations in NaV1.8 experience paroxysmal pain caused by small fiber neuropathy (damage to Aδ fibers and unmyelinated C-type fibers, which are mainly responsible for pain transmission). Diseases such as chronic inflammation and diabetes can cause increased expression of NaV1.8 or changes in its properties, thereby sensitizing nociceptive neurons and causing various types of pain. NaV1.8 gene knockout mice are insensitive to pain.

[0005] JMKX000623, an innovative drug independently developed by Shanghai Jiyu Pharmaceuticals, is a highly selective sodium channel blocker. It inhibits the influx of sodium ions, thereby preventing the onset and transmission of pain. It has demonstrated significant analgesic effects in multiple preclinical animal pain models and can reduce the use of opioid analgesics. On March 12, 2022, its Clinical Trial Application (IND) for this drug was approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration.

[0006] Pharmaceutical cocrystals are crystals formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a specific ratio. The formation of cocrystals can improve a drug's physicochemical properties and enhance its clinical therapeutic effects, while also enriching its crystalline forms. However, the development of pharmaceutical cocrystals is challenging, requiring in-depth research and evaluation of cocrystal ligand selection, preparation processes, and physical property characterization.

[0007] Summary of the Invention

[0008] The present invention provides a salt form or co-crystal of a pharmaceutically acceptable salt of a compound represented by Formula I;

[0009] The pharmaceutically acceptable salt form or co-crystal is a salt form or co-crystal formed by the compound of formula I and an acid or a base, preferably a salt form or co-crystal formed by the compound of formula I and an acid.

[0010] According to an embodiment of the present invention, the acid can be selected from an inorganic acid or an organic acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, 3,5-dihydroxybenzoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid , 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxybenzoic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, gentisic acid, trans-aconitic acid, hemisulfuric acid or thiocyanic acid, and nicotinamide, 1,4-benzenediol or pamoic acid. As an example, the acid can be selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, 3,5-dihydroxybenzoic acid, gentisic acid, p-hydroxybenzoic acid, oxalic acid, p-toluenesulfonic acid and trans-aconitic acid.

[0011] According to an embodiment of the present invention, the base may be selected from inorganic bases, such as alkali metal hydroxides or alkaline earth metal hydroxides, preferably sodium hydroxide or potassium hydroxide.

[0012] According to a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula I is selected from one of its hydrochloride, hydrobromide, sulfate and p-toluenesulfonate.

[0013] According to a preferred embodiment of the present invention, the co-crystal of the pharmaceutically acceptable salt of the compound of formula I is selected from one of its fumaric acid co-crystal, maleic acid co-crystal, tartaric acid co-crystal (L-tartaric acid co-crystal), 3,5-dihydroxybenzoic acid co-crystal, gentisic acid co-crystal, p-hydroxybenzoic acid co-crystal, oxalic acid co-crystal and trans-aconitic acid co-crystal.

[0014] According to a more preferred embodiment of the present invention, the co-crystal of the pharmaceutically acceptable salt of the compound of formula I is a co-crystal formed by the compound of formula I and fumaric acid, that is, the compound of formula I-fumaric acid co-crystal.

[0015] According to an embodiment of the present invention, in the salt form or cocrystal of the pharmaceutically acceptable salt of the compound of formula I, the molar ratio of the compound of formula I to the acid or base can be independently selected from 1:1, 2:1 or 3:1, provided that the ions of the compound of formula I in the salt form or cocrystal are charged in balance with the ions of the acid or base. For example, when the number of ionizable hydrogen atoms in the acid (such as hydrochloric acid, p-toluenesulfonic acid) is 1, the molar ratio of the compound of formula I to the acid is 1:1; when the number of ionizable hydrogen atoms in the acid (such as sulfuric acid, fumaric acid, maleic acid, p-hydroxybenzoic acid, tartaric acid, oxalic acid) is 2, the molar ratio of the compound of formula I to the acid can be 1:1 or 2:1; when the number of ionizable hydrogen atoms in the acid (such as 3,5-dihydroxybenzoic acid, gentisic acid, trans-aconitic acid) is 3, the molar ratio of the compound of formula I to the acid is 1:1, 2:1 or 3:1.

[0016] The present invention also provides a method for preparing a salt form or co-crystal of a pharmaceutically acceptable salt of a compound of formula I, which comprises reacting the compound of formula I with the acid or base to obtain a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I.

[0017] According to an embodiment of the present invention, the preparation method comprises reacting the compound of formula I with the acid or base in a solvent to prepare a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I.

[0018] According to an embodiment of the present invention, the acid or base independently of each other has the above-mentioned definition.

[0019] According to an embodiment of the present invention, the solvent may be selected from alcohols, ketones, esters, ethers, a combination of two or more of the solvents, or a mixture of the above solvents or combinations with water.

[0020] According to an embodiment of the present invention, the alcohols may be selected from alcohols having 1 to 8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination of two or more thereof; the ketones may be selected from ketones having 3 to 10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone, or a combination of two or more thereof; the esters may be selected from organic carboxylic acid esters, such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination of two or more thereof; the ethers may be linear or branched alkyl ethers or cyclic ether compounds, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination of two or more thereof.

[0021] According to an embodiment of the present invention, the molar ratio of the compound of formula I to the acid or base can be 1:0.2 to 1:3, 1:0.8 to 1:1.5, preferably 1:0.5 to 1:1.5, and more preferably 1:0.6 to 1:1.3.

[0022] According to an embodiment of the present invention, the salt form and / or co-crystal of the pharmaceutically acceptable salt of the compound represented by Formula I may be selected from:

[0023] Hydrochloride Type A; Hydrobromide Type A, Hydrobromide Type B, Hydrobromide Type C, Hydrobromide Type D, Hydrobromide Type E; Sulfate Type A; Fumaric acid eutectic Type A; Maleic acid eutectic Type A, Maleic acid eutectic Type B; Tartaric acid eutectic Type A, Tartaric acid eutectic Type B, Tartaric acid eutectic Type C; 3,5-Dihydroxybenzoic acid eutectic Type A, 3,5-Dihydroxybenzoic acid eutectic Type B; Gentisic acid eutectic Type A; p-Hydroxybenzoic acid eutectic Type A; Oxalic acid eutectic Type A; p-Toluenesulfonate Type A; Trans-aconitic acid eutectic Type A, Trans-aconitic acid eutectic Type B.

[0024] A hydrochloride Type A of a compound of formula I, wherein the hydrochloride Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 18.06±0.2°, 18.80±0.2°, and 22.24±0.2°.

[0025] According to an embodiment of the present invention, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.06±0.2°, 18.80±0.2°, 21.35±0.2°, 22.24±0.2°, and 26.67±0.2°.

[0026] According to an embodiment of the present invention, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.06±0.2°, 18.80±0.2°, 21.35±0.2°, 22.24±0.2°, 22.67±0.2°, 23.02±0.2°, 25.68±0.2°, and 26.67±0.2°.

[0027] According to an embodiment of the present invention, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.06±0.2°, 18.80±0.2°, 21.35±0.2°, 22.24±0.2°, 22.67±0.2°, 23.02±0.2°, 24.26±0.2°, 25.68±0.2°, 26.67±0.2°, and 30.19±0.2°.

[0028] According to an embodiment of the present invention, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Table 1-1, wherein the error range of the 2θ angle is ±0.20°:

[0029] Table 1-1 XRPD analysis data of hydrochloride Type A

[0030] According to an embodiment of the present invention, the hydrochloride salt Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .

[0031] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrochloride Type A shows an endothermic peak when heated to a peak temperature of approximately 160.6°C.

[0032] According to an embodiment of the present invention, the hydrochloride salt Type A has a DSC graph substantially as shown in FIG5 .

[0033] According to an embodiment of the present invention, the hydrochloride Type A has a weight loss of about 4.6% in the range of 100°C to 200°C according to thermogravimetric analysis (TGA).

[0034] According to an embodiment of the present invention, the hydrochloride salt Type A has a TGA graph substantially as shown in FIG5 .

[0035] According to an embodiment of the present invention, the hydrochloride Type A is an anhydrate or a hydrate of the hydrochloride of the compound of formula I.

[0036] According to an embodiment of the present invention, the molar ratio of the compound of formula I to the hydrochloride in the hydrochloride Type A is 1:1, for example, it is a hydrate of the monohydrochloride of the compound of formula I.

[0037] A hydrobromide salt Type A of a compound of formula I, wherein the hydrobromide salt Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 21.95±0.2°, 24.55±0.2°, and 25.08±0.2°.

[0038] According to an embodiment of the present invention, the hydrobromide Type A has characteristic peaks at 21.95±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, and 26.77±0.2° in X-ray powder diffraction using Cu-Kα radiation expressed in 2θ angles.

[0039] According to an embodiment of the present invention, the hydrobromide Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.19±0.2°, 21.95±0.2°, 22.53±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, 26.77±0.2°, and 28.89±0.2°.

[0040] According to an embodiment of the present invention, the hydrobromide Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 4.19±0.2°, 18.61±0.2°, 21.95±0.2°, 22.53±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, 26.77±0.2°, 27.51±0.2°, and 28.89±0.2° having characteristic peaks.

[0041] According to an embodiment of the present invention, the hydrobromide Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Table 1-2, wherein the error range of the 2θ angle is ±0.20°:

[0042] Table 1-2 XRPD analysis data of hydrobromide Type A

[0043] According to an embodiment of the present invention, the hydrobromide salt Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .

[0044] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type A shows an endothermic peak near a peak temperature of 90.1°C and / or 183.7°C, and an exothermic peak near a peak temperature of 128.2°C.

[0045] According to an embodiment of the present invention, the hydrobromide salt Type A has a DSC graph substantially as shown in FIG. 10 .

[0046] According to an embodiment of the present invention, the hydrobromide salt Type A has a weight loss of about 4.1% in the range from room temperature to 150°C according to thermogravimetric analysis (TGA).

[0047] According to an embodiment of the present invention, the hydrobromide salt Type A has a TGA graph substantially as shown in FIG. 10 .

[0048] According to an embodiment of the present invention, the hydrobromide Type A is an anhydrate or a hydrate of the hydrobromide of the compound of formula I.

[0049] According to an embodiment of the present invention, the molar ratio of the compound of formula I to the hydrobromide in the hydrobromide Type A is 1:1, for example, it is a hydrate of the monohydrobromide of the compound of formula I.

[0050] A Type B hydrobromide of a compound of formula I, wherein the Type B hydrobromide uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 18.30±0.2°, 25.23±0.2°, and 27.55±0.2°.

[0051] According to an embodiment of the present invention, the hydrobromide Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.30±0.2°, 21.54±0.2°, 25.23±0.2°, 27.41±0.2°, and 27.55±0.2°.

[0052] According to an embodiment of the present invention, the hydrobromide Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.73±0.2°, 14.64±0.2°, 18.30±0.2°, 21.54±0.2°, 25.23±0.2°, 26.94±0.2°, 27.41±0.2°, and 27.55±0.2°.

[0053] According to an embodiment of the present invention, the hydrobromide Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 4.73±0.2°, 14.64±0.2°, 18.30±0.2°, 21.54±0.2°, 24.55±0.2°, 25.23±0.2°, 26.94±0.2°, 27.16±0.2°, 27.41±0.2°, and 27.55±0.2° having characteristic peaks.

[0054] According to an embodiment of the present invention, the hydrobromide Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-3, wherein the error range of the 2θ angle is ±0.20°:

[0055] Table 1-3 XRPD analysis data of hydrobromide Type B

[0056] According to an embodiment of the present invention, the hydrobromide salt Type B has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .

[0057] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type B shows an endothermic peak near a peak temperature of 91.5°C and an exothermic peak near a peak temperature of 220.3°C.

[0058] According to an embodiment of the present invention, the hydrobromide salt Type B has a DSC graph substantially as shown in FIG. 16 .

[0059] According to an embodiment of the present invention, the hydrobromide salt Type B has a weight loss of about 3.3% in the range from room temperature to 150°C according to thermogravimetric analysis (TGA).

[0060] According to an embodiment of the present invention, the hydrobromide salt Type B has a TGA graph substantially as shown in FIG. 16 .

[0061] According to an embodiment of the present invention, the hydrobromide Type B is an anhydrate or a hydrate of the hydrobromide of the compound of formula I.

[0062] According to an embodiment of the present invention, the hydrobromide Type B is a hydrate of the hydrobromide of the compound of formula I.

[0063] A Type C hydrobromide of a compound of formula I, wherein the Type C hydrobromide has characteristic peaks at 4.09±0.2°, 22.26±0.2°, and 26.56±0.2° in X-ray powder diffraction using Cu-Kα radiation and expressed in 2θ angles.

[0064] According to an embodiment of the present invention, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.09±0.2°, 17.52±0.2°, 21.25±0.2°, 22.26±0.2°, and 26.56±0.2°.

[0065] According to an embodiment of the present invention, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.09±0.2°, 6.34±0.2°, 17.52±0.2°, 18.45±0.2°, 21.25±0.2°, 22.26±0.2°, 22.82±0.2°, and 26.56±0.2°.

[0066] According to an embodiment of the present invention, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 4.09±0.2°, 6.34±0.2°, 11.10±0.2°, 17.52±0.2°, 18.45±0.2°, 21.25±0.2°, 22.26±0.2°, 22.82±0.2°, 23.64±0.2°, and 26.56±0.2° having characteristic peaks.

[0067] According to an embodiment of the present invention, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-4, wherein the error range of the 2θ angle is ±0.20°:

[0068] Table 1-4 XRPD analysis data of hydrobromide Type C

[0069] According to an embodiment of the present invention, the hydrobromide salt Type C has an X-ray powder diffraction pattern substantially as shown in FIG. 18 .

[0070] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type C shows an endothermic peak when heated to a peak temperature of 90.4°C and / or 177.6°C.

[0071] According to an embodiment of the present invention, the hydrobromide salt Type C has a DSC graph substantially as shown in FIG. 19 .

[0072] According to an embodiment of the present invention, the hydrobromide salt Type C has a weight loss of about 2.2% in the range from room temperature to 150°C according to thermogravimetric analysis (TGA).

[0073] According to an embodiment of the present invention, the hydrobromide salt Type C has a TGA graph substantially as shown in FIG. 19 .

[0074] According to an embodiment of the present invention, the hydrobromide Type C is an anhydrate or a hydrate of the hydrobromide of the compound of formula I.

[0075] According to an embodiment of the present invention, the hydrobromide Type C is the anhydrate of the hydrobromide of the compound of formula I.

[0076] A Type D hydrobromide of a compound of formula I, wherein the Type D hydrobromide uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 3.72±0.2°, 17.89±0.2°, and 28.71±0.2°.

[0077] According to an embodiment of the present invention, the hydrobromide Type D has characteristic peaks at 3.72±0.2°, 17.89±0.2°, 21.48±0.2°, 25.08±0.2°, and 28.71±0.2° in X-ray powder diffraction using Cu-Kα radiation expressed in 2θ angles.

[0078] According to an embodiment of the present invention, the hydrobromide Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.72±0.2°, 17.89±0.2°, 20.71±0.2°, 21.48±0.2°, 22.34±0.2°, 25.08±0.2°, 27.31±0.2°, and 28.71±0.2°.

[0079] According to an embodiment of the present invention, the hydrobromide Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 3.72±0.2°, 17.89±0.2°, 19.79±0.2°, 20.71±0.2°, 21.48±0.2°, 22.34±0.2°, 22.53±0.2°, 25.08±0.2°, 27.31±0.2°, and 28.71±0.2° having characteristic peaks.

[0080] According to an embodiment of the present invention, the hydrobromide Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-5, wherein the error range of the 2θ angle is ±0.20°:

[0081] Table 1-5 XRPD analysis data of hydrobromide Type D

[0082] According to an embodiment of the present invention, the hydrobromide salt Type D has an X-ray powder diffraction pattern substantially as shown in FIG. 21 .

[0083] A Type E hydrobromide of a compound of formula I, wherein the Type E hydrobromide has characteristic peaks at 21.00±0.2°, 21.46±0.2°, and 27.22±0.2° in X-ray powder diffraction using Cu-Kα radiation and expressed in 2θ angles.

[0084] According to an embodiment of the present invention, the hydrobromide Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.00±0.2°, 21.46±0.2°, 22.92±0.2°, 27.22±0.2°, and 28.21±0.2°.

[0085] According to an embodiment of the present invention, the hydrobromide Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.00±0.2°, 21.46±0.2°, 22.92±0.2°, 23.19±0.2°, 24.94±0.2°, 26.61±0.2°, 27.22±0.2°, and 28.21±0.2°.

[0086] According to an embodiment of the present invention, the hydrobromide Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 21.00±0.2°, 21.46±0.2°, 22.92±0.2°, 23.19±0.2°, 23.76±0.2°, 24.94±0.2°, 26.61±0.2°, 27.22±0.2°, 28.21±0.2°, and 29.14±0.2° having characteristic peaks.

[0087] According to an embodiment of the present invention, the hydrobromide Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-6, wherein the error range of the 2θ angle is ±0.20°:

[0088] Table 1-6 XRPD analysis data of hydrobromide Type E

[0089] According to an embodiment of the present invention, the hydrobromide salt Type E has an X-ray powder diffraction pattern substantially as shown in FIG. 23 .

[0090] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type E shows an endothermic peak when heated to a peak temperature of approximately 199.5°C.

[0091] According to an embodiment of the present invention, the hydrobromide salt Type E has a DSC graph substantially as shown in FIG. 24 .

[0092] According to an embodiment of the present invention, the hydrobromide salt Type E has a TGA graph substantially as shown in FIG. 24 .

[0093] According to an embodiment of the present invention, the hydrobromide Type E is the anhydrate of the hydrobromide of the compound of formula I.

[0094] According to an embodiment of the present invention, the molar ratio of the compound of formula I to the hydrobromide in the hydrobromide Type E is 1:(0.5-1), for example, 1:0.6, such as the anhydrous form of the 0.6 hydrobromide of the compound of formula I.

[0095] A Type A sulfate of a compound of formula I, wherein the Type A sulfate has characteristic peaks at 25.10±0.2°, 25.16±0.2°, and 29.63±0.2° in X-ray powder diffraction using Cu-Kα radiation and expressed in 2θ angles.

[0096] According to an embodiment of the present invention, the sulfate Type A has characteristic peaks at 17.87±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2° in X-ray powder diffraction using Cu-Kα radiation expressed in 2θ angles.

[0097] According to an embodiment of the present invention, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.30±0.2°, 17.05±0.2°, 17.87±0.2°, 21.97±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2°.

[0098] According to an embodiment of the present invention, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.30±0.2°, 17.05±0.2°, 17.87±0.2°, 18.30±0.2°, 20.80±0.2°, 21.97±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2°.

[0099] According to an embodiment of the present invention, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-7, wherein the error range of the 2θ angle is ±0.20°:

[0100] Table 1-7 XRPD analysis data of sulfate Type A

[0101] According to an embodiment of the present invention, the sulfate salt Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 26 .

[0102] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the sulfate Type A shows an endothermic peak when heated to a peak temperature of 81.1°C and / or 156.9°C.

[0103] According to an embodiment of the present invention, the sulfate Type A has a DSC graph substantially as shown in FIG. 27 .

[0104] According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the Type A sulfate shows a weight loss of about 6.2% in the range from room temperature to 150°C.

[0105] According to an embodiment of the present invention, the sulfate Type A has a TGA graph substantially as shown in FIG. 27 .

[0106] According to an embodiment of the present invention, the sulfate Type A is a hydrate of the sulfate of the compound of formula I.

[0107] According to an embodiment of the present invention, the sulfate Type A is a hydrate of the monosulfate of the compound of formula I.

[0108] A fumaric acid cocrystal Type A of a compound of formula I, wherein the fumaric acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.34±0.2°, 24.09±0.2°, and 25.95±0.2°.

[0109] According to an embodiment of the present invention, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.93±0.2°, 17.34±0.2°, 22.03±0.2°, 24.09±0.2°, and 25.95±0.2°.

[0110] According to an embodiment of the present invention, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.93±0.2°, 16.86±0.2°, 17.34±0.2°, 22.03±0.2°, 22.46±0.2°, 24.09±0.2°, 25.95±0.2°, and 30.21±0.2°.

[0111] According to an embodiment of the present invention, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.93±0.2°, 16.86±0.2°, 17.34±0.2°, 21.27±0.2°, 22.03±0.2°, 22.46±0.2°, 24.09±0.2°, 25.95±0.2°, 28.83±0.2°, and 30.21±0.2°.

[0112] According to an embodiment of the present invention, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-8, wherein the error range of the 2θ angle is ±0.20°:

[0113] Table 1-8 XRPD analysis data of fumaric acid cocrystal Type A

[0114] According to an embodiment of the present invention, the fumaric acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 85.

[0115] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the fumaric acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of approximately 170.1°C.

[0116] According to an embodiment of the present invention, the fumaric acid cocrystal Type A has a DSC graph substantially as shown in FIG86 .

[0117] According to an embodiment of the present invention, the fumaric acid cocrystal Type A has a TGA graph substantially as shown in Figure 86.

[0118] According to an embodiment of the present invention, the fumaric acid cocrystal Type A is the fumaric acid cocrystal anhydrate of the compound of formula I.

[0119] According to an embodiment of the present invention, the molar ratio of the compound of formula I to fumaric acid in the fumaric acid cocrystal Type A is 1:1, for example, the monofumaric acid cocrystal anhydrate of the compound of formula I.

[0120] A maleic acid cocrystal Type A of a compound of formula I, wherein the maleic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 19.58±0.2°, 22.36±0.2°, and 25.31±0.2°.

[0121] According to an embodiment of the present invention, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 19.58±0.2°, 22.36±0.2°, 22.73±0.2°, 23.45±0.2°, and 25.31±0.2°.

[0122] According to an embodiment of the present invention, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.11±0.2°, 19.58±0.2°, 21.50±0.2°, 22.36±0.2°, 22.73±0.2°, 23.45±0.2°, 25.31±0.2°, and 29.28±0.2°.

[0123] According to an embodiment of the present invention, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 15.42±0.2°, 17.11±0.2°, 19.58±0.2°, 21.50±0.2°, 22.36±0.2°, 22.73±0.2°, 23.45±0.2°, 24.26±0.2°, 25.31±0.2°, and 29.28±0.2°.

[0124] According to an embodiment of the present invention, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-9, wherein the error range of the 2θ angle is ±0.20°:

[0125] Table 1-9 XRPD analysis data of maleic acid cocrystal Type A

[0126] According to an embodiment of the present invention, the maleic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 34 .

[0127] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type A shows endothermic peaks appearing around peak temperatures of 107.8°C, 118.5°C and / or 155.6°C.

[0128] According to an embodiment of the present invention, the maleic acid cocrystal Type A has a DSC graph substantially as shown in FIG. 35 .

[0129] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the maleic acid cocrystal Type A shows a weight loss of about 11.4% in the range of 100°C to 200°C.

[0130] According to an embodiment of the present invention, the maleic acid cocrystal Type A has a TGA graph substantially as shown in FIG. 35 .

[0131] According to an embodiment of the present invention, the maleic acid cocrystal Type A is the anhydrate of the maleic acid cocrystal of the compound of formula I.

[0132] According to an embodiment of the present invention, the molar ratio of the compound of formula I to maleic acid in the maleic acid cocrystal Type A is 1:(0.5-1), for example 1:0.6, such as the anhydrate of the compound of formula I and 0.6 maleic acid cocrystal.

[0133] A maleic acid cocrystal Type B of a compound of formula I, wherein the maleic acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 22.57±0.2°, 25.78±0.2°, and 26.94±0.2°.

[0134] According to an embodiment of the present invention, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.92±0.2°, 22.57±0.2°, 24.92±0.2°, 25.78±0.2°, and 26.94±0.2°.

[0135] According to an embodiment of the present invention, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.31±0.2°, 16.92±0.2°, 20.32±0.2°, 22.57±0.2°, 24.92±0.2°, 25.78±0.2°, 26.94±0.2°, and 27.22±0.2°.

[0136] According to an embodiment of the present invention, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.17±0.2°, 16.31±0.2°, 16.92±0.2°, 18.80±0.2°, 20.32±0.2°, 22.57±0.2°, 24.92±0.2°, 25.78±0.2°, 26.94±0.2°, and 27.22±0.2°.

[0137] According to an embodiment of the present invention, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-10, wherein the error range of the 2θ angle is ±0.20°:

[0138] Table 1-10 XRPD analysis data of maleic acid cocrystal Type B

[0139] According to an embodiment of the present invention, the maleic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in FIG. 37 .

[0140] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type B shows an endothermic peak when heated to a peak temperature of approximately 127.3°C.

[0141] According to an embodiment of the present invention, the maleic acid cocrystal Type B has a DSC graph substantially as shown in FIG. 38 .

[0142] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the maleic acid cocrystal Type B shows a weight loss of about 19.5% in the range of 100°C to 200°C.

[0143] According to an embodiment of the present invention, the maleic acid cocrystal Type B has a TGA graph substantially as shown in FIG. 38 .

[0144] According to an embodiment of the present invention, the maleic acid cocrystal Type B is the anhydrate of the maleic acid cocrystal of the compound of formula I.

[0145] According to an embodiment of the present invention, the molar ratio of the compound of formula I to maleic acid in the maleic acid cocrystal Type B is 1:1, for example, it is an anhydrate of the monomaleic acid cocrystal of the compound of formula I.

[0146] A tartaric acid cocrystal Type A of a compound of formula I, wherein the tartaric acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.79±0.2°, 25.43±0.2°, and 26.38±0.2°.

[0147] According to an embodiment of the present invention, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.38±0.2°, 18.84±0.2°, 21.79±0.2°, 25.43±0.2°, and 26.38±0.2°.

[0148] According to an embodiment of the present invention, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.38±0.2°, 18.84±0.2°, 21.00±0.2°, 21.79±0.2°, 23.74±0.2°, 24.73±0.2°, 25.43±0.2°, and 26.38±0.2°.

[0149] According to an embodiment of the present invention, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.38±0.2°, 18.84±0.2°, 19.58±0.2°, 21.00±0.2°, 21.79±0.2°, 23.74±0.2°, 24.73±0.2°, 25.43±0.2°, 26.38±0.2°, and 28.85±0.2°.

[0150] According to an embodiment of the present invention, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-11, wherein the error range of the 2θ angle is ±0.20°:

[0151] Table 1-11 XRPD analysis data of tartaric acid cocrystal Type A

[0152] According to an embodiment of the present invention, the tartaric acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 40 .

[0153] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type A shows endothermic peaks appearing near peak temperatures of 87.5°C, 102.6°C, 135.7°C and / or 187.5°C.

[0154] According to an embodiment of the present invention, the tartaric acid cocrystal Type A has a DSC graph substantially as shown in FIG41 .

[0155] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the tartaric acid cocrystal Type A shows a weight loss of about 2.2% in the range from room temperature to 150°C.

[0156] According to an embodiment of the present invention, the tartaric acid cocrystal Type A has a TGA graph substantially as shown in FIG41 .

[0157] According to an embodiment of the present invention, the tartaric acid cocrystal Type A is the anhydrate of the tartaric acid cocrystal of the compound of formula I.

[0158] According to an embodiment of the present invention, the molar ratio of the compound of formula I to tartaric acid in the tartaric acid cocrystal Type A is 1:(1-2), for example 1:1.1, such as the anhydrate of the tartaric acid cocrystal of compound of formula I 1.1.

[0159] A tartaric acid cocrystal Type B of a compound of formula I, wherein the tartaric acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, and 20.30±0.2°.

[0160] According to an embodiment of the present invention, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, 5.53±0.2°, 18.20±0.2°, and 20.30±0.2°.

[0161] According to an embodiment of the present invention, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, 5.53±0.2°, 6.28±0.2°, 12.27±0.2°, 17.50±0.2°, 18.20±0.2°, and 20.30±0.2°.

[0162] According to an embodiment of the present invention, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, 5.53±0.2°, 6.28±0.2°, 12.27±0.2°, 16.27±0.2°, 17.50±0.2°, 18.20±0.2°, 20.30±0.2°, and 27.04±0.2°.

[0163] According to an embodiment of the present invention, the tartaric acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-12, wherein the error range of the 2θ angle is ±0.20°:

[0164] Table 1-12 XRPD analysis data of tartaric acid cocrystal Type B

[0165] According to an embodiment of the present invention, the tartaric acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in FIG. 44 .

[0166] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type B shows an endothermic peak when heated to a peak temperature of 88.4°C and / or 172.5°C.

[0167] According to an embodiment of the present invention, the tartaric acid cocrystal Type B has a DSC graph substantially as shown in FIG. 45 .

[0168] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the tartaric acid eutectic Type B shows a weight loss of about 3.3% in the range from room temperature to 150°C.

[0169] According to an embodiment of the present invention, the tartaric acid eutectic Type B has a TGA graph substantially as shown in FIG. 45 .

[0170] According to an embodiment of the present invention, the tartaric acid cocrystal Type B is an anhydrate or a hydrate of the tartaric acid cocrystal of the compound of formula I.

[0171] According to an embodiment of the present invention, the molar ratio of the compound of formula I to tartaric acid in the tartaric acid cocrystal Type B is 1:(1-2), for example 1:1.3, such as a hydrate of the tartaric acid cocrystal of compound of formula I 1.3.

[0172] A tartaric acid cocrystal Type C of a compound of formula I, wherein the tartaric acid cocrystal Type C uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.85±0.2°, 12.99±0.2°, and 21.27±0.2°.

[0173] According to an embodiment of the present invention, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.73±0.2°, 6.85±0.2°, 12.19±0.2°, 12.99±0.2°, and 21.27±0.2°.

[0174] According to an embodiment of the present invention, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.51±0.2°, 6.73±0.2°, 6.85±0.2°, 12.19±0.2°, 12.99±0.2°, 20.78±0.2°, 21.27±0.2°, and 25.88±0.2°.

[0175] According to an embodiment of the present invention, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.51±0.2°, 6.73±0.2°, 6.85±0.2°, 12.19±0.2°, 12.99±0.2°, 20.16±0.2°, 20.78±0.2°, 20.98±0.2°, 21.27±0.2°, and 25.88±0.2°.

[0176] According to an embodiment of the present invention, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-13, wherein the error range of the 2θ angle is ±0.20°:

[0177] Table 1-13 XRPD analysis data of tartaric acid cocrystal Type C

[0178] According to an embodiment of the present invention, the tartaric acid cocrystal Type C has an X-ray powder diffraction pattern substantially as shown in Figure 49.

[0179] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type C shows endothermic peaks appearing near peak temperatures of 87.4°C, 113.2°C, 137.2°C and / or 189.5°C.

[0180] According to an embodiment of the present invention, the tartaric acid eutectic Type C has a DSC graph substantially as shown in FIG50 .

[0181] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the tartaric acid eutectic Type C shows a weight loss of about 1.9% in the range from room temperature to 150°C.

[0182] According to an embodiment of the present invention, the tartaric acid eutectic Type C has a TGA graph substantially as shown in FIG. 50 .

[0183] According to an embodiment of the present invention, the tartaric acid cocrystal Type C is an anhydrate or a hydrate of the tartaric acid cocrystal of the compound of formula I.

[0184] According to an embodiment of the present invention, the molar ratio of the compound of formula I to tartaric acid in the tartaric acid cocrystal Type C is 1:1, for example, it is a hydrate of the monotartaric acid cocrystal of the compound of formula I.

[0185] A 3,5-dihydroxybenzoic acid cocrystal Type A of a compound of formula I, wherein the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.19±0.2°, 22.92±0.2°, and 27.49±0.2°.

[0186] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.80±0.2°, 19.23±0.2°, 21.19±0.2°, 22.92±0.2°, and 27.49±0.2°.

[0187] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.80±0.2°, 19.23±0.2°, 19.70±0.2°, 21.19±0.2°, 22.92±0.2°, 25.66±0.2°, 26.13±0.2°, and 27.49±0.2°.

[0188] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.80±0.2°, 19.23±0.2°, 19.70±0.2°, 21.19±0.2°, 21.50±0.2°, 22.92±0.2°, 25.66±0.2°, 25.90±0.2°, 26.13±0.2°, and 27.49±0.2°.

[0189] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-14, wherein the error range of the 2θ angle is ±0.20°:

[0190] Table 1-14 XRPD analysis data of 3,5-dihydroxybenzoic acid cocrystal Type A

[0191] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 52 .

[0192] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the 3,5-dihydroxybenzoic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of approximately 203.1°C.

[0193] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A has a DSC graph substantially as shown in FIG53 .

[0194] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A has a TGA graph substantially as shown in FIG53 .

[0195] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A is an anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of the compound of formula I.

[0196] According to an embodiment of the present invention, the molar ratio of the compound of formula I to 3,5-dihydroxybenzoic acid in the 3,5-dihydroxybenzoic acid cocrystal Type A is 1:1, for example, it is an anhydrate of the compound of formula I and 3,5-dihydroxybenzoic acid cocrystal.

[0197] A 3,5-dihydroxybenzoic acid cocrystal Type B of a compound of formula I, wherein the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 23.47±0.2°, and 28.05±0.2°.

[0198] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 17.40±0.2°, 21.79±0.2°, 23.47±0.2°, and 28.05±0.2°.

[0199] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 17.40±0.2°, 17.56±0.2°, 21.79±0.2°, 23.17±0.2°, 23.47±0.2°, 28.05±0.2°, and 28.31±0.2°.

[0200] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 17.40±0.2°, 17.56±0.2°, 21.79±0.2°, 23.17±0.2°, 23.47±0.2°, 24.32±0.2°, 26.73±0.2°, 28.05±0.2°, and 28.31±0.2°.

[0201] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-15, wherein the error range of the 2θ angle is ±0.20°:

[0202] Table 1-15 XRPD analysis data of 3,5-dihydroxybenzoic acid cocrystal Type B

[0203] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in FIG. 55 .

[0204] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the 3,5-dihydroxybenzoic acid cocrystal Type B shows an endothermic peak near a peak temperature of 170.5 and / or 203.6°C, and an exothermic peak near a peak temperature of 172.5°C.

[0205] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B has a DSC graph substantially as shown in FIG. 56 .

[0206] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the 3,5-dihydroxybenzoic acid cocrystal Type B shows a weight loss of about 0.2% in the range from room temperature to 200°C.

[0207] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B has a TGA graph substantially as shown in FIG. 56 .

[0208] According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B is an anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of Formula I.

[0209] According to an embodiment of the present invention, the molar ratio of the compound of formula I to 3,5-dihydroxybenzoic acid in the 3,5-dihydroxybenzoic acid cocrystal Type B is 1:1, for example, it is an anhydrate of the compound of formula I and 3,5-dihydroxybenzoic acid cocrystal.

[0210] A gentisic acid cocrystal Type A of a compound of formula I, wherein the gentisic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 19.29±0.2°, 23.45±0.2°, and 27.47±0.2°.

[0211] According to an embodiment of the present invention, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 15.03±0.2°, 19.29±0.2°, 23.45±0.2°, 27.47±0.2°, and 27.80±0.2°.

[0212] According to an embodiment of the present invention, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.26±0.2°, 15.03±0.2°, 19.29±0.2°, 23.45±0.2°, 26.63±0.2°, 26.98±0.2°, 27.47±0.2°, and 27.80±0.2°.

[0213] According to an embodiment of the present invention, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.26±0.2°, 15.03±0.2°, 19.29±0.2°, 21.25±0.2°, 23.45±0.2°, 26.63±0.2°, 26.98±0.2°, 27.47±0.2°, 27.80±0.2°, and 29.39±0.2°.

[0214] According to an embodiment of the present invention, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-16, wherein the error range of the 2θ angle is ±0.20°:

[0215] Table 1-16 XRPD analysis data of gentisic acid cocrystal Type A

[0216] According to an embodiment of the present invention, the gentisic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 58.

[0217] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the gentisic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of approximately 166.7°C.

[0218] According to an embodiment of the present invention, the gentisic acid cocrystal Type A has a DSC graph substantially as shown in Figure 59.

[0219] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the gentisic acid cocrystal Type A shows a weight loss of about 0.2% in the range from room temperature to 150°C.

[0220] According to an embodiment of the present invention, the gentisic acid cocrystal Type A has a TGA graph substantially as shown in Figure 59.

[0221] According to an embodiment of the present invention, the gentisic acid cocrystal Type A is the anhydrate of the gentisic acid cocrystal of the compound of formula I.

[0222] According to an embodiment of the present invention, the molar ratio of the compound of formula I to gentisic acid in the gentisic acid cocrystal Type A is 1:1, for example, it is an anhydrate of the monogentisic acid cocrystal of the compound of formula I.

[0223] A p-hydroxybenzoic acid cocrystal Type A of a compound of formula I, wherein the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.93±0.2°, 24.77±0.2°, and 26.85±0.2°.

[0224] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.68±0.2°, 21.93±0.2°, 23.43±0.2°, 24.77±0.2°, and 26.85±0.2°.

[0225] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.31±0.2°, 17.52±0.2°, 21.68±0.2°, 21.93±0.2°, 23.43±0.2°, 24.77±0.2°, 26.32±0.2°, and 26.85±0.2°.

[0226] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.31±0.2°, 17.13±0.2°, 17.52±0.2°, 21.68±0.2°, 21.93±0.2°, 23.43±0.2°, 24.77±0.2°, 25.00±0.2°, 26.32±0.2°, and 26.85±0.2°.

[0227] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-17, wherein the error range of the 2θ angle is ±0.20°:

[0228] Table 1-17 XRPD analysis data of p-hydroxybenzoic acid cocrystal Type A

[0229] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 61.

[0230] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the p-hydroxybenzoic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of approximately 124.4°C.

[0231] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A has a DSC graph substantially as shown in FIG. 62 .

[0232] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the p-hydroxybenzoic acid cocrystal Type A shows a weight loss of about 0.1% in the range from room temperature to 150°C.

[0233] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A has a TGA graph substantially as shown in FIG. 62 .

[0234] According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A is the anhydrate of the p-hydroxybenzoic acid cocrystal of the compound of formula I.

[0235] According to an embodiment of the present invention, the molar ratio of the compound of formula I to p-hydroxybenzoic acid in the p-hydroxybenzoic acid cocrystal Type A is 1:(0.5-1), for example 1:0.5, such as the anhydrate of the compound of formula I and 0.5 p-hydroxybenzoic acid cocrystal.

[0236] An oxalic acid cocrystal Type A of a compound of formula I, wherein the oxalic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.64±0.2°, 26.69±0.2°, and 27.96±0.2°.

[0237] According to an embodiment of the present invention, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.64±0.2°, 17.01±0.2°, 20.96±0.2°, 26.69±0.2°, and 27.96±0.2°.

[0238] According to an embodiment of the present invention, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.37±0.2°, 16.64±0.2°, 17.01±0.2°, 20.96±0.2°, 22.57±0.2°, 26.69±0.2°, 27.96±0.2°, and 29.04±0.2°.

[0239] According to an embodiment of the present invention, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.37±0.2°, 16.64±0.2°, 17.01±0.2°, 17.67±0.2°, 20.96±0.2°, 22.57±0.2°, 25.90±0.2°, 26.69±0.2°, 27.96±0.2°, and 29.04±0.2°.

[0240] According to an embodiment of the present invention, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-18, wherein the error range of the 2θ angle is ±0.20°:

[0241] Table 1-18 XRPD analysis data of oxalic acid cocrystal Type A

[0242] According to an embodiment of the present invention, the oxalic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 64.

[0243] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the oxalic acid cocrystal Type A shows endothermic peaks appearing around peak temperatures of 105.0°C, 160.7°C and / or 203.7°C.

[0244] According to an embodiment of the present invention, the oxalic acid cocrystal Type A has a DSC graph substantially as shown in FIG. 65 .

[0245] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the oxalic acid cocrystal Type A shows a weight loss of about 0.8% in the range of room temperature to 150°C, and / or a weight loss of about 9.0% in the range of 150°C to 250°C.

[0246] According to an embodiment of the present invention, the oxalic acid cocrystal Type A has a TGA graph substantially as shown in FIG. 65 .

[0247] According to an embodiment of the present invention, the oxalic acid cocrystal Type A is the anhydrate of the oxalic acid cocrystal of the compound of formula I.

[0248] According to an embodiment of the present invention, the molar ratio of the compound of formula I to oxalic acid in the oxalic acid cocrystal Type A is 1:(0.5-1), for example 1:0.5, such as the anhydrate of the 0.5 oxalic acid cocrystal of the compound of formula I.

[0249] A p-toluenesulfonate Type A of a compound of formula I, wherein the p-toluenesulfonate Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 17.36±0.2°, 21.93±0.2°, and 24.55±0.2°.

[0250] According to an embodiment of the present invention, the p-toluenesulfonate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.36±0.2°, 21.93±0.2°, 23.49±0.2°, 24.55±0.2°, and 25.82±0.2°.

[0251] According to an embodiment of the present invention, the p-toluenesulfonate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.10±0.2°, 17.36±0.2°, 18.53±0.2°, 21.93±0.2°, 23.49±0.2°, 24.55±0.2°, 25.82±0.2°, and 28.77±0.2°.

[0252] According to an embodiment of the present invention, the p-toluenesulfonate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.10±0.2°, 17.36±0.2°, 18.53±0.2°, 19.35±0.2°, 21.93±0.2°, 23.49±0.2°, 24.55±0.2°, 25.82±0.2°, 28.77±0.2°, and 31.20±0.2°.

[0253] According to an embodiment of the present invention, the p-toluenesulfonate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-19, wherein the error range of the 2θ angle is ±0.20°:

[0254] Table 1-19 XRPD analysis data of p-toluenesulfonate Type A

[0255] According to an embodiment of the present invention, the p-toluenesulfonate salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 67.

[0256] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the p-toluenesulfonate Type A shows an endothermic peak when heated to a peak temperature of approximately 127.7°C.

[0257] According to an embodiment of the present invention, the p-toluenesulfonate salt Type A has a DSC graph substantially as shown in FIG. 68 .

[0258] According to an embodiment of the present invention, the p-toluenesulfonate salt Type A has a TGA graph substantially as shown in FIG. 68 .

[0259] According to an embodiment of the present invention, the p-toluenesulfonate Type A is the anhydrate of the p-toluenesulfonate of the compound of formula I.

[0260] According to an embodiment of the present invention, the molar ratio of the compound of formula I to p-toluenesulfonic acid in the p-toluenesulfonate Type A is 1:1, for example, it is an anhydrous form of the p-toluenesulfonate of the compound of formula I.

[0261] A trans-aconitic acid cocrystal Type A of a compound of formula I, wherein the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.44±0.2°, 22.73±0.2°, and 23.54±0.2°.

[0262] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.21±0.2°, 17.44±0.2°, 22.73±0.2°, 23.54±0.2°, and 24.32±0.2°.

[0263] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.55±0.2°, 17.21±0.2°, 17.44±0.2°, 22.20±0.2°, 22.73±0.2°, 23.54±0.2°, 24.32±0.2°, and 26.28±0.2°.

[0264] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.55±0.2°, 11.82±0.2°, 11.88±0.2°, 17.21±0.2°, 17.44±0.2°, 22.20±0.2°, 22.49±0.2°, 22.73±0.2°, 23.54±0.2°, 24.32±0.2°, 26.28±0.2°, and 27.98±0.2°.

[0265] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-20, wherein the error range of the 2θ angle is ±0.20°:

[0266] Table 1-20 XRPD analysis data of trans-aconitic acid cocrystal Type A

[0267] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in FIG. 70 .

[0268] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the trans-aconitic acid cocrystal Type A shows endothermic peaks appearing near peak temperatures of 55.6°C, 104.9°C, 114.9°C, 129.9°C, 136.1°C and / or 149.9°C.

[0269] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A has a DSC graph substantially as shown in FIG. 71 .

[0270] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type A shows a weight loss of about 5.7% in the range from room temperature to 120°C.

[0271] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A has a TGA graph substantially as shown in FIG71 .

[0272] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A is an ethanol solvate of the trans-aconitic acid cocrystal of the compound of formula I.

[0273] According to an embodiment of the present invention, the molar ratio of the compound of formula I to trans-aconitic acid in the trans-aconitic acid cocrystal Type A is 1:1, for example, it is an ethanol solvate of the compound of formula I and mono-trans-aconitic acid cocrystal.

[0274] A trans-aconitic acid cocrystal Type B of a compound of formula I, wherein the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 11.69±0.2°, 17.09±0.2°, and 23.47±0.2°.

[0275] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.29±0.2°, 11.69±0.2°, 17.09±0.2°, 23.47±0.2°, and 26.28±0.2°.

[0276] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.29±0.2°, 11.69±0.2°, 17.09±0.2°, 19.44±0.2°, 22.03±0.2°, 23.47±0.2°, 26.28±0.2°, and 27.90±0.2°.

[0277] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.29±0.2°, 11.69±0.2°, 16.26±0.2°, 17.09±0.2°, 19.44±0.2°, 21.21±0.2°, 22.03±0.2°, 23.47±0.2°, 26.28±0.2°, and 27.90±0.2°.

[0278] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Table 1-21, wherein the error range of the 2θ angle is ±0.20°:

[0279] Table 1-21 XRPD analysis data of trans-aconitic acid cocrystal Type B

[0280] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 75.

[0281] According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the trans-aconitic acid cocrystal Type B shows endothermic peaks appearing near peak temperatures of 78.3°C, 106.5°C, 118.0°C, 137.1°C and / or 148.0°C.

[0282] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B has a DSC graph substantially as shown in FIG. 76 .

[0283] According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type B shows a weight loss of about 3.0% in the range from room temperature to 120°C.

[0284] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B has a TGA graph substantially as shown in FIG. 76 .

[0285] According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B is a hydrate of the trans-aconitic acid cocrystal of the compound of formula I.

[0286] According to an embodiment of the present invention, the molar ratio of the compound of formula I to trans-aconitic acid in the trans-aconitic acid cocrystal Type B is 1:(1-2), for example 1:1.1, such as a hydrate of the compound of formula I 1.1 trans-aconitic acid cocrystal.

[0287] The present invention also provides a method for preparing a salt form or co-crystal of a pharmaceutically acceptable salt of the compound represented by Formula I, comprising the following steps:

[0288] Dissolving the compound represented by Formula I and the acid in an organic solvent and stirring to obtain the salt form or co-crystal;

[0289] and / or, dissolving the compound represented by Formula I and the acid in an organic solvent, stirring, and crystallizing to obtain the salt form or co-crystal;

[0290] and / or, dissolving the compound represented by Formula I and the acid in an organic solvent, stirring, crystallizing, and volatilizing to obtain the salt form or co-crystal;

[0291] and / or, dissolving the compound represented by formula I and the acid in an organic solvent, stirring, crystallizing, and back-titration to obtain the salt form or co-crystal;

[0292] According to an embodiment of the present invention, the organic solvent is selected from at least one of methanol, ethanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether, ethylene glycol methyl ether, dimethyl sulfoxide, dichloromethane, and tetrahydrofuran; preferably at least one of ethyl acetate, ethanol, n-heptane, methanol, methyl tert-butyl ether, and acetone; for example, selected from ethyl acetate, ethanol / n-heptane (1 / 9, v / v), methanol / MTBE (1 / 9, v / v) or acetone / MTBE (1 / 9, v / v).

[0293] According to an embodiment of the present invention, the molar ratio of the compound represented by Formula I to the acid can be 1:(0.2-3), 1:(0.5-1.5), for example 1:(0.6-1.3), such as 1:0.6, 1:1, 1:1.1, 1:1.

[0294] According to an embodiment of the present invention, the mass volume ratio of the compound represented by Formula I to the organic solvent can be (10-50) mg:1 mL, for example, (20-40) mg:1 mL, such as 28 mg:1 mL, 29 mg:1 mL, 30 mg:1 mL, 31 mg:1 mL, 32 mg:1 mL, 33 mg:1 mL, and 34 mg:1 mL.

[0295] According to an embodiment of the present invention, the stirring temperature may be 0-40°C, such as 10-30°C, for example, room temperature (25°C); the stirring time may be 5 min-5 days, for example, 2-3 days.

[0296] According to an embodiment of the present invention, the crystallization method is to stand at low temperature, and the crystallization temperature can be -20°C to 10°C, such as -15°C to 5°C; the crystallization time can be 4h-5 days, for example, 1-4 days; for example, first place it in a 4°C refrigerator to cool and crystallize, and then place it at -15°C and stand for 1-4 days.

[0297] According to an embodiment of the present invention, the volatilization is volatilization at room temperature.

[0298] According to an embodiment of the present invention, the back-titration is to drop the reaction solution into an anti-solvent; the anti-solvent can be selected from at least one of n-heptane and methyl tert-butyl ether.

[0299] The present invention also provides a pharmaceutical composition comprising at least one of a salt form or a co-crystal of a pharmaceutically acceptable salt of the compound of Formula I, and optionally a pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is in the form of a preparation.

[0300] The present invention also provides a preparation comprising at least one of a salt form or a co-crystal of a pharmaceutically acceptable salt of the compound of formula I, and optionally a pharmaceutically acceptable excipient.

[0301] The present invention also provides use of a salt form or co-crystal of a pharmaceutically acceptable salt of any of the above-mentioned compounds of formula I or the above-mentioned pharmaceutical composition in the preparation of a drug for inhibiting voltage-gated sodium channels.

[0302] According to an embodiment of the present invention, the voltage-gated sodium channel is NaV1.8.

[0303] The present invention also provides the use of a salt form or cocrystal of a pharmaceutically acceptable salt of any of the above-mentioned compounds of Formula I or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing and / or alleviating and / or relieving a disease, preferably pain or cough.

[0304] According to an embodiment of the present invention, the disease is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and cardiac arrhythmia.

[0305] According to an embodiment of the present invention, the intestinal pain is selected from inflammatory bowel disease pain, Crohn's disease pain and interstitial cystitis pain.

[0306] According to an embodiment of the present invention, the neuropathic pain is selected from the group consisting of post-herpetic neuralgia, diabetic neuropathy, HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morto's neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, neuralgia induced by drug therapy, neuralgia induced by cancer chemotherapy, neuralgia induced by antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy and trigeminal autonomic cephalus.

[0307] According to an embodiment of the present invention, the musculoskeletal pain is selected from the group consisting of osteoarthritis pain, back pain, cold pain, burn pain and dental pain.

[0308] According to an embodiment of the present invention, the inflammatory pain is selected from rheumatoid arthritis pain and vulvodynia.

[0309] According to an embodiment of the present invention, the primary pain is selected from fibromyalgia.

[0310] The present invention also provides a method for preventing and / or treating diseases related to voltage-gated sodium channels, comprising administering to an individual in need thereof a therapeutically effective amount of a salt form or cocrystal of a pharmaceutically acceptable salt of the compound of Formula I as described above, or at least one of the pharmaceutical compositions.

[0311] The therapeutic methods of the present invention may include administering a pharmaceutically acceptable salt form or cocrystal of a compound of Formula I of the present invention, or a pharmaceutical composition thereof, alone, or administering one, two, or more pharmaceutically acceptable salt forms or cocrystals of a compound of Formula I of the present invention, or a pharmaceutical composition thereof, in combination with one, two, or more other chemotherapeutic agents. Administration of multiple drugs may be carried out simultaneously or sequentially. Beneficial effects

[0312] The present invention provides a salt form or cocrystal of a pharmaceutically acceptable salt of the compound of formula I and a method for preparing the same. The salt form or cocrystal has a good inhibitory effect on voltage-gated sodium channels and good stability, can meet the needs of clinical drug preparation development, and has very important clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0313] Figure 1 is the XRPD pattern of the compound of formula I in free form.

[0314] Figure 2 shows the TGA and DSC diagrams of the free form of the compound of formula I.

[0315] Figure 3 Free form of compound of formula I 1 H NMR spectrum.

[0316] Figure 4 XRPD pattern of hydrochloride Type A.

[0317] Figure 5 DSC and TGA graphs of Type A hydrochloride.

[0318] Figure 6 Hydrochloride Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0319] Figure 7 XRPD comparison of hydrochloride Type A before and after hot stage experiment.

[0320] Figure 8 TGA graph of the hydrochloride Type A sample after hot stage experiment.

[0321] Figure 9 XRPD pattern of hydrobromide salt Type A.

[0322] Figure 10 DSC and TGA graphs of Type A hydrobromide.

[0323] Figure 11 Hydrobromide Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0324] Figure 12 XRPD comparison of hydrobromide Type A before and after hot stage experiment.

[0325] Figure 13 TGA graph of the hydrobromide Type A sample after hot stage experiment.

[0326] Figure 14 XRPD pattern of hydrobromide salt Type B.

[0327] Figure 15: Comparison of hydrobromide Type A and hydrobromide Type B.

[0328] Figure 16 DSC and TGA graphs of Type B hydrobromide.

[0329] Figure 17 Hydrobromide Type B 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0330] Figure 18 XRPD pattern of Type C hydrobromide salt.

[0331] Figure 19 DSC and TGA graphs of Type C hydrobromide.

[0332] Figure 20 Hydrobromide Type C 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0333] Figure 21 XRPD pattern of Type D hydrobromide salt.

[0334] Figure 22 XRPD comparison of hydrobromide Type D after 1 day of storage.

[0335] Figure 23 shows the XRPD pattern of the hydrobromide salt Type E.

[0336] Figure 24 DSC and TGA graphs of Type E hydrobromide.

[0337] Figure 25 Hydrobromide Type E 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0338] Figure 26 XRPD pattern of sulfate Type A

[0339] Figure 27 DSC and TGA graphs of sulfate Type A.

[0340] Figure 28 Sulfate Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0341] Figure 29 XRPD comparison of sulfate Type A before and after hot stage experiment.

[0342] Figure 30 TGA graph of the sample after the sulfate Type A hot stage experiment.

[0343] Figure 31 XRPD pattern of fumaric acid cocrystal Type A.

[0344] Figure 32 DSC and TGA graphs of fumaric acid cocrystal Type A.

[0345] Figure 33 Fumaric acid eutectic Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0346] Figure 34 XRPD pattern of maleic acid cocrystal Type A.

[0347] Figure 35 DSC and TGA graphs of maleic acid cocrystal Type A.

[0348] Figure 36 Maleic acid eutectic Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0349] Figure 37 XRPD pattern of maleic acid cocrystal Type B.

[0350] Figure 38 DSC and TGA graphs of maleic acid cocrystal Type B.

[0351] Figure 39 Maleic acid eutectic Type B 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0352] Figure 40 XRPD pattern of tartaric acid cocrystal Type A.

[0353] Figure 41 DSC and TGA graphs of tartaric acid cocrystal Type A.

[0354] Figure 42 Tartaric acid eutectic Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0355] Figure 43 XRPD comparison of tartaric acid eutectic Type A before and after heating.

[0356] Figure 44 XRPD pattern of tartaric acid cocrystal Type B.

[0357] Figure 45 DSC and TGA graphs of tartaric acid cocrystal Type B.

[0358] Figure 46 Tartaric acid eutectic Type B 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0359] Figure 47 XRPD comparison of tartaric acid eutectic Type B before and after heating.

[0360] Figure 48 TGA graph of the sample after Type B hot stage experiment of tartaric acid eutectic.

[0361] Figure 49 XRPD pattern of tartaric acid cocrystal Type C.

[0362] Figure 50 DSC and TGA graphs of tartaric acid cocrystal Type C.

[0363] Figure 51 Tartaric acid eutectic Type C 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0364] Figure 52 XRPD pattern of 3,5-dihydroxybenzoic acid cocrystal Type A.

[0365] Figure 53 DSC and TGA graphs of 3,5-dihydroxybenzoic acid cocrystal Type A.

[0366] Figure 54 3,5-dihydroxybenzoic acid cocrystal Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0367] Figure 55 XRPD pattern of 3,5-dihydroxybenzoic acid cocrystal Type B.

[0368] Figure 56 DSC and TGA graphs of 3,5-dihydroxybenzoic acid cocrystal Type B.

[0369] Figure 57 3,5-Dihydroxybenzoic acid cocrystal Type B 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0370] Figure 58 XRPD pattern of gentisic acid cocrystal Type A.

[0371] Figure 59 DSC and TGA graphs of gentisic acid cocrystal Type A.

[0372] Figure 60 Gentisic acid cocrystal Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0373] Figure 61 XRPD pattern of p-hydroxybenzoic acid cocrystal Type A.

[0374] Figure 62 DSC and TGA graphs of p-hydroxybenzoic acid cocrystal Type A.

[0375] Figure 63 Para-hydroxybenzoic acid cocrystal Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0376] Figure 64 XRPD pattern of oxalic acid cocrystal Type A.

[0377] Figure 65 DSC and TGA graphs of oxalic acid cocrystal Type A.

[0378] Figure 66 Oxalic acid eutectic Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0379] Figure 67 XRPD pattern of p-toluenesulfonate Type A.

[0380] Figure 68 DSC and TGA charts of Type A p-toluenesulfonate.

[0381] Figure 69 p-Toluenesulfonate Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0382] Figure 70 shows the XRPD pattern of trans-aconitic acid cocrystal Type A.

[0383] Figure 71 DSC and TGA graphs of trans-aconitic acid cocrystal Type A.

[0384] Figure 72 Trans-aconitic acid eutectic Type A 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0385] Figure 73 XRPD comparison of trans-aconitic acid cocrystal Type A before and after hot stage.

[0386] Figure 74 TGA graph of trans-aconitic acid eutectic Type A sample after hot stage.

[0387] Figure 75 XRPD pattern of trans-aconitic acid cocrystal Type B.

[0388] Figure 76 DSC and TGA graphs of trans-aconitic acid cocrystal Type B.

[0389] Figure 77 Trans-aconitic acid eutectic Type B 1 H NMR spectra: (a) comparison with the free state; (b) integration results.

[0390] Figure 78 XRPD comparison of trans-aconitic acid cocrystal Type B before and after hot stage.

[0391] Figure 79: XRPD comparison of the solid remaining after oxalic acid cocrystal Type A was shaken in water for 2 hours.

[0392] Figure 80 Oxalic acid eutectic Type A remaining solid after shaking in water for 2 hours 1 H NMR spectra: (a) comparison with oxalic acid cocrystal Type A; (b) integration results.

[0393] Figure 81 is a comparison of XRPD patterns of the solid remaining after Type A p-toluenesulfonate was shaken in water for 2 h.

[0394] Figure 82: Residual solids after 2h shaking of p-toluenesulfonate Type A in water 1 H NMR spectra: (a) comparison with p-toluenesulfonate Type A; (b) integration results.

[0395] Figure 83 Comparison of XRPD patterns of the solids remaining after shaking maleic acid cocrystal Type B, hydrochloride Type A, and hydrobromide Type E in water for 2 hours.

[0396] Figure 84: Solids remaining after shaking maleic acid eutectic Type B in water for 2 hours 1 H NMR spectra: (a) comparison with maleic acid cocrystal Type B; (b) integration results.

[0397] Figure 85 XRPD pattern of fumaric acid cocrystal Type A.

[0398] Figure 86 TGA and DSC graphs of fumaric acid cocrystal Type A.

[0399] Figure 87 NMR spectrum of fumaric acid cocrystal Type A.

[0400] Figure 88 Fumaric acid cocrystal Type A (a) DVS curve; (b) XRPD pattern before and after DVS test.

[0401] Figure 89 PLM image of fumaric acid cocrystal Type A.

[0402] Figure 90 XRPD pattern of stability study of fumaric acid cocrystal Type A.

[0403] Figure 91: XRPD comparison of the solid remaining after fumaric acid cocrystal Type A was shaken in biological medium for 24 hours.

[0404] Figure 92. XRPD comparison of the solid remaining after maleic acid cocrystal Type B was shaken in biological medium for 24 hours.

[0405] Figure 93 is a comparison of XRPD patterns of the solid remaining after Type A hydrochloride was shaken in biological medium for 24 hours.

[0406] Figure 94 is a comparison of XRPD patterns of the solid remaining after free Form A was shaken in biological medium for 24 hours.

[0407] Definitions and Explanations of Terms

[0408] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0409] "API" or "free form" refers to the free base form of the compound of Formula I.

[0410] "Eutecrystal" refers to a single-phase crystalline material comprising two or more components in a specific stoichiometric ratio, wherein the arrangement in the crystal lattice is not based on ionic bonds (such as those formed with salts) and at least two of the components are solid at room temperature.

[0411] The "salt forms" or "co-crystals" of the present invention include hydrates, non-solvates (anhydrates) and crystalline forms of solvates of the compounds.

[0412] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0413] "Anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0414] "Solvate" refers to a crystal having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. A hydrate may or may not have other solvents other than water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice of the substance.

[0415] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. According to the instrument conditions used in the test of the present invention, the diffraction peak has an error tolerance of ±0.2°.

[0416] Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The height of the melting peak of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in the test of the present invention, the melting peak has an error tolerance of ±3°C.

[0417] Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon.

[0418] Solids with the same chemical composition often form isomers, or variants, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphasic phenomenon. When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will undergo significant changes. When the temperature of the crystal transformation is within the measurable range, this transformation process can be observed on the differential scanning calorimetry (DSC) graph, which is characterized by having an exothermic peak reflecting this transformation process and two or more endothermic peaks, which are respectively characteristic endothermic peaks of the different crystal forms before and after the transformation. The crystalline form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.

[0419] Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or solvent in the crystals. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and samples. Based on the instrumentation used in the present test, the mass change has an error tolerance of ±0.3%.

[0420] The moisture adsorption / desorption isotherm (DVS) is a method that measures the adsorption and desorption behavior of water by measuring the weight change of a solid under various relative humidity conditions.

[0421] In the context of the present invention, the 2θ values ​​in the X-ray powder diffraction pattern are all in degrees (°).

[0422] When referring to a spectrum and / or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and is not attributable to background noise.

[0423] The term "substantially as shown" 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 X-ray powder diffraction pattern or DSC pattern or TGA results are shown in its pattern.

[0424] “Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

[0425] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0426] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents. DETAILED DESCRIPTION

[0427] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0428] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0429] Analytical methods

[0430] 1. NMR analysis ( 1 H NMR)

[0431] 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).

[0432] 2. X-ray powder diffraction (XRPD)

[0433] 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.

[0434] 3. Thermogravimetric analysis (TGA)

[0435] 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.

[0436] 4. Differential Scanning Calorimetry (DSC)

[0437] 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.

[0438] 5. Dynamic moisture sorption and desorption analysis (DVS)

[0439] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient profile 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 completion of the test, the samples were analyzed by XRPD to confirm any changes in the solid form.

[0440] 6. Polarized Light Microscopy (PLM)

[0441] The polarizing microscope model is Nikon Ci-POL (Nikon, JP). A small amount of sample is placed on a glass slide and the sample morphology is observed using a suitable lens.

[0442] 7. High Performance Liquid Chromatography (HPLC)

[0443] The HPLC model was Waters Acquity Arc-2489 (Waters, US), and the test conditions were shown in Table 1.

[0444] Table 1 HPLC test conditions

[0445] 8. Ion Chromatography (IC)

[0446] The ion chromatograph model was ICS 5000 (Thermo Fisher, US), and the instrument parameters are shown in Table 2.

[0447] Table 2 IC test parameters

[0448] Among them, the compound of formula I can be prepared according to the existing technology. For example, it is prepared according to the method described in the patent application disclosure WO2021047622A1, but the starting material is not a limiting condition for preparing the co-crystal of the present invention. The relevant characterization data are shown in Figures 1 to 3. The XRPD results show that the compound of formula I is a solid with good crystallinity, named free form A. The TGA results show that it does not lose weight during heating to 200°C, and decomposition may occur above 300°C. The DSC results show an endothermic signal at 90°C and a melting endothermic peak at 151°C. The NMR results are used to judge the subsequent sample salt formation and co-crystal formation.

[0449] The relevant information of the raw material drug (compound of formula I) used in the present invention is shown in the following table:

[0450] Experimental methods

[0451] 1. Raw material solubility test

[0452] Weigh approximately 20 mg of sample into an EP tube. Add a defined amount of solvent incrementally at room temperature (~25°C). Stir the solution and observe whether the solid is completely dissolved. If the solid remains insoluble after adding 10.0 mL of solvent, discontinue the experiment. Estimate the solubility of the compound in the solvent based on the volume of solvent used to completely dissolve the solid.

[0453] 2. Reaction crystallization method

[0454] About 32.1 mg (0.07 mmol) of sample and 1.1 equivalents of acid were added to a certain amount of the selected solvent system, suspended at room temperature for 2-3 days, the suspension was centrifuged, and the solid was dried under vacuum at room temperature.

[0455] 3. Cooling crystallization method

[0456] If no solid precipitates after the solution is suspended at room temperature in the reactive crystallization method, place the solution in a 4°C refrigerator to cool and crystallize for 1 day. Then, place the cooled clarified solution in a -15°C refrigerator to cool and crystallize for 1-4 days. The solution with precipitated solids should be centrifuged and the solids should be vacuum dried at room temperature.

[0457] 4. Back-titration crystallization method

[0458] If insufficient solids precipitate from the solution during the cooling crystallization method, divide the resulting solution into two portions. Add one portion to a predetermined volume of antisolvent and stir at room temperature for one day. For the portion of the solution that does not produce sufficient solids after back-titration, allow it to stand at -15°C for one day. Centrifuge the solution that produces sufficient solids, and dry the solids under vacuum at room temperature.

[0459] 5. Solvent evaporation method

[0460] If insufficient solid is precipitated from the solution during the cooling crystallization method, the resulting solution is divided into two parts, and one part is left open at room temperature until the solvent is completely evaporated to obtain a solid.

[0461] 6. Thermal transfer method

[0462] An Instec HCS424GXY hot stage (Instec Inc., US) was used to perform XRPD analysis. A 6-8 mg sample was placed on a glass slide and placed on the hot stage. The sample was heated to the target temperature at a rate of 20°C / min and kept at this temperature for 10 min. The sample was then cooled naturally to room temperature and the solid was subjected to XRPD analysis.

[0463] 7. Stability study methods

[0464] About 20 mg of sample was weighed and placed in a weighing bottle, which was then placed under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated conditions (40°C / 75% RH). Samples were taken on days 7 and 15 for XRPD characterization and HPLC testing.

[0465] 8. Solubility test

[0466] 8.1 Water Solubility Assessment

[0467] Samples of different salt forms, cocrystals, or free forms were added to 2.0 mL of water and shaken at 25°C for 2 hours before sampling. The sampled solution was filtered through a 0.22 μm water filter. Samples with higher concentrations were appropriately diluted with diluent. The peak area of ​​the solution was measured by HPLC. The concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material, and the dilution factor. Furthermore, XRPD analysis was performed on the remaining solid.

[0468] 8.2 Solubility test in biological media

[0469] The preparation process of the bio-media is shown in Table 3. Samples of various salt forms, cocrystals, or free forms were added to 4.0 mL of bio-media and shaken at 37°C for 24 hours. Samples were taken at 0.5, 2, and 24 hours. The sampled solutions were filtered through a 0.22 μm aqueous filter. Samples with higher concentrations were diluted with appropriate diluents. The peak areas of the solutions were measured using HPLC. Finally, the concentrations of the compounds in the solutions were calculated based on the peak areas, the HPLC standard curve of the raw materials, and the dilution factor. Furthermore, the pH of the supernatant after the test was measured, and the remaining solids were subjected to XRPD analysis.

[0470] Table 3 Preparation process of biological medium

[0471] Example 1

[0472] The hydrochloride Type A is obtained by back titrating a solution of the starting material (compound of Formula I) and hydrochloric acid suspended in ethyl acetate in n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 4 to 8.

[0473] XRPD results showed that the hydrochloride salt Type A was a well-crystalline solid. TGA results showed no weight loss from room temperature to 100°C, a 4.6% weight loss from 100°C to 200°C, and possible decomposition after 300°C. DSC results revealed a broad endothermic signal between 130°C and 190°C. NMR results showed shifts in the NMR peaks corresponding to the drug substance at 10.8 ppm, 8.6 ppm, 8.0 ppm, and 7.4 ppm compared to the free form. The NMR integration results were generally consistent with those of the drug substance, suggesting salt formation. No significant residual organic solvent signal peaks were observed. In a hot stage experiment (053-25-17), the hydrochloride salt Type A was heated to 120°C and held at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD pattern of the sample showed no significant change. The TGA weight loss of the sample after the hot stage experiment was not significantly reduced. Ion chromatography results showed a chloride ion content of 7.1%, indicating an approximate molar ratio of drug substance to hydrochloric acid of 1:1.

[0474] Example 2-1

[0475] The hydrobromide salt Type A can be obtained by back titrating a solution of the raw material and hydrobromic acid suspended in ethyl acetate in n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 9 to 13.

[0476] XRPD results indicated that the hydrobromide salt Type A was a well-crystalline solid. TGA results revealed a 4.1% weight loss upon heating to 150°C, with possible decomposition occurring after 225°C. DSC results revealed endothermic signals at 90°C and 184°C, and an exothermic signal at 128°C. NMR results revealed shifts in the NMR peaks corresponding to the drug substance at 10.8 ppm, 8.6 ppm, 8.0 ppm, and 7.4 ppm compared to the free form. The NMR integration results were generally consistent with those of the drug substance, suggesting salt formation. No significant residual organic solvent peaks were observed. In a hot-stage experiment (053-25-18), the hydrobromide salt Type A melted at 100°C. The TGA weight loss of the sample after the hot-stage experiment did not significantly decrease. The sample was then heated to 70°C and held at that temperature for 10 minutes. After cooling to room temperature, the XRPD pattern remained unchanged, and the TGA weight loss did not significantly decrease. The ion chromatography results showed that the bromide ion content in the sample was 14.8%, and the calculated molar ratio of the raw material drug and hydrobromic acid was approximately 1:1.

[0477] Example 2-2

[0478] The hydrobromide salt Type B was obtained by back titrating a solution of the raw material and hydrobromic acid suspended in ethanol / n-heptane (1 / 9, v / v) in n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 14 to 17.

[0479] XRPD results showed that Type B hydrobromide was a well-crystalline solid. A comparison of the XRPD patterns of Type A and Type B hydrobromide suggested that Type B may contain a small amount of Type A hydrobromide. TGA results showed that the sample lost 3.3% weight during heating to 150°C and may have decomposed after 225°C. DSC results revealed an endothermic signal at 92°C and an exothermic signal corresponding to decomposition at 220°C. NMR results showed that the nuclear magnetic resonance peaks corresponding to the drug substance at approximately 10.8ppm, 8.6ppm, 8.0ppm, and 7.4ppm shifted compared to the free state. The NMR integration results were essentially consistent with those of the raw material, suggesting that the sample had formed a salt. No significant residual organic solvent signal peaks were observed.

[0480] Example 2-3

[0481] The hydrobromide salt Type C was obtained by back titrating a solution of the raw material and hydrobromic acid suspended in methanol / MTBE (1 / 9, v / v) in MTBE. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 18 to 20.

[0482] XRPD results indicated that the hydrobromide salt Type C was a solid with average crystallinity. TGA results indicated a 2.2% weight loss upon heating to 150°C, with possible decomposition occurring after 200°C. DSC results revealed an endothermic signal at 90°C and an endothermic signal corresponding to decomposition at 178°C. NMR results indicated a shift in the NMR peaks corresponding to the API at approximately 8.6 ppm, 8.0 ppm, and 7.4 ppm compared to the free form. The NMR integration results were generally consistent with those of the API, suggesting salt formation. No significant residual organic solvent signal peaks were observed.

[0483] Examples 2-4

[0484] The hydrobromide salt Type D was obtained by volatilization experiments using a solution of the raw material and hydrobromic acid suspended in methanol / MTBE (1 / 9, v / v). The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 21 and 22.

[0485] XRPD results showed that Type D hydrobromide was a generally crystalline solid. After standing at room temperature for one day, Type D hydrobromide transformed into a solid that may have been mixed with Type A hydrobromide.

[0486] Examples 2-5

[0487] In a repeated experiment to prepare Type B hydrobromide, Type E hydrobromide was obtained by back titrating a solution of the starting material and hydrobromic acid suspended in ethanol / n-heptane (1 / 9, v / v) in n-heptane. Specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 23 to 25.

[0488] XRPD results indicated that the hydrobromide salt Type E was a well-crystalline solid. TGA results showed no weight loss upon heating to 150°C, but decomposition may occur after 250°C. DSC results revealed an endothermic signal at 200°C. NMR results showed that the NMR peaks corresponding to the API at 10.8 ppm, 8.6 ppm, 8.0 ppm, and 7.4 ppm were shifted compared to the free form. The NMR integration results were generally consistent with those of the API, suggesting salt formation. Peaks at 3.4 ppm and 1.1 ppm corresponded to characteristic signals of ethanol, suggesting the presence of a small amount of residual ethanol. Ion chromatography results indicated a bromide ion content of 8.7%, indicating a calculated molar ratio of API to hydrobromic acid of approximately 1:0.6.

[0489] Example 3

[0490] Sulfate Type A was obtained by suspending the raw materials and sulfuric acid in ethanol / n-heptane (1 / 9, v / v). The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 26 to 30.

[0491] XRPD results indicated that Type A sulfate was a well-crystalline solid. TGA results revealed a 6.2% weight loss upon heating to 150°C, with possible decomposition occurring after 250°C. DSC revealed broad endothermic signals at 81°C and 157°C. NMR results revealed shifts in the NMR peaks corresponding to the API at 10.8 ppm, 8.6 ppm, 8.0 ppm, and 7.4 ppm compared to the free form. The NMR integration results were consistent with those of the API, suggesting salt formation. The NMR peaks at 1.1 ppm and 3.7 ppm corresponded to characteristic peaks of ethyl sulfate. Based on the integration of the peak near 1.1 ppm, the molar ratio of API to ethyl sulfate was approximately 1:0.1, suggesting the presence of a small amount of ethyl sulfate in the sample. A hot stage experiment (053-23-48) revealed that Type A sulfate was heated to 120°C for 10 minutes and then cooled to room temperature. The TGA results showed a significant decrease in weight loss after the hot stage experiment.

[0492] Example 4

[0493] Fumaric acid cocrystal Type A is obtained by suspending the raw materials and fumaric acid in four solvent systems used, for example, in ethyl acetate. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 31 to 33.

[0494] XRPD results indicated that Type A fumaric acid cocrystal was a well-crystalline solid. TGA results revealed a 0.1% weight loss upon heating to 150°C, with possible decomposition occurring after 210°C. DSC results revealed a melting endotherm at 169.7°C. NMR results showed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The peak near 6.6 ppm corresponded to the characteristic signal peak of fumaric acid, and the integration results indicated an approximately 1:1 molar ratio of API to fumaric acid. No significant residual organic solvent was observed.

[0495] Example 5-1

[0496] Maleic acid cocrystal Type A was obtained by suspending the raw materials and maleic acid in ethanol / n-heptane (1 / 9, v / v) at room temperature. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 34 to 36.

[0497] XRPD results indicated that maleic acid cocrystal Type A was a well-crystalline solid. TGA results revealed no weight loss upon heating to 100°C, but an 11.4% weight loss between 100°C and 200°C. Decomposition of the maleic acid cocrystal may occur above 150°C. DSC results revealed endothermic signals at 108°C and 119°C, with a broad endothermic signal at 156°C. NMR results revealed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The peak near 6.25 ppm corresponded to the characteristic signal of maleic acid. Based on the integration results, the molar ratio of API to maleic acid was calculated to be approximately 1:0.6, resulting in a theoretical maleic acid content of 13.2%, which is close to the weight loss observed in the TGA. No significant residual organic solvent signal peaks were observed.

[0498] Example 5-2

[0499] Maleic acid cocrystal Type B can be obtained by back-titration of a solution of the free raw material and maleic acid suspended in ethyl acetate in n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 37 to 39.

[0500] XRPD results indicated that maleic acid cocrystal Type B was a well-crystalline solid. TGA results revealed no weight loss upon heating to 100°C, but a 19.5% weight loss between 100°C and 200°C. Decomposition of the maleic acid cocrystal may occur above 150°C. DSC results revealed an endothermic signal at 127°C. NMR results showed no significant shift in the NMR peak corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The peak near 6.25 ppm corresponds to the characteristic signal of maleic acid. Based on the integration results, the molar ratio of API to maleic acid was estimated to be approximately 1:1, resulting in a calculated theoretical maleic acid content of 20.2%, which is close to the weight loss observed in the TGA. Characteristic peaks of ethyl acetate were observed at 4.0 ppm, 2.0 ppm, and 1.2 ppm, suggesting the presence of a small amount of residual ethyl acetate.

[0501] Example 6-1

[0502] Tartaric acid eutectic Type A was obtained by suspending the raw materials and tartaric acid in ethanol / n-heptane (1 / 9, v / v) at room temperature. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 40 to 43.

[0503] XRPD results indicated that tartaric acid cocrystal Type A was a well-crystalline solid. TGA results revealed a 2.2% weight loss upon heating to 150°C, with possible decomposition occurring above 200°C. DSC results revealed endothermic signals at 88°C, 103°C, and 136°C, with a broad endothermic signal at 188°C. NMR results showed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The peak near 4.3 ppm corresponds to the characteristic signal of tartaric acid, and the integration results indicate an approximate molar ratio of API to tartaric acid of 1:1.1. A characteristic signal peak of ethanol was observed near 1.05 ppm, and the integration value indicated an approximate molar ratio of API to ethanol of 1:0.25. The theoretical ethanol content was 1.8%, which is close to the weight loss observed in the TGA. In the hot stage experiment, the tartaric acid eutectic Type A (053-23-33) was heated to 100°C and kept at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results showed no significant change.

[0504] Example 6-2

[0505] Tartaric acid cocrystal Type B was obtained by back-titration of a solution of the raw material and tartaric acid suspended in ethyl acetate at room temperature into n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 44 to 48.

[0506] XRPD results indicated that tartaric acid cocrystal Type B was a solid with average crystallinity. TGA results revealed a 3.3% weight loss upon heating to 150°C, with possible decomposition occurring above 200°C. DSC results revealed an endothermic peak at 88°C corresponding to weight loss and an endothermic signal at 173°C corresponding to decomposition. NMR results showed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The peak near 4.3 ppm corresponds to the characteristic signal of tartaric acid, and the integration results indicate an approximate molar ratio of API to tartaric acid of 1:1.3. Characteristic peaks of n-heptane were observed near 0.9 ppm and 1.25 ppm, and the integration of the peak near 0.9 ppm indicates an approximate molar ratio of API to n-heptane of 1:0.15. The theoretical n-heptane content was 2.2%, slightly lower than the weight loss observed in the TGA. In the hot stage experiment, the tartaric acid eutectic Type B (053-23-45) was heated to 70°C and held at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results showed no significant change. The sample after the hot stage experiment showed less weight loss in the TGA. The sample melted after heating to 100°C.

[0507] Example 6-3

[0508] Tartaric acid eutectic Type C was obtained in a volatilization experiment by reacting the raw materials with tartaric acid in ethyl acetate at room temperature. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 49 to 51.

[0509] XRPD results showed that tartaric acid cocrystal Type C was a solid with average crystallinity. TGA results revealed a 1.9% weight loss upon heating to 150°C, with possible decomposition occurring after 180°C. DSC results revealed endothermic signals at 87°C, 113°C, 137°C, and 190°C. NMR results showed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The peak near 4.3 ppm corresponds to the characteristic peak of tartaric acid, and the integration results indicate an approximately 1:1 molar ratio of API to tartaric acid. Characteristic peaks of ethyl acetate were observed at 4.0 ppm, 2.0 ppm, and 1.2 ppm. The integration of the peak near 4.0 ppm indicates an approximately 1:0.09 molar ratio of API to ethyl acetate, with a theoretical ethyl acetate content of 1.5%, similar to the weight loss in the TGA results.

[0510] Example 7-1

[0511] 3,5-Dihydroxybenzoic acid cocrystal Type A was obtained by suspending the raw materials and 3,5-dihydroxybenzoic acid in ethyl acetate. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 52 to 54.

[0512] XRPD results showed that 3,5-dihydroxybenzoic acid cocrystal Type A was a well-crystalline solid. TGA results showed no weight loss during heating to 150°C, but decomposition may occur after 275°C. DSC results revealed a melting endotherm at 203°C. NMR results showed no significant shift in the NMR peaks corresponding to the API compared to the free state, and the NMR integration results were generally consistent with those of the API. The NMR peaks near 9.5 ppm, 6.8 ppm, and 6.4 ppm corresponded to characteristic signal peaks of 3,5-dihydroxybenzoic acid. Based on the integration of the peak near 6.4 ppm, the molar ratio of the API to 3,5-dihydroxybenzoic acid was approximately 1:1. No significant residual organic solvent was observed.

[0513] Example 7-2

[0514] 3,5-Dihydroxybenzoic acid cocrystal Type B was obtained by suspending the raw materials and 3,5-dihydroxybenzoic acid in ethanol / n-heptane (1 / 9, v / v). The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 55 to 57.

[0515] XRPD results showed that 3,5-dihydroxybenzoic acid cocrystal Type B was a well-crystalline solid. TGA results revealed a 0.2% weight loss during heating to 200°C, with potential decomposition occurring after 275°C. DSC results revealed melting signals accompanied by recrystallization at 171°C and 173°C, and a melting endotherm at 204°C. NMR results revealed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The NMR peaks near 9.5 ppm, 6.8 ppm, and 6.4 ppm corresponded to characteristic signal peaks of 3,5-dihydroxybenzoic acid. Based on the integration of the peak near 6.4 ppm, the molar ratio of the API to 3,5-dihydroxybenzoic acid was approximately 1:1. No significant residual organic solvent was observed.

[0516] Example 8

[0517] Gentisic acid cocrystal Type A was obtained by suspending the raw materials and gentisic acid in ethyl acetate. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 58 to 60.

[0518] XRPD results showed that gentisic acid cocrystal Type A was a well-crystalline solid. TGA results indicated a 0.2% weight loss upon heating to 150°C, with possible decomposition occurring after 200°C. DSC results revealed a melting endotherm at 167°C. NMR results revealed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The NMR peaks near 9.1 ppm, 7.1 ppm, 6.9 ppm, and 6.8 ppm corresponded to characteristic signal peaks of gentisic acid, and the integration of the peak near 6.8 ppm indicated an approximately 1:1 molar ratio of the API to gentisic acid. No significant residual organic solvent was observed.

[0519] Example 9

[0520] Para-hydroxybenzoic acid cocrystal Type A was obtained by back titrating a solution of the raw material and para-hydroxybenzoic acid suspended in ethyl acetate in n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 61 to 63.

[0521] XRPD results showed that Type A p-hydroxybenzoic acid cocrystal was a well-crystalline solid. TGA results revealed a 0.1% weight loss upon heating to 150°C, with possible decomposition occurring after 200°C. DSC results revealed a melting endotherm at 124°C. NMR results revealed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. The NMR peaks near 10.2 ppm, 7.8 ppm, and 6.8 ppm corresponded to characteristic signal peaks of p-hydroxybenzoic acid. Based on the integration of the peak near 6.8 ppm, the molar ratio of the API to p-hydroxybenzoic acid was calculated to be approximately 1:0.5. No significant residual organic solvent was observed.

[0522] Example 10

[0523] Oxalic acid cocrystal Type A was obtained by suspending the raw materials and oxalic acid in ethyl acetate. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 64 to 66.

[0524] XRPD results indicated that Type A oxalic acid cocrystal was a well-crystalline solid. TGA results revealed a 0.8% weight loss upon heating to 150°C and a 9.0% weight loss between 150°C and 250°C, likely corresponding to the decomposition and removal of oxalic acid from the oxalic acid cocrystal. DSC results revealed an endothermic signal at 105°C, a melting endothermic peak at 161°C, and a broad endothermic signal at 204°C corresponding to the TGA weight loss. NMR results showed no significant shift in the NMR peak corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API; no significant residual organic solvent was observed. Ion chromatography results indicated an oxalate content of 7.9%, yielding a calculated molar ratio of API to oxalic acid of approximately 1:0.5 (consistent with the 9.0% weight loss observed in the TGA signal).

[0525] Example 11

[0526] The p-toluenesulfonate salt Type A was obtained by suspending the raw materials and p-toluenesulfonic acid in ethanol / n-heptane (1 / 9, v / v). The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 67 to 69.

[0527] XRPD results showed that Type A p-toluenesulfonate was a well-crystalline solid. TGA results showed no weight loss during heating to 200°C, but decomposition may have occurred after 250°C. DSC results revealed a melting endotherm at 128°C. NMR results showed that the NMR peaks at 10.8ppm, 8.6ppm, 8.0ppm, and 7.4ppm corresponding to the API were shifted compared to the free state. The NMR integration results were generally consistent with those of the API, suggesting that the sample had formed a salt. The NMR peaks near 7.5ppm, 7.1ppm, and 2.3ppm corresponded to the characteristic signal peaks of p-toluenesulfonic acid. Based on the integration results of the peak near 7.1ppm, the molar ratio of the API to p-toluenesulfonic acid was approximately 1:1. No significant residual organic solvent was observed.

[0528] Example 12-1

[0529] Trans-aconitic acid cocrystal Type A was obtained by suspending the raw materials and trans-aconitic acid in ethanol / n-heptane (1 / 9, v / v) at room temperature. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 70 to 74.

[0530] XRPD results showed that trans-aconitic acid cocrystal Type A was a solid with average crystallinity. TGA results revealed a 5.7% weight loss upon heating to 120°C, with potential decomposition occurring above 125°C. DSC results revealed endothermic signals associated with melting and decomposition between 80°C and 180°C. NMR results showed no significant shift in the NMR peaks corresponding to the API compared to the free form, and the NMR integration results were generally consistent with those of the API. Peaks near 6.7 ppm and 3.7 ppm correspond to characteristic trans-aconitic acid peaks, and the integration of the peak near 6.7 ppm indicates an approximate 1:1 molar ratio of API to trans-aconitic acid. Peaks characteristic of ethanol were observed near 1.1 ppm and 3.4 ppm, and the integration of the peak near 1.1 ppm indicates an approximate 1:0.8 molar ratio of API to ethanol, with a theoretical ethanol content of 5.5%, similar to the weight loss observed in the TGA results. In a hot stage experiment, trans-aconitic acid cocrystal Type A (053-23-34) was heated to 120°C and held at that temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results changed. The TGA weight loss of the sample after the hot stage experiment was significantly reduced.

[0531] Example 12-2

[0532] Trans-aconitic acid cocrystal Type B was obtained by back titration of the clear solution obtained after the reaction of the raw material and trans-aconitic acid in ethyl acetate in n-heptane. The specific conditions are shown in Example 13. The relevant characterization data are shown in Figures 75 to 78.

[0533] XRPD results showed that trans-aconitic acid cocrystal Type B was a solid with average crystallinity. TGA results showed a 3.0% weight loss upon heating to 120°C, with possible decomposition occurring above 125°C. DSC results revealed endothermic signals associated with melting and decomposition between 70°C and 180°C. NMR results showed no significant shift in the NMR peaks corresponding to the drug substance compared to the free form, and the NMR integration results were generally consistent with those of the drug substance. Peaks near 6.7 ppm and 3.7 ppm corresponded to characteristic trans-aconitic acid peaks, and the integration of the peak near 6.7 ppm indicated an approximately 1:1.1 molar ratio of drug substance to trans-aconitic acid. Characteristic peaks of ethyl acetate were observed at 4.0 ppm, 2.0 ppm, and 1.2 ppm, suggesting the presence of a small amount of residual ethyl acetate. In a hot-stage experiment (053-23-47), trans-aconitic acid cocrystal Type B was heated to 110°C for 10 minutes and then cooled to room temperature. XRPD results indicated that the sample was amorphous.

[0534] The relevant information of the salt forms and co-crystals of the compounds of formula I prepared in the above examples are summarized in the following table:

[0535] a Approximate values ​​calculated based on ion chromatography results, and the rest are based on NMR results

[0536] Example 13

[0537] Approximately 31.2 mg (0.07 mmol) of sample and 1.1 equivalents of acid were weighed and added to ethyl acetate, ethanol / n-heptane (1 / 9, v / v), methanol / MTBE (1 / 9, v / v), and acetone / MTBE (1 / 9, v / v). The mixture was stirred at room temperature for 2-3 days. If a clear solution was obtained, the solution was cooled in a 4°C refrigerator to crystallize and then allowed to stand at -15°C for 1-4 days. If the solution remained clear after cooling, the solution was divided into two portions: one for a two-week volatilization experiment (retaining the original experiment number), and the other for a six-fold volume of antisolvent and stirred at room temperature for one day (a new experiment number). The portion of the solution that produced insufficient solids after the addition of antisolvent was allowed to stand at -15°C for one day. During the experiment, the solution with precipitated solids was centrifuged and dried under vacuum at room temperature. The wet sample from the volatilization experiment was directly subjected to XRPD analysis, while the samples from the remaining experiments were subjected to XRPD analysis after vacuum drying at room temperature. The experimental results are shown in Tables 4 to 6.

[0538] Table 4 Results of preliminary screening experiments on salt forms and cocrystals (1) a The total volume of solvent for all experiments was 1.0 mL, and the samples were suspended at room temperature for 2 days and allowed to stand at -15°C for 1 day. b Dilute to 1M with ethanol before use

[0539] Table 5 Results of preliminary screening experiments on salt forms and cocrystals (2) a The total volume of solvent for all experiments was 1.0 mL, and the samples were suspended at room temperature for 3 days and allowed to stand at -15°C for 4 days. b Dilute to 1M with ethanol before use c Results after cooling to -15℃ d Results after 4℃ cooling e According to the NMR results, the data is not shown

[0540] Table 6 Results of reverse drop crystallization experiments for salt type and eutectic preparation experiments a Results of -15℃ cooling after back-drip

[0541] Example 14

[0542] To ensure that the preparation of the salt form or co-crystal of the compound of formula I is reproducible, the present invention has repeated the preparation experiment. A certain amount of raw materials and 1.1 equivalents of acid were weighed respectively, added to ethyl acetate, ethanol / n-heptane (1 / 9, v / v), methanol / MTBE (1 / 9, v / v) or acetone / MTBE (1 / 9, v / v), and stirred at room temperature for 2-3 days; if it is a clear solution or the amount of solid is insufficient, the solution is placed in a -15°C refrigerator and allowed to stand for 1 day. If it is still a clear solution or the amount of solid is insufficient after cooling, the solution is added to 4 times the volume of anti-solvent and stirred at room temperature for 1 day, or the clear solution or the solution with insufficient solid amount obtained after suspension at room temperature is directly added to 4 times the volume of anti-solvent. During the experiment, the solution with sufficient solid precipitation was centrifuged, and the solid was vacuum dried at room temperature. The experimental results are shown in Table 7.

[0543] Table 7 Repeated preparation experimental results a Hydrochloric acid, sulfuric acid and hydrobromic acid were diluted to 1M with ethanol before use. b The result of direct back-titration without cooling the supernatant after suspension c The volume of antisolvent is 6 times that of good solvent d Suspend at room temperature for 2 days, and the rest of the experiments were 3 days

[0544] Example 15

[0545] The salt form and co-crystal of the compound of formula I were prepared on a laboratory scale. The preparation process is shown in Table 8.

[0546] Table 8 Scale-up preparation of target salt forms and cocrystals

[0547] Fumaric acid cocrystal Type A (053-30-01) was further characterized by XRPD, TGA, DSC, NMR, and PLM. The characterization results are shown in Figures 85 to 89. XRPD results showed that fumaric acid cocrystal Type A was a well-crystalline solid. TGA results showed that fumaric acid cocrystal Type A did not lose weight when heated to 150°C, but decomposition may occur above 210°C. DSC results showed that fumaric acid cocrystal Type A had a melting endotherm at 170.1°C. NMR results showed that the NMR peak corresponding to the API did not shift significantly compared to the free state, and the NMR integration results were basically consistent with those of the API. The peak near 6.6 ppm corresponds to the characteristic signal peak of fumaric acid. Based on the integration results, the molar ratio of API to fumaric acid was calculated to be approximately 1:0.9. No significant residual organic solvent was observed. DVS results showed that the scaled-up fumaric acid cocrystal Type A gained 0.04% weight at 95% humidity and lost 0.04% weight at 0% humidity. During adsorption, the weight gain was 0.00% at 80% humidity, indicating that Type A is virtually hygroscopic. PLM images revealed rod-shaped particles with a particle size generally less than 10 μm. Type A is a well-crystalline anhydrate with virtually no hygroscopicity.

[0548] Test Example 1: Hot Stage Experiment

[0549] A 6-8 mg sample was placed on a glass slide on a hot plate, heated to the target temperature at a rate of 20°C / min, and kept constant at that temperature for 10 min. The solid was then cooled naturally to room temperature and subjected to XRPD testing. The results are shown in Table 9.

[0550] Table 9 Hot stage test results

[0551] Test Example 2: Solubility in Water

[0552] In order to facilitate the comparison of the advantages of different salt forms and cocrystals, the solubility of different salt forms, cocrystals and free forms in water was evaluated. The corresponding results are shown in Table 10 and Figures 79 to 84.

[0553] The results showed that, with the exception of maleic acid cocrystal Type B, the solubility of the remaining salts and cocrystals in 25°C water after 2 hours was lower than that of free Form A. The XRPD patterns of the remaining solids of free Form A, fumaric acid cocrystal Type A, and gentisic acid cocrystal Type A showed no significant changes after solubility testing. The XRPD patterns of the remaining solids of oxalic acid cocrystal Type A and p-toluenesulfonate salt Type A changed after solubility testing, transforming into a new solid form. The XRPD patterns of the remaining solids of hydrochloride salt Type A, hydrobromide salt Type E, and maleic acid cocrystal Type B changed after solubility testing, transforming into another identical solid form (designated free Form C). NMR results showed that the integrals of the remaining solids of oxalic acid cocrystal Type A and p-toluenesulfonate salt Type A and maleic acid cocrystal Type B were consistent with those of the free form, with no obvious ligand signal peaks observed, suggesting that the samples had dissociated into other free crystalline forms.

[0554] Table 10 Water solubility test results a The starting material did not undergo crystal transformation before the experiment b The concentration of the free form was calculated based on the standard curve

[0555] Test Example 3 Biological Media Solubility Test

[0556] Dynamic solubility measurements were performed on fumaric acid cocrystal Type A, maleic acid cocrystal Type B, hydrochloride Type A, and free Form A in three biological media (FaSSIF, FeSSIF, and FaSSGF). The corresponding results are shown in Table 11 and Figures 91 to 94.

[0557] The results showed that the 24-hour solubility of fumaric acid eutectic Type A, maleic acid eutectic Type B, hydrochloride Type A, and free Form A in the media ranked as FeSSIF > FaSSIF > FaSSGF. The solubilities of fumaric acid eutectic Type A, maleic acid eutectic Type B, and free Form A in FaSSIF and FeSSIF after 24 hours were lower than those after 2 hours, and no solubility was detected in FaSSGF. The solubility of hydrochloride Type A in all three media after 24 hours was lower than that after 2 hours. The residual solid of fumaric acid eutectic Type A in FaSSGF after 24 hours remained as fumaric acid eutectic Type A, while the residual solid of the other samples in the three biological media after 24 hours was all free Form B. The pH of the solutions of fumaric acid eutectic Type A, maleic acid eutectic Type B, and hydrochloride Type A decreased after 24 hours in FaSSIF and FeSSIF, while the pH of the media for the other samples did not change significantly after 24 hours.

[0558] Table 11 Dynamic solubility test in biological media a The lower limit of the standard curve is 0.1 μg / mL b Calculate the concentration of the corresponding free state in the solution according to the standard curve

[0559] Test Example 4: Stability Study

[0560] The stability of fumaric acid cocrystal Type A was studied under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated conditions (40°C / 75% RH). Samples were taken for XRPD and HPLC characterization at 7 and 15 days, respectively. The results are shown in Tables 12 and 13 and Figure 90. The XRPD results showed that fumaric acid cocrystal Type A was stable under high temperature, high humidity, light, and accelerated conditions for 7 and 15 days, with no crystal transformation and no significant change in appearance. In terms of chemical purity, fumaric acid cocrystal Type A did not change significantly under all test conditions.

[0561] Table 12 Stability study results

[0562] Table 13 HPLC purity analysis results of fumaric acid cocrystal Type A stability samples

[0563] In the systematic evaluation of fumaric acid cocrystal Type A, in addition to basic sample characterization and solubility evaluation, hygroscopicity and stability were also investigated. The evaluation results showed:

[0564] 1) In terms of hygroscopicity, fumaric acid eutectic Type A is almost non-hygroscopic.

[0565] 2) In terms of stability, fumaric acid cocrystal Type A did not undergo crystal transformation after 7 days and 15 days under high temperature, high humidity, light, and accelerated conditions, and its appearance and purity did not change significantly.

[0566] Test Example 5 Pharmacokinetic Experiment

[0567] The vehicle was 0.5% MC. Beagle dogs were fasted overnight and fed 4 hours after dosing. N = 4 dogs. Weigh before dosing, and the dose was calculated based on body weight. Doses were 10 mg / kg and 30 mg / kg; the dosing volume was 5 mL / kg. Blood was collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 48, and 72 hours after dosing.

[0568] Blood samples were collected from the forelimb vein, approximately 1 mL per sample, anticoagulated with sodium heparin, placed on ice, and centrifuged within 1 hour to separate plasma (2200 g, 10 minutes, 2-8°C). Plasma samples were stored at -80°C until analysis.

[0569] · LC-MS / MS was used to determine the concentration of the target analyte in beagle dog plasma. The pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on the plasma concentration data at different time points, providing the AUC 0-t , AUC 0-∞ 、C max 、T max , and T 1 / 2 Parameters and their means and standard deviations.

[0570] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the claims of this application.

Claims

1. A salt form or co-crystal of a pharmaceutically acceptable salt of a compound of formula I; The salt form or co-crystal of the pharmaceutically acceptable salt is a salt form or co-crystal formed by the compound of formula I and an acid or a base, preferably a salt form or co-crystal formed by the compound of formula I and an acid; Preferably, the acid can be selected from an inorganic acid or an organic acid, such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, 3,5-dihydroxybenzoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2- Hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxybenzoic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, L-tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, gentisic acid, trans-aconitic acid, hemisulfuric acid or thiocyanic acid, and nicotinamide, 1,4-benzenediol or pamoic acid. As an example, the acid may be selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, 3,5-dihydroxybenzoic acid, gentisic acid, p-hydroxybenzoic acid, oxalic acid, p-toluenesulfonic acid and trans-aconitic acid; Preferably, the base may be selected from inorganic bases, such as alkali metal hydroxides or alkaline earth metal hydroxides, preferably sodium hydroxide or potassium hydroxide.

2. The salt form or co-crystal according to claim 1, characterized in that: The pharmaceutically acceptable salt of the compound of formula I is selected from one of its hydrochloride, hydrobromide, sulfate and p-toluenesulfonate; Preferably, the co-crystal of the pharmaceutically acceptable salt of the compound of formula I is selected from one of its fumaric acid co-crystal, maleic acid co-crystal, tartaric acid co-crystal (L-tartaric acid co-crystal), 3,5-dihydroxybenzoic acid co-crystal, gentisic acid co-crystal, p-hydroxybenzoic acid co-crystal, oxalic acid co-crystal and trans-aconitic acid co-crystal.

3. The salt form or co-crystal according to claim 1 or 2, characterized in that: The co-crystal of the pharmaceutically acceptable salt of the compound of formula I is a co-crystal formed by the compound of formula I and fumaric acid, namely, the co-crystal of the compound of formula I and fumaric acid.

4. The salt form or co-crystal according to any one of claims 1 to 3, characterized in that: The salt form and / or co-crystal of the pharmaceutically acceptable salt of the compound represented by Formula I may be selected from: Hydrochloride Type A; Hydrobromide Type A, Hydrobromide Type B, Hydrobromide Type C, Hydrobromide Type D, Hydrobromide Type E; Sulfate Type A; Fumaric acid eutectic Type A; Maleic acid eutectic Type A, maleic acid eutectic Type B; tartaric acid eutectic Type A, tartaric acid eutectic Type B, tartaric acid eutectic Type C; 3,5-dihydroxybenzoic acid eutectic Type A, 3,5-dihydroxybenzoic acid eutectic Type B; gentisic acid eutectic Type A; p-hydroxybenzoic acid eutectic Type A; oxalic acid eutectic Type A; p-toluenesulfonate Type A; trans-aconitic acid eutectic Type A, trans-aconitic acid eutectic Type B; A hydrochloride Type A of a compound of formula I, wherein the hydrochloride Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 18.06±0.2°, 18.80±0.2°, and 22.24±0.2°; Preferably, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.06±0.2°, 18.80±0.2°, 21.35±0.2°, 22.24±0.2°, and 26.67±0.2°; Preferably, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.06±0.2°, 18.80±0.2°, 21.35±0.2°, 22.24±0.2°, 22.67±0.2°, 23.02±0.2°, 25.68±0.2°, and 26.67±0.2°; Preferably, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.06±0.2°, 18.80±0.2°, 21.35±0.2°, 22.24±0.2°, 22.67±0.2°, 23.02±0.2°, 24.26±0.2°, 25.68±0.2°, 26.67±0.2°, and 30.19±0.2°; Preferably, the hydrochloride Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Table 1-1, wherein the error range of the 2θ angle is ±0.20°: Table 1-1 XRPD analysis data of hydrochloride Type A Preferably, the hydrochloride salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 4; Preferably, differential scanning calorimetry (DSC) analysis of the hydrochloride Type A shows an endothermic peak when heated to a peak temperature of about 160.6°C; Preferably, the hydrochloride salt Type A has a DSC graph substantially as shown in Figure 5; Preferably, the hydrochloride Type A has a weight loss of about 4.6% in the range of 100°C to 200°C by thermogravimetric analysis (TGA); Preferably, the hydrochloride salt Type A has a TGA graph substantially as shown in Figure 5; Preferably, the hydrochloride Type A is an anhydrate or hydrate of the hydrochloride of the compound of formula I; A hydrobromide salt Type A of a compound of formula I, wherein the hydrobromide salt Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 21.95±0.2°, 24.55±0.2°, and 25.08±0.2°; Preferably, the hydrobromide salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.95±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, and 26.77±0.2°; Preferably, the hydrobromide salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.19±0.2°, 21.95±0.2°, 22.53±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, 26.77±0.2°, and 28.89±0.2°; Preferably, the hydrobromide salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.19±0.2°, 18.61±0.2°, 21.95±0.2°, 22.53±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, 26.77±0.2°, 27.51±0.2°, and 28.89±0.2°; Preferably, the hydrobromide salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Table 1-2, wherein the error range of the 2θ angle is ±0.20°: Table 1-2 XRPD analysis data of hydrobromide Type A Preferably, the hydrobromide salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 9; Preferably, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type A shows an endothermic peak when heated to a peak temperature of 90.1°C and / or 183.7°C, and an exothermic peak near a peak temperature of 128.2°C; Preferably, the hydrobromide salt Type A has a DSC graph substantially as shown in Figure 10; Preferably, the hydrobromide salt Type A has a weight loss of about 4.1% in the range of room temperature to 150°C by thermogravimetric analysis (TGA); Preferably, the hydrobromide salt Type A has a TGA graph substantially as shown in Figure 10; Preferably, the hydrobromide Type A is an anhydrate or hydrate of the hydrobromide of the compound of formula I; A hydrobromide salt Type B of a compound of formula I, wherein the hydrobromide salt Type B uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 18.30±0.2°, 25.23±0.2°, and 27.55±0.2°; Preferably, the hydrobromide salt Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 18.30±0.2°, 21.54±0.2°, 25.23±0.2°, 27.41±0.2°, and 27.55±0.2°; Preferably, the hydrobromide salt Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.73±0.2°, 14.64±0.2°, 18.30±0.2°, 21.54±0.2°, 25.23±0.2°, 26.94±0.2°, 27.41±0.2°, and 27.55±0.2°; Preferably, the hydrobromide salt Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.73±0.2°, 14.64±0.2°, 18.30±0.2°, 21.54±0.2°, 24.55±0.2°, 25.23±0.2°, 26.94±0.2°, 27.16±0.2°, 27.41±0.2°, and 27.55±0.2°; Preferably, the hydrobromide salt Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-3, wherein the error range of the 2θ angle is ±0.20°: Table 1-3 XRPD analysis data of hydrobromide Type B Preferably, the hydrobromide salt Type B has an X-ray powder diffraction pattern substantially as shown in Figure 14; Preferably, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type B shows an endothermic peak near a peak temperature of 91.5°C and an exothermic peak near a peak temperature of 220.3°C when heated; Preferably, the hydrobromide salt Type B has a DSC graph substantially as shown in Figure 16; Preferably, the hydrobromide salt Type B has a weight loss of about 3.3% in the range of room temperature to 150° C. by thermogravimetric analysis (TGA); Preferably, the hydrobromide salt Type B has a TGA graph substantially as shown in Figure 16; Preferably, the hydrobromide salt Type B is an anhydrate or hydrate of the hydrobromide salt of the compound of formula I; A hydrobromide salt Type C of a compound of formula I, wherein the hydrobromide salt Type C uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.09±0.2°, 22.26±0.2°, and 26.56±0.2°; Preferably, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.09±0.2°, 17.52±0.2°, 21.25±0.2°, 22.26±0.2°, and 26.56±0.2°; Preferably, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.09±0.2°, 6.34±0.2°, 17.52±0.2°, 18.45±0.2°, 21.25±0.2°, 22.26±0.2°, 22.82±0.2°, and 26.56±0.2°; Preferably, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.09±0.2°, 6.34±0.2°, 11.10±0.2°, 17.52±0.2°, 18.45±0.2°, 21.25±0.2°, 22.26±0.2°, 22.82±0.2°, 23.64±0.2°, and 26.56±0.2°; Preferably, the hydrobromide Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-4, wherein the error range of the 2θ angle is ±0.20°: Table 1-4 XRPD analysis data of hydrobromide Type C Preferably, the hydrobromide salt Type C has an X-ray powder diffraction pattern substantially as shown in Figure 18; Preferably, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type C shows an endothermic peak when heated to a peak temperature of 90.4°C and / or 177.6°C; Preferably, the hydrobromide salt Type C has a DSC graph substantially as shown in Figure 19; Preferably, the hydrobromide salt Type C has a weight loss of about 2.2% in the range of room temperature to 150° C. by thermogravimetric analysis (TGA); Preferably, the hydrobromide salt Type C has a TGA graph substantially as shown in Figure 19; Preferably, the hydrobromide Type C is an anhydrate or hydrate of the hydrobromide of the compound of formula I; A hydrobromide salt Type D of a compound of formula I, wherein the hydrobromide salt Type D has characteristic peaks at 3.72±0.2°, 17.89±0.2°, and 28.71±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Preferably, the hydrobromide Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.72±0.2°, 17.89±0.2°, 21.48±0.2°, 25.08±0.2°, and 28.71±0.2°; Preferably, the hydrobromide salt Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.72±0.2°, 17.89±0.2°, 20.71±0.2°, 21.48±0.2°, 22.34±0.2°, 25.08±0.2°, 27.31±0.2°, and 28.71±0.2°; Preferably, the hydrobromide Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.72±0.2°, 17.89±0.2°, 19.79±0.2°, 20.71±0.2°, 21.48±0.2°, 22.34±0.2°, 22.53±0.2°, 25.08±0.2°, 27.31±0.2°, and 28.71±0.2°; Preferably, the hydrobromide salt Type D uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-5, wherein the error range of the 2θ angle is ±0.20°: Table 1-5 XRPD analysis data of hydrobromide Type D Preferably, the hydrobromide salt Type D has an X-ray powder diffraction pattern substantially as shown in Figure 21; A hydrobromide salt Type E of a compound of formula I, wherein the hydrobromide salt Type E uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 21.00±0.2°, 21.46±0.2°, and 27.22±0.2°; Preferably, the hydrobromide salt Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.00±0.2°, 21.46±0.2°, 22.92±0.2°, 27.22±0.2°, and 28.21±0.2°; Preferably, the hydrobromide salt Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.00±0.2°, 21.46±0.2°, 22.92±0.2°, 23.19±0.2°, 24.94±0.2°, 26.61±0.2°, 27.22±0.2°, and 28.21±0.2°; Preferably, the hydrobromide Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.00±0.2°, 21.46±0.2°, 22.92±0.2°, 23.19±0.2°, 23.76±0.2°, 24.94±0.2°, 26.61±0.2°, 27.22±0.2°, 28.21±0.2°, and 29.14±0.2°; Preferably, the hydrobromide salt Type E uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-6, wherein the error range of the 2θ angle is ±0.20°: Table 1-6 XRPD analysis data of hydrobromide Type E Preferably, the hydrobromide salt Type E has an X-ray powder diffraction pattern substantially as shown in Figure 23; Preferably, differential scanning calorimetry (DSC) analysis of the hydrobromide salt Type E shows an endothermic peak when heated to a peak temperature of about 199.5°C; Preferably, the hydrobromide salt Type E has a DSC graph substantially as shown in Figure 24; Preferably, the hydrobromide salt Type E has a TGA graph substantially as shown in Figure 24; Preferably, the hydrobromide salt Type E is an anhydrate of the hydrobromide salt of the compound of formula I; A sulfate salt Type A of a compound of formula I, wherein the sulfate salt Type A has characteristic peaks at 25.10±0.2°, 25.16±0.2°, and 29.63±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Preferably, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.87±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2°; Preferably, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.30±0.2°, 17.05±0.2°, 17.87±0.2°, 21.97±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2°; Preferably, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 4.30±0.2°, 17.05± There are characteristic peaks at 0.2°, 17.87±0.2°, 18.30±0.2°, 20.80±0.2°, 21.97±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2°; Preferably, the sulfate Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-7, wherein the error range of the 2θ angle is ±0.20°: Table 1-7 XRPD analysis data of sulfate Type A Preferably, the sulfate Type A has an X-ray powder diffraction pattern substantially as shown in Figure 26; Preferably, differential scanning calorimetry (DSC) analysis of the sulfate Type A shows an endothermic peak when heated to a peak temperature of 81.1°C and / or 156.9°C; Preferably, the sulfate Type A has a DSC graph substantially as shown in Figure 27; Preferably, the thermogravimetric analysis (TGA) of the sulfate Type A shows a weight loss of about 6.2% in the range of room temperature to 150°C; Preferably, the sulfate Type A has a TGA graph substantially as shown in Figure 27; Preferably, the sulfate Type A is a hydrate of the sulfate of the compound of formula I; A fumaric acid cocrystal Type A of a compound of formula I, wherein the fumaric acid cocrystal Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 17.34±0.2°, 24.09±0.2°, and 25.95±0.2°; Preferably, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.93±0.2°, 17.34±0.2°, 22.03±0.2°, 24.09±0.2°, and 25.95±0.2°; Preferably, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.93±0.2°, 16.86±0.2°, 17.34±0.2°, 22.03±0.2°, 22.46±0.2°, 24.09±0.2°, 25.95±0.2°, and 30.21±0.2°; Preferably, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.93±0.2°, 16.86±0.2°, 17.34±0.2°, 21.27±0.2°, 22.03±0.2°, 22.46±0.2°, 24.09±0.2°, 25.95±0.2°, 28.83±0.2°, and 30.21±0.2°; Preferably, the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-8, wherein the error range of the 2θ angle is ±0.20°: Table 1-8 XRPD analysis data of fumaric acid eutectic Type A Preferably, the fumaric acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 85; Preferably, differential scanning calorimetry (DSC) analysis of the fumaric acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of about 170.1°C; Preferably, the fumaric acid cocrystal Type A has a DSC graph substantially as shown in Figure 86; Preferably, the fumaric acid cocrystal Type A has a TGA graph substantially as shown in Figure 86; Preferably, the fumaric acid cocrystal Type A is a fumaric acid cocrystal anhydrate of the compound of formula I; A maleic acid cocrystal Type A of a compound of formula I, wherein the maleic acid cocrystal Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 19.58±0.2°, 22.36±0.2°, and 25.31±0.2°; Preferably, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 19.58±0.2°, 22.36±0.2°, 22.73±0.2°, 23.45±0.2°, and 25.31±0.2°; Preferably, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.11±0.2°, 19.58±0.2°, 21.50±0.2°, 22.36±0.2°, 22.73±0.2°, 23.45±0.2°, 25.31±0.2°, and 29.28±0.2°; Preferably, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 15.42±0.2°, 17.11±0.2°, 19.58±0.2°, 21.50±0.2°, 22.36±0.2°, 22.73±0.2°, 23.45±0.2°, 24.26±0.2°, 25.31±0.2°, and 29.28±0.2°; Preferably, the maleic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-9, wherein the error range of the 2θ angle is ±0.20°: Table 1-9 XRPD analysis data of maleic acid cocrystal Type A Preferably, the maleic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 34; Preferably, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type A shows endothermic peaks near the peak temperatures of 107.8°C, 118.5°C and / or 155.6°C when heated; Preferably, the maleic acid cocrystal Type A has a DSC graph substantially as shown in Figure 35; Preferably, the thermogravimetric analysis (TGA) of the maleic acid cocrystal Type A shows a weight loss of about 11.4% in the range of 100° C. to 200° C.; Preferably, the maleic acid cocrystal Type A has a TGA graph substantially as shown in Figure 35; Preferably, the maleic acid cocrystal Type A is an anhydrate of the maleic acid cocrystal of the compound of formula I; A maleic acid cocrystal Type B of a compound of formula I, wherein the maleic acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 22.57±0.2°, 25.78±0.2°, and 26.94±0.2°; Preferably, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.92±0.2°, 22.57±0.2°, 24.92±0.2°, 25.78±0.2°, and 26.94±0.2°; Preferably, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.31±0.2°, 16.92±0.2°, 20.32±0.2°, 22.57±0.2°, 24.92±0.2°, 25.78±0.2°, 26.94±0.2°, and 27.22±0.2°; Preferably, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.17±0.2°, 16.31±0.2°, 16.92±0.2°, 18.80±0.2°, 20.32±0.2°, 22.57±0.2°, 24.92±0.2°, 25.78±0.2°, 26.94±0.2°, and 27.22±0.2°; Preferably, the maleic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-10, wherein the error range of the 2θ angle is ±0.20°: Table 1-10 XRPD analysis data of maleic acid cocrystal Type B Preferably, the maleic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 37; Preferably, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type B shows an endothermic peak when heated to a peak temperature of 127.3°C; Preferably, the maleic acid cocrystal Type B has a DSC graph substantially as shown in Figure 38; Preferably, the thermogravimetric analysis (TGA) of the maleic acid eutectic Type B shows a weight loss of about 19.5% in the range of 100° C. to 200° C.; Preferably, the maleic acid cocrystal Type B has a TGA graph substantially as shown in Figure 38; Preferably, the maleic acid cocrystal Type B is an anhydrate of the maleic acid cocrystal of the compound of formula I; A tartaric acid cocrystal Type A of a compound of formula I, wherein the tartaric acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.79±0.2°, 25.43±0.2°, and 26.38±0.2°; Preferably, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.38±0.2°, 18.84±0.2°, 21.79±0.2°, 25.43±0.2°, and 26.38±0.2°; Preferably, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.38±0.2°, 18.84±0.2°, 21.00±0.2°, 21.79±0.2°, 23.74±0.2°, 24.73±0.2°, 25.43±0.2°, and 26.38±0.2°; Preferably, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.38±0.2°, 18.84±0.2°, 19.58±0.2°, 21.00±0.2°, 21.79±0.2°, 23.74±0.2°, 24.73±0.2°, 25.43±0.2°, 26.38±0.2°, and 28.85±0.2°; Preferably, the tartaric acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-11, wherein the error range of the 2θ angle is ±0.20°: Table 1-11 XRPD analysis data of tartaric acid cocrystal Type A Preferably, the tartaric acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 40; Preferably, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type A shows endothermic peaks when heated to peak temperatures of 87.5°C, 102.6°C, 135.7°C and / or 187.5°C; Preferably, the tartaric acid cocrystal Type A has a DSC graph substantially as shown in Figure 41; Preferably, the thermogravimetric analysis (TGA) of the tartaric acid eutectic Type A shows a weight loss of about 2.2% in the range of room temperature to 150°C; Preferably, the tartaric acid cocrystal Type A has a TGA graph substantially as shown in Figure 41; Preferably, the tartaric acid cocrystal Type A is an anhydrate of the tartaric acid cocrystal of the compound of formula I; A tartaric acid cocrystal Type B of a compound of formula I, wherein the tartaric acid cocrystal Type B uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 4.03±0.2°, 5.18±0.2°, and 20.30±0.2°; Preferably, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, 5.53±0.2°, 18.20±0.2°, and 20.30±0.2°; Preferably, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, 5.53±0.2°, 6.28±0.2°, 12.27±0.2°, 17.50±0.2°, 18.20±0.2°, and 20.30±0.2°; Preferably, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.03±0.2°, 5.18±0.2°, 5.53±0.2°, 6.28±0.2°, 12.27±0.2°, 16.27±0.2°, 17.50±0.2°, 18.20±0.2°, 20.30±0.2°, and 27.04±0.2°; Preferably, the tartaric acid eutectic Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-12, wherein the error range of the 2θ angle is ±0.20°: Table 1-12 XRPD analysis data of tartaric acid cocrystal Type B Preferably, the tartaric acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 44; Preferably, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type B shows an endothermic peak when heated to a peak temperature of 88.4°C and / or 172.5°C; Preferably, the tartaric acid eutectic Type B has a DSC graph substantially as shown in Figure 45; Preferably, the thermogravimetric analysis (TGA) of the tartaric acid eutectic Type B shows a weight loss of about 3.3% in the range of room temperature to 150°C; Preferably, the tartaric acid cocrystal Type B has a TGA graph substantially as shown in Figure 45; Preferably, the tartaric acid cocrystal Type B is an anhydrate or hydrate of the tartaric acid cocrystal of the compound of formula I; A tartaric acid cocrystal Type C of a compound of formula I, wherein the tartaric acid cocrystal Type C uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.85±0.2°, 12.99±0.2°, and 21.27±0.2°; Preferably, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.73±0.2°, 6.85±0.2°, 12.19±0.2°, 12.99±0.2°, and 21.27±0.2°; Preferably, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.51±0.2°, 6.73±0.2°, 6.85±0.2°, 12.19±0.2°, 12.99±0.2°, 20.78±0.2°, 21.27±0.2°, and 25.88±0.2°; Preferably, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.51±0.2°, 6.73±0.2°, 6.85±0.2°, 12.19±0.2°, 12.99±0.2°, 20.16±0.2°, 20.78±0.2°, 20.98±0.2°, 21.27±0.2°, and 25.88±0.2°; Preferably, the tartaric acid eutectic Type C uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-13, wherein the error range of the 2θ angle is ±0.20°: Table 1-13 XRPD analysis data of tartaric acid eutectic Type C Preferably, the tartaric acid cocrystal Type C has an X-ray powder diffraction pattern substantially as shown in Figure 49; Preferably, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type C shows endothermic peaks near the peak temperatures of 87.4°C, 113.2°C, 137.2°C and / or 189.5°C; Preferably, the tartaric acid eutectic Type C has a DSC graph substantially as shown in Figure 50; Preferably, the thermogravimetric analysis (TGA) of the tartaric acid eutectic Type C shows a weight loss of about 1.9% in the range of room temperature to 150°C; Preferably, the tartaric acid eutectic Type C has a TGA graph substantially as shown in Figure 50; Preferably, the tartaric acid cocrystal Type C is an anhydrate or hydrate of the tartaric acid cocrystal of the compound of formula I; A 3,5-dihydroxybenzoic acid cocrystal Type A of a compound of formula I, wherein the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.19±0.2°, 22.92±0.2°, and 27.49±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.80±0.2°, 19.23±0.2°, 21.19±0.2°, 22.92±0.2°, and 27.49±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.80±0.2°, 19.23±0.2°, 19.70±0.2°, 21.19±0.2°, 22.92±0.2°, 25.66±0.2°, 26.13±0.2°, and 27.49±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.80±0.2°, 19.23±0.2°, 19.70±0.2°, 21.19±0.2°, 21.50±0.2°, 22.92±0.2°, 25.66±0.2°, 25.90±0.2°, 26.13±0.2°, and 27.49±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-14, wherein the error range of the 2θ angle is ±0.20°: Table 1-14 XRPD analysis data of 3,5-dihydroxybenzoic acid cocrystal Type A Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 52; Preferably, differential scanning calorimetry (DSC) analysis of the 3,5-dihydroxybenzoic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of 203.1°C; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A has a DSC graph substantially as shown in FIG53 ; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A has a TGA graph substantially as shown in Figure 53; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A is an anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of the compound of formula I; A 3,5-dihydroxybenzoic acid cocrystal Type B of a compound of formula I, wherein the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 23.47±0.2°, and 28.05±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 17.40±0.2°, 21.79±0.2°, 23.47±0.2°, and 28.05±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 17.40±0.2°, 17.56±0.2°, 21.79±0.2°, 23.17±0.2°, 23.47±0.2°, 28.05±0.2°, and 28.31±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.10±0.2°, 17.40±0.2°, 17.56±0.2°, 21.79±0.2°, 23.17±0.2°, 23.47±0.2°, 24.32±0.2°, 26.73±0.2°, 28.05±0.2°, and 28.31±0.2°; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-15, wherein the error range of the 2θ angle is ±0.20°: Table 1-15 XRPD analysis data of 3,5-dihydroxybenzoic acid cocrystal Type B Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 55; Preferably, differential scanning calorimetry (DSC) analysis of the 3,5-dihydroxybenzoic acid cocrystal Type B shows an endothermic peak near a peak temperature of 170.5 and / or 203.6° C., and an exothermic peak near a peak temperature of 172.5° C.; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B has a DSC graph substantially as shown in FIG56 ; Preferably, the thermogravimetric analysis (TGA) of the 3,5-dihydroxybenzoic acid cocrystal Type B shows a weight loss of about 0.2% in the range of room temperature to 200°C; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B has a TGA graph substantially as shown in FIG56 ; Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B is an anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of the compound of formula I; A gentisic acid cocrystal Type A of a compound of formula I, wherein the gentisic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 19.29±0.2°, 23.45±0.2°, and 27.47±0.2°; Preferably, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 15.03±0.2°, 19.29±0.2°, 23.45±0.2°, 27.47±0.2°, and 27.80±0.2°; Preferably, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.26±0.2°, 15.03±0.2°, 19.29±0.2°, 23.45±0.2°, 26.63±0.2°, 26.98±0.2°, 27.47±0.2°, and 27.80±0.2°; Preferably, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 13.26±0.2°, 15.03±0.2°, 19.29±0.2°, 21.25±0.2°, 23.45±0.2°, 26.63±0.2°, 26.98±0.2°, 27.47±0.2°, 27.80±0.2°, and 29.39±0.2°; Preferably, the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-16, wherein the error range of the 2θ angle is ±0.20°: Table 1-16 XRPD analysis data of gentisic acid cocrystal Type A Preferably, the gentisic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 58; Preferably, differential scanning calorimetry (DSC) analysis of the gentisic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of about 166.7°C; Preferably, the gentisic acid cocrystal Type A has a DSC graph substantially as shown in Figure 59; Preferably, the thermogravimetric analysis (TGA) of the gentisic acid cocrystal Type A shows a weight loss of about 0.2% in the range from room temperature to 150°C; Preferably, the gentisic acid cocrystal Type A has a TGA graph substantially as shown in Figure 59; Preferably, the gentisic acid cocrystal Type A is an anhydrate of the gentisic acid cocrystal of the compound of formula I; A p-hydroxybenzoic acid cocrystal Type A of a compound of formula I, wherein the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.93±0.2°, 24.77±0.2°, and 26.85±0.2°; Preferably, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 21.68±0.2°, 21.93±0.2°, 23.43±0.2°, 24.77±0.2°, and 26.85±0.2°; Preferably, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.31±0.2°, 17.52±0.2°, 21.68±0.2°, 21.93±0.2°, 23.43±0.2°, 24.77±0.2°, 26.32±0.2°, and 26.85±0.2°; Preferably, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.31±0.2°, 17.13±0.2°, 17.52±0.2°, 21.68±0.2°, 21.93±0.2°, 23.43±0.2°, 24.77±0.2°, 25.00±0.2°, 26.32±0.2°, and 26.85±0.2°; Preferably, the p-hydroxybenzoic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-17, wherein the error range of the 2θ angle is ±0.20°: Table 1-17 XRPD analysis data of p-hydroxybenzoic acid cocrystal Type A Preferably, the p-hydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 61; Preferably, differential scanning calorimetry (DSC) analysis of the p-hydroxybenzoic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of about 124.4°C; Preferably, the p-hydroxybenzoic acid cocrystal Type A has a DSC graph substantially as shown in Figure 62; Preferably, the thermogravimetric analysis (TGA) of the p-hydroxybenzoic acid cocrystal Type A shows a weight loss of about 0.1% in the range from room temperature to 150° C.; Preferably, the p-hydroxybenzoic acid cocrystal Type A has a TGA graph substantially as shown in Figure 62; Preferably, the p-hydroxybenzoic acid cocrystal Type A is an anhydrate of the p-hydroxybenzoic acid cocrystal of the compound of formula I; An oxalic acid cocrystal Type A of a compound of formula I, wherein the oxalic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.64±0.2°, 26.69±0.2°, and 27.96±0.2°; Preferably, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 16.64±0.2°, 17.01±0.2°, 20.96±0.2°, 26.69±0.2°, and 27.96±0.2°; Preferably, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.37±0.2°, 16.64±0.2°, 17.01±0.2°, 20.96±0.2°, 22.57±0.2°, 26.69±0.2°, 27.96±0.2°, and 29.04±0.2°; Preferably, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 14.37±0.2°, 16.64±0.2°, 17.01±0.2°, 17.67±0.2°, 20.96±0.2°, 22.57±0.2°, 25.90±0.2°, 26.69±0.2°, 27.96±0.2°, and 29.04±0.2°; Preferably, the oxalic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-18, wherein the error range of the 2θ angle is ±0.20°: Table 1-18 XRPD analysis data of oxalic acid cocrystal Type A Preferably, the oxalic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 64; Preferably, differential scanning calorimetry (DSC) analysis of the oxalic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of 105.0°C, 160.7°C and / or 203.7°C; Preferably, the oxalic acid cocrystal Type A has a DSC graph substantially as shown in Figure 65; Preferably, the thermogravimetric analysis (TGA) of the oxalic acid cocrystal Type A shows a weight loss of about 0.8% in the range of room temperature to 150° C., and / or a weight loss of about 9.0% in the range of 150° C. to 250° C.; Preferably, the oxalic acid cocrystal Type A has a TGA graph substantially as shown in Figure 65; Preferably, the oxalic acid cocrystal Type A is an anhydrate of the oxalic acid cocrystal of the compound of formula I; A p-toluenesulfonate salt Type A of a compound of formula I, wherein the p-toluenesulfonate salt Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 17.36±0.2°, 21.93±0.2°, and 24.55±0.2°; Preferably, the p-toluenesulfonate salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.36±0.2°, 21.93±0.2°, 23.49±0.2°, 24.55±0.2°, and 25.82±0.2°; Preferably, the p-toluenesulfonate salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.10±0.2°, 17.36±0.2°, 18.53±0.2°, 21.93±0.2°, 23.49±0.2°, 24.55±0.2°, 25.82±0.2°, and 28.77±0.2°; Preferably, the p-toluenesulfonate salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.10±0.2°, 17.36±0.2°, 18.53±0.2°, 19.35±0.2°, 21.93±0.2°, 23.49±0.2°, 24.55±0.2°, 25.82±0.2°, 28.77±0.2°, and 31.20±0.2°; Preferably, the p-toluenesulfonate salt Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-19, wherein the error range of the 2θ angle is ±0.20°: Table 1-19 XRPD analysis data of p-toluenesulfonate Type A Preferably, the p-toluenesulfonate salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 67; Preferably, differential scanning calorimetry (DSC) analysis of the p-toluenesulfonate salt Type A shows an endothermic peak when heated to a peak temperature of about 127.7°C; Preferably, the p-toluenesulfonate salt Type A has a DSC graph substantially as shown in Figure 68; Preferably, the p-toluenesulfonate salt Type A has a TGA graph substantially as shown in Figure 68; Preferably, the p-toluenesulfonate salt Type A is an anhydrous form of the p-toluenesulfonate salt of the compound of formula I; A trans-aconitic acid cocrystal Type A of a compound of formula I, wherein the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.44±0.2°, 22.73±0.2°, and 23.54±0.2°; Preferably, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.21±0.2°, 17.44±0.2°, 22.73±0.2°, 23.54±0.2°, and 24.32±0.2°; Preferably, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.55±0.2°, 17.21±0.2°, 17.44±0.2°, 22.20±0.2°, 22.73±0.2°, 23.54±0.2°, 24.32±0.2°, and 26.28±0.2°; Preferably, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.55±0.2°, 11.82±0.2°, 11.88±0.2°, 17.21±0.2°, 17.44±0.2°, 22.20±0.2°, 22.49±0.2°, 22.73±0.2°, 23.54±0.2°, 24.32±0.2°, 26.28±0.2°, and 27.98±0.2°; Preferably, the trans-aconitic acid cocrystal Type A uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-20, wherein the error range of the 2θ angle is ±0.20°: Table 1-20 XRPD analysis data of trans-aconitic acid cocrystal Type A Preferably, the trans-aconitic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 70; Preferably, differential scanning calorimetry (DSC) analysis of the trans-aconitic acid cocrystal Type A shows endothermic peaks when heated to peak temperatures near 55.6°C, 104.9°C, 114.9°C, 129.9°C, 136.1°C and / or 149.9°C; Preferably, the trans-aconitic acid cocrystal Type A has a DSC graph substantially as shown in Figure 71; Preferably, the thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type A shows a weight loss of about 5.7% in the range from room temperature to 120°C; Preferably, the trans-aconitic acid cocrystal Type A has a TGA graph substantially as shown in Figure 71; Preferably, the trans-aconitic acid cocrystal Type A is an ethanol solvate of the trans-aconitic acid cocrystal of the compound of formula I; A trans-aconitic acid cocrystal Type B of a compound of formula I, wherein the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 11.69±0.2°, 17.09±0.2°, and 23.47±0.2°; Preferably, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.29±0.2°, 11.69±0.2°, 17.09±0.2°, 23.47±0.2°, and 26.28±0.2°; Preferably, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.29±0.2°, 11.69±0.2°, 17.09±0.2°, 19.44±0.2°, 22.03±0.2°, 23.47±0.2°, 26.28±0.2°, and 27.90±0.2°; Preferably, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.29±0.2°, 11.69±0.2°, 16.26±0.2°, 17.09±0.2°, 19.44±0.2°, 21.21±0.2°, 22.03±0.2°, 23.47±0.2°, 26.28±0.2°, and 27.90±0.2°; Preferably, the trans-aconitic acid cocrystal Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Tables 1-21, wherein the error range of the 2θ angle is ±0.20°: Table 1-21 XRPD analysis data of trans-aconitic acid cocrystal Type B Preferably, the trans-aconitic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 75; Preferably, differential scanning calorimetry (DSC) analysis of the trans-aconitic acid cocrystal Type B shows endothermic peaks when heated to peak temperatures near 78.3°C, 106.5°C, 118.0°C, 137.1°C and / or 148.0°C; Preferably, the trans-aconitic acid cocrystal Type B has a DSC graph substantially as shown in Figure 76; Preferably, the thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type B shows a weight loss of about 3.0% in the range of room temperature to 120°C; Preferably, the trans-aconitic acid cocrystal Type B has a TGA graph substantially as shown in Figure 76; Preferably, the trans-aconitic acid cocrystal Type B is a hydrate of the trans-aconitic acid cocrystal of the compound of formula I.

5. A method for preparing the salt form or co-crystal according to any one of claims 1 to 4, comprising reacting the compound of formula I with the acid or base to obtain a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I; Preferably, the preparation method comprises reacting the compound of formula I with the acid or base in a solvent to prepare a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I; Preferably, the molar ratio of the compound of formula I to the acid or base can be 1:0.2 to 1:3, 1:0.8 to 1:1.5, preferably 1:0.5 to 1:1.5, and more preferably 1:0.6 to 1:1.

3.

6. The preparation method according to claim 5, characterized in that: The following steps are involved: Dissolving the compound represented by formula I and the acid in an organic solvent and stirring to obtain the salt form or co-crystal; and / or, dissolving the compound represented by formula I and the acid in an organic solvent, stirring, and crystallizing to obtain the salt form or co-crystal; and / or, dissolving the compound represented by formula I and the acid in an organic solvent, stirring, crystallizing, and volatilizing to obtain the salt form or co-crystal; and / or, dissolving the compound represented by formula I and the acid in an organic solvent, stirring, crystallizing, and back-titration to obtain the salt form or co-crystal; Preferably, the organic solvent is selected from at least one of methanol, ethanol, acetone, ethyl acetate, n-heptane, methyl tert-butyl ether, ethylene glycol methyl ether, dimethyl sulfoxide, dichloromethane, and tetrahydrofuran; preferably at least one of ethyl acetate, ethanol, n-heptane, methanol, methyl tert-butyl ether, and acetone; for example, selected from ethyl acetate, ethanol / n-heptane (1 / 9, v / v), methanol / MTBE (1 / 9, v / v), or acetone / MTBE (1 / 9, v / v); Preferably, the molar ratio of the compound represented by formula I to the acid can be 1:(0.2-3), 1:(0.5-1.5), for example 1:(0.6-1.3), such as 1:0.6, 1:1, 1:1.1, 1:1; Preferably, the mass volume ratio of the compound represented by Formula I to the organic solvent can be (10-50) mg:1 mL, for example (20-40) mg:1 mL; Preferably, the back-titration is to drop the reaction solution into an anti-solvent; the anti-solvent may be selected from at least one of n-heptane and methyl tert-butyl ether.

7. A pharmaceutical composition comprising at least one of the salt forms or co-crystals according to any one of claims 1 to 4, and optionally a pharmaceutically acceptable excipient.

8. A preparation comprising at least one of the salt forms or co-crystals according to any one of claims 1 to 4, and optionally a pharmaceutically acceptable excipient.

9. Use of the salt form or co-crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 7 in the preparation of a drug for inhibiting voltage-gated sodium channels; Preferably, the voltage-gated sodium channel is NaV1.

8.

10. Use of the salt form or co-crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing and / or alleviating and / or alleviating a disease, wherein the disease is preferably pain or cough; Preferably, the disease is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and cardiac arrhythmia; Preferably, the intestinal pain is selected from inflammatory bowel disease pain, Crohn's disease pain and interstitial cystitis pain; Preferably, the neuropathic pain is selected from the group consisting of post-herpetic neuralgia, diabetic neuropathy, HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morto's neuroma, nerve compression injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy and trigeminal autonomic headache; Preferably, the musculoskeletal pain is selected from osteoarthritis pain, back pain, cold pain, burn pain and toothache; Preferably, the inflammatory pain is selected from rheumatoid arthritis pain and vulvar pain; Preferably, the primary pain is selected from fibromyalgia.

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