WO2024255834A1 - Salt form and co-crystal of pyridine-n-oxide, preparation method therefor and use thereof - Google Patents

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

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WO2024255834A1
WO2024255834A1 PCT/CN2024/099160 CN2024099160W WO2024255834A1 WO 2024255834 A1 WO2024255834 A1 WO 2024255834A1 CN 2024099160 W CN2024099160 W CN 2024099160W WO 2024255834 A1 WO2024255834 A1 WO 2024255834A1
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acid
ray powder
powder diffraction
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张勇
程宏明
王明力
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Shanghai Jemincare Pharmaceuticals Co Ltd
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Shanghai Jemincare Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a salt form, a cocrystal, a preparation method and an application of a pyridine nitrogen oxide compound.
  • NaV1.8 sodium channel subtype 1.8
  • afferent neurons including sensory neurons. It controls the flow of sodium ions into and out of cells, and plays an important role in maintaining the excitability of nociceptive sensory neurons, the release and persistence of action potentials, and the regulation of pain sensitivity.
  • Patients with NaV1.8 activating mutations experience paroxysmal pain caused by small fiber neuropathy (damage to A ⁇ fibers and unmyelinated C-type fibers, which are mainly responsible for pain transmission).
  • Diseases such as chronic inflammation and diabetes can cause increased expression or changes in the properties of NaV1.8, thereby sensitizing nociceptive neurons and causing a variety of pain.
  • NaV1.8 gene knockout mice are insensitive to pain.
  • JMKX000623 is a highly selective sodium channel blocker independently developed by Shanghai Jiyu. It blocks the influx of sodium ions to prevent the occurrence and transmission of pain. It has shown significant analgesic effects in multiple preclinical animal pain models and can reduce the dosage of opioid analgesics.
  • IND new drug clinical trial application
  • CDE Center for Drug Evaluation
  • Drug cocrystals refer to crystals formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a certain ratio. By forming cocrystals, drugs can improve their physical and chemical properties and enhance their clinical therapeutic effects on the one hand, and on the other hand, cocrystals can enrich their crystal forms. However, the development of drug cocrystals is difficult, and in-depth research and evaluation are required on cocrystal ligand selection, preparation process, and physical property characterization.
  • the present invention provides a salt form or co-crystal of a pharmaceutically acceptable salt of a compound represented by Formula I;
  • 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.
  • 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
  • an organic acid such as hydro
  • the acid can be selected from 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 One of aconitic acid and trans-aconitic acid.
  • the base may be selected from inorganic bases, such as alkali metal hydroxides or alkaline earth metal hydroxides, preferably sodium hydroxide or potassium hydroxide.
  • the pharmaceutically acceptable salt of the compound of formula I is selected from one of its hydrochloride, hydrobromide, sulfate and p-toluenesulfonate.
  • 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.
  • 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.
  • 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 co-crystal are in charge balance with the ions of the acid or base.
  • 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.
  • the number of ionizable hydrogen atoms in the acid such as hydrochloric acid, p-toluenesulfonic acid
  • the molar ratio of the compound of formula I to the acid is 1:1
  • the number of ionizable hydrogen atoms in the acid such as sulfuric acid, fumaric acid, maleic acid, p-hydroxybenzoic acid
  • 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, the preparation method comprising reacting the compound of formula I with the acid or base to prepare a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I.
  • 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.
  • the acid or base independently of each other has the above-mentioned definition.
  • 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 the combination with water.
  • 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 carboxylates, 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
  • 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.
  • the salt form and/or co-crystal of the pharmaceutically acceptable salt of the compound represented by Formula I can 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 Type A hydrochloride salt of a compound of formula I wherein the Type A hydrochloride salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 18.06 ⁇ 0.2°, 18.80 ⁇ 0.2°, and 22.24 ⁇ 0.2°.
  • the hydrochloride Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrochloride Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrochloride Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrochloride Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-1, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrochloride Type A has an X-ray powder diffraction pattern substantially as shown in Figure 4.
  • DSC differential scanning calorimetry
  • the hydrochloride Type A has a DSC graph basically as shown in Figure 5.
  • thermogravimetric analysis (TGA) of the hydrochloride Type A shows a weight loss of about 4.6% in the range of 100°C to 200°C.
  • the hydrochloride Type A has a TGA chart basically as shown in Figure 5.
  • the hydrochloride Type A is an anhydrate or hydrate of the hydrochloride of the compound of formula I.
  • 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.
  • a Type A hydrobromide salt of a compound of formula I wherein the Type A hydrobromide salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 21.95 ⁇ 0.2°, 24.55 ⁇ 0.2°, and 25.08 ⁇ 0.2°.
  • the hydrobromide Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-2, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrobromide Type A has an X-ray powder diffraction pattern substantially as shown in Figure 9.
  • differential scanning calorimetry (DSC) analysis of the hydrobromide 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 appears near a peak temperature of 128.2°C.
  • the hydrobromide Type A has a DSC graph basically as shown in Figure 10.
  • thermogravimetric analysis (TGA) of the hydrobromide Type A shows a weight loss of about 4.1% in the range of room temperature to 150°C.
  • the hydrobromide Type A has a TGA graph basically as shown in Figure 10.
  • the hydrobromide Type A is an anhydrate or hydrate of the hydrobromide of the compound of formula I.
  • 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.
  • a Type B hydrobromide salt of a compound of formula I wherein the Type B hydrobromide salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 18.30 ⁇ 0.2°, 25.23 ⁇ 0.2°, and 27.55 ⁇ 0.2°.
  • the hydrobromide Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-3, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrobromide Type B has an X-ray powder diffraction pattern basically as shown in Figure 14.
  • differential scanning calorimetry (DSC) analysis of the hydrobromide Type B shows an endothermic peak near the peak temperature of 91.5°C when heated, and an exothermic peak near the peak temperature of 220.3°C.
  • the hydrobromide Type B has a DSC graph basically as shown in Figure 16.
  • thermogravimetric analysis (TGA) of the hydrobromide salt Type B shows a weight loss of about 3.3% in the range of room temperature to 150°C.
  • the hydrobromide Type B has a TGA graph basically as shown in Figure 16.
  • the hydrobromide Type B is an anhydrate or hydrate of the hydrobromide of the compound of formula I.
  • the hydrobromide Type B is a hydrate of the hydrobromide of the compound of formula I.
  • a Type C hydrobromide salt of a compound of formula I wherein the Type C hydrobromide salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 4.09 ⁇ 0.2°, 22.26 ⁇ 0.2°, and 26.56 ⁇ 0.2°.
  • the hydrobromide Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Tables 1-4, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrobromide Type C has an X-ray powder diffraction pattern basically as shown in Figure 18.
  • DSC differential scanning calorimetry
  • the hydrobromide Type C has a DSC graph basically as shown in Figure 19.
  • thermogravimetric analysis (TGA) of the hydrobromide Type C shows a weight loss of about 2.2% in the range of room temperature to 150°C.
  • the hydrobromide Type C has a TGA graph basically as shown in Figure 19.
  • the hydrobromide Type C is an anhydrate or hydrate of the hydrobromide of the compound of formula I.
  • the hydrobromide Type C is the anhydrate of the hydrobromide of the compound of formula I.
  • a Type D hydrobromide salt of a compound of formula I wherein the Type D hydrobromide salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 3.72 ⁇ 0.2°, 17.89 ⁇ 0.2°, and 28.71 ⁇ 0.2°.
  • the hydrobromide Type D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type D uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Tables 1-5, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrobromide Type D has an X-ray powder diffraction pattern basically as shown in Figure 21.
  • a Type E hydrobromide salt of a compound of formula I wherein the Type E hydrobromide salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 21.00 ⁇ 0.2°, 21.46 ⁇ 0.2°, and 27.22 ⁇ 0.2°.
  • the hydrobromide Type E uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide salt Type E uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles is 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°, 28.21 ⁇ 0.2° There are characteristic peaks.
  • the hydrobromide Type E uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the hydrobromide Type E uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-6, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the hydrobromide Type E has an X-ray powder diffraction pattern basically as shown in Figure 23.
  • DSC differential scanning calorimetry
  • the hydrobromide Type E has a DSC graph basically as shown in Figure 24.
  • the hydrobromide Type E has a TGA graph basically as shown in Figure 24.
  • the hydrobromide Type E is the anhydrate of the hydrobromide of the compound of formula I.
  • 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 0.6 hydrobromide of the compound of formula I.
  • a sulfate salt Type A of a compound of formula I wherein the sulfate salt Type A uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 25.10 ⁇ 0.2°, 25.16 ⁇ 0.2°, and 29.63 ⁇ 0.2°.
  • the sulfate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the sulfate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the sulfate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the sulfate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Tables 1-7, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the sulfate Type A has an X-ray powder diffraction pattern basically as shown in Figure 26.
  • 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.
  • the sulfate Type A has a DSC graph basically as shown in Figure 27.
  • 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.
  • the sulfate Type A has a TGA graph basically as shown in Figure 27.
  • the sulfate Type A is a hydrate of the sulfate of the compound of formula I.
  • the sulfate Type A is a hydrate of the monosulfate 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-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 17.34 ⁇ 0.2°, 24.09 ⁇ 0.2°, and 25.95 ⁇ 0.2°.
  • the fumaric acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the fumaric acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the fumaric acid eutectic Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the fumaric acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-8, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the fumaric acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 85.
  • DSC differential scanning calorimetry
  • the fumaric acid eutectic Type A has a DSC graph basically as shown in Figure 86.
  • the fumaric acid eutectic Type A has a TGA graph basically as shown in Figure 86.
  • the fumaric acid eutectic Type A is anhydrous fumaric acid eutectic of compound I.
  • the molar ratio of the compound of formula I to fumaric acid in the fumaric acid eutectic Type A is 1:1, for example, it is the monofumaric acid eutectic 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-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 19.58 ⁇ 0.2°, 22.36 ⁇ 0.2°, and 25.31 ⁇ 0.2°.
  • the maleic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the maleic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the maleic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the maleic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-9, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the maleic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 34.
  • the maleic acid cocrystal Type A has a DSC graph basically as shown in Figure 35.
  • thermogravimetric analysis (TGA) of the maleic acid eutectic Type A shows a weight loss of approximately 11.4% in the range of 100°C to 200°C.
  • the maleic acid cocrystal Type A has a TGA graph basically as shown in Figure 35.
  • 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 anhydrous form of the compound of formula I 0.6 maleic acid cocrystal.
  • a maleic acid cocrystal Type B of a compound of formula I wherein the maleic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 22.57 ⁇ 0.2°, 25.78 ⁇ 0.2°, and 26.94 ⁇ 0.2°.
  • the maleic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the maleic acid eutectic Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the maleic acid eutectic Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Tables 1-10, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • 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.
  • the maleic acid eutectic Type B has a DSC graph basically as shown in Figure 38.
  • thermogravimetric analysis (TGA) of the maleic acid eutectic Type B shows that the eutectic has a temperature of about 100°C to 200°C. 19.5% weight loss.
  • the maleic acid eutectic Type B has a TGA graph basically as shown in Figure 38.
  • the maleic acid cocrystal Type B is the anhydrate of the maleic acid cocrystal of the compound of formula I.
  • 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 monomaleic 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-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 21.79 ⁇ 0.2°, 25.43 ⁇ 0.2°, and 26.38 ⁇ 0.2°.
  • the tartaric acid eutectic Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Tables 1-11, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the tartaric acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 40.
  • DSC differential scanning calorimetry
  • the tartaric acid eutectic Type A has a DSC graph basically as shown in Figure 41.
  • 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.
  • the tartaric acid eutectic Type A has a TGA graph basically as shown in Figure 41.
  • the tartaric acid eutectic Type A is the anhydrate of the tartaric acid eutectic of the compound of formula I.
  • 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. It is the anhydrate of tartaric acid cocrystal of compound 1.1 of formula I.
  • the tartaric acid eutectic Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-12, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the tartaric acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 44.
  • differential scanning calorimetry (DSC) analysis of the tartaric acid eutectic Type B shows an endothermic peak when heated to a peak temperature of 88.4°C and/or 172.5°C.
  • the tartaric acid eutectic Type B has a DSC graph basically as shown in Figure 45.
  • 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.
  • the tartaric acid eutectic Type B has a TGA graph basically as shown in Figure 45.
  • the tartaric acid cocrystal Type B is an anhydrate or hydrate of the tartaric acid cocrystal of the compound of formula I.
  • 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 the hydrate of the tartaric acid cocrystal of compound of formula I 1.3.
  • the tartaric acid eutectic Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the tartaric acid eutectic Type C uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-13, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the tartaric acid cocrystal Type C has an X-ray powder diffraction pattern basically as shown in Figure 49.
  • DSC differential scanning calorimetry
  • the tartaric acid eutectic Type C has a DSC graph basically as shown in Figure 50.
  • thermogravimetric analysis (TGA) of the tartaric acid eutectic Type C shows a weight loss of approximately 1.9% in the range of room temperature to 150°C.
  • the tartaric acid eutectic Type C has a TGA graph basically as shown in Figure 50.
  • the tartaric acid cocrystal Type C is an anhydrate or hydrate of the tartaric acid cocrystal of the compound of formula I.
  • the molar ratio of the compound of formula I to tartaric acid in the tartaric acid eutectic Type C is 1:1, for example, it is a hydrate of monotartaric acid eutectic of the compound of formula I.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Tables 1-14, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the 3,5-dihydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 52.
  • 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.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A has a DSC graph basically as shown in Figure 53.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A has a TGA graph basically as shown in Figure 53.
  • the 3,5-dihydroxybenzoic acid cocrystal Type A is the anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of compound I.
  • 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 anhydrous form of the compound of formula I and mono-3,5-dihydroxybenzoic acid cocrystal.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-15, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the 3,5-dihydroxybenzoic acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 55.
  • differential scanning calorimetry (DSC) analysis of the 3,5-dihydroxybenzoic acid cocrystal Type B shows an endothermic peak when heated to a peak temperature near 170.5 and/or 203.6°C, and an exothermic peak near a peak temperature of 172.5°C.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B has a DSC graph basically as shown in Figure 56.
  • 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.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B has a TGA graph basically as shown in Figure 56.
  • the 3,5-dihydroxybenzoic acid cocrystal Type B is the anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of compound I.
  • 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 anhydrous form of the compound of formula I and mono-3,5-dihydroxybenzoic acid cocrystal.
  • a gentisic acid cocrystal Type A of a compound of formula I wherein the gentisic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 19.29 ⁇ 0.2°, 23.45 ⁇ 0.2°, and 27.47 ⁇ 0.2°.
  • the gentisic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the gentisic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the gentisic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the gentisic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-16, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the gentisic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 58.
  • differential scanning calorimetry (DSC) analysis of the gentisic acid cocrystal Type A shows an endothermic peak when heated to near the peak temperature of 166.7°C.
  • the gentisic acid cocrystal Type A has a DSC graph basically as shown in Figure 59.
  • thermogravimetric analysis (TGA) of the gentisic acid cocrystal Type A shows a weight loss of about 0.2% in the range of room temperature to 150°C.
  • the gentisic acid cocrystal Type A has a TGA graph basically as shown in Figure 59.
  • the gentisic acid cocrystal Type A is the anhydrate of the gentisic acid cocrystal of compound I.
  • 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.
  • a p-hydroxybenzoic acid cocrystal Type A of a compound of formula I wherein the p-hydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 21.93 ⁇ 0.2°, 24.77 ⁇ 0.2°, and 26.85 ⁇ 0.2°.
  • the p-hydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the p-hydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the p-hydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the p-hydroxybenzoic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-17, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the p-hydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 61.
  • 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.
  • the p-hydroxybenzoic acid cocrystal Type A has a DSC graph basically as shown in Figure 62.
  • thermogravimetric analysis (TGA) of the p-hydroxybenzoic acid cocrystal Type A shows a weight loss of about 0.1% in the range of room temperature to 150°C.
  • the p-hydroxybenzoic acid cocrystal Type A has a TGA graph basically as shown in Figure 62.
  • the p-hydroxybenzoic acid cocrystal Type A is the anhydrate of the p-hydroxybenzoic acid cocrystal of the compound of formula I.
  • 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 anhydrous p-hydroxybenzoic acid cocrystal of compound of formula I and 0.5 p-hydroxybenzoic acid.
  • a Type A oxalic acid cocrystal of a compound of formula I wherein the Type A oxalic acid cocrystal uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 16.64 ⁇ 0.2°, 26.69 ⁇ 0.2°, and 27.96 ⁇ 0.2°.
  • the oxalic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the oxalic acid eutectic Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the oxalic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the oxalic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-18, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the oxalic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 64.
  • differential scanning calorimetry (DSC) analysis of the oxalic acid cocrystal Type A shows endothermic peaks appearing near the peak temperatures of 105.0°C, 160.7°C and/or 203.7°C when heated.
  • the oxalic acid eutectic Type A has a DSC graph basically as shown in Figure 65.
  • 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.
  • the oxalic acid eutectic Type A has a TGA graph basically as shown in Figure 65.
  • the oxalic acid cocrystal Type A is the anhydrate of the oxalic acid cocrystal of the compound of formula I.
  • 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 anhydrous form of the 0.5 oxalic acid cocrystal of the compound of formula I.
  • a Type A p-toluenesulfonate salt of a compound of formula I wherein the Type A p-toluenesulfonate salt uses Cu-K ⁇ radiation and has characteristic peaks in X-ray powder diffraction expressed in 2 ⁇ angles at 17.36 ⁇ 0.2°, 21.93 ⁇ 0.2°, and 24.55 ⁇ 0.2°.
  • the p-toluenesulfonate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the p-toluenesulfonate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the p-toluenesulfonate Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the p-toluenesulfonate salt Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-19, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the p-toluenesulfonate Type A has an X-ray powder diffraction pattern basically as shown in Figure 67.
  • 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.
  • the p-toluenesulfonate Type A has a DSC graph basically as shown in Figure 68.
  • the p-toluenesulfonate Type A has a TGA chart basically as shown in Figure 68.
  • the p-toluenesulfonate Type A is the anhydrous p-toluenesulfonate of the compound of formula I.
  • 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 mono-p-toluenesulfonate of the compound of formula I.
  • trans-aconitic acid cocrystal Type A of a compound of formula I wherein the trans-aconitic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks at 17.44 ⁇ 0.2°, 22.73 ⁇ 0.2°, and 23.54 ⁇ 0.2°.
  • the trans-aconitic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the trans-aconitic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the trans-aconitic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the trans-aconitic acid cocrystal Type A uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-20, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the trans-aconitic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 70.
  • 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.
  • the trans-aconitic acid cocrystal Type A has a DSC graph basically as shown in Figure 71.
  • thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type A shows a weight loss of about 5.7% in the range of room temperature to 120°C.
  • the trans-aconitic acid cocrystal Type A has a TGA diagram basically as shown in Figure 71.
  • the trans-aconitic acid cocrystal Type A is an ethanol solvate of the trans-aconitic acid cocrystal of the compound of formula I.
  • 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 mono-trans-aconitic acid cocrystal of the compound of formula I.
  • the trans-aconitic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the trans-aconitic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the trans-aconitic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ 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°.
  • the trans-aconitic acid cocrystal Type B uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angles has characteristic peaks as shown in Table 1-21, wherein the error range of the 2 ⁇ angle is ⁇ 0.20°:
  • the trans-aconitic acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 75.
  • 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.
  • the trans-aconitic acid cocrystal Type B has a DSC graph basically as shown in Figure 76.
  • 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.
  • the trans-aconitic acid cocrystal Type B has a TGA graph basically as shown in Figure 76.
  • the trans-aconitic acid cocrystal Type B is a hydrate of the trans-aconitic acid cocrystal of the compound of formula I.
  • 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.
  • 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:
  • 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).
  • 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.
  • 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, 34 mg:1 mL.
  • 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.
  • 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, such as 1-4 days; for example, first place it in a 4°C refrigerator to cool down for crystallization, and then place it at -15°C and stand for 1-4 days.
  • the volatilization is volatilization at room temperature.
  • 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.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the salt forms or co-crystals of the pharmaceutically acceptable salt of the compound of formula I, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is in the form of a preparation.
  • the present invention also provides a preparation comprising at least one of the salt forms or co-crystals of the pharmaceutically acceptable salt of the compound of formula I, and optionally a pharmaceutically acceptable excipient.
  • the present invention also provides the 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.
  • the voltage-gated sodium channel is NaV1.8.
  • the present invention also provides the 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 treating and/or preventing and/or alleviating and/or relieving a disease, wherein the disease is preferably pain or cough.
  • 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 arrhythmia.
  • the intestinal pain is selected from inflammatory bowel disease pain, Crohn's disease pain and interstitial cystitis pain.
  • the neuropathic pain is selected from 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, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy and trigeminal autonomic headache.
  • the musculoskeletal pain is selected from osteoarthritis pain, back pain, cold pain, burn pain and dental pain.
  • the inflammatory pain is selected from rheumatoid arthritis pain and vulvar pain.
  • the primary pain is selected from fibromyalgia.
  • 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 co-crystal of a pharmaceutically acceptable salt of the compound of formula I as described above or at least one of the pharmaceutical compositions.
  • the treatment method of the present invention may include administering a salt form or co-crystal of a pharmaceutically acceptable salt of a compound of formula I of the present invention or said pharmaceutical composition alone, and administering one, two or more salt forms or co-crystals of a pharmaceutically acceptable salt of a compound of formula I of the present invention or said pharmaceutical composition in combination with one, two or more other chemotherapeutic agents.
  • the administration of multiple drugs may be carried out simultaneously or sequentially.
  • the present invention provides a salt form or co-crystal of a pharmaceutically acceptable salt of a compound of formula I and a preparation method thereof.
  • the salt form or co-crystal 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.
  • FIG1 is an XRPD pattern of the compound of formula I in free form.
  • FIG2 shows TGA and DSC diagrams of the free compound of formula I.
  • FIG3 is a 1 H NMR spectrum of the compound of formula I in free form.
  • Figure 6 1 H NMR spectrum of Type A hydrochloride: (a) comparison with the free state; (b) integration results.
  • FIG. 8 TGA graph of the hydrochloride salt Type A sample after hot stage experiment.
  • Figure 11 1 H NMR spectrum of hydrobromide salt Type A: (a) comparison with the free state; (b) integration result.
  • FIG. 13 TGA graph of the sample after the hydrobromide Type A hot stage experiment.
  • Figure 17 1 H NMR spectrum of hydrobromide salt Type B: (a) comparison with the free state; (b) integration result.
  • Figure 20 1 H NMR spectrum of Type C hydrobromide: (a) comparison with the free state; (b) integration results.
  • Figure 25 1 H NMR spectrum of hydrobromide salt Type E: (a) comparison with the free state; (b) integration result.
  • Figure 28 1 H NMR spectrum of sulfate Type A: (a) comparison with the free state; (b) integration result.
  • Figure 33 1 H NMR spectrum of fumaric acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 36 1 H NMR spectrum of maleic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 39 1 H NMR spectrum of maleic acid cocrystal Type B: (a) comparison with the free state; (b) integration result.
  • Figure 42 1 H NMR spectrum of tartaric acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 43 XRPD comparison of tartaric acid eutectic Type A before and after heating.
  • Figure 46 1 H NMR spectrum of tartaric acid cocrystal Type B: (a) comparison with the free state; (b) integration result.
  • Figure 51 1 H NMR spectrum of tartaric acid cocrystal Type C: (a) comparison with the free state; (b) integration result.
  • Figure 54 1 H NMR spectrum of 3,5-dihydroxybenzoic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 58 XRPD pattern of gentisic acid cocrystal Type A.
  • Figure 60 1 H NMR spectrum of gentisic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 63 1 H NMR spectrum of p-hydroxybenzoic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 64 XRPD pattern of oxalic acid cocrystal Type A.
  • Figure 66 1 H NMR spectrum of oxalic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 69 1 H NMR spectrum of p-toluenesulfonate Type A: (a) comparison with the free state; (b) integration result.
  • Figure 70 XRPD pattern of trans-aconitic acid cocrystal Type A.
  • Figure 72 1 H NMR spectrum of trans-aconitic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.
  • Figure 74 TGA graph of the trans-aconitic acid eutectic Type A sample after hot stage.
  • Figure 77 1 H NMR spectrum of trans-aconitic acid cocrystal Type B: (a) comparison with the free state; (b) integration result.
  • Figure 80 1 H NMR spectrum of the solid remaining after oxalic acid cocrystal Type A was shaken in water for 2 h: (a) comparison with oxalic acid cocrystal Type A; (b) integration result.
  • Figure 81 XRPD comparison of the solid remaining after Type A p-toluenesulfonate was shaken in water for 2 hours.
  • Figure 83 XRPD comparison of the solid remaining after oscillating in water for 2 hours between maleic acid cocrystal Type B, hydrochloride Type A and hydrobromide Type E.
  • Figure 84 1 H NMR spectrum of the solid remaining after maleic acid cocrystal Type B was shaken in water for 2 h: (a) comparison with maleic acid cocrystal Type B; (b) integration result.
  • Figure 88 Fumaric acid eutectic Type A (a) DVS curve; (b) XRPD pattern before and after DVS test.
  • API or “free state” refers to the free base form of the compound of Formula I.
  • “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 a salt) and at least two of the components are solid at room temperature.
  • the “salt form” or “co-crystal” of the present invention includes hydrates, non-solvates (anhydrates) and crystalline forms of solvates of the compound.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving 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, tolu
  • Anti-solvent refers to a fluid that promotes precipitation of a product (or a product precursor) from a solvent.
  • the anti-solvent may 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 may be the same liquid as the solvent but at a different temperature, or it may be a different liquid from the solvent.
  • Solidvate means that the crystal has a solvent on the surface, in the crystal lattice, or 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, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, 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 on the surface and in the crystal lattice is water.
  • the hydrate On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents except water.
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms.
  • the peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and 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.
  • the measurement of 2 ⁇ of the XRPD spectrum may have experimental errors, and the measurement of 2 ⁇ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2 ⁇ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ⁇ 0.2° for the diffraction peak.
  • DSC Differential scanning calorimetry
  • an inert reference material usually ⁇ -Al 2 O 3
  • the height of the melting peak of a 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 of 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.
  • 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, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the melting peak has an error tolerance of ⁇ 3°C.
  • DSC Differential scanning calorimetry
  • Solids with the same chemical composition often form isomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase phenomenon.
  • crystal transformation When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly.
  • DSC differential scanning calorimetry
  • this transformation process can be observed on the differential scanning calorimetry (DSC) graph, characterized in that the DSC graph has an exothermic peak reflecting this transformation process, and at the same time has two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after the transformation.
  • the crystal form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.
  • Thermogravimetric analysis is a technique for measuring the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of crystal water or crystallization solvent in the crystals.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. According to the instrument conditions used in the test of the present invention, the mass change has an error tolerance of ⁇ 0.3%.
  • the moisture adsorption/desorption isotherm measurement is a measurement method that measures the adsorption and desorption behavior of moisture by measuring the weight change of a solid object under various relative humidity conditions.
  • a peak refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.
  • 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 the DSC pattern or the TGA results are shown in the pattern thereof.
  • “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%.
  • the solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2 ⁇ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 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.
  • thermogravimetric analyzer is TA Discovery 55 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.
  • the model of the differential scanning calorimeter was TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes and heated to the final temperature at a rate of 10 °C/min, with nitrogen purge rate of 50 mL/min in the furnace.
  • Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode, with humidity changes of 50%-95%-0%-50%. The humidity change for each gradient in the range of 0% to 90% was 10%. The gradient endpoint was determined using the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient endpoint. After the test was completed, the sample was subjected to XRPD analysis to confirm whether the solid morphology had changed.
  • the model of polarizing microscope is Nikon Ci-POL (Nikon, JP). Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.
  • HPLC model was Waters Acquity Arc-2489 (Waters, US), and the test conditions were shown in Table 1.
  • the ion chromatograph model was ICS 5000 (Thermo Fisher, US), and the instrument parameters are shown in Table 2.
  • the compound of formula I can be prepared according to the prior art. 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 that there is an endothermic signal at 90°C and a melting endothermic peak at 151°C.
  • the NMR results are used for subsequent sample salt formation and eutectic judgment.
  • the resulting solution is divided into two parts, one part is added to a certain volume of anti-solvent, and stirred at room temperature for 1 day.
  • the solution with insufficient solids after back-titration is left to stand at -15°C for 1 day.
  • the solution with sufficient solids precipitated is centrifuged and the solid is dried under vacuum at room temperature.
  • the resulting solution is divided into two portions, and one portion is left open at room temperature until the solvent is completely evaporated to obtain a solid.
  • An Instec HCS424GXY hot stage (Instec Inc., US) was used to perform XRPD testing on a solid sample.
  • a 6-8 mg sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 20°C/min and kept at a constant temperature for 10 min. The solid was then naturally cooled to room temperature and tested by XRPD.
  • Samples of different salt forms, cocrystals or free states were added to 2.0 mL of water and shaken at 25°C for 2 hours before sampling; the sampled solution was filtered with a 0.22 ⁇ m water filter membrane, and some samples with higher concentrations were appropriately diluted with diluents, and the signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution multiple. In addition, the remaining solid was tested by XRPD.
  • the preparation process of the biological medium is shown in Table 3.
  • Samples of different salt forms, cocrystals or free states were added to 4.0 mL of the biological medium and shaken at 37 ° C for 24 h, and samples were taken at 0.5 h, 2 h and 24 h.
  • the sampled solution was filtered with a 0.22 ⁇ m water filter membrane, and some samples with higher concentrations were appropriately diluted with diluents.
  • the signal peak area of the solution was measured by HPLC, and finally the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution multiple.
  • the pH value of the supernatant after the test was tested, and the remaining solid was tested by XRPD.
  • the hydrochloride salt Type A is obtained by back titrating the solution of the raw material (compound of formula I) and hydrochloric acid suspended in ethyl acetate in n-heptane.
  • the specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 4 to 8.
  • XRPD results showed that the hydrochloride Type A was a well-crystalline solid.
  • TGA results showed that the sample had no weight loss from room temperature to 100°C, lost 4.6% from 100°C to 200°C, and may decompose after 300°C.
  • DSC results showed a broad endothermic signal from 130°C to 190°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding API at 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; there was no obvious residual organic solvent signal peak.
  • the hydrochloride Type A was heated to 120°C and kept at a constant temperature for 10min. After cooling naturally to room temperature, the sample XRPD did not change significantly. The weight loss of the sample in TGA after the hot stage experiment did not decrease significantly. The ion chromatography results showed that the chloride ion content in the sample was 7.1%, and the molar ratio of the API and hydrochloric acid was calculated to be approximately 1:1.
  • Hydrobromide 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, and the relevant characterization data are shown in Figures 9 to 13.
  • XRPD results showed that Type A hydrobromide was a well-crystalline solid.
  • TGA results showed that the sample lost 4.1% of its weight during heating to 150°C and may decompose after 225°C.
  • DSC results showed endothermic signals at 90°C and 184°C and exothermic signals at 128°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding API at around 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; there was no obvious residual organic solvent signal peak.
  • Type A hydrobromide was heated to 100°C to melt, and the weight loss of the sample after the hot stage experiment in TGA did not decrease significantly; then it was heated to 70°C and kept at a constant temperature for 10 minutes. After naturally cooling to room temperature, the sample XRPD did not change significantly, and the weight loss in TGA did not decrease significantly.
  • 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.
  • Hydrobromide Type B is 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, and the relevant characterization data are shown in Figures 14 to 17.
  • hydrobromide Type B is a well-crystalline solid.
  • the XRPD comparison of hydrobromide Type A and hydrobromide Type B suggests that hydrobromide Type B may contain a small amount of hydrobromide Type A.
  • TGA results show that the sample loses 3.3% of its weight during heating to 150°C and may decompose after 225°C.
  • DSC results show an endothermic signal at 92°C and an exothermic signal corresponding to decomposition at 220°C.
  • Hydrobromide Type C is 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.
  • XRPD results showed that Type C hydrobromide was a solid with general crystallinity.
  • TGA results showed that the sample lost 2.2% of its weight during heating to 150°C and may decompose after 200°C.
  • DSC results showed an endothermic signal at 90°C and an endothermic signal corresponding to decomposition at 178°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw material at around 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw material, suggesting that the sample was salted; there was no obvious residual organic solvent signal peak.
  • Hydrobromide Type D is obtained in a volatilization experiment by suspending the raw material and hydrobromic acid in methanol/MTBE (1/9, v/v). The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 21 to 22.
  • Type D hydrobromide was a solid with average crystallinity.
  • Type D hydrobromide turned into a solid that may be mixed with Type A hydrobromide after being left at room temperature for 1 day.
  • hydrobromide Type E 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, and the relevant characterization data are shown in Figures 23 to 25.
  • XRPD results showed that the hydrobromide salt Type E was a well-crystalline solid.
  • TGA results showed that the sample did not lose weight during heating to 150°C, and decomposition may occur after 250°C.
  • DSC results showed an endothermic signal at 200°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw materials near 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; the peaks near 3.4ppm and 1.1ppm corresponded to the characteristic signal peaks of ethanol, suggesting that the sample had a small amount of ethanol residue.
  • Ion chromatography results showed that the sample The bromide ion content in the product is 8.7%, and the molar ratio of the raw material to hydrobromic acid is calculated to be approximately 1:0.6.
  • Sulfate Type A is obtained by suspending the raw material and sulfuric acid in ethanol/n-heptane (1/9, v/v). The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 26 to 30.
  • XRPD results showed that sulfate Type A was a solid with good crystallinity.
  • TGA results showed that the sample lost 6.2% of its weight during heating to 150°C and may decompose after 250°C.
  • DSC results showed that there were broad endothermic signals at 81°C and 157°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding API at 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; the nuclear magnetic peaks at 1.1ppm and 3.7ppm corresponded to the characteristic signal peaks of ethyl sulfate.
  • the molar ratio of the API and ethyl sulfate was approximately 1:0.1, suggesting that the sample may contain a small amount of ethyl sulfate.
  • the hot stage experiment (053-23-48) showed that sulfate Type A was heated to 120°C and kept at a constant temperature for 10min, and the sample XRPD changed after naturally cooling to room temperature. The weight loss of the sample in TGA after the hot stage experiment was significantly reduced.
  • Fumaric acid eutectic Type A is obtained by suspending the raw material and fumaric acid in four solvent systems used, for example, in ethyl acetate. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 31 to 33.
  • XRPD results showed that fumaric acid eutectic Type A was a well-crystalline solid.
  • TGA results showed that the sample lost 0.1% weight during heating to 150°C and may decompose after 210°C.
  • DSC results showed a melting endothermic peak at 169.7°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw materials; the peak near 6.6ppm corresponded to the characteristic signal peak of fumaric acid, and the molar ratio of the API and fumaric acid was approximately 1:1 according to the integration results; no obvious residual organic solvent was observed.
  • Maleic acid cocrystal Type A is obtained by suspending the raw material and maleic acid in ethanol/n-heptane (1/9, v/v) at room temperature. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 34 to 36.
  • XRPD results showed that maleic acid cocrystal Type A was a well-crystalline solid.
  • TGA results showed that the sample had no weight loss during heating to 100°C, and lost 11.4% of its weight during the period from 100°C to 200°C.
  • Maleic acid cocrystal decomposition may occur after 150°C.
  • DSC results showed endothermic signals at 108°C and 119°C, and a broad endothermic signal at 156°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw materials; the peak near 6.25ppm corresponded to the characteristic signal peak of maleic acid. According to the integration results, the molar ratio of the API and maleic acid was approximately 1:0.6, and the theoretical content of maleic acid was calculated to be 13.2%, which was close to the weight loss in TGA; no obvious residual organic solvent signal peak was observed.
  • 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, and the relevant characterization data are shown in Figures 37 to 39.
  • XRPD results showed that maleic acid cocrystal Type B was a solid with good crystallinity.
  • TGA results showed that the sample had no weight loss during heating to 100°C, and lost 19.5% of its weight during heating from 100°C to 200°C.
  • Maleic acid cocrystal decomposition may occur after 150°C.
  • DSC results showed an endothermic signal at 127°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw material; the peak near 6.25ppm corresponded to the characteristic signal peak of maleic acid.
  • the molar ratio of the API and maleic acid was approximately 1:1, and the theoretical content of maleic acid was calculated to be 20.2%, which was close to the weight loss in TGA; the characteristic signal peaks of ethyl acetate were seen near 4.0ppm, 2.0ppm and 1.2ppm, suggesting that a small amount of ethyl acetate remained in the sample.
  • Tartaric acid eutectic Type A is obtained by suspending the raw material and tartaric acid in ethanol/n-heptane (1/9, v/v) at room temperature. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 40 to 43.
  • XRPD results showed that tartaric acid eutectic Type A was a well-crystalline solid.
  • TGA results showed that the sample lost 2.2% of its weight during heating to 150°C, and decomposition may occur after 200°C.
  • DSC results showed endothermic signals at 88°C, 103°C and 136°C, and a broad endothermic signal at 188°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw material; the peak near 4.3ppm corresponded to the characteristic signal peak of tartaric acid, and according to the integration results, the molar ratio of the API and tartaric acid was approximately 1:1.1; the characteristic signal peak of ethanol was visible near 1.05ppm, and the molar ratio of the API and ethanol was approximately 1:0.25 from the integration value, and the theoretical content of ethanol was 1.8%, which was close to the weight loss in TGA.
  • tartaric acid eutectic Type A was heated to 100°C and kept at this temperature for 10 min. After naturally cooling to room temperature, the XRPD results showed no significant changes.
  • Tartaric acid eutectic Type B is 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, and the relevant characterization data are shown in Figures 44 to 48.
  • XRPD results show that tartaric acid cocrystal Type B is a solid with average crystallinity.
  • TGA results show that the sample loses 3.3% of its weight during heating to 150°C, and may decompose after 200°C.
  • DSC results show that there is an endothermic peak corresponding to weight loss at 88°C, and an endothermic signal corresponding to decomposition at 173°C.
  • NMR results show that compared with the free state, there is no obvious shift in the nuclear magnetic peak of the corresponding raw material, and the NMR integration results are basically consistent with the raw material; the peak near 4.3ppm corresponds to the characteristic signal peak of tartaric acid, and according to the integration results, the molar ratio of the raw material and tartaric acid is approximately 1:1.3; the characteristic signal peaks of n-heptane can be seen near 0.9ppm and 1.25ppm, and the integral value of the peak near 0.9ppm shows that the molar ratio of the raw material and n-heptane is approximately The ratio of n-heptane to tartaric acid was 1:0.15, and the theoretical content of n-heptane was 2.2%, which was slightly lower than the weight loss in TGA.
  • the tartaric acid eutectic Type B (053-23-45) was heated to 70°C and kept at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results did not change significantly. The weight loss of the sample after the hot stage experiment in TGA was reduced; the sample melted after heating to 100°C.
  • Tartaric acid eutectic Type C was obtained in a volatilization experiment from a clear solution obtained by reacting the raw materials with tartaric acid in ethyl acetate at room temperature. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 49 to 51.
  • XRPD results showed that tartaric acid eutectic Type C was a solid with general crystallinity.
  • TGA results showed that the sample lost 1.9% of its weight during heating to 150°C, and decomposition may occur after 180°C.
  • DSC results showed endothermic signals at 87°C, 113°C, 137°C and 190°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw material; the peak near 4.3ppm corresponded to the characteristic signal peak of tartaric acid, and the molar ratio of the API and tartaric acid was approximately 1:1 according to the integration results; the characteristic signal peaks of ethyl acetate were visible near 4.0ppm, 2.0ppm and 1.2ppm, and the integral value of the peak near 4.0ppm showed that the molar ratio of the API and ethyl acetate was approximately 1:0.09, and the theoretical content of ethyl acetate was 1.5%, which was close to the weight loss in TGA.
  • 3,5-dihydroxybenzoic acid cocrystal Type A is obtained by suspending the raw material and 3,5-dihydroxybenzoic acid in ethyl acetate.
  • the specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 52 to 54.
  • XRPD results showed that 3,5-dihydroxybenzoic acid cocrystal Type A was a well-crystalline solid.
  • TGA results showed that the sample did not lose weight during heating to 150°C, and decomposition may occur after 275°C.
  • DSC results showed a melting endothermic peak at 203°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; the nuclear magnetic peaks near 9.5ppm, 6.8ppm and 6.4ppm corresponded to the characteristic signal peaks of 3,5-dihydroxybenzoic acid. According to the integration results of the peak near 6.4ppm, it was judged that the molar ratio of the raw material and 3,5-dihydroxybenzoic acid was approximately 1:1; no obvious residual organic solvent was observed.
  • 3,5-dihydroxybenzoic acid cocrystal Type B is obtained by suspending the raw material 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.
  • XRPD results showed that 3,5-dihydroxybenzoic acid cocrystal Type B was a well-crystalline solid.
  • TGA results showed that the sample lost 0.2% of its weight during heating to 200°C, and decomposition may occur after 275°C.
  • DSC results showed that there were signals of melting accompanied by recrystallization at 171°C and 173°C, and a melting endothermic peak at 204°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw materials had no obvious shift, and the NMR integration results were basically consistent with the raw materials; the nuclear magnetic peaks near 9.5ppm, 6.8ppm and 6.4ppm corresponded to the characteristic signal peaks of 3,5-dihydroxybenzoic acid. According to the integration results of the peak near 6.4ppm, it was judged that the molar ratio of the raw material and 3,5-dihydroxybenzoic acid was approximately 1:1; no obvious residual organic solvent was observed.
  • Gentisic acid cocrystal Type A is obtained by suspending the raw material and gentisic acid in ethyl acetate. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 58 to 60.
  • XRPD results showed that gentisic acid cocrystal Type A was a well-crystalline solid.
  • TGA results showed that the sample lost 0.2% weight during heating to 150°C and may decompose after 200°C.
  • DSC results showed a melting endothermic peak at 167°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; the nuclear magnetic peaks near 9.1ppm, 7.1ppm, 6.9ppm and 6.8ppm corresponded to the characteristic signal peaks of gentisic acid. According to the integration results of the peak near 6.8ppm, the molar ratio of the raw material and gentisic acid was approximately 1:1; no obvious residual organic solvent was observed.
  • Para-hydroxybenzoic acid cocrystal Type A is obtained by back-titration of 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, and the relevant characterization data are shown in Figures 61 to 63.
  • XRPD results showed that p-hydroxybenzoic acid cocrystal Type A was a well-crystalline solid.
  • TGA results showed that the sample lost 0.1% of its weight during heating to 150°C and may decompose after 200°C.
  • DSC results showed a melting endothermic peak at 124°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; the nuclear magnetic peaks near 10.2ppm, 7.8ppm and 6.8ppm corresponded to the characteristic signal peaks of p-hydroxybenzoic acid, and the molar ratio of the raw material and p-hydroxybenzoic acid calculated based on the integration results of the peak near 6.8ppm was approximately 1:0.5; no obvious residual organic solvent was observed.
  • Oxalic acid cocrystal Type A is obtained by suspending the raw material 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.
  • XRPD results showed that oxalic acid eutectic Type A was a well-crystalline solid.
  • TGA results showed that the sample had a 0.8% weight loss during heating to 150°C and a 9.0% weight loss from 150°C to 250°C, which may correspond to the decomposition of the oxalic acid eutectic and the removal of oxalic acid.
  • DSC results showed an endothermic signal at 105°C, a melting endothermic peak at 161°C, and a broad endothermic signal corresponding to TGA weight loss at 204°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; no obvious residual organic solvent was observed. Ion chromatography results showed that the oxalate content in the sample was 7.9%, and the calculated molar ratio of the raw material to oxalic acid was approximately 1:0.5 (consistent with the 9.0% weight loss in the TGA signal).
  • Toluenesulfonate Type A is obtained by suspending the raw material 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.
  • XRPD results showed that p-toluenesulfonate Type A was a well-crystalline solid.
  • TGA results showed that the sample did not lose weight during heating to 200°C, and decomposition may occur after 250°C.
  • DSC results showed a melting endothermic peak at 128°C.
  • NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw material at 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw material, suggesting that the sample was salted; the nuclear magnetic peaks near 7.5ppm, 7.1ppm and 2.3ppm corresponded to the characteristic signal peaks of p-toluenesulfonic acid. According to the integration results of the peak near 7.1ppm, it was judged that the molar ratio of the raw material and p-toluenesulfonic acid was approximately 1:1; no obvious residual organic solvent was observed.
  • Trans-aconitic acid cocrystal Type A is obtained by suspending the raw material 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.
  • XRPD results show that trans-aconitic acid cocrystal Type A is a solid with general crystallinity.
  • TGA results show that the sample loses 5.7% of its weight during heating to 120°C, and may decompose after 125°C.
  • DSC results show that there is an endothermic signal of melting accompanied by decomposition between 80°C and 180°C.
  • NMR results show that compared with the free state, the nuclear magnetic peak of the corresponding raw material has no obvious shift, and the NMR integration results are basically consistent with the raw material; the peaks near 6.7ppm and 3.7ppm correspond to the characteristic signal peaks of trans-aconitic acid.
  • the molar ratio of the raw material and trans-aconitic acid is approximately 1:1; the characteristic signal peaks of ethanol can be seen near 1.1ppm and 3.4ppm.
  • the molar ratio of the raw material and ethanol is approximately 1:0.8, and the theoretical content of ethanol is 5.5%, which is close to the weight loss in TGA.
  • trans-aconitic acid eutectic Type A was heated to 120°C and kept at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results changed. The weight loss of the sample after the hot stage experiment in TGA was significantly reduced.
  • Trans-aconitic acid cocrystal Type B is obtained by back titration of the clarified solution 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, and the relevant characterization data are shown in Figures 75 to 78.
  • XRPD results show that trans-aconitic acid cocrystal Type B is a solid with general crystallinity.
  • TGA results show that the sample loses 3.0% of its weight during heating to 120°C, and may decompose after 125°C.
  • DSC results show that there are endothermic signals of melting and decomposition at 70°C to 180°C.
  • NMR results show that compared with the free state, the nuclear magnetic peaks of the corresponding raw material have no obvious shift, and the NMR integration results are basically consistent with the raw material; the peaks near 6.7ppm and 3.7ppm correspond to the characteristic signal peaks of trans-aconitic acid.
  • trans-aconitic acid cocrystal Type B was heated to 110°C and kept at a constant temperature for 10min. After cooling naturally to room temperature, the XRPD results became amorphous.
  • 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.
  • fumaric acid cocrystal Type A (053-30-01) was characterized by XRPD, TGA, DSC, NMR, and PLM, and the characterization results are shown in Figures 85 to 89.
  • XRPD results show that fumaric acid cocrystal Type A is a solid with good crystallinity.
  • TGA results show that fumaric acid cocrystal Type A does not lose weight when heated to 150°C, and may decompose above 210°C.
  • DSC results show that fumaric acid cocrystal Type A has a melting endothermic peak at 170.1°C.
  • NMR results show that compared with the free state, the nuclear magnetic peak of the corresponding raw material has no obvious shift, and the NMR integration results are basically the same as the raw material.
  • the peak near 6.6ppm corresponds to the characteristic signal peak of fumaric acid.
  • the molar ratio of the API to fumaric acid is approximately 1:0.9; no obvious residual organic solvent is observed.
  • DVS results show that the enlarged prepared fumaric acid eutectic Type A gains 0.04% weight at 95% humidity and loses 0.04% weight at 0% humidity. During the adsorption process, it gains 0.00% weight at 80% humidity, indicating that fumaric acid eutectic Type A has almost no hygroscopicity.
  • PLM images show that fumaric acid eutectic Type A is a rod-shaped particle with a particle size generally less than 10 ⁇ m. Fumaric acid eutectic Type A is an anhydrous substance with good crystallinity and almost no hygroscopicity.
  • the XRPD of the remaining solid of oxalic acid cocrystal Type A changed after the solubility test; the XRPD of the remaining solid of p-toluenesulfonate Type A changed after the solubility test and transformed into a new solid form; the XRPD of the remaining solid of hydrochloride Type A, hydrobromide Type E and maleic acid cocrystal Type B changed after the solubility test and transformed into another identical solid form (named as free form Type C).
  • the stability of fumaric acid eutectic Type A was studied under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500Lux), and accelerated (40°C/75% RH) conditions. Samples were taken for XRPD and HPLC characterization at 7 days and 15 days, respectively. The results are shown in Table 12, Table 13 and Figure 90. The XRPD results show that fumaric acid eutectic Type A is stable under high temperature, high humidity, light, and accelerated conditions for 7 days and 15 days, without any crystal transformation and no significant change in appearance. In terms of chemical purity, fumaric acid eutectic Type A has no significant change under all test conditions.
  • fumaric acid eutectic Type A is almost non-hygroscopic.
  • fumaric acid eutectic Type A did not undergo crystal transformation under high temperature, high humidity, light and accelerated conditions for 7 days and 15 days, and there was no significant change in appearance and purity.
  • Plasma samples were stored in a -80°C refrigerator before analysis.
  • ⁇ LC-MS/MS was used to determine the concentration of the target analyte in beagle dog plasma.
  • Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters based on the blood drug concentration data at different time points, providing parameters such as AUC 0-t , AUC 0- ⁇ , C max , T max , and T 1/2 and their mean and standard deviation.

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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

吡啶氮氧化合物的盐型、共晶及其制备方法和应用Salt form, eutectic of pyridine nitrogen oxide compound, preparation method and application thereof

本申请要求享有申请人于2023年6月14日向中国国家知识产权局提交的，专利申请号为202310705174.7，名称为“吡啶氮氧化合物的盐型、共晶及其制备方法和应用”的在先申请的优先权权益。该在先申请的全文通过引用的方式结合于本申请中。This application claims the priority of the prior application filed by the applicant with the State Intellectual Property Office of China on June 14, 2023, with patent application number 202310705174.7 and titled “Salt forms, co-crystals, preparation methods and applications of pyridine nitrogen oxide compounds”. The entire text of the prior application is incorporated into this application by reference.

技术领域Technical Field

本发明属于医药领域，具体涉及吡啶氮氧化合物的盐型、共晶及其制备方法和应用。The invention belongs to the field of medicine, and specifically relates to a salt form, a cocrystal, a preparation method and an application of a pyridine nitrogen oxide compound.

背景技术Background Art

疼痛是临床上最常见的症状之一，是继呼吸、脉搏、血压和体温之后的第五生命体征，严重影响患者的生活质量。据统计，2018年全球镇痛药市场约为360亿美元，预计2023年将达到560亿美元。其中急性中重度主要依赖于阿片类药物，占镇痛药市场份额的三分之二左右，未来将以2.5％的年复合增长率稳定增长。而以神经病理性疼痛(neuropathic pain)和关节炎疼痛为主的慢性疼痛患者数量逐年增加，预计市场将呈现18％左右的年复合增长率，是驱动未来十年全球疼痛市场持续增长的主要推动力。Pain is one of the most common clinical symptoms. It is the fifth vital sign after respiration, pulse, blood pressure and body temperature, which seriously affects the quality of life of patients. According to statistics, the global analgesic market was about 36 billion US dollars in 2018 and is expected to reach 56 billion US dollars 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 chronic pain patients, mainly neuropathic pain and arthritis pain, is increasing year by year. The market is expected to show an annual compound growth rate of about 18%, which is the main driving force for the continued growth of the global pain market in the next decade.

近年来的研究成果逐步揭示了钠离子通道亚型1.8(NaV1.8)在痛觉的发生和传递方面起重要作用。NaV1.8是一种电压门控钠离子通道，主要表达在包括感觉神经元在内的传入神经元上，通过控制钠离子进出细胞，在维持伤害性感觉神经元的兴奋性、动作电位的发放和持续以及痛觉敏感性的调节等方面，发挥着重要作用。NaV1.8激活性突变病人出现小纤维神经病变(主要负责痛觉传递的Aδ纤维和无髓纤维C型纤维受损)导致的阵发性疼痛。慢性炎症和糖尿病等疾病会引起NaV1.8表达增加或性质改变从而敏化伤害感受神经元，引起多种疼痛。而NaV1.8基因敲除小鼠对痛觉不敏感。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. It controls the flow of sodium ions into and out of cells, and plays an important role in maintaining the excitability of nociceptive sensory neurons, the release and persistence of action potentials, and the regulation of pain sensitivity. Patients with NaV1.8 activating mutations 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 or changes in the properties of NaV1.8, thereby sensitizing nociceptive neurons and causing a variety of pain. NaV1.8 gene knockout mice are insensitive to pain.

创新药JMKX000623是上海济煜自主研发的高选择性钠离子通道阻滞剂，通过阻滞钠离子内流而阻止痛觉发生和传递，在多个临床前动物疼痛模型中显示出显著的镇痛作用，并可减少阿片类镇痛药物的用量。2022年3月12日，其新药临床试验申请(IND)获得中国国家药监局药品审评中心(CDE)批准1。The innovative drug JMKX000623 is a highly selective sodium channel blocker independently developed by Shanghai Jiyu. It blocks the influx of sodium ions to prevent the occurrence and transmission of pain. It has shown significant analgesic effects in multiple preclinical animal pain models and can reduce the dosage of opioid analgesics. On March 12, 2022, its new drug clinical trial application (IND) was approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration1.

药物共晶是指活性药物分子与共晶配体以一定比例，通过分子间非共价相互作用力形成的晶体。药物通过形成共晶，一方面可以改善其理化性质和提高临床治疗作用，另一方面共晶可以丰富其结晶形式。然而药物共晶体的开发难度较大，需要对共晶配体选择、制备工艺和物性表征等方面进行深入研究和评估。Drug cocrystals refer to crystals formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a certain ratio. By forming cocrystals, drugs can improve their physical and chemical properties and enhance their clinical therapeutic effects on the one hand, and on the other hand, cocrystals can enrich their crystal forms. However, the development of drug cocrystals is difficult, and in-depth research and evaluation are required on cocrystal ligand selection, preparation process, and physical property characterization.

发明内容Summary of the invention

本发明提供了一种式I所示化合物药学上可接受的盐的盐型或共晶；
The present invention provides a salt form or co-crystal of a pharmaceutically acceptable salt of a compound represented by Formula I;

所述药学上可接受的盐的盐型或共晶为式Ⅰ化合物与酸或碱形成的盐型或共晶，优选式Ⅰ化合物与酸形成的盐型或共晶。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.

根据本发明的实施方案，所述酸可以选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、3,5-二羟基苯甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、对羟基苯甲酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、龙胆酸、反式乌头酸、半硫酸或硫氰酸，以及烟酰胺、1,4-苯二酚或双羟萘酸。作为实例，所述酸可以选自盐酸、氢溴酸、硫酸、富马酸、马来酸、酒石酸、3,5-二羟基苯甲酸、龙胆酸、对羟基苯甲酸、草酸、对甲苯磺 酸和反式乌头酸中的一种。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 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 One of aconitic acid and trans-aconitic acid.

根据本发明的实施方案，所述碱可以选自无机碱，例如碱金属氢氧化物或碱土金属的氢氧化物，优选为氢氧化钠或氢氧化钾。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.

根据本发明优选的实施方案，所述式Ⅰ化合物药学上可接受的盐的盐型选自其盐酸盐、氢溴酸盐、硫酸盐和对甲苯磺酸盐中的一种。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.

根据本发明优选的实施方案，所述式Ⅰ化合物药学上可接受的盐的共晶选自其富马酸共晶、马来酸共晶、酒石酸共晶(L-酒石酸共晶)、3,5-二羟基苯甲酸共晶、龙胆酸共晶、对羟基苯甲酸共晶、草酸共晶和反式乌头酸共晶中的一种。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.

根据本发明更优选的实施方案，所述式Ⅰ化合物药学上可接受的盐的共晶是式Ⅰ化合物与富马酸形成的共晶，即式Ⅰ化合物富马酸共晶。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.

根据本发明的实施方案，所述式I化合物药学上可接受的盐的盐型或共晶中，式I化合物与所述的酸或碱的摩尔比可以独立地选自1:1、2:1或3:1，条件是所述盐型或共晶中式I化合物的离子与酸或碱的离子电荷平衡。例如，当所述的酸(如盐酸、对甲苯磺酸、)中可电离的氢原子数为1时，式I化合物与所述的酸的摩尔比为1:1；当所述的酸(如硫酸、富马酸、马来酸、对羟基苯甲酸、酒石酸、草酸)中可电离的氢原子数为2时，式I化合物与所述的酸的摩尔比可以为1:1或2:1；当所述的酸(如3,5-二羟基苯甲酸、龙胆酸、反式乌头酸)中可电离的氢原子数为3时，式I化合物与所述的酸的摩尔比为1:1、2:1或3:1。According to an embodiment of the present invention, in the salt form or co-crystal 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 co-crystal are in charge 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.

本发明还提供一种式Ⅰ化合物药学上可接受的盐的盐型或共晶的制备方法，所述制备方法包括将式Ⅰ化合物与所述酸或碱反应，制备得到式Ⅰ化合物药学上可接受的盐的盐型或共晶。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, the preparation method comprising reacting the compound of formula I with the acid or base to prepare a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I.

根据本发明的实施方案，所述制备方法包括将式Ⅰ化合物与所述酸或碱在溶剂中反应，制备得到式I化合物药学上可接受的盐的盐型或共晶。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.

根据本发明的实施方案，所述酸或碱彼此独立地具有上文所述的定义。According to an embodiment of the present invention, the acid or base independently of each other has the above-mentioned definition.

根据本发明的实施方案，所述溶剂可以选自醇类、酮类、酯类、醚类，所述溶剂中两种以上的组合，或上述溶剂或组合分别与水的混合物。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 the combination with water.

根据本发明的实施方案，所述醇类可以选自具有1-8个碳原子的醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇或其中两种以上的组合；所述酮类可以选自具有3-10个碳原子的酮，例如丙酮、丁酮、戊酮、甲基乙基酮、4-甲基-2-戊酮或其中两种以上的组合；所述酯类可以选自有机羧酸酯，例如甲酸甲酯、乙酸乙酯、甲酸异丁酯、乙酸异丙酯或其中两种以上的组合；所述醚类可以为直链或支链烷基醚或环醚类化合物，例如甲基叔丁基醚、四氢呋喃、2-甲基-四氢呋喃或其中两种以上的组合。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 carboxylates, 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.

根据本发明的实施方案，所述式Ⅰ化合物与所述酸或碱的摩尔比可以为1:0.2～1:3，1:0.8～1:1.5，优选为1:0.5～1:1.5，更优选为1:0.6～1:1.3。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.

根据本发明的实施方案，式I所示化合物药学上可接受的盐的盐型和/或共晶可以选自：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 can be selected from:

盐酸盐Type A；氢溴酸盐Type A、氢溴酸盐Type B、氢溴酸盐Type C、氢溴酸盐Type D、氢溴酸盐Type E；硫酸盐Type A；富马酸共晶Type A；马来酸共晶Type A、马来酸共晶Type B；酒石酸共晶Type A、酒石酸共晶Type B、酒石酸共晶Type C；3,5-二羟基苯甲酸共晶Type A、3,5-二羟基苯甲酸共晶Type B；龙胆酸共晶Type A；对羟基苯甲酸共晶Type A；草酸共晶Type A；对甲苯磺酸盐Type A；反式乌头酸共晶Type A、反式乌头酸共晶Type B。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.

一种式Ⅰ化合物的盐酸盐Type A，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.06±0.2°、18.80±0.2°、22.24±0.2°处具有特征峰。A Type A hydrochloride salt of a compound of formula I, wherein the Type A hydrochloride salt 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°.

根据本发明的实施方案，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.06±0.2°、18.80±0.2°、21.35±0.2°、22.24±0.2°、26.67±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.67±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、30.19±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-1所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°:

表1-1盐酸盐Type A的XRPD解析数据

Table 1-1 XRPD analysis data of hydrochloride Type A

根据本发明的实施方案，所述盐酸盐Type A具有基本如图4所示的X射线粉末衍射图。According to an embodiment of the present invention, the hydrochloride Type A has an X-ray powder diffraction pattern substantially as shown in Figure 4.

根据本发明的实施方案，所述盐酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度160.6℃附近出现吸热峰。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.

根据本发明的实施方案，所述盐酸盐Type A具有基本如图5所示的DSC图。According to an embodiment of the present invention, the hydrochloride Type A has a DSC graph basically as shown in Figure 5.

根据本发明的实施方案，所述盐酸盐Type A的热重分析(TGA)显示在100℃至200℃区间内具有约4.6％的失重。According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the hydrochloride Type A shows a weight loss of about 4.6% in the range of 100°C to 200°C.

根据本发明的实施方案，所述盐酸盐Type A具有基本如图5所示的TGA图。According to an embodiment of the present invention, the hydrochloride Type A has a TGA chart basically as shown in Figure 5.

根据本发明的实施方案，所述盐酸盐Type A为式Ⅰ化合物盐酸盐的无水物或水合物。According to an embodiment of the present invention, the hydrochloride Type A is an anhydrate or hydrate of the hydrochloride of the compound of formula I.

根据本发明的实施方案，所述盐酸盐Type A中式Ⅰ化合物与盐酸盐的摩尔比为1:1，例如为式Ⅰ化合物单盐酸盐的水合物。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.

一种式Ⅰ化合物的氢溴酸盐Type A，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.95±0.2°、24.55±0.2°、25.08±0.2°处具有特征峰。A Type A hydrobromide salt of a compound of formula I, wherein the Type A hydrobromide salt 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°.

根据本发明的实施方案，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.95±0.2°、24.50±0.2°、24.55±0.2°、25.08±0.2°、26.77±0.2°处具有特征峰。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 21.95±0.2°, 24.50±0.2°, 24.55±0.2°, 25.08±0.2°, and 26.77±0.2°.

根据本发明的实施方案，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.89±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.89±0.2°处具有特征峰。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°, 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°.

根据本发明的实施方案，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-2所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°:

表1-2氢溴酸盐Type A的XRPD解析数据

Table 1-2 XRPD analysis data of hydrobromide Type A

根据本发明的实施方案，所述氢溴酸盐Type A具有基本如图9所示的X射线粉末衍射图。According to an embodiment of the present invention, the hydrobromide Type A has an X-ray powder diffraction pattern substantially as shown in Figure 9.

根据本发明的实施方案，所述氢溴酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度90.1℃和/或183.7℃附近出现吸热峰，峰值温度128.2℃附近出现放热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide 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 appears near a peak temperature of 128.2°C.

根据本发明的实施方案，所述氢溴酸盐Type A具有基本如图10所示的DSC图。According to an embodiment of the present invention, the hydrobromide Type A has a DSC graph basically as shown in Figure 10.

根据本发明的实施方案，所述氢溴酸盐Type A的热重分析(TGA)显示在室温至150℃区间内具有约4.1％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the hydrobromide Type A shows a weight loss of about 4.1% in the range of room temperature to 150°C.

根据本发明的实施方案，所述氢溴酸盐Type A具有基本如图10所示的TGA图。According to an embodiment of the present invention, the hydrobromide Type A has a TGA graph basically as shown in Figure 10.

根据本发明的实施方案，所述氢溴酸盐Type A为式Ⅰ化合物氢溴酸盐的无水物或水合物。According to an embodiment of the present invention, the hydrobromide Type A is an anhydrate or hydrate of the hydrobromide of the compound of formula I.

根据本发明的实施方案，所述氢溴酸盐Type A中式Ⅰ化合物与氢溴酸盐的摩尔比为1:1，例如为式Ⅰ化合物单氢溴酸盐的水合物。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.

一种式Ⅰ化合物的氢溴酸盐Type B，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.30±0.2°、25.23±0.2°、27.55±0.2°处具有特征峰。A Type B hydrobromide salt of a compound of formula I, wherein the Type B hydrobromide salt 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°.

根据本发明的实施方案，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.30±0.2°、21.54±0.2°、25.23±0.2°、27.41±0.2°、27.55±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.55±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.55±0.2°处具有特征峰。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°, 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°.

根据本发明的实施方案，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-3所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-3, wherein the error range of the 2θ angle is ±0.20°:

表1-3氢溴酸盐Type B的XRPD解析数据

Table 1-3 XRPD analysis data of hydrobromide Type B

根据本发明的实施方案，所述氢溴酸盐Type B具有基本如图14所示的X射线粉末衍射图。According to an embodiment of the present invention, the hydrobromide Type B has an X-ray powder diffraction pattern basically as shown in Figure 14.

根据本发明的实施方案，所述氢溴酸盐Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度91.5℃附近出现吸热峰，峰值温度220.3℃附近出现放热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide Type B shows an endothermic peak near the peak temperature of 91.5°C when heated, and an exothermic peak near the peak temperature of 220.3°C.

根据本发明的实施方案，所述氢溴酸盐Type B具有基本如图16所示的DSC图。According to an embodiment of the present invention, the hydrobromide Type B has a DSC graph basically as shown in Figure 16.

根据本发明的实施方案，所述氢溴酸盐Type B的热重分析(TGA)显示在室温至150℃区间内具有约3.3％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the hydrobromide salt Type B shows a weight loss of about 3.3% in the range of room temperature to 150°C.

根据本发明的实施方案，所述氢溴酸盐Type B具有基本如图16所示的TGA图。According to an embodiment of the present invention, the hydrobromide Type B has a TGA graph basically as shown in Figure 16.

根据本发明的实施方案，所述氢溴酸盐Type B为式Ⅰ化合物氢溴酸盐的无水物或水合物。According to an embodiment of the present invention, the hydrobromide Type B is an anhydrate or hydrate of the hydrobromide of the compound of formula I.

根据本发明的实施方案，所述氢溴酸盐Type B为式Ⅰ化合物氢溴酸盐的水合物。According to an embodiment of the present invention, the hydrobromide Type B is a hydrate of the hydrobromide of the compound of formula I.

一种式Ⅰ化合物的氢溴酸盐Type C，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.09±0.2°、22.26±0.2°、26.56±0.2°处具有特征峰。A Type C hydrobromide salt of a compound of formula I, wherein the Type C hydrobromide salt uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 4.09±0.2°, 22.26±0.2°, and 26.56±0.2°.

根据本发明的实施方案，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.09±0.2°、17.52±0.2°、21.25±0.2°、22.26±0.2°、26.56±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.56±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.56±0.2°处具有特征峰。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°, 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°.

根据本发明的实施方案，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-4所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°:

表1-4氢溴酸盐Type C的XRPD解析数据

Table 1-4 XRPD analysis data of hydrobromide Type C

根据本发明的实施方案，所述氢溴酸盐Type C具有基本如图18所示的X射线粉末衍射图。According to an embodiment of the present invention, the hydrobromide Type C has an X-ray powder diffraction pattern basically as shown in Figure 18.

根据本发明的实施方案，所述氢溴酸盐Type C的差示扫描量热法(DSC)分析显示在加热至峰值温度90.4℃和/或177.6℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide Type C shows an endothermic peak when heated to a peak temperature of 90.4°C and/or 177.6°C.

根据本发明的实施方案，所述氢溴酸盐Type C具有基本如图19所示的DSC图。According to an embodiment of the present invention, the hydrobromide Type C has a DSC graph basically as shown in Figure 19.

根据本发明的实施方案，所述氢溴酸盐Type C的热重分析(TGA)显示在室温至150℃区间内具有约2.2％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the hydrobromide Type C shows a weight loss of about 2.2% in the range of room temperature to 150°C.

根据本发明的实施方案，所述氢溴酸盐Type C具有基本如图19所示的TGA图。According to an embodiment of the present invention, the hydrobromide Type C has a TGA graph basically as shown in Figure 19.

根据本发明的实施方案，所述氢溴酸盐Type C为式Ⅰ化合物氢溴酸盐的无水物或水合物。According to an embodiment of the present invention, the hydrobromide Type C is an anhydrate or hydrate of the hydrobromide of the compound of formula I.

根据本发明的实施方案，所述氢溴酸盐Type C为式Ⅰ化合物氢溴酸盐的无水物。According to an embodiment of the present invention, the hydrobromide Type C is the anhydrate of the hydrobromide of the compound of formula I.

一种式Ⅰ化合物的氢溴酸盐Type D，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.72±0.2°、17.89±0.2°、28.71±0.2°处具有特征峰。A Type D hydrobromide salt of a compound of formula I, wherein the Type D hydrobromide salt 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°.

根据本发明的实施方案，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.72±0.2°、17.89±0.2°、21.48±0.2°、25.08±0.2°、28.71±0.2°处具有特征峰。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°, 21.48±0.2°, 25.08±0.2°, and 28.71±0.2°.

根据本发明的实施方案，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.71±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.71±0.2°处具有特征峰。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°, 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°.

根据本发明的实施方案，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-5所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°:

表1-5氢溴酸盐Type D的XRPD解析数据
Table 1-5 XRPD analysis data of hydrobromide Type D

根据本发明的实施方案，所述氢溴酸盐Type D具有基本如图21所示的X射线粉末衍射图。According to an embodiment of the present invention, the hydrobromide Type D has an X-ray powder diffraction pattern basically as shown in Figure 21.

一种式Ⅰ化合物的氢溴酸盐Type E，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.00±0.2°、21.46±0.2°、27.22±0.2°处具有特征峰。A Type E hydrobromide salt of a compound of formula I, wherein the Type E hydrobromide salt 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°.

根据本发明的实施方案，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.00±0.2°、21.46±0.2°、22.92±0.2°、27.22±0.2°、28.21±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.21±0.2° 处具有特征峰。According to an embodiment of the present invention, the hydrobromide salt 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°, 24.94±0.2°, 26.61±0.2°, 27.22±0.2°, 28.21±0.2° There are characteristic peaks.

根据本发明的实施方案，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.14±0.2°处具有特征峰。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°, 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°.

根据本发明的实施方案，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-6所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-6, wherein the error range of the 2θ angle is ±0.20°:

表1-6氢溴酸盐Type E的XRPD解析数据
Table 1-6 XRPD analysis data of hydrobromide Type E

根据本发明的实施方案，所述氢溴酸盐Type E具有基本如图23所示的X射线粉末衍射图。According to an embodiment of the present invention, the hydrobromide Type E has an X-ray powder diffraction pattern basically as shown in Figure 23.

根据本发明的实施方案，所述氢溴酸盐Type E的差示扫描量热法(DSC)分析显示在加热至峰值温度199.5℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the hydrobromide Type E shows an endothermic peak when heated to a peak temperature of approximately 199.5°C.

根据本发明的实施方案，所述氢溴酸盐Type E具有基本如图24所示的DSC图。According to an embodiment of the present invention, the hydrobromide Type E has a DSC graph basically as shown in Figure 24.

根据本发明的实施方案，所述氢溴酸盐Type E具有基本如图24所示的TGA图。According to an embodiment of the present invention, the hydrobromide Type E has a TGA graph basically as shown in Figure 24.

根据本发明的实施方案，所述氢溴酸盐Type E为式Ⅰ化合物氢溴酸盐的无水物。According to an embodiment of the present invention, the hydrobromide Type E is the anhydrate of the hydrobromide of the compound of formula I.

根据本发明的实施方案，所述氢溴酸盐Type E中式Ⅰ化合物与氢溴酸盐的摩尔比为1:(0.5-1)，例如为1:0.6，如为式Ⅰ化合物0.6氢溴酸盐的无水物。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 0.6 hydrobromide of the compound of formula I.

一种式Ⅰ化合物的硫酸盐Type A，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在25.10±0.2°、25.16±0.2°、29.63±0.2°处具有特征峰。A sulfate salt Type A of a compound of formula I, wherein the sulfate salt Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 25.10±0.2°, 25.16±0.2°, and 29.63±0.2°.

根据本发明的实施方案，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.87±0.2°、25.10±0.2°、25.16±0.2°、29.70±0.2°、29.63±0.2°处具有特征峰。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 17.87±0.2°, 25.10±0.2°, 25.16±0.2°, 29.70±0.2°, and 29.63±0.2°.

根据本发明的实施方案，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.63±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.63±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-7所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°:

表1-7硫酸盐Type A的XRPD解析数据

Table 1-7 XRPD analysis data of sulfate Type A

根据本发明的实施方案，所述硫酸盐Type A具有基本如图26所示的X射线粉末衍射图。According to an embodiment of the present invention, the sulfate Type A has an X-ray powder diffraction pattern basically as shown in Figure 26.

根据本发明的实施方案，所述硫酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度81.1℃和/或156.9℃附近出现吸热峰。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.

根据本发明的实施方案，所述硫酸盐Type A具有基本如图27所示的DSC图。According to an embodiment of the present invention, the sulfate Type A has a DSC graph basically as shown in Figure 27.

根据本发明的实施方案，所述硫酸盐Type A的热重分析(TGA)显示在室温至150℃区间内具有约6.2％的失重。According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述硫酸盐Type A具有基本如图27所示的TGA图。According to an embodiment of the present invention, the sulfate Type A has a TGA graph basically as shown in Figure 27.

根据本发明的实施方案，所述硫酸盐Type A为式Ⅰ化合物硫酸盐的水合物。According to an embodiment of the present invention, the sulfate Type A is a hydrate of the sulfate of the compound of formula I.

根据本发明的实施方案，所述硫酸盐Type A为式Ⅰ化合物单硫酸盐的水合物。According to an embodiment of the present invention, the sulfate Type A is a hydrate of the monosulfate of the compound of formula I.

一种式Ⅰ化合物的富马酸共晶Type A，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.34±0.2°、24.09±0.2°、25.95±0.2°处具有特征峰。A fumaric acid cocrystal Type A of a compound of formula I, wherein the fumaric acid cocrystal Type A uses Cu-Kα radiation, and the 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°.

根据本发明的实施方案，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在8.93±0.2°、17.34±0.2°、22.03±0.2°、24.09±0.2°、25.95±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、30.21±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、30.21±0.2°处具有特征峰。According to an embodiment of the present invention, the fumaric acid eutectic 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°.

根据本发明的实施方案，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-8所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-8, wherein the error range of the 2θ angle is ±0.20°:

表1-8富马酸共晶Type A的XRPD解析数据

Table 1-8 XRPD analysis data of fumaric acid eutectic Type A

根据本发明的实施方案，所述富马酸共晶Type A具有基本如图85所示的X射线粉末衍射图。According to an embodiment of the present invention, the fumaric acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 85.

根据本发明的实施方案，所述富马酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度170.1℃附近出现吸热峰。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.

根据本发明的实施方案，所述富马酸共晶Type A具有基本如图86所示的DSC图。According to an embodiment of the present invention, the fumaric acid eutectic Type A has a DSC graph basically as shown in Figure 86.

根据本发明的实施方案，所述富马酸共晶Type A具有基本如图86所示的TGA图。According to an embodiment of the present invention, the fumaric acid eutectic Type A has a TGA graph basically as shown in Figure 86.

根据本发明的实施方案，所述富马酸共晶Type A为式Ⅰ化合物富马酸共晶无水物。According to an embodiment of the present invention, the fumaric acid eutectic Type A is anhydrous fumaric acid eutectic of compound I.

根据本发明的实施方案，所述富马酸共晶Type A中式Ⅰ化合物与富马酸的摩尔比为1:1，例如为式Ⅰ化合物单富马酸共晶无水物。According to an embodiment of the present invention, the molar ratio of the compound of formula I to fumaric acid in the fumaric acid eutectic Type A is 1:1, for example, it is the monofumaric acid eutectic anhydrate of the compound of formula I.

一种式Ⅰ化合物的马来酸共晶Type A，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.58±0.2°、22.36±0.2°、25.31±0.2°处具有特征峰。A maleic acid cocrystal Type A of a compound of formula I, wherein 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°, and 25.31±0.2°.

根据本发明的实施方案，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.58±0.2°、22.36±0.2°、22.73±0.2°、23.45±0.2°、25.31±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.28±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.28±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-9所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-9, wherein the error range of the 2θ angle is ±0.20°:

表1-9马来酸共晶Type A的XRPD解析数据

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

根据本发明的实施方案，所述马来酸共晶Type A具有基本如图34所示的X射线粉末衍射图。According to an embodiment of the present invention, the maleic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 34.

根据本发明的实施方案，所述马来酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度107.8℃、118.5℃和/或155.6℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type A shows the appearance of endothermic peaks when heated to peak temperatures near 107.8°C, 118.5°C and/or 155.6°C.

根据本发明的实施方案，所述马来酸共晶Type A具有基本如图35所示的DSC图。According to an embodiment of the present invention, the maleic acid cocrystal Type A has a DSC graph basically as shown in Figure 35.

根据本发明的实施方案，所述马来酸共晶Type A的热重分析(TGA)显示在100℃至200℃区间内具有约11.4％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the maleic acid eutectic Type A shows a weight loss of approximately 11.4% in the range of 100°C to 200°C.

根据本发明的实施方案，所述马来酸共晶Type A具有基本如图35所示的TGA图。According to an embodiment of the present invention, the maleic acid cocrystal Type A has a TGA graph basically as shown in Figure 35.

根据本发明的实施方案，所述马来酸共晶Type A为式Ⅰ化合物马来酸共晶的无水物。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.

根据本发明的实施方案，所述马来酸共晶Type A中式Ⅰ化合物与马来酸的摩尔比为1:(0.5-1)，例如1:0.6，如为式Ⅰ化合物0.6马来酸共晶的无水物。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 anhydrous form of the compound of formula I 0.6 maleic acid cocrystal.

一种式Ⅰ化合物的马来酸共晶Type B，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在22.57±0.2°、25.78±0.2°、26.94±0.2°处具有特征峰。A maleic acid cocrystal Type B of a compound of formula I, wherein the maleic acid cocrystal Type B uses Cu-Kα radiation, and the 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°.

根据本发明的实施方案，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.92±0.2°、22.57±0.2°、24.92±0.2°、25.78±0.2°、26.94±0.2°处具有特征峰。According to an embodiment of the present invention, the maleic acid eutectic 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°.

根据本发明的实施方案，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.22±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.22±0.2°处具有特征峰。According to an embodiment of the present invention, the maleic acid eutectic 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°.

根据本发明的实施方案，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-10所示的特征峰，其中所述2θ角度的误差范围为±0.20°：According to an embodiment of the present invention, the maleic 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 1-10, wherein the error range of the 2θ angle is ±0.20°:

表1-10马来酸共晶Type B的XRPD解析数据
Table 1-10 XRPD analysis data of maleic acid cocrystal Type B

根据本发明的实施方案，所述马来酸共晶Type B具有基本如图37所示的X射线粉末衍射图。According to an embodiment of the present invention, the maleic acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 37.

根据本发明的实施方案，所述马来酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度127.3℃附近出现吸热峰。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.

根据本发明的实施方案，所述马来酸共晶Type B具有基本如图38所示的DSC图。According to an embodiment of the present invention, the maleic acid eutectic Type B has a DSC graph basically as shown in Figure 38.

根据本发明的实施方案，所述马来酸共晶Type B的热重分析(TGA)显示在100℃至200℃区间内具有约 19.5％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the maleic acid eutectic Type B shows that the eutectic has a temperature of about 100°C to 200°C. 19.5% weight loss.

根据本发明的实施方案，所述马来酸共晶Type B具有基本如图38所示的TGA图。According to an embodiment of the present invention, the maleic acid eutectic Type B has a TGA graph basically as shown in Figure 38.

根据本发明的实施方案，所述马来酸共晶Type B为式Ⅰ化合物马来酸共晶的无水物。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.

根据本发明的实施方案，所述马来酸共晶Type B中式Ⅰ化合物与马来酸的摩尔比为1:1，例如为式Ⅰ化合物单马来酸共晶的无水物。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 monomaleic acid cocrystal of the compound of formula I.

一种式Ⅰ化合物的酒石酸共晶Type A，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.79±0.2°、25.43±0.2°、26.38±0.2°处具有特征峰。A tartaric acid cocrystal Type A of a compound of formula I, wherein the tartaric acid cocrystal Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 21.79±0.2°, 25.43±0.2°, and 26.38±0.2°.

根据本发明的实施方案，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在13.38±0.2°、18.84±0.2°、21.79±0.2°、25.43±0.2°、26.38±0.2°处具有特征峰。According to an embodiment of the present invention, the tartaric acid eutectic 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°.

根据本发明的实施方案，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.38±0.2°处具有特征峰。According to an embodiment of the present invention, the tartaric acid eutectic 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°.

根据本发明的实施方案，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.85±0.2°处具有特征峰。According to an embodiment of the present invention, the tartaric acid eutectic 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°.

根据本发明的实施方案，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-11所示的特征峰，其中所述2θ角度的误差范围为±0.20°：According to an embodiment of the present invention, the tartaric acid eutectic 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°:

表1-11酒石酸共晶Type A的XRPD解析数据
Table 1-11 XRPD analysis data of tartaric acid cocrystal Type A

根据本发明的实施方案，所述酒石酸共晶Type A具有基本如图40所示的X射线粉末衍射图。According to an embodiment of the present invention, the tartaric acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 40.

根据本发明的实施方案，所述酒石酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度87.5℃、102.6℃、135.7℃和/或187.5℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type A shows endothermic peaks when heated to peak temperatures near 87.5°C, 102.6°C, 135.7°C and/or 187.5°C.

根据本发明的实施方案，所述酒石酸共晶Type A具有基本如图41所示的DSC图。According to an embodiment of the present invention, the tartaric acid eutectic Type A has a DSC graph basically as shown in Figure 41.

根据本发明的实施方案，所述酒石酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约2.2％的失重。According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述酒石酸共晶Type A具有基本如图41所示的TGA图。According to an embodiment of the present invention, the tartaric acid eutectic Type A has a TGA graph basically as shown in Figure 41.

根据本发明的实施方案，所述酒石酸共晶Type A为式Ⅰ化合物酒石酸共晶的无水物。According to an embodiment of the present invention, the tartaric acid eutectic Type A is the anhydrate of the tartaric acid eutectic of the compound of formula I.

根据本发明的实施方案，所述酒石酸共晶Type A中式Ⅰ化合物与酒石酸的摩尔比为1:(1-2)，例如1:1.1，如 为式Ⅰ化合物1.1酒石酸共晶的无水物。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. It is the anhydrate of tartaric acid cocrystal of compound 1.1 of formula I.

一种式Ⅰ化合物的酒石酸共晶Type B，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.03±0.2°、5.18±0.2°、20.30±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.03±0.2°、5.18±0.2°、5.53±0.2°、18.20±0.2°、20.30±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、20.30±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.04±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-12所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 as shown in Table 1-12, wherein the error range of the 2θ angle is ±0.20°:

表1-12酒石酸共晶Type B的XRPD解析数据
Table 1-12 XRPD analysis data of tartaric acid cocrystal Type B

根据本发明的实施方案，所述酒石酸共晶Type B具有基本如图44所示的X射线粉末衍射图。According to an embodiment of the present invention, the tartaric acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 44.

根据本发明的实施方案，所述酒石酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度88.4℃和/或172.5℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the tartaric acid eutectic Type B shows an endothermic peak when heated to a peak temperature of 88.4°C and/or 172.5°C.

根据本发明的实施方案，所述酒石酸共晶Type B具有基本如图45所示的DSC图。According to an embodiment of the present invention, the tartaric acid eutectic Type B has a DSC graph basically as shown in Figure 45.

根据本发明的实施方案，所述酒石酸共晶Type B的热重分析(TGA)显示在室温至150℃区间内具有约3.3％的失重。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 of room temperature to 150°C.

根据本发明的实施方案，所述酒石酸共晶Type B具有基本如图45所示的TGA图。According to an embodiment of the present invention, the tartaric acid eutectic Type B has a TGA graph basically as shown in Figure 45.

根据本发明的实施方案，所述酒石酸共晶Type B为式Ⅰ化合物酒石酸共晶的无水物或水合物。According to an embodiment of the present invention, the tartaric acid cocrystal Type B is an anhydrate or hydrate of the tartaric acid cocrystal of the compound of formula I.

根据本发明的实施方案，所述酒石酸共晶Type B中式Ⅰ化合物与酒石酸的摩尔比为1:(1-2)，例如1:1.3，如为式Ⅰ化合物1.3酒石酸共晶的水合物。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 the hydrate of the tartaric acid cocrystal of compound of formula I 1.3.

一种式Ⅰ化合物的酒石酸共晶Type C，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.85±0.2°、12.99±0.2°、21.27±0.2°处具有特征峰。A tartaric acid cocrystal Type C of a compound of formula I, wherein the tartaric acid cocrystal Type C uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 6.85±0.2°, 12.99±0.2°, and 21.27±0.2°.

根据本发明的实施方案，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.73±0.2°、6.85±0.2°、12.19±0.2°、12.99±0.2°、21.27±0.2°处具有特征峰。 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°.

根据本发明的实施方案，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.88±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.88±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-13所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-13, wherein the error range of the 2θ angle is ±0.20°:

表1-13酒石酸共晶Type C的XRPD解析数据
Table 1-13 XRPD analysis data of tartaric acid eutectic Type C

根据本发明的实施方案，所述酒石酸共晶Type C具有基本如图49所示的X射线粉末衍射图。According to an embodiment of the present invention, the tartaric acid cocrystal Type C has an X-ray powder diffraction pattern basically as shown in Figure 49.

根据本发明的实施方案，所述酒石酸共晶Type C的差示扫描量热法(DSC)分析显示在加热至峰值温度87.4℃、113.2℃、137.2℃和/或189.5℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the tartaric acid eutectic Type C shows endothermic peaks when heated to peak temperatures near 87.4°C, 113.2°C, 137.2°C and/or 189.5°C.

根据本发明的实施方案，所述酒石酸共晶Type C具有基本如图50所示的DSC图。According to an embodiment of the present invention, the tartaric acid eutectic Type C has a DSC graph basically as shown in Figure 50.

根据本发明的实施方案，所述酒石酸共晶Type C的热重分析(TGA)显示在室温至150℃区间内具有约1.9％的失重。According to an embodiment of the present invention, thermogravimetric analysis (TGA) of the tartaric acid eutectic Type C shows a weight loss of approximately 1.9% in the range of room temperature to 150°C.

根据本发明的实施方案，所述酒石酸共晶Type C具有基本如图50所示的TGA图。According to an embodiment of the present invention, the tartaric acid eutectic Type C has a TGA graph basically as shown in Figure 50.

根据本发明的实施方案，所述酒石酸共晶Type C为式Ⅰ化合物酒石酸共晶的无水物或水合物。According to an embodiment of the present invention, the tartaric acid cocrystal Type C is an anhydrate or hydrate of the tartaric acid cocrystal of the compound of formula I.

根据本发明的实施方案，所述酒石酸共晶Type C中式Ⅰ化合物与酒石酸的摩尔比为1:1，例如为式Ⅰ化合物单酒石酸共晶的水合物。According to an embodiment of the present invention, the molar ratio of the compound of formula I to tartaric acid in the tartaric acid eutectic Type C is 1:1, for example, it is a hydrate of monotartaric acid eutectic of the compound of formula I.

一种式Ⅰ化合物的3,5-二羟基苯甲酸共晶Type A，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.19±0.2°、22.92±0.2°、27.49±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.80±0.2°、19.23±0.2°、21.19±0.2°、22.92±0.2°、27.49±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.49±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.49±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-14所示的特征峰，其中所述2θ角度的误差范围为±0.20°： 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°:

表1-14 3,5-二羟基苯甲酸共晶Type A的XRPD解析数据
Table 1-14 XRPD analysis data of 3,5-dihydroxybenzoic acid cocrystal Type A

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A具有基本如图52所示的X射线粉末衍射图。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 52.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度203.1℃附近出现吸热峰。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.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A具有基本如图53所示的DSC图。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A has a DSC graph basically as shown in Figure 53.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A具有基本如图53所示的TGA图。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A has a TGA graph basically as shown in Figure 53.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A为式Ⅰ化合物3,5-二羟基苯甲酸共晶的无水物。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type A is the anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of compound I.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type A中式Ⅰ化合物与3,5-二羟基苯甲酸的摩尔比为1:1，例如为式Ⅰ化合物单3,5-二羟基苯甲酸共晶的无水物。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 anhydrous form of the compound of formula I and mono-3,5-dihydroxybenzoic acid cocrystal.

一种式Ⅰ化合物的3,5-二羟基苯甲酸共晶Type B，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.10±0.2°、23.47±0.2°、28.05±0.2°处具有特征峰。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 the 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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.10±0.2°、17.40±0.2°、21.79±0.2°、23.47±0.2°、28.05±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.31±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.31±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-15所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-15, wherein the error range of the 2θ angle is ±0.20°:

表1-15 3,5-二羟基苯甲酸共晶Type B的XRPD解析数据

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

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B具有基本如图55所示的X射线粉末衍射图。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 55.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度170.5和/或203.6℃附近出现吸热峰，峰值温度172.5℃附近出现放热峰。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 when heated to a peak temperature near 170.5 and/or 203.6°C, and an exothermic peak near a peak temperature of 172.5°C.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B具有基本如图56所示的DSC图。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B has a DSC graph basically as shown in Figure 56.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B的热重分析(TGA)显示在室温至200℃区间内具有约0.2％的失重。According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B具有基本如图56所示的TGA图。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B has a TGA graph basically as shown in Figure 56.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B为式Ⅰ化合物3,5-二羟基苯甲酸共晶的无水物。According to an embodiment of the present invention, the 3,5-dihydroxybenzoic acid cocrystal Type B is the anhydrate of the 3,5-dihydroxybenzoic acid cocrystal of compound I.

根据本发明的实施方案，所述3,5-二羟基苯甲酸共晶Type B中式Ⅰ化合物与3,5-二羟基苯甲酸的摩尔比为1:1，例如为式Ⅰ化合物单3,5-二羟基苯甲酸共晶的无水物。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 anhydrous form of the compound of formula I and mono-3,5-dihydroxybenzoic acid cocrystal.

一种式Ⅰ化合物的龙胆酸共晶Type A，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.29±0.2°、23.45±0.2°、27.47±0.2°处具有特征峰。A gentisic acid cocrystal Type A of a compound of formula I, wherein the gentisic acid cocrystal Type A uses Cu-Kα radiation, and the 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°.

根据本发明的实施方案，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.03±0.2°、19.29±0.2°、23.45±0.2°、27.47±0.2°、27.80±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.80±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.39±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-16所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-16, wherein the error range of the 2θ angle is ±0.20°:

表1-16龙胆酸共晶Type A的XRPD解析数据

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

根据本发明的实施方案，所述龙胆酸共晶Type A具有基本如图58所示的X射线粉末衍射图。According to an embodiment of the present invention, the gentisic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 58.

根据本发明的实施方案，所述龙胆酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度166.7℃附近出现吸热峰。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 near the peak temperature of 166.7°C.

根据本发明的实施方案，所述龙胆酸共晶Type A具有基本如图59所示的DSC图。According to an embodiment of the present invention, the gentisic acid cocrystal Type A has a DSC graph basically as shown in Figure 59.

根据本发明的实施方案，所述龙胆酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约0.2％的失重。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 of room temperature to 150°C.

根据本发明的实施方案，所述龙胆酸共晶Type A具有基本如图59所示的TGA图。According to an embodiment of the present invention, the gentisic acid cocrystal Type A has a TGA graph basically as shown in Figure 59.

根据本发明的实施方案，所述龙胆酸共晶Type A为式Ⅰ化合物龙胆酸共晶的无水物。According to an embodiment of the present invention, the gentisic acid cocrystal Type A is the anhydrate of the gentisic acid cocrystal of compound I.

根据本发明的实施方案，所述龙胆酸共晶Type A中式Ⅰ化合物与龙胆酸的摩尔比为1:1，例如为式Ⅰ化合物单龙胆酸共晶的无水物。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.

一种式Ⅰ化合物的对羟基苯甲酸共晶Type A，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.93±0.2°、24.77±0.2°、26.85±0.2°处具有特征峰。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 the 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°.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.68±0.2°、21.93±0.2°、23.43±0.2°、24.77±0.2°、26.85±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.85±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.85±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-17所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-17, wherein the error range of the 2θ angle is ±0.20°:

表1-17对羟基苯甲酸共晶Type A的XRPD解析数据

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

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A具有基本如图61所示的X射线粉末衍射图。According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 61.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度124.4℃附近出现吸热峰。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.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A具有基本如图62所示的DSC图。According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A has a DSC graph basically as shown in Figure 62.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约0.1％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the p-hydroxybenzoic acid cocrystal Type A shows a weight loss of about 0.1% in the range of room temperature to 150°C.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A具有基本如图62所示的TGA图。According to an embodiment of the present invention, the p-hydroxybenzoic acid cocrystal Type A has a TGA graph basically as shown in Figure 62.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A为式Ⅰ化合物对羟基苯甲酸共晶的无水物。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.

根据本发明的实施方案，所述对羟基苯甲酸共晶Type A中式Ⅰ化合物与对羟基苯甲酸的摩尔比为1:(0.5-1)，例如1:0.5，如为式Ⅰ化合物0.5对羟基苯甲酸共晶的无水物。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 anhydrous p-hydroxybenzoic acid cocrystal of compound of formula I and 0.5 p-hydroxybenzoic acid.

一种式Ⅰ化合物的草酸共晶Type A，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.64±0.2°、26.69±0.2°、27.96±0.2°处具有特征峰。A Type A oxalic acid cocrystal of a compound of formula I, wherein the Type A oxalic acid cocrystal uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 16.64±0.2°, 26.69±0.2°, and 27.96±0.2°.

根据本发明的实施方案，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.64±0.2°、17.01±0.2°、20.96±0.2°、26.69±0.2°、27.96±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.04±0.2°处具有特征峰。According to an embodiment of the present invention, the oxalic acid eutectic 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°.

根据本发明的实施方案，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.04±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-18所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-18, wherein the error range of the 2θ angle is ±0.20°:

表1-18草酸共晶Type A的XRPD解析数据
Table 1-18 XRPD analysis data of oxalic acid cocrystal Type A

根据本发明的实施方案，所述草酸共晶Type A具有基本如图64所示的X射线粉末衍射图。According to an embodiment of the present invention, the oxalic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 64.

根据本发明的实施方案，所述草酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度105.0℃、160.7℃和/或203.7℃附近出现吸热峰。According to an embodiment of the present invention, differential scanning calorimetry (DSC) analysis of the oxalic acid cocrystal Type A shows endothermic peaks appearing near the peak temperatures of 105.0°C, 160.7°C and/or 203.7°C when heated.

根据本发明的实施方案，所述草酸共晶Type A具有基本如图65所示的DSC图。According to an embodiment of the present invention, the oxalic acid eutectic Type A has a DSC graph basically as shown in Figure 65.

根据本发明的实施方案，所述草酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约0.8％的失重，和/或在150℃至250℃区间内具有约9.0％的失重。 According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述草酸共晶Type A具有基本如图65所示的TGA图。According to an embodiment of the present invention, the oxalic acid eutectic Type A has a TGA graph basically as shown in Figure 65.

根据本发明的实施方案，所述草酸共晶Type A为式Ⅰ化合物草酸共晶的无水物。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.

根据本发明的实施方案，所述草酸共晶Type A中式Ⅰ化合物与草酸的摩尔比为1:(0.5-1)，例如1:0.5，如为式Ⅰ化合物0.5草酸共晶的无水物。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 anhydrous form of the 0.5 oxalic acid cocrystal of the compound of formula I.

一种式Ⅰ化合物的对甲苯磺酸盐Type A，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.36±0.2°、21.93±0.2°、24.55±0.2°处具有特征峰。A Type A p-toluenesulfonate salt of a compound of formula I, wherein the Type A p-toluenesulfonate salt 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°.

根据本发明的实施方案，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.36±0.2°、21.93±0.2°、23.49±0.2°、24.55±0.2°、25.82±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.77±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、31.20±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-19所示的特征峰，其中所述2θ角度的误差范围为±0.20°：According to an embodiment of the present invention, 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 Table 1-19, wherein the error range of the 2θ angle is ±0.20°:

表1-19对甲苯磺酸盐Type A的XRPD解析数据
Table 1-19 XRPD analysis data of p-toluenesulfonate Type A

根据本发明的实施方案，所述对甲苯磺酸盐Type A具有基本如图67所示的X射线粉末衍射图。According to an embodiment of the present invention, the p-toluenesulfonate Type A has an X-ray powder diffraction pattern basically as shown in Figure 67.

根据本发明的实施方案，所述对甲苯磺酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度127.7℃附近出现吸热峰。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.

根据本发明的实施方案，所述对甲苯磺酸盐Type A具有基本如图68所示的DSC图。According to an embodiment of the present invention, the p-toluenesulfonate Type A has a DSC graph basically as shown in Figure 68.

根据本发明的实施方案，所述对甲苯磺酸盐Type A具有基本如图68所示的TGA图。According to an embodiment of the present invention, the p-toluenesulfonate Type A has a TGA chart basically as shown in Figure 68.

根据本发明的实施方案，所述对甲苯磺酸盐Type A为式Ⅰ化合物对甲苯磺酸盐的无水物。According to an embodiment of the present invention, the p-toluenesulfonate Type A is the anhydrous p-toluenesulfonate of the compound of formula I.

根据本发明的实施方案，所述对甲苯磺酸盐Type A中式Ⅰ化合物与对甲苯磺酸的摩尔比为1:1，例如为式Ⅰ化合物单对甲苯磺酸盐的无水物。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 mono-p-toluenesulfonate of the compound of formula I.

一种式Ⅰ化合物的反式乌头酸共晶Type A，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.44±0.2°、22.73±0.2°、23.54±0.2°处具有特征峰。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 the 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°.

根据本发明的实施方案，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.21±0.2°、17.44±0.2°、22.73±0.2°、23.54±0.2°、24.32±0.2°处具有特征峰。 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°.

根据本发明的实施方案，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.28±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.98±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-20所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-20, wherein the error range of the 2θ angle is ±0.20°:

表1-20反式乌头酸共晶Type A的XRPD解析数据
Table 1-20 XRPD analysis data of trans-aconitic acid cocrystal Type A

根据本发明的实施方案，所述反式乌头酸共晶Type A具有基本如图70所示的X射线粉末衍射图。According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A has an X-ray powder diffraction pattern basically as shown in Figure 70.

根据本发明的实施方案，所述反式乌头酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度55.6℃、104.9℃、114.9℃、129.9℃、136.1℃和/或149.9℃附近出现吸热峰。According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述反式乌头酸共晶Type A具有基本如图71所示的DSC图。According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A has a DSC graph basically as shown in Figure 71.

根据本发明的实施方案，所述反式乌头酸共晶Type A的热重分析(TGA)显示在室温至120℃区间内具有约5.7％的失重。According to an embodiment of the present invention, the thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type A shows a weight loss of about 5.7% in the range of room temperature to 120°C.

根据本发明的实施方案，所述反式乌头酸共晶Type A具有基本如图71所示的TGA图。According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type A has a TGA diagram basically as shown in Figure 71.

根据本发明的实施方案，所述反式乌头酸共晶Type A为式Ⅰ化合物反式乌头酸共晶的乙醇溶剂合物。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.

根据本发明的实施方案，所述反式乌头酸共晶Type A中式Ⅰ化合物与反式乌头酸的摩尔比为1:1，例如为式Ⅰ化合物单反式乌头酸共晶的乙醇溶剂合物。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 mono-trans-aconitic acid cocrystal of the compound of formula I.

一种式Ⅰ化合物的反式乌头酸共晶Type B，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.69±0.2°、17.09±0.2°、23.47±0.2°处具有特征峰。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 the 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°.

根据本发明的实施方案，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在8.29±0.2°、11.69±0.2°、17.09±0.2°、23.47±0.2°、26.28±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.90±0.2°处具有特征峰。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°.

根据本发明的实施方案，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.90±0.2°处具有特征峰。 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°.

根据本发明的实施方案，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-21所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°:

表1-21反式乌头酸共晶Type B的XRPD解析数据
Table 1-21 XRPD analysis data of trans-aconitic acid cocrystal Type B

根据本发明的实施方案，所述反式乌头酸共晶Type B具有基本如图75所示的X射线粉末衍射图。According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B has an X-ray powder diffraction pattern basically as shown in Figure 75.

根据本发明的实施方案，所述反式乌头酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度78.3℃、106.5℃、118.0℃、137.1℃和/或148.0℃附近出现吸热峰。According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述反式乌头酸共晶Type B具有基本如图76所示的DSC图。According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B has a DSC graph basically as shown in Figure 76.

根据本发明的实施方案，所述反式乌头酸共晶Type B的热重分析(TGA)显示在室温至120℃区间内具有约3.0％的失重。According to an embodiment of the present invention, 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.

根据本发明的实施方案，所述反式乌头酸共晶Type B具有基本如图76所示的TGA图。According to an embodiment of the present invention, the trans-aconitic acid cocrystal Type B has a TGA graph basically as shown in Figure 76.

根据本发明的实施方案，所述反式乌头酸共晶Type B为式Ⅰ化合物反式乌头酸共晶的水合物。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.

根据本发明的实施方案，所述反式乌头酸共晶Type B中式Ⅰ化合物与反式乌头酸的摩尔比为1:(1-2)，例如1:1.1，如为式Ⅰ化合物1.1反式乌头酸共晶的水合物。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.

本发明还提供式I所示化合物药学上可接受的盐的盐型或共晶的制备方法，包括以下步骤：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:

将式I所示化合物与所述酸溶于有机溶剂中，搅拌，得到所述盐型或共晶；Dissolving the compound represented by formula I and the acid in an organic solvent and stirring to obtain the salt form or co-crystal;

和/或，将式I所示化合物与所述酸溶于有机溶剂中，搅拌，析晶，得到所述盐型或共晶；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;

和/或，将式I所示化合物与所述酸溶于有机溶剂中，搅拌，析晶，挥发，得到所述盐型或共晶；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;

和/或，将式I所示化合物与所述酸溶于有机溶剂中，搅拌，析晶，反滴，得到所述盐型或共晶；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;

根据本发明的实施方案，所述有机溶剂选自甲醇、乙醇、丙酮、乙酸乙酯、正庚烷、甲基叔丁基醚、乙二醇甲醚、二甲基亚砜、二氯甲烷、四氢呋喃中的至少一种；优选乙酸乙酯、乙醇、正庚烷、甲醇、甲基叔丁基醚、丙酮中的至少一种；例如选自乙酸乙酯、乙醇/正庚烷(1/9，v/v)、甲醇/MTBE(1/9，v/v)或丙酮/MTBE(1/9，v/v)。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).

根据本发明的实施方案，式I所示化合物与所述酸的摩尔比可以为1:(0.2-3)，1:(0.5-1.5)，例如1:(0.6-1.3)，如1:0.6、1:1、1:1.1、1:1。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.

根据本发明的实施方案，式I所示化合物与所述有机溶剂的质量体积比可以为(10-50)mg:1mL，例如(20-40)mg:1mL，如28mg:1mL、29mg:1mL、30mg:1mL、31mg:1mL、32mg:1mL、33mg:1mL、34mg:1mL。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, 34 mg:1 mL.

根据本发明的实施方案，所述搅拌的温度可以为0-40℃，如10-30℃，例如为室温(25℃)；所述搅拌的时间可以为5min-5天，例如2-3天。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.

根据本发明的实施方案，所述析晶的方法为在低温下静置，所述析晶的温度可以为-20℃至10℃，如-15℃至5℃；所述析晶的时间可以为4h-5天，例如1-4天；例如先置于4℃冰箱降温析晶，然后置于-15℃静置1-4天。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, such as 1-4 days; for example, first place it in a 4°C refrigerator to cool down for crystallization, and then place it at -15°C and stand for 1-4 days.

根据本发明的实施方案，所述挥发为室温挥发。According to an embodiment of the present invention, the volatilization is volatilization at room temperature.

根据本发明的实施方案，所述反滴是将反应溶液滴加到反溶剂中；所述反溶剂可以选自正庚烷或甲基叔丁基醚中的至少一种。According to an embodiment of the present invention, 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.

本发明还提供一种药物组合物，包含所述式Ⅰ化合物药学上可接受的盐的盐型或共晶中的至少一种，以及任选存在的药学上可接受的辅料。优选地，所述药物组合物为制剂形式。 The present invention also provides a pharmaceutical composition comprising at least one of the salt forms or co-crystals of the 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.

本发明还提供一种制剂，包含所述式Ⅰ化合物药学上可接受的盐的盐型或共晶中的至少一种，以及任选存在的药学上可接受的辅料。The present invention also provides a preparation comprising at least one of the salt forms or co-crystals of the pharmaceutically acceptable salt of the compound of formula I, and optionally a pharmaceutically acceptable excipient.

本发明还提供上述任一所述的式Ⅰ化合物药学上可接受的盐的盐型或共晶或上述药物组合物在制备用于抑制电压门控型钠通道的药物中的用途。The present invention also provides the 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.

根据本发明的实施方案，所述电压门控型钠通道是NaV1.8。According to an embodiment of the present invention, the voltage-gated sodium channel is NaV1.8.

本发明还提供上述任一所述的式Ⅰ化合物药学上可接受的盐的盐型或共晶或上述药物组合物在制备用于治疗和/或预防和/或减轻和/或缓解疾病的药物中的用途，所述疾病优选为疼痛、咳嗽。The present invention also provides the 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 treating and/or preventing and/or alleviating and/or relieving a disease, wherein the disease is preferably pain or cough.

根据本发明的实施方案，所述疾病选自慢性疼痛、肠痛、神经性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原发性疼痛、手术后疼痛、内脏痛、多发性硬化症、夏-马-图三氏综合症、失禁和心律失常。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 arrhythmia.

根据本发明的实施方案，所述肠痛选自炎性肠病疼痛、克罗恩病疼痛和间质性膀胱炎疼痛。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.

根据本发明的实施方案，所述神经性疼痛选自疱疹后神经痛、糖尿病性神经痛、HIV相关性感觉神经病、三叉神经痛、口灼伤综合症、截肢术后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、Morto神经瘤、神经挤压损伤、脊管狭窄、腕管综合症、神经根痛、坐骨神经痛、神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合症、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、脊髓损伤后疼痛、原发性小纤维神经病、原发性感觉神经病和三叉自主神经性头痛。According to an embodiment of the present invention, the neuropathic pain is selected from 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, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy and trigeminal autonomic headache.

根据本发明的实施方案，所述肌肉骨骼痛选自骨关节炎疼痛、背痛、冷痛、烧伤疼痛和牙痛。According to an embodiment of the present invention, the musculoskeletal pain is selected from osteoarthritis pain, back pain, cold pain, burn pain and dental pain.

根据本发明的实施方案，所述炎性疼痛选自类风湿性关节炎疼痛和外阴痛。According to an embodiment of the present invention, the inflammatory pain is selected from rheumatoid arthritis pain and vulvar pain.

根据本发明的实施方案，所述原发性疼痛选自纤维肌痛。According to an embodiment of the present invention, the primary pain is selected from fibromyalgia.

本发明还提供一种与电压门控型钠通道相关的疾病的预防和/或治疗方法，包括向有此需要的个体施用治疗有效量的如上所述式Ⅰ化合物药学上可接受的盐的盐型或共晶或所述药物组合物中的至少一种。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 co-crystal of a pharmaceutically acceptable salt of the compound of formula I as described above or at least one of the pharmaceutical compositions.

本发明的治疗方法可包括单独给予本发明式Ⅰ化合物药学上可接受的盐的盐型或共晶或所述药物组合物，以及将本发明式Ⅰ化合物药学上可接受的盐的盐型或共晶或所述药物组合物的一种、两种或更多种与一种、两种或更多种其它化学治疗剂组合给药。多种药物的给药可以同时或相继进行。The treatment method of the present invention may include administering a salt form or co-crystal of a pharmaceutically acceptable salt of a compound of formula I of the present invention or said pharmaceutical composition alone, and administering one, two or more salt forms or co-crystals of a pharmaceutically acceptable salt of a compound of formula I of the present invention or said pharmaceutical composition in combination with one, two or more other chemotherapeutic agents. The administration of multiple drugs may be carried out simultaneously or sequentially.

有益效果Beneficial Effects

本发明提供式Ⅰ化合物药学上可接受的盐的盐型或共晶及其制备方法，该盐型或共晶具有较好的抑制电压门控型钠通道的作用，且稳定性好，能够满足临床药物制剂开发需要，具有非常重要的临床应用价值。The present invention provides a salt form or co-crystal of a pharmaceutically acceptable salt of a compound of formula I and a preparation method thereof. The salt form or co-crystal 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.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1游离态式I化合物的XRPD图。FIG1 is an XRPD pattern of the compound of formula I in free form.

图2游离态式I化合物的TGA和DSC图。FIG2 shows TGA and DSC diagrams of the free compound of formula I.

图3游离态式I化合物的1H NMR图。FIG3 is a 1 H NMR spectrum of the compound of formula I in free form.

图4盐酸盐Type A的XRPD图。Figure 4 XRPD pattern of hydrochloride Type A.

图5盐酸盐Type A的DSC和TGA图。Figure 5 DSC and TGA graphs of Type A hydrochloride.

图6盐酸盐Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 6 1 H NMR spectrum of Type A hydrochloride: (a) comparison with the free state; (b) integration results.

图7盐酸盐Type A热台实验前后XRPD对比图。Figure 7 XRPD comparison of Type A hydrochloride before and after hot stage experiment.

图8盐酸盐Type A热台实验后样品的TGA图。Figure 8 TGA graph of the hydrochloride salt Type A sample after hot stage experiment.

图9氢溴酸盐Type A的XRPD图。Figure 9 XRPD pattern of hydrobromide salt Type A.

图10氢溴酸盐Type A的DSC和TGA图。Figure 10 DSC and TGA graphs of hydrobromide Type A.

图11氢溴酸盐Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 11 1 H NMR spectrum of hydrobromide salt Type A: (a) comparison with the free state; (b) integration result.

图12氢溴酸盐Type A热台实验前后XRPD对比图。Figure 12 XRPD comparison of Type A hydrobromide before and after hot stage experiment.

图13氢溴酸盐Type A热台实验后样品的TGA图。Figure 13 TGA graph of the sample after the hydrobromide Type A hot stage experiment.

图14氢溴酸盐Type B的XRPD图。Figure 14 XRPD pattern of hydrobromide salt Type B.

图15氢溴酸盐Type A和氢溴酸盐Type B的对比图。Figure 15 Comparison of hydrobromide Type A and hydrobromide Type B.

图16氢溴酸盐Type B的DSC和TGA图。Figure 16 DSC and TGA graphs of hydrobromide Type B.

图17氢溴酸盐Type B的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 17 1 H NMR spectrum of hydrobromide salt Type B: (a) comparison with the free state; (b) integration result.

图18氢溴酸盐Type C的XRPD图。Figure 18 XRPD pattern of hydrobromide Type C.

图19氢溴酸盐Type C的DSC和TGA图。Figure 19 DSC and TGA graphs of Type C hydrobromide.

图20氢溴酸盐Type C的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 20 1 H NMR spectrum of Type C hydrobromide: (a) comparison with the free state; (b) integration results.

图21氢溴酸盐Type D的XRPD图。Figure 21 XRPD pattern of hydrobromide salt Type D.

图22氢溴酸盐Type D放置1天后的XRPD对比图。Figure 22 XRPD comparison of hydrobromide Type D after 1 day of storage.

图23氢溴酸盐Type E的XRPD图。Figure 23 XRPD pattern of hydrobromide salt Type E.

图24氢溴酸盐Type E的DSC和TGA图。Figure 24 DSC and TGA graphs of hydrobromide Type E.

图25氢溴酸盐Type E的1H NMR图：(a)与游离态对比图；(b)积分结果。 Figure 25 1 H NMR spectrum of hydrobromide salt Type E: (a) comparison with the free state; (b) integration result.

图26硫酸盐Type A的XRPD图Figure 26 XRPD pattern of sulfate Type A

图27硫酸盐Type A的DSC和TGA图。Figure 27 DSC and TGA graphs of sulfate Type A.

图28硫酸盐Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 28 1 H NMR spectrum of sulfate Type A: (a) comparison with the free state; (b) integration result.

图29硫酸盐Type A热台实验前后XRPD对比图。Figure 29 XRPD comparison before and after sulfate Type A hot stage experiment.

图30硫酸盐Type A热台实验后样品的TGA图。Figure 30 TGA graph of the sample after sulfate Type A hot stage experiment.

图31富马酸共晶Type A的XRPD图。Figure 31 XRPD pattern of fumaric acid cocrystal Type A.

图32富马酸共晶Type A的DSC和TGA图。Figure 32 DSC and TGA graphs of fumaric acid eutectic Type A.

图33富马酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 33 1 H NMR spectrum of fumaric acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图34马来酸共晶Type A的XRPD图。Figure 34 XRPD pattern of maleic acid cocrystal Type A.

图35马来酸共晶Type A的DSC和TGA图。Figure 35 DSC and TGA graphs of maleic acid cocrystal Type A.

图36马来酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 36 1 H NMR spectrum of maleic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图37马来酸共晶Type B的XRPD图。Figure 37 XRPD pattern of maleic acid cocrystal Type B.

图38马来酸共晶Type B的DSC和TGA图。Figure 38 DSC and TGA graphs of maleic acid eutectic Type B.

图39马来酸共晶Type B的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 39 1 H NMR spectrum of maleic acid cocrystal Type B: (a) comparison with the free state; (b) integration result.

图40酒石酸共晶Type A的XRPD图。Figure 40 XRPD pattern of tartaric acid cocrystal Type A.

图41酒石酸共晶Type A的DSC和TGA图。Figure 41 DSC and TGA graphs of tartaric acid eutectic Type A.

图42酒石酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 42 1 H NMR spectrum of tartaric acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图43酒石酸共晶Type A热台前后XRPD对比图。Figure 43 XRPD comparison of tartaric acid eutectic Type A before and after heating.

图44酒石酸共晶Type B的XRPD图。Figure 44 XRPD pattern of tartaric acid cocrystal Type B.

图45酒石酸共晶Type B的DSC和TGA图。Figure 45 DSC and TGA graphs of tartaric acid eutectic Type B.

图46酒石酸共晶Type B的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 46 1 H NMR spectrum of tartaric acid cocrystal Type B: (a) comparison with the free state; (b) integration result.

图47酒石酸共晶Type B热台前后XRPD对比图。Figure 47 XRPD comparison of tartaric acid eutectic Type B before and after hot stage.

图48酒石酸共晶Type B热台实验后样品的TGA图。Figure 48 TGA graph of the sample after tartaric acid eutectic Type B hot stage experiment.

图49酒石酸共晶Type C的XRPD图。Figure 49 XRPD pattern of tartaric acid cocrystal Type C.

图50酒石酸共晶Type C的DSC和TGA图。Figure 50 DSC and TGA graphs of tartaric acid eutectic Type C.

图51酒石酸共晶Type C的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 51 1 H NMR spectrum of tartaric acid cocrystal Type C: (a) comparison with the free state; (b) integration result.

图52 3,5-二羟基苯甲酸共晶Type A的XRPD图。Figure 52 XRPD pattern of 3,5-dihydroxybenzoic acid cocrystal Type A.

图53 3,5-二羟基苯甲酸共晶Type A的DSC和TGA图。Figure 53 DSC and TGA graphs of 3,5-dihydroxybenzoic acid cocrystal Type A.

图54 3,5-二羟基苯甲酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 54 1 H NMR spectrum of 3,5-dihydroxybenzoic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图55 3,5-二羟基苯甲酸共晶Type B的XRPD图。Figure 55 XRPD pattern of 3,5-dihydroxybenzoic acid cocrystal Type B.

图56 3,5-二羟基苯甲酸共晶Type B的DSC和TGA图。Figure 56 DSC and TGA graphs of 3,5-dihydroxybenzoic acid cocrystal Type B.

图57 3,5-二羟基苯甲酸共晶Type B的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 57 1 H NMR spectrum of 3,5-dihydroxybenzoic acid cocrystal Type B: (a) comparison with the free state; (b) integration result.

图58龙胆酸共晶Type A的XRPD图。Figure 58 XRPD pattern of gentisic acid cocrystal Type A.

图59龙胆酸共晶Type A的DSC和TGA图。Figure 59 DSC and TGA graphs of gentisic acid cocrystal Type A.

图60龙胆酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 60 1 H NMR spectrum of gentisic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图61对羟基苯甲酸共晶Type A的XRPD图。Figure 61 XRPD pattern of p-hydroxybenzoic acid cocrystal Type A.

图62对羟基苯甲酸共晶Type A的DSC和TGA图。Figure 62 DSC and TGA graphs of p-hydroxybenzoic acid cocrystal Type A.

图63对羟基苯甲酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 63 1 H NMR spectrum of p-hydroxybenzoic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图64草酸共晶Type A的XRPD图。Figure 64 XRPD pattern of oxalic acid cocrystal Type A.

图65草酸共晶Type A的DSC和TGA图。Figure 65 DSC and TGA graphs of oxalic acid eutectic Type A.

图66草酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 66 1 H NMR spectrum of oxalic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图67对甲苯磺酸盐Type A的XRPD图。Figure 67 XRPD pattern of p-toluenesulfonate Type A.

图68对甲苯磺酸盐Type A的DSC和TGA图。Figure 68 DSC and TGA graphs of p-toluenesulfonate Type A.

图69对甲苯磺酸盐Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 69 1 H NMR spectrum of p-toluenesulfonate Type A: (a) comparison with the free state; (b) integration result.

图70反式乌头酸共晶Type A的XRPD图。Figure 70 XRPD pattern of trans-aconitic acid cocrystal Type A.

图71反式乌头酸共晶Type A的DSC和TGA图。Figure 71 DSC and TGA graphs of trans-aconitic acid cocrystal Type A.

图72反式乌头酸共晶Type A的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 72 1 H NMR spectrum of trans-aconitic acid cocrystal Type A: (a) comparison with the free state; (b) integration result.

图73反式乌头酸共晶Type A热台前后XRPD对比图。Figure 73 XRPD comparison of trans-aconitic acid eutectic Type A before and after hot stage.

图74反式乌头酸共晶Type A热台后样品的TGA图。Figure 74 TGA graph of the trans-aconitic acid eutectic Type A sample after hot stage.

图75反式乌头酸共晶Type B的XRPD图。Figure 75 XRPD pattern of trans-aconitic acid cocrystal Type B.

图76反式乌头酸共晶Type B的DSC和TGA图。Figure 76 DSC and TGA graphs of trans-aconitic acid cocrystal Type B.

图77反式乌头酸共晶Type B的1H NMR图：(a)与游离态对比图；(b)积分结果。Figure 77 1 H NMR spectrum of trans-aconitic acid cocrystal Type B: (a) comparison with the free state; (b) integration result.

图78反式乌头酸共晶Type B热台前后XRPD对比图。Figure 78 XRPD comparison of trans-aconitic acid eutectic Type B before and after heating.

图79草酸共晶Type A在水中振荡2h后剩余固体XRPD对比图。 Figure 79 XRPD comparison of the solid remaining after oxalic acid cocrystal Type A was shaken in water for 2 hours.

图80草酸共晶Type A水中振荡2h后剩余固体的1H NMR图：(a)与草酸共晶Type A对比图；(b)积分结果。Figure 80 1 H NMR spectrum of the solid remaining after oxalic acid cocrystal Type A was shaken in water for 2 h: (a) comparison with oxalic acid cocrystal Type A; (b) integration result.

图81对甲苯磺酸盐Type A在水中振荡2h后剩余固体XRPD对比图。Figure 81 XRPD comparison of the solid remaining after Type A p-toluenesulfonate was shaken in water for 2 hours.

图82对甲苯磺酸盐Type A水中振荡2h后剩余固体的1H NMR图：(a)与对甲苯磺酸盐Type A对比图；(b)积分结果。Figure 82 1 H NMR graph of the solid remaining after Type A p-toluenesulfonate was shaken in water for 2 h: (a) comparison with Type A p-toluenesulfonate; (b) integration result.

图83马来酸共晶Type B和盐酸盐Type A、氢溴酸盐Type E在水中振荡2h后剩余固体XRPD对比图。Figure 83 XRPD comparison of the solid remaining after oscillating in water for 2 hours between maleic acid cocrystal Type B, hydrochloride Type A and hydrobromide Type E.

图84马来酸共晶Type B水中振荡2h后剩余固体的1H NMR图：(a)与马来酸共晶Type B对比图；(b)积分结果。Figure 84 1 H NMR spectrum of the solid remaining after maleic acid cocrystal Type B was shaken in water for 2 h: (a) comparison with maleic acid cocrystal Type B; (b) integration result.

图85富马酸共晶Type A的XRPD图。Figure 85 XRPD pattern of fumaric acid cocrystal Type A.

图86富马酸共晶Type A的TGA和DSC图。Figure 86 TGA and DSC graphs of fumaric acid cocrystal Type A.

图87富马酸共晶Type A的NMR图。Figure 87 NMR spectrum of fumaric acid cocrystal Type A.

图88富马酸共晶Type A(a)DVS曲线；(b)DVS测试前后的XRPD图。Figure 88 Fumaric acid eutectic Type A (a) DVS curve; (b) XRPD pattern before and after DVS test.

图89富马酸共晶Type A的PLM图像。Figure 89 PLM image of fumaric acid eutectic Type A.

图90富马酸共晶Type A稳定性研究的XRPD图。Figure 90 XRPD pattern of stability study of fumaric acid cocrystal Type A.

图91富马酸共晶Type A在生物介质中振荡24h后剩余固体XRPD对比图。Figure 91 XRPD comparison of the remaining solid of fumaric acid cocrystal Type A after oscillation in biological medium for 24 hours.

图92马来酸共晶Type B在生物介质中振荡24h后剩余固体XRPD对比图。Figure 92 XRPD comparison of the solid remaining after maleic acid cocrystal Type B was shaken in biological medium for 24 hours.

图93盐酸盐Type A在生物介质中振荡24h后剩余固体XRPD对比图。Figure 93 XRPD comparison of the remaining solid of Type A hydrochloride after oscillation in biological medium for 24 hours.

图94游离态Form A在生物介质中振荡24h后剩余固体XRPD对比图。Figure 94 XRPD comparison of the solid remaining after free Form A was oscillated in biological medium for 24 hours.

术语定义与说明Definition and explanation of terms

除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本申请说明书和/或权利要求书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and/or claims of this application.

“API”或“游离态”均是指式I所示化合物的游离碱形式。"API" or "free state" refers to the free base form of the compound of Formula I.

“共晶”是指以特定化学计量比包含两种或更多种组分的单相结晶材料，其中晶格中的排列不是基于离子键(如与盐形成的离子键)并且所述组分中至少两种在室温下为固体。"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 a salt) and at least two of the components are solid at room temperature.

本发明的的“盐型”或“共晶”包括化合物的水合物、非溶剂合物(无水合物)以及溶剂合物的晶型形式。The "salt form" or "co-crystal" of the present invention includes hydrates, non-solvates (anhydrates) and crystalline forms of solvates of the compound.

“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、1-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving 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.

“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。"Anti-solvent" refers to a fluid that promotes precipitation of a product (or a product precursor) from a solvent. The anti-solvent may 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 may be the same liquid as the solvent but at a different temperature, or it may be a different liquid from the solvent.

“溶剂化物”是指晶体在表面上、或在晶格中、或者在表面上和在晶格中具有溶剂，其中，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、或在晶格中、或者在表面上和在晶格中的溶剂是水。在物质的表面上、或在晶格中、或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。"Solvate" means that the crystal has a solvent on the surface, in the crystal lattice, or 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, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water. On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents except water.

X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施例中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本发明试验所用仪器状况，衍射峰存在±0.2°的误差容限。X-ray powder diffraction (XRPD) can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms. The peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and 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 spectrum may have experimental errors, and the measurement of 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ±0.2° for the diffraction peak.

差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al2O3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施例中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本发明试验所用仪器状况，熔化峰存在±3℃的误差容限。 Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al 2 O 3 ) as a function of temperature by continuous heating or cooling under program control. The height of the melting peak of a 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 of 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, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, the melting peak has an error tolerance of ±3°C.

差示扫描量热(DSC)还可用于检测分析晶型是否有转晶或混晶现象。Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon.

化学组成相同的固体，在不同的热力学条件下，常会形成晶体结构不同的同质异构体，或称为变体，这种现象称为同质多晶或同质多相现象。当温度和压力条件变化时，变体之间会发生相互转变，此现象称为晶型转变。由于晶型转变，晶体的力学、电学、磁学等性能会发生巨大的变化。当晶型转变的温度在可测范围内时，在差示扫描量热(DSC)图上可观察到这一转变过程，其特征在于，DSC图具有反映这一转变过程的放热峰，且同时具有两个或多个吸热峰，分别为转变前后的不同晶型的特征吸热峰。本发明化合物的晶型或无定形在适当条件下可发生晶型转变。Solids with the same chemical composition often form isomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase phenomenon. When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly. 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, characterized in that the DSC graph has an exothermic peak reflecting this transformation process, and at the same time has two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after the transformation. The crystal form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.

热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。根据本发明试验所用的仪器状况，质量变化存在±0.3％的误差容限。Thermogravimetric analysis (TGA) is a technique for measuring the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of crystal water or crystallization solvent in the crystals. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. According to the instrument conditions used in the test of the present invention, the mass change has an error tolerance of ±0.3%.

水分吸附脱附等温线测定(DVS)是通过对测定对象的固体于各相对湿度条件下测定重量变化而计测水分的吸附、脱附行为的测定法。The moisture adsorption/desorption isotherm measurement (DVS) is a measurement method that measures the adsorption and desorption behavior of moisture by measuring the weight change of a solid object under various relative humidity conditions.

在本发明的上下文中，X射线粉末衍射图中的2θ值均以度(°)为单位。In the context of the present invention, 2θ values in X-ray powder diffraction patterns are given in degrees (°).

当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。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 which cannot be attributed to background noise.

术语“基本上如图所示”是指X射线粉末衍射图或DSC图或TGA结果中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。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 the DSC pattern or the TGA results are shown in the pattern thereof.

“相对强度”是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。“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%.

在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。In the context of the present invention, when or whether the words "about" or "approximately" are 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 range of the mean. Whenever a number having a value of N is disclosed, any number having a value within N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.

术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

具体实施方式DETAILED DESCRIPTION

下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations 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 in the scope of protection intended by the present disclosure.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

分析方法Analytical methods

1.核磁分析(1H NMR)1. Nuclear magnetic resonance analysis ( 1 H NMR)

将若干毫克固体样品溶解于二甲基亚砜-d6溶剂中，在Bruker AVANCE NEO 400(Bruker，GER)上进行核磁分析。Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by NMR on Bruker AVANCE NEO 400 (Bruker, GER).

2.X射线粉末衍射(XRPD)2. X-ray powder diffraction (XRPD)

实验所得固体样品用X射线粉末衍射仪Bruker D8 Advance(Bruker，GER)进行分析。2θ扫描角度从3°到45°，扫描步长为0.02°，曝光时间为0.08秒。测试样品时光管电压和电流分别为40kV和40mA，样品盘为零背景样品盘。The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds. When testing the samples, the tube voltage and current were 40 kV and 40 mA respectively, and the sample pan was a zero background sample pan.

3.热重分析(TGA)3. Thermogravimetric analysis (TGA)

热重分析仪的型号为TA Discovery 55(TA，US)。将2-5mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。The model of the thermogravimetric analyzer is TA Discovery 55 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.

4.差式扫描量热分析(DSC)4. Differential Scanning Calorimetry (DSC)

差示扫描量热分析仪的型号为TA Discovery 2500(TA，US)。1-2mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为50mL/min。The model of the differential scanning calorimeter was TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes and heated to the final temperature at a rate of 10 °C/min, with nitrogen purge rate of 50 mL/min in the furnace.

5.动态水分吸脱附分析(DVS)5. Dynamic moisture sorption and desorption analysis (DVS)

动态水分吸脱附分析采用DVS Intrinsic(SMS，UK)进行测定。测试采用梯度模式，湿度变化为50％-95％-0％-50％，在0％至90％范围内每个梯度的湿度变化量为10％，梯度终点采用dm/dt方式进行判断，以dm/dt小于0.002％并维持10分钟为梯度终点。测试完成后，对样品进行XRPD分析确认固体形态是否发生变化。Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode, with humidity changes of 50%-95%-0%-50%. The humidity change for each gradient in the range of 0% to 90% was 10%. The gradient endpoint was determined using the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient endpoint. After the test was completed, the sample was subjected to XRPD analysis to confirm whether the solid morphology had changed.

6.偏光显微镜分析(PLM)6. Polarized light microscopy (PLM)

偏光显微镜的型号为Nikon Ci-POL(Nikon，JP)。将少量样品放置在载玻片上，选择合适的镜头观察样品形貌。The model of polarizing microscope is Nikon Ci-POL (Nikon, JP). Place a small amount of sample on a glass slide and select a suitable lens to observe the sample morphology.

7.高效液相色谱(HPLC) 7. High Performance Liquid Chromatography (HPLC)

高效液相色谱型号为Waters Acquity Arc-2489(Waters，US)，测试条件如表1所示。The HPLC model was Waters Acquity Arc-2489 (Waters, US), and the test conditions were shown in Table 1.

表1 HPLC测试条件
Table 1 HPLC test conditions

8.离子色谱(IC)8. Ion Chromatography (IC)

离子色谱型号为ICS 5000(Thermo Fisher，US)，仪器参数如表2所示。The ion chromatograph model was ICS 5000 (Thermo Fisher, US), and the instrument parameters are shown in Table 2.

表2 IC测试参数
Table 2 IC test parameters

其中，式I化合物可根据现有技术制备得到。例如根据专利申请公开WO2021047622A1中所记载的方法制备获得，但起始物并非制备本发明共晶体的限定条件。相关表征数据如图1至图3所示。XRPD结果显示式I化合物为结晶性较好的固体，命名为游离态Form A。TGA结果显示其在加热至200℃过程中无失重，在300℃以上可能发生分解。DSC结果显示在90℃有吸热信号，在151℃有熔融吸热峰。NMR结果用于后续样品成盐和成共晶判断。Among them, the compound of formula I can be prepared according to the prior art. 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 that there is an endothermic signal at 90°C and a melting endothermic peak at 151°C. The NMR results are used for subsequent sample salt formation and eutectic judgment.

本发明使用的原料药(式I化合物)的相关信息见下表：
The relevant information of the raw material drug (compound of formula I) used in the present invention is shown in the following table:

实验方法Experimental methods

1.原料溶解度测试1. Raw material solubility test

称取20mg左右样品，加入EP管中，室温下(～25℃)逐次加入一定量溶剂，搅拌溶液并观察固体是否完全溶解，若加到10.0mL溶剂后仍未溶清，则停止实验。根据固体完全溶解时所用的溶剂体积估算化合物在该溶剂中的溶解度。Weigh about 20 mg of sample and add it to an EP tube. At room temperature (~25°C), add a certain amount of solvent gradually. Stir the solution and observe whether the solid is completely dissolved. If it is still not dissolved after adding 10.0 mL of solvent, stop the experiment. Estimate the solubility of the compound in the solvent based on the volume of solvent used when the solid is completely dissolved.

2.反应结晶法2. Reaction crystallization method

将约32.1mg(0.07mmol)左右样品和1.1当量的酸加入至一定量所选溶剂体系中，室温混悬2-3天，将悬 浮液离心分离，并将固体室温真空干燥。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, and the suspension was The suspension was separated by centrifugation and the solid was dried under vacuum at room temperature.

3.降温析晶法3. Cooling crystallization method

若反应结晶法中溶液室温悬浮后无固体析出，将溶液置于4℃冰箱降温析晶1天，然后将降温后的澄清液置于-15℃冰箱降温析晶1-4天。将有固体析出的溶液离心分离，并将固体室温真空干燥。If no solid precipitates after the solution is suspended at room temperature in the reaction crystallization method, place the solution in a 4°C refrigerator to cool and crystallize for 1 day, and then place the cooled clarified solution in a -15°C refrigerator to cool and crystallize for 1-4 days. Centrifuge the solution with solid precipitation and vacuum dry the solid at room temperature.

4.反滴析晶法4. Back-trickling crystallization method

若降温析晶法中溶液无足量固体析出，将所得溶液分成两份，一份加入一定体积的反溶剂中，室温搅拌1天。对部分反滴后固体量不足的溶液于-15℃静置1天。将有足量固体析出的溶液离心分离，并将固体室温真空干燥。If the solution does not have enough solids precipitated in the cooling crystallization method, the resulting solution is divided into two parts, one part is added to a certain volume of anti-solvent, and stirred at room temperature for 1 day. The solution with insufficient solids after back-titration is left to stand at -15°C for 1 day. The solution with sufficient solids precipitated is centrifuged and the solid is dried under vacuum at room temperature.

5.溶剂挥发法5. Solvent evaporation method

若降温析晶法中溶液无足量固体析出，将所得溶液分成两份，一份在室温敞口静置，直至溶剂完全挥发得到固体。If insufficient solid is precipitated from the solution during the cooling crystallization method, the resulting solution is divided into two portions, and one portion is left open at room temperature until the solvent is completely evaporated to obtain a solid.

6.热转晶法6. Thermal transfer method

采用Instec HCS424GXY热台(Instec Inc.，US)进行，将6-8mg样品置于玻璃片放在热台上，以20℃/min的速率加热至目标温度，并恒温10min，然后自然降温冷却至室温后对固体进行XRPD测试。An Instec HCS424GXY hot stage (Instec Inc., US) was used to perform XRPD testing on a solid sample. A 6-8 mg sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 20°C/min and kept at a constant temperature for 10 min. The solid was then naturally cooled to room temperature and tested by XRPD.

7.稳定性研究方法7. Stability study methods

称取20mg左右样品置于称量瓶中，分别放置在高温(60℃)、高湿(25℃/92.5％ RH)、光照(25℃/4500Lux)、加速(40℃/75％ RH)下，于7天和15天取样进行XRPD表征和HPLC测试。About 20 mg of sample was weighed and placed in a weighing bottle, and placed under high temperature (60℃), high humidity (25℃/92.5% RH), light (25℃/4500Lux), and acceleration (40℃/75% RH). Samples were taken at 7 days and 15 days for XRPD characterization and HPLC testing.

8.溶解度测试8. Solubility test

8.1水溶解度评估8.1 Water Solubility Assessment

将不同盐型、共晶或游离态的样品加入2.0mL水中在25℃恒温震荡2h后取样；将取样的溶液用0.22μm水系滤膜过滤，对部分浓度较高的样品用稀释剂进行适当稀释，用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度。此外，对剩余固体进行XRPD测试。Samples of different salt forms, cocrystals or free states were added to 2.0 mL of water and shaken at 25°C for 2 hours before sampling; the sampled solution was filtered with a 0.22 μm water filter membrane, and some samples with higher concentrations were appropriately diluted with diluents, and the signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution multiple. In addition, the remaining solid was tested by XRPD.

8.2生物介质溶解度测试8.2 Solubility test in biological media

生物介质的配置过程如表3所示。将不同盐型、共晶或游离态的样品加入4.0mL生物介质中在37℃恒温震荡24h，分别于0.5h，2h和24h取样。将取样的溶液用0.22μm水系滤膜过滤，对部分浓度较高的样品用稀释剂进行适当稀释，用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度。此外，取测试后的上清液测试其pH值，对剩余固体进行XRPD测试。The preparation process of the biological medium is shown in Table 3. Samples of different salt forms, cocrystals or free states were added to 4.0 mL of the biological medium and shaken at 37 ° C for 24 h, and samples were taken at 0.5 h, 2 h and 24 h. The sampled solution was filtered with a 0.22 μm water filter membrane, and some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of the solution was measured by HPLC, and finally the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution multiple. In addition, the pH value of the supernatant after the test was tested, and the remaining solid was tested by XRPD.

表3生物介质的配制过程

Table 3 Preparation process of biological medium

实施例1Example 1

盐酸盐Type A通过原料(式I化合物)与盐酸在乙酸乙酯中悬浮后的溶液于正庚烷中反滴得到，具体条件见实施例13，相关表征数据如图4至图8所示。The hydrochloride salt Type A is obtained by back titrating the solution of the raw material (compound of formula I) and hydrochloric acid suspended in ethyl acetate in n-heptane. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 4 to 8.

XRPD结果显示盐酸盐Type A为结晶性好的固体。TGA结果显示样品在室温至100℃过程中无失重，100℃至200℃失重4.6％，在300℃后可能发生分解。DSC结果显示在130℃至190℃有较宽的吸热信号。NMR结果显示，与游离态相比，对应原料药的在10.8ppm、8.6ppm、8.0ppm和7.4ppm附近的核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；无明显残留有机溶剂信号峰。热台实验(053-25-17)中盐酸盐Type A加热至120℃并恒温10min，自然降温至室温后样品XRPD无显著变化。热台实验后的样品在TGA中的失重未明显减少。离子色谱结果显示样品中氯离子含量为7.1％，计算可得原料药和盐酸摩尔比例近似为1：1。XRPD results showed that the hydrochloride Type A was a well-crystalline solid. TGA results showed that the sample had no weight loss from room temperature to 100°C, lost 4.6% from 100°C to 200°C, and may decompose after 300°C. DSC results showed a broad endothermic signal from 130°C to 190°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding API at 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; there was no obvious residual organic solvent signal peak. In the hot stage experiment (053-25-17), the hydrochloride Type A was heated to 120°C and kept at a constant temperature for 10min. After cooling naturally to room temperature, the sample XRPD did not change significantly. The weight loss of the sample in TGA after the hot stage experiment did not decrease significantly. The ion chromatography results showed that the chloride ion content in the sample was 7.1%, and the molar ratio of the API and hydrochloric acid was calculated to be approximately 1:1.

实施例2-1Example 2-1

氢溴酸盐Type A可以通过原料与氢溴酸在乙酸乙酯中悬浮后的溶液于正庚烷中反滴得到，具体条件见实施例13，相关表征数据如图9至图13所示。Hydrobromide 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, and the relevant characterization data are shown in Figures 9 to 13.

XRPD结果显示氢溴酸盐Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中失重4.1％，在225℃后可能发生分解。DSC结果显示在90℃和184℃有吸热信号，在128℃有放热信号。NMR结果显示，与游离态相比，对应原料药的在10.8ppm、8.6ppm、8.0ppm和7.4ppm附近的核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；无明显残留有机溶剂信号峰。热台实验(053-25-18)中氢溴酸盐Type A加热至100℃熔融，热台实验后的样品在TGA中的失重未明显减少；然后加热至70℃并恒温10min，自然降温至室温后样品XRPD无显著变化，TGA中的失重未明显减少。离子色谱结果显示样品中溴离子含量为14.8％，计算可得原料药和氢溴酸摩尔比例近似为1：1。XRPD results showed that Type A hydrobromide was a well-crystalline solid. TGA results showed that the sample lost 4.1% of its weight during heating to 150°C and may decompose after 225°C. DSC results showed endothermic signals at 90°C and 184°C and exothermic signals at 128°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding API at around 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; there was no obvious residual organic solvent signal peak. In the hot stage experiment (053-25-18), Type A hydrobromide was heated to 100°C to melt, and the weight loss of the sample after the hot stage experiment in TGA did not decrease significantly; then it was heated to 70°C and kept at a constant temperature for 10 minutes. After naturally cooling to room temperature, the sample XRPD did not change significantly, and the weight loss in TGA did not decrease significantly. 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.

实施例2-2Example 2-2

氢溴酸盐Type B通过原料与氢溴酸在乙醇/正庚烷(1/9，v/v)中悬浮后的溶液于正庚烷中反滴得到，具体条件见实施例13，相关表征数据如图14至图17所示。Hydrobromide Type B is 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, and the relevant characterization data are shown in Figures 14 to 17.

XRPD结果显示氢溴酸盐Type B为结晶性好的固体。氢溴酸盐Type A和氢溴酸盐Type B的XRPD对比图暗示氢溴酸盐Type B可能含有少量的氢溴酸盐Type A。TGA结果显示样品在加热至150℃过程中失重3.3％，在225℃后可能发生分解。DSC结果显示在92℃有吸热信号，在220℃有对应分解的放热信号。NMR结果显示，与游离态相比，对应原料药的在10.8ppm、8.6ppm、8.0ppm和7.4ppm附近的核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；无明显残留有机溶剂信号峰。XRPD results show that hydrobromide Type B is a well-crystalline solid. The XRPD comparison of hydrobromide Type A and hydrobromide Type B suggests that hydrobromide Type B may contain a small amount of hydrobromide Type A. TGA results show that the sample loses 3.3% of its weight during heating to 150°C and may decompose after 225°C. DSC results show an endothermic signal at 92°C and an exothermic signal corresponding to decomposition at 220°C. NMR results show that compared with the free state, the nuclear magnetic peaks of the corresponding raw materials near 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm are shifted, and the NMR integration results are basically consistent with the raw materials, suggesting that the sample is salted; there is no obvious residual organic solvent signal peak.

实施例2-3Example 2-3

氢溴酸盐Type C通过原料与氢溴酸在甲醇/MTBE(1/9，v/v)中悬浮后的溶液于MTBE中反滴得到，具体条件见实施例13，相关表征数据如图18至图20所示。Hydrobromide Type C is 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.

XRPD结果显示氢溴酸盐Type C为结晶性一般的固体。TGA结果显示样品在加热至150℃过程中失重2.2％，在200℃后可能发生分解。DSC结果显示在90℃有吸热信号，在178℃有对应分解的吸热信号。NMR结果显示，与游离态相比，对应原料药的在8.6ppm、8.0ppm和7.4ppm附近的核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；无明显残留有机溶剂信号峰。XRPD results showed that Type C hydrobromide was a solid with general crystallinity. TGA results showed that the sample lost 2.2% of its weight during heating to 150°C and may decompose after 200°C. DSC results showed an endothermic signal at 90°C and an endothermic signal corresponding to decomposition at 178°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw material at around 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw material, suggesting that the sample was salted; there was no obvious residual organic solvent signal peak.

实施例2-4Embodiment 2-4

氢溴酸盐Type D通过原料与氢溴酸在甲醇/MTBE(1/9，v/v)中悬浮后的溶液在挥发实验中得到，具体条件见实施例13，相关表征数据如图21至图22所示。Hydrobromide Type D is obtained in a volatilization experiment by suspending the raw material and hydrobromic acid in methanol/MTBE (1/9, v/v). The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 21 to 22.

XRPD结果显示氢溴酸盐Type D为结晶性一般的固体。氢溴酸盐Type D在室温放置1天后转变为可能混有氢溴酸盐Type A的固体。XRPD results showed that Type D hydrobromide was a solid with average crystallinity. Type D hydrobromide turned into a solid that may be mixed with Type A hydrobromide after being left at room temperature for 1 day.

实施例2-5Embodiment 2-5

在重复制备氢溴酸盐Type B的实验中，通过原料与氢溴酸在乙醇/正庚烷(1/9，v/v)中悬浮后的溶液于正庚烷中反滴得到氢溴酸盐Type E，具体条件见实施例13，相关表征数据如图23至图25所示。In the experiment of repeatedly preparing hydrobromide Type B, hydrobromide Type E 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, and the relevant characterization data are shown in Figures 23 to 25.

XRPD结果显示氢溴酸盐Type E为结晶性好的固体。TGA结果显示样品在加热至150℃过程中无失重，在250℃后可能发生分解。DSC结果显示在200℃有吸热信号。NMR结果显示，与游离态相比，对应原料药的在10.8ppm、8.6ppm、8.0ppm和7.4ppm附近的核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；在3.4ppm和1.1ppm附近的峰对应乙醇的特征信号峰，暗示样品有少量乙醇残留。离子色谱结果显示样 品中溴离子含量为8.7％，计算可得原料药和氢溴酸摩尔比例近似为1：0.6。XRPD results showed that the hydrobromide salt Type E was a well-crystalline solid. TGA results showed that the sample did not lose weight during heating to 150°C, and decomposition may occur after 250°C. DSC results showed an endothermic signal at 200°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw materials near 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; the peaks near 3.4ppm and 1.1ppm corresponded to the characteristic signal peaks of ethanol, suggesting that the sample had a small amount of ethanol residue. Ion chromatography results showed that the sample The bromide ion content in the product is 8.7%, and the molar ratio of the raw material to hydrobromic acid is calculated to be approximately 1:0.6.

实施例3Example 3

硫酸盐Type A通过原料与硫酸在乙醇/正庚烷(1/9，v/v)中悬浮得到，具体条件见实施例13，相关表征数据如图26至图30所示。Sulfate Type A is obtained by suspending the raw material and sulfuric acid in ethanol/n-heptane (1/9, v/v). The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 26 to 30.

XRPD结果显示硫酸盐Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中失重6.2％，在250℃后可能发生分解。DSC结果显示在81℃和157℃有较宽的吸热信号。NMR结果显示，与游离态相比，对应原料药的在10.8ppm、8.6ppm、8.0ppm和7.4ppm附近的核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；在1.1ppm和3.7ppm附近的核磁峰对应乙基硫酸的特征信号峰，根据1.1ppm附近峰的积分结果判断原料药和乙基硫酸的摩尔比例近似为1：0.1，暗示样品中可能含有少量乙基硫酸盐。热台实验(053-23-48)表明硫酸盐Type A加热至120℃并恒温10min，自然降温至室温后样品XRPD发生变化。热台实验后的样品在TGA中的失重显著减少。XRPD results showed that sulfate Type A was a solid with good crystallinity. TGA results showed that the sample lost 6.2% of its weight during heating to 150°C and may decompose after 250°C. DSC results showed that there were broad endothermic signals at 81°C and 157°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding API at 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw materials, suggesting that the sample was salted; the nuclear magnetic peaks at 1.1ppm and 3.7ppm corresponded to the characteristic signal peaks of ethyl sulfate. According to the integration results of the peaks near 1.1ppm, the molar ratio of the API and ethyl sulfate was approximately 1:0.1, suggesting that the sample may contain a small amount of ethyl sulfate. The hot stage experiment (053-23-48) showed that sulfate Type A was heated to 120°C and kept at a constant temperature for 10min, and the sample XRPD changed after naturally cooling to room temperature. The weight loss of the sample in TGA after the hot stage experiment was significantly reduced.

实施例4Example 4

富马酸共晶Type A通过原料与富马酸在四种所用溶剂体系中悬浮得到，比如在乙酸乙酯中悬浮得到，具体条件见实施例13，相关表征数据如图31至图33所示。Fumaric acid eutectic Type A is obtained by suspending the raw material and fumaric acid in four solvent systems used, for example, in ethyl acetate. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 31 to 33.

XRPD结果显示富马酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中有0.1％的失重，在210℃后可能发生分解。DSC结果显示在169.7℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在6.6ppm附近的峰对应富马酸的特征信号峰,根据积分结果计算原料药和富马酸摩尔比例近似为1:1；未见明显残留有机溶剂。XRPD results showed that fumaric acid eutectic Type A was a well-crystalline solid. TGA results showed that the sample lost 0.1% weight during heating to 150°C and may decompose after 210°C. DSC results showed a melting endothermic peak at 169.7°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw materials; the peak near 6.6ppm corresponded to the characteristic signal peak of fumaric acid, and the molar ratio of the API and fumaric acid was approximately 1:1 according to the integration results; no obvious residual organic solvent was observed.

实施例5-1Example 5-1

马来酸共晶Type A通过原料与马来酸在乙醇/正庚烷(1/9，v/v)中室温悬浮得到，具体条件见实施例13，相关表征数据如图34至图36所示。Maleic acid cocrystal Type A is obtained by suspending the raw material and maleic acid in ethanol/n-heptane (1/9, v/v) at room temperature. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 34 to 36.

XRPD结果显示马来酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至100℃过程中无失重，在100℃至200℃过程中失重11.4％，在150℃后可能发生马来酸共晶分解。DSC结果显示在108℃和119℃有吸热信号，在156℃有较宽的吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在6.25ppm附近的峰对应马来酸的特征信号峰，根据积分结果计算原料药和马来酸的摩尔比例近似为1：0.6，计算得马来酸理论含量为13.2％，和TGA中失重接近；未见明显残留有机溶剂信号峰。XRPD results showed that maleic acid cocrystal Type A was a well-crystalline solid. TGA results showed that the sample had no weight loss during heating to 100°C, and lost 11.4% of its weight during the period from 100°C to 200°C. Maleic acid cocrystal decomposition may occur after 150°C. DSC results showed endothermic signals at 108°C and 119°C, and a broad endothermic signal at 156°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw materials; the peak near 6.25ppm corresponded to the characteristic signal peak of maleic acid. According to the integration results, the molar ratio of the API and maleic acid was approximately 1:0.6, and the theoretical content of maleic acid was calculated to be 13.2%, which was close to the weight loss in TGA; no obvious residual organic solvent signal peak was observed.

实施例5-2Example 5-2

马来酸共晶Type B可以通过将游离态原料与马来酸在乙酸乙酯中悬浮后的溶液于正庚烷中反滴得到，具体条件见实施例13，相关表征数据如图37至图39所示。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, and the relevant characterization data are shown in Figures 37 to 39.

XRPD结果显示马来酸共晶Type B为结晶性好的固体。TGA结果显示样品在加热至100℃过程中无失重，100℃至200℃过程中失重19.5％，在150℃后可能发生马来酸共晶分解。DSC结果显示在127℃有吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在6.25ppm附近的峰对应马来酸的特征信号峰，根据积分结果判断原料药和马来酸的摩尔比例近似为1：1，计算得马来酸理论含量为20.2％，和TGA中失重接近；在4.0ppm、2.0ppm和1.2ppm附近可见乙酸乙酯的特征信号峰，暗示样品有少量乙酸乙酯残留。XRPD results showed that maleic acid cocrystal Type B was a solid with good crystallinity. TGA results showed that the sample had no weight loss during heating to 100°C, and lost 19.5% of its weight during heating from 100°C to 200°C. Maleic acid cocrystal decomposition may occur after 150°C. DSC results showed an endothermic signal at 127°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw material; the peak near 6.25ppm corresponded to the characteristic signal peak of maleic acid. According to the integration results, the molar ratio of the API and maleic acid was approximately 1:1, and the theoretical content of maleic acid was calculated to be 20.2%, which was close to the weight loss in TGA; the characteristic signal peaks of ethyl acetate were seen near 4.0ppm, 2.0ppm and 1.2ppm, suggesting that a small amount of ethyl acetate remained in the sample.

实施例6-1Example 6-1

酒石酸共晶Type A通过原料与酒石酸在乙醇/正庚烷(1/9，v/v)中室温悬浮得到，具体条件见实施例13，相关表征数据如图40至图43所示。Tartaric acid eutectic Type A is obtained by suspending the raw material and tartaric acid in ethanol/n-heptane (1/9, v/v) at room temperature. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 40 to 43.

XRPD结果显示酒石酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中失重2.2％，在200℃后可能发生分解。DSC结果显示在88℃、103℃和136℃有吸热信号，在188℃有较宽的吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在4.3ppm附近的峰对应酒石酸的特征信号峰，根据积分结果判断原料药和酒石酸的摩尔比例近似为1：1.1；在1.05ppm附近可见乙醇的特征信号峰，由积分值可得原料药和乙醇的摩尔比例近似为1：0.25，乙醇理论含量为1.8％，和TGA中失重接近。热台实验中(053-23-33)酒石酸共晶Type A加热至100℃并恒温10min，自然降温至室温后XRPD结果无显著变化。XRPD results showed that tartaric acid eutectic Type A was a well-crystalline solid. TGA results showed that the sample lost 2.2% of its weight during heating to 150°C, and decomposition may occur after 200°C. DSC results showed endothermic signals at 88°C, 103°C and 136°C, and a broad endothermic signal at 188°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw material; the peak near 4.3ppm corresponded to the characteristic signal peak of tartaric acid, and according to the integration results, the molar ratio of the API and tartaric acid was approximately 1:1.1; the characteristic signal peak of ethanol was visible near 1.05ppm, and the molar ratio of the API and ethanol was approximately 1:0.25 from the integration value, and the theoretical content of ethanol was 1.8%, which was close to the weight loss in TGA. In the hot stage experiment, (053-23-33) tartaric acid eutectic Type A was heated to 100°C and kept at this temperature for 10 min. After naturally cooling to room temperature, the XRPD results showed no significant changes.

实施例6-2Example 6-2

酒石酸共晶Type B通过原料与酒石酸在乙酸乙酯中室温悬浮后的溶液反滴于正庚烷中得到，具体条件见实施例13，相关表征数据如图44至图48所示。Tartaric acid eutectic Type B is 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, and the relevant characterization data are shown in Figures 44 to 48.

XRPD结果显示酒石酸共晶Type B为结晶性一般的固体。TGA结果显示样品在加热至150℃过程中失重3.3％，在200℃后可能发生分解。DSC结果显示在88℃有对应失重的吸热峰，在173℃有对应分解的吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在4.3ppm附近的峰对应酒石酸的特征信号峰，根据积分结果判断原料药和酒石酸的摩尔比例近似为1：1.3；在0.9ppm和1.25ppm附近可见正庚烷的特征信号峰，由0.9ppm附近峰的积分值可得原料药和正庚烷摩尔比例近似 为1：0.15，正庚烷理论含量为2.2％，略低于TGA中失重。热台实验中(053-23-45)酒石酸共晶Type B加热至70℃并恒温10min，自然降温至室温后XRPD结果无显著变化，热台实验后的样品在TGA中失重减少；加热至100℃后样品熔融。XRPD results show that tartaric acid cocrystal Type B is a solid with average crystallinity. TGA results show that the sample loses 3.3% of its weight during heating to 150°C, and may decompose after 200°C. DSC results show that there is an endothermic peak corresponding to weight loss at 88°C, and an endothermic signal corresponding to decomposition at 173°C. NMR results show that compared with the free state, there is no obvious shift in the nuclear magnetic peak of the corresponding raw material, and the NMR integration results are basically consistent with the raw material; the peak near 4.3ppm corresponds to the characteristic signal peak of tartaric acid, and according to the integration results, the molar ratio of the raw material and tartaric acid is approximately 1:1.3; the characteristic signal peaks of n-heptane can be seen near 0.9ppm and 1.25ppm, and the integral value of the peak near 0.9ppm shows that the molar ratio of the raw material and n-heptane is approximately The ratio of n-heptane to tartaric acid was 1:0.15, and the theoretical content of n-heptane was 2.2%, which was slightly lower than the weight loss in TGA. In the hot stage experiment, the tartaric acid eutectic Type B (053-23-45) was heated to 70°C and kept at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results did not change significantly. The weight loss of the sample after the hot stage experiment in TGA was reduced; the sample melted after heating to 100°C.

实施例6-3Example 6-3

酒石酸共晶Type C通过原料与酒石酸在乙酸乙酯中室温反应后的澄清溶液在挥发实验中得到，具体条件见实施例13，相关表征数据如图49至图51所示。Tartaric acid eutectic Type C was obtained in a volatilization experiment from a clear solution obtained by reacting the raw materials with tartaric acid in ethyl acetate at room temperature. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 49 to 51.

XRPD结果显示酒石酸共晶Type C为结晶性一般的固体。TGA结果显示样品在加热至150℃过程中失重1.9％，在180℃后可能发生分解。DSC结果显示在87℃、113℃、137℃和190℃有吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在4.3ppm附近的峰对应酒石酸的特征信号峰，根据积分结果判断原料药和酒石酸的摩尔比例近似为1：1；在4.0ppm、2.0ppm和1.2ppm附近可见乙酸乙酯的特征信号峰，由4.0ppm附近峰的积分值可得原料药和乙酸乙酯摩尔比例近似为1：0.09，乙酸乙酯理论含量为1.5％，和TGA中失重接近。XRPD results showed that tartaric acid eutectic Type C was a solid with general crystallinity. TGA results showed that the sample lost 1.9% of its weight during heating to 150°C, and decomposition may occur after 180°C. DSC results showed endothermic signals at 87°C, 113°C, 137°C and 190°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding API had no obvious shift, and the NMR integration results were basically consistent with the raw material; the peak near 4.3ppm corresponded to the characteristic signal peak of tartaric acid, and the molar ratio of the API and tartaric acid was approximately 1:1 according to the integration results; the characteristic signal peaks of ethyl acetate were visible near 4.0ppm, 2.0ppm and 1.2ppm, and the integral value of the peak near 4.0ppm showed that the molar ratio of the API and ethyl acetate was approximately 1:0.09, and the theoretical content of ethyl acetate was 1.5%, which was close to the weight loss in TGA.

实施例7-1Example 7-1

3,5-二羟基苯甲酸共晶Type A通过原料与3,5-二羟基苯甲酸在乙酸乙酯中悬浮得到，具体条件见实施例13，相关表征数据如图52至图54所示。3,5-dihydroxybenzoic acid cocrystal Type A is obtained by suspending the raw material and 3,5-dihydroxybenzoic acid in ethyl acetate. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 52 to 54.

XRPD结果显示3,5-二羟基苯甲酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中无失重，在275℃后可能发生分解。DSC结果显示在203℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在9.5ppm、6.8ppm和6.4ppm附近的核磁峰对应3,5-二羟基苯甲酸的特征信号峰，根据6.4ppm附近峰的积分结果判断原料药和3,5-二羟基苯甲酸摩尔比例近似为1：1；未见明显残留有机溶剂。XRPD results showed that 3,5-dihydroxybenzoic acid cocrystal Type A was a well-crystalline solid. TGA results showed that the sample did not lose weight during heating to 150°C, and decomposition may occur after 275°C. DSC results showed a melting endothermic peak at 203°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; the nuclear magnetic peaks near 9.5ppm, 6.8ppm and 6.4ppm corresponded to the characteristic signal peaks of 3,5-dihydroxybenzoic acid. According to the integration results of the peak near 6.4ppm, it was judged that the molar ratio of the raw material and 3,5-dihydroxybenzoic acid was approximately 1:1; no obvious residual organic solvent was observed.

实施例7-2Example 7-2

3,5-二羟基苯甲酸共晶Type B通过原料与3,5-二羟基苯甲酸在乙醇/正庚烷(1/9，v/v)中悬浮得到，具体条件见实施例13，相关表征数据如图55至图57所示。3,5-dihydroxybenzoic acid cocrystal Type B is obtained by suspending the raw material 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.

XRPD结果显示3,5-二羟基苯甲酸共晶Type B为结晶性好的固体。TGA结果显示样品在加热至200℃过程中失重0.2％，在275℃后可能发生分解。DSC结果显示在171℃和173℃有熔融伴随重结晶的信号，在204℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在9.5ppm、6.8ppm和6.4ppm附近的核磁峰对应3,5-二羟基苯甲酸的特征信号峰，根据6.4ppm附近峰的积分结果判断原料药和3,5-二羟基苯甲酸摩尔比例近似为1：1；未见明显残留有机溶剂。XRPD results showed that 3,5-dihydroxybenzoic acid cocrystal Type B was a well-crystalline solid. TGA results showed that the sample lost 0.2% of its weight during heating to 200°C, and decomposition may occur after 275°C. DSC results showed that there were signals of melting accompanied by recrystallization at 171°C and 173°C, and a melting endothermic peak at 204°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw materials had no obvious shift, and the NMR integration results were basically consistent with the raw materials; the nuclear magnetic peaks near 9.5ppm, 6.8ppm and 6.4ppm corresponded to the characteristic signal peaks of 3,5-dihydroxybenzoic acid. According to the integration results of the peak near 6.4ppm, it was judged that the molar ratio of the raw material and 3,5-dihydroxybenzoic acid was approximately 1:1; no obvious residual organic solvent was observed.

实施例8Example 8

龙胆酸共晶Type A通过原料与龙胆酸在乙酸乙酯中悬浮得到，具体条件见实施例13，相关表征数据如图58至图60所示。Gentisic acid cocrystal Type A is obtained by suspending the raw material and gentisic acid in ethyl acetate. The specific conditions are shown in Example 13, and the relevant characterization data are shown in Figures 58 to 60.

XRPD结果显示龙胆酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中有0.2％的失重，在200℃后可能发生分解。DSC结果显示在167℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在9.1ppm、7.1ppm、6.9ppm和6.8ppm附近的核磁峰对应龙胆酸的特征信号峰，根据6.8ppm附近峰的积分结果判断原料药和龙胆酸的摩尔比例近似为1：1；未见明显残留有机溶剂。XRPD results showed that gentisic acid cocrystal Type A was a well-crystalline solid. TGA results showed that the sample lost 0.2% weight during heating to 150°C and may decompose after 200°C. DSC results showed a melting endothermic peak at 167°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; the nuclear magnetic peaks near 9.1ppm, 7.1ppm, 6.9ppm and 6.8ppm corresponded to the characteristic signal peaks of gentisic acid. According to the integration results of the peak near 6.8ppm, the molar ratio of the raw material and gentisic acid was approximately 1:1; no obvious residual organic solvent was observed.

实施例9Example 9

对羟基苯甲酸共晶Type A通过原料与对羟基苯甲酸在乙酸乙酯中悬浮后的溶液于正庚烷中反滴得到，具体条件见实施例13，相关表征数据如图61至图63所示。Para-hydroxybenzoic acid cocrystal Type A is obtained by back-titration of 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, and the relevant characterization data are shown in Figures 61 to 63.

XRPD结果显示对羟基苯甲酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程失重0.1％，在200℃后可能发生分解。DSC结果显示在124℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在10.2ppm、7.8ppm和6.8ppm附近的核磁峰对应对羟基苯甲酸的特征信号峰，根据6.8ppm附近峰的积分结果计算原料药和对羟基苯甲酸的摩尔比例近似为1：0.5；未见明显残留有机溶剂。XRPD results showed that p-hydroxybenzoic acid cocrystal Type A was a well-crystalline solid. TGA results showed that the sample lost 0.1% of its weight during heating to 150°C and may decompose after 200°C. DSC results showed a melting endothermic peak at 124°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; the nuclear magnetic peaks near 10.2ppm, 7.8ppm and 6.8ppm corresponded to the characteristic signal peaks of p-hydroxybenzoic acid, and the molar ratio of the raw material and p-hydroxybenzoic acid calculated based on the integration results of the peak near 6.8ppm was approximately 1:0.5; no obvious residual organic solvent was observed.

实施例10Example 10

草酸共晶Type A通过原料与草酸在乙酸乙酯中悬浮得到，具体条件见实施例13，相关表征数据如图64至图66所示。Oxalic acid cocrystal Type A is obtained by suspending the raw material 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.

XRPD结果显示草酸共晶Type A为结晶性好的固体。TGA结果显示样品在加热至150℃过程中有0.8％的失重，150℃至250℃有9.0％的失重，可能对应草酸共晶分解、脱去草酸的过程。DSC结果显示在105℃有吸热信号，161℃有熔融吸热峰，在204℃有对应TGA失重的较宽的吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；未见明显残留有机溶剂。离子色谱结果显示样品中草酸根含量为7.9％，计算可得原料药和草酸摩尔比例近似为1：0.5(与TGA信号中的9.0％失重量吻合)。XRPD results showed that oxalic acid eutectic Type A was a well-crystalline solid. TGA results showed that the sample had a 0.8% weight loss during heating to 150°C and a 9.0% weight loss from 150°C to 250°C, which may correspond to the decomposition of the oxalic acid eutectic and the removal of oxalic acid. DSC results showed an endothermic signal at 105°C, a melting endothermic peak at 161°C, and a broad endothermic signal corresponding to TGA weight loss at 204°C. NMR results showed that compared with the free state, the nuclear magnetic peak of the corresponding raw material had no obvious shift, and the NMR integration results were basically consistent with the raw material; no obvious residual organic solvent was observed. Ion chromatography results showed that the oxalate content in the sample was 7.9%, and the calculated molar ratio of the raw material to oxalic acid was approximately 1:0.5 (consistent with the 9.0% weight loss in the TGA signal).

实施例11 Embodiment 11

对甲苯磺酸盐Type A通过原料与对甲苯磺酸在乙醇/正庚烷(1/9，v/v)中悬浮得到，具体条件见实施例13，相关表征数据如图67至图69所示。Toluenesulfonate Type A is obtained by suspending the raw material 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.

XRPD结果显示对甲苯磺酸盐Type A为结晶性好的固体。TGA结果显示样品在加热至200℃过程中无失重，在250℃后可能发生分解。DSC结果显示在128℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的在10.8ppm、8.6ppm、8.0ppm和7.4ppm核磁峰发生偏移，NMR积分结果与原料基本一致，暗示样品成盐；在7.5ppm、7.1ppm和2.3ppm附近的核磁峰对应对甲苯磺酸的特征信号峰，根据7.1ppm附近峰的积分结果判断原料药和对甲苯磺酸的摩尔比例近似为1：1；未见明显残留有机溶剂。XRPD results showed that p-toluenesulfonate Type A was a well-crystalline solid. TGA results showed that the sample did not lose weight during heating to 200°C, and decomposition may occur after 250°C. DSC results showed a melting endothermic peak at 128°C. NMR results showed that compared with the free state, the nuclear magnetic peaks of the corresponding raw material at 10.8ppm, 8.6ppm, 8.0ppm and 7.4ppm shifted, and the NMR integration results were basically consistent with the raw material, suggesting that the sample was salted; the nuclear magnetic peaks near 7.5ppm, 7.1ppm and 2.3ppm corresponded to the characteristic signal peaks of p-toluenesulfonic acid. According to the integration results of the peak near 7.1ppm, it was judged that the molar ratio of the raw material and p-toluenesulfonic acid was approximately 1:1; no obvious residual organic solvent was observed.

实施例12-1Example 12-1

反式乌头酸共晶Type A通过原料与反式乌头酸在乙醇/正庚烷(1/9，v/v)中室温悬浮得到，具体条件见实施例13，相关表征数据如图70至图74所示。Trans-aconitic acid cocrystal Type A is obtained by suspending the raw material 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.

XRPD结果显示反式乌头酸共晶Type A为结晶性一般的固体。TGA结果显示样品在加热至120℃过程中失重5.7％，在125℃后可能发生分解。DSC结果显示在80℃至180℃有熔融伴随分解的吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在6.7ppm和3.7ppm附近的峰对应反式乌头酸的特征信号峰，根据6.7ppm附近峰的积分结果计算原料药和反式乌头酸的摩尔比例近似为1：1；在1.1ppm和3.4ppm附近可见乙醇的特征信号峰，根据1.1ppm附近峰的积分结果判断原料药和乙醇的摩尔比例近似为1：0.8，乙醇理论含量为5.5％，和TGA中失重接近。热台实验中(053-23-34)反式乌头酸共晶Type A加热至120℃并恒温10min，自然降温至室温后XRPD结果发生变化。热台实验后的样品在TGA中的失重明显减少。XRPD results show that trans-aconitic acid cocrystal Type A is a solid with general crystallinity. TGA results show that the sample loses 5.7% of its weight during heating to 120°C, and may decompose after 125°C. DSC results show that there is an endothermic signal of melting accompanied by decomposition between 80°C and 180°C. NMR results show that compared with the free state, the nuclear magnetic peak of the corresponding raw material has no obvious shift, and the NMR integration results are basically consistent with the raw material; the peaks near 6.7ppm and 3.7ppm correspond to the characteristic signal peaks of trans-aconitic acid. According to the integration results of the peaks near 6.7ppm, the molar ratio of the raw material and trans-aconitic acid is approximately 1:1; the characteristic signal peaks of ethanol can be seen near 1.1ppm and 3.4ppm. According to the integration results of the peaks near 1.1ppm, the molar ratio of the raw material and ethanol is approximately 1:0.8, and the theoretical content of ethanol is 5.5%, which is close to the weight loss in TGA. In the hot stage experiment, (053-23-34) trans-aconitic acid eutectic Type A was heated to 120℃ and kept at this temperature for 10 minutes. After cooling naturally to room temperature, the XRPD results changed. The weight loss of the sample after the hot stage experiment in TGA was significantly reduced.

实施例12-2Example 12-2

反式乌头酸共晶Type B通过原料与反式乌头酸在乙酸乙酯中反应后的澄清溶液于正庚烷中反滴得到，具体条件见实施例13，相关表征数据如图75至图78所示。Trans-aconitic acid cocrystal Type B is obtained by back titration of the clarified solution 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, and the relevant characterization data are shown in Figures 75 to 78.

XRPD结果显示反式乌头酸共晶Type B为结晶性一般的固体。TGA结果显示样品在加热至120℃过程中失重3.0％，在125℃后可能发生分解。DSC结果显示在70℃至180℃有熔融伴随分解的吸热信号。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一致；在6.7ppm和3.7ppm附近的峰对应反式乌头酸的特征信号峰，根据6.7ppm附近峰的积分结果判断原料药和反式乌头酸的摩尔比例近似为1：1.1；在4.0ppm、2.0ppm和1.2ppm附近可见乙酸乙酯的特征信号峰，暗示样品有少量乙酸乙酯残留。热台实验中(053-23-47)反式乌头酸共晶Type B加热至110℃并恒温10min，自然降温至室温后XRPD结果变为无定型。XRPD results show that trans-aconitic acid cocrystal Type B is a solid with general crystallinity. TGA results show that the sample loses 3.0% of its weight during heating to 120°C, and may decompose after 125°C. DSC results show that there are endothermic signals of melting and decomposition at 70°C to 180°C. NMR results show that compared with the free state, the nuclear magnetic peaks of the corresponding raw material have no obvious shift, and the NMR integration results are basically consistent with the raw material; the peaks near 6.7ppm and 3.7ppm correspond to the characteristic signal peaks of trans-aconitic acid. According to the integration results of the peaks near 6.7ppm, it is judged that the molar ratio of the raw material and trans-aconitic acid is approximately 1:1.1; the characteristic signal peaks of ethyl acetate can be seen near 4.0ppm, 2.0ppm and 1.2ppm, suggesting that there is a small amount of ethyl acetate remaining in the sample. In the hot stage experiment (053-23-47), trans-aconitic acid cocrystal Type B was heated to 110°C and kept at a constant temperature for 10min. After cooling naturally to room temperature, the XRPD results became amorphous.

以上实施例中制备的式I化合物的盐型和共晶的相关信息汇总于下表：

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:

a根据离子色谱结果计算的近似值，其余均依据NMR结果 a Approximate value calculated based on ion chromatography results, the rest are based on NMR results

实施例13Embodiment 13

分别称取31.2mg(0.07mmol)左右样品和1.1当量的酸，加入乙酸乙酯、乙醇/正庚烷(1/9，v/v)、甲醇/MTBE(1/9，v/v)和丙酮/MTBE(1/9，v/v)，室温条件下搅拌2-3天；若为澄清溶液，则将溶液置于4℃冰箱降温析晶，然后置于-15℃静置1-4天。若降温后仍为澄清溶液，则将溶液分为两份，一份进行两周挥发实验(保留原实验编号)，一份加入6倍体积的反溶剂中，室温搅拌1天(新实验编号)，对部分加入反溶剂后固体量不足的溶液于-15℃静置1天。实验过程中将有固体析出的溶液离心分离，并将固体室温真空干燥。对挥发实验得到的湿样直接进行XRPD测试，对其余实验得到的样品在室温真空干燥后进行XRPD测试。实验结果如表4至表6所示。Weigh about 31.2 mg (0.07 mmol) of sample and 1.1 equivalents of acid, add ethyl acetate, ethanol/n-heptane (1/9, v/v), methanol/MTBE (1/9, v/v) and acetone/MTBE (1/9, v/v), and stir at room temperature for 2-3 days; if it is a clear solution, place the solution in a 4°C refrigerator to cool and crystallize, and then place it at -15°C for 1-4 days. If it is still a clear solution after cooling, divide the solution into two parts, one for two weeks of volatilization experiment (keep the original experimental number), and one part is added to 6 times the volume of anti-solvent, stirred at room temperature for 1 day (new experimental number), and the solution with insufficient solid content after adding anti-solvent is placed at -15°C for 1 day. During the experiment, the solution with solid precipitation was centrifuged and the solid was vacuum dried at room temperature. The wet sample obtained from the volatilization experiment was directly tested by XRPD, and the samples obtained from the other experiments were tested by XRPD after vacuum drying at room temperature. The experimental results are shown in Tables 4 to 6.

表4盐型和共晶初筛实验结果(1)


a所有实验溶剂总体积均为1.0mL,在室温下悬浮2天，在-15℃静置1天
b用乙醇稀释至1M后使用Table 4 Results of preliminary screening experiments on salt forms and cocrystals (1)


a The total volume of all experimental solvents was 1.0 mL, 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

表5盐型和共晶初筛实验结果(2)

a所有实验溶剂总体积均为1.0mL,在室温下悬浮3天，在-15℃静置4天
b用乙醇稀释至1M后使用
c-15℃降温后的结果
d 4℃降温后的结果
e根据核磁结果判断，数据未显示 Table 5 Results of preliminary screening experiments on salt forms and cocrystals (2)

a The total volume of all experimental solvents was 1.0 mL, 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
The results after cooling down to -15℃
d Results after 4℃ cooling
e Judging from the NMR results, data not shown

表6盐型和共晶制备实验反滴析晶实验结果

a反滴后-15℃降温的结果Table 6 Results of reverse drop crystallization experiments for salt type and eutectic preparation experiments

a The result of cooling to -15℃ after back-titration

实施例14Embodiment 14

为确保式I化合物盐型或共晶的制备具有可重现性，本发明重复进行了制备实验。分别称取一定量原料和1.1当量的酸，加入乙酸乙酯、乙醇/正庚烷(1/9，v/v)、甲醇/MTBE(1/9，v/v)或丙酮/MTBE(1/9，v/v)中，室温条件下搅拌2-3天；若为澄清溶液或固体量不足，则将溶液置于-15℃冰箱静置1天。若降温后仍为澄清溶液或固体量不足，则将溶液加入4倍体积的反溶剂中，室温搅拌1天，或者直接将室温悬浮后得到的澄清或固体量不足的溶液加入4倍体积的反溶剂中。实验过程中将有足量固体析出的溶液离心分离，并将固体室温真空干燥。实验结果如表7所示。To ensure that the preparation of the salt form or cocrystal 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 insufficient amount of solid 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.

表7重复制备实验结果


a盐酸、硫酸和氢溴酸均用乙醇稀释至1M后使用
b悬浮后清液未进行降温实验，直接进行反滴的结果
c反溶剂体积为良溶剂6倍
d室温悬浮2天，其余实验均为3天Table 7 Repeated preparation experimental results


aHydrochloric acid, sulfuric acid and hydrobromic acid are diluted to 1M with ethanol before use
b The result of direct back-titration without cooling the clear liquid after suspension
c The volume of the antisolvent is 6 times that of the good solvent
d Suspended at room temperature for 2 days, and the rest of the experiments were 3 days

实施例15Embodiment 15

对式I化合物的盐型和共晶进行实验室级别的放大制备，制备过程如表8所示。The salt form and co-crystal of the compound of formula I were prepared on a laboratory scale, and the preparation process is shown in Table 8.

表8目标盐型和共晶的放大制备
Table 8 Scale-up preparation of target salt forms and cocrystals

进一步，对富马酸共晶Type A(053-30-01)进行了XRPD、TGA、DSC、NMR、和PLM表征，表征结果如图85至图89所示。XRPD结果显示富马酸共晶Type A为结晶性好的固体。TGA结果显示富马酸共晶Type A在加热至150℃过程无失重，在210℃以上可能发生分解。DSC结果显示富马酸共晶Type A在170.1℃有熔融吸热峰。NMR结果显示，与游离态相比，对应原料药的核磁峰无明显偏移，NMR积分结果与原料基本一 致；在6.6ppm附近的峰对应富马酸的特征信号峰，根据积分结果计算原料药和富马酸摩尔比例近似为1:0.9；未见明显残留有机溶剂。DVS结果显示放大制备的富马酸共晶Type A在95％湿度下增重0.04％，在0％湿度下失重0.04％，在吸附过程中，80％湿度下增重0.00％，表明富马酸共晶Type A几乎没有引湿性。PLM图像显示富马酸共晶Type A为棒状颗粒，粒径普遍小于10μm。富马酸共晶Type A为结晶性好的无水物，几乎无引湿性。Furthermore, fumaric acid cocrystal Type A (053-30-01) was characterized by XRPD, TGA, DSC, NMR, and PLM, and the characterization results are shown in Figures 85 to 89. XRPD results show that fumaric acid cocrystal Type A is a solid with good crystallinity. TGA results show that fumaric acid cocrystal Type A does not lose weight when heated to 150°C, and may decompose above 210°C. DSC results show that fumaric acid cocrystal Type A has a melting endothermic peak at 170.1°C. NMR results show that compared with the free state, the nuclear magnetic peak of the corresponding raw material has no obvious shift, and the NMR integration results are basically the same as the raw material. The peak near 6.6ppm corresponds to the characteristic signal peak of fumaric acid. According to the integral results, the molar ratio of the API to fumaric acid is approximately 1:0.9; no obvious residual organic solvent is observed. DVS results show that the enlarged prepared fumaric acid eutectic Type A gains 0.04% weight at 95% humidity and loses 0.04% weight at 0% humidity. During the adsorption process, it gains 0.00% weight at 80% humidity, indicating that fumaric acid eutectic Type A has almost no hygroscopicity. PLM images show that fumaric acid eutectic Type A is a rod-shaped particle with a particle size generally less than 10μm. Fumaric acid eutectic Type A is an anhydrous substance with good crystallinity and almost no hygroscopicity.

测试例1热台实验Test Example 1 Hot Stage Experiment

将6-8mg样品置于玻璃片放在热台上，以20℃/min的速率加热至目标温度，并恒温10min，然后自然降温冷却至室温后对固体进行XRPD测试，结果如表9所示。6-8 mg of sample was placed on a glass slide on a hot stage, heated to the target temperature at a rate of 20°C/min, and kept at a constant temperature for 10 min. Then, the solid was naturally cooled to room temperature and subjected to XRPD testing. The results are shown in Table 9.

表9热台实验结果
Table 9 Hot stage test results

测试例2水中溶解度测试Test Example 2: Solubility in water

为了便于比较不同盐型和共晶的优势，对不同盐型、共晶和游离态在水中进行溶解度评估，相应结果见表10和图79至图84。In order to facilitate the comparison of the advantages of different salt forms and cocrystals, the solubility of different salt forms, cocrystals and free states in water was evaluated, and the corresponding results are shown in Table 10 and Figures 79 to 84.

结果显示，除马来酸共晶Type B外，其余盐和共晶在25℃水中2h后的溶解度均小于游离态Form A。游离态Form A、富马酸共晶Type A和龙胆酸共晶Type A在溶解度测试后剩余固体的XRPD无显著变化。草酸共晶Type A在溶解度测试后剩余固体的XRPD发生变化；对甲苯磺酸盐Type A在溶解度测试后剩余固体的XRPD发生变化，转变为新的固体形态；盐酸盐Type A、氢溴酸盐Type E和马来酸共晶Type B在溶解度测试后剩余固体的XRPD发生变化，均转变为另一种相同的固体形态(命名为游离态Type C)。NMR结果显示草酸共晶Type A溶解度测试后的剩余固体与游离态的积分一致；对甲苯磺酸盐Type A和马来酸共晶Type B溶解度测试后的剩余固体与游离态的积分一致，未见明显配体信号峰，暗示样品均已解离为游离态的其它晶型。The results showed that, except for maleic acid cocrystal Type B, the solubility of the remaining salts and cocrystals in 25°C water after 2h was lower than that of free Form A. There was no significant change in the XRPD of the remaining solid of free Form A, fumaric acid cocrystal Type A and gentisic acid cocrystal Type A after the solubility test. The XRPD of the remaining solid of oxalic acid cocrystal Type A changed after the solubility test; the XRPD of the remaining solid of p-toluenesulfonate Type A changed after the solubility test and transformed into a new solid form; the XRPD of the remaining solid of hydrochloride Type A, hydrobromide Type E and maleic acid cocrystal Type B changed after the solubility test and transformed into another identical solid form (named as free form Type C). NMR results showed that the remaining solid after the solubility test of oxalic acid cocrystal Type A was consistent with the integral of the free state; the remaining solid after the solubility test of toluenesulfonate Type A and maleic acid cocrystal Type B was consistent with the integral of the free state, and no obvious ligand signal peak was observed, suggesting that the samples had dissociated into other free crystal forms.

表10水溶解度测试结果

a起始原料在实验前无转晶发生
b根据标准曲线计算的游离态的浓度Table 10 Water solubility test results

a The starting material did not undergo crystal transformation before the experiment
b Free state concentration calculated from the standard curve

测试例3生物介质溶解度测试Test Example 3 Biological Media Solubility Test

对富马酸共晶Type A、马来酸共晶Type B、盐酸盐Type A和游离态Form A在3种生物介质(FaSSIF、FeSSIF和FaSSGF)中进行动态溶解度测定，相应结果见表11和图91至图94。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.

结果显示，富马酸共晶Type A、马来酸共晶Type B、盐酸盐Type A和游离态Form A在介质中的24h溶解度排序均为FeSSIF>FaSSIF>FaSSGF；富马酸共晶Type A、马来酸共晶Type B和游离态Form A在FaSSIF和 FeSSIF中的溶解度在24h的值低于2h的值，在FaSSGF中未检出；盐酸盐Type A在三种介质中的溶解度在24h的值均低于2h的值。富马酸共晶Type A在FaSSGF 24h后的剩余固体仍为富马酸共晶Type A，其余样品在三种生物介质中24h后的剩余固体均为游离态Type B。富马酸共晶Type A、马来酸共晶Type B和盐酸盐Type A在FaSSIF和FeSSIF中24h后溶液pH减小，其余样品24h后介质的pH均无显著变化。The results showed that the 24h solubility of fumaric acid eutectic Type A, maleic acid eutectic Type B, hydrochloride Type A and free Form A in the medium were ranked as FeSSIF>FaSSIF>FaSSGF; The solubility in FeSSIF at 24h was lower than that in 2h, and was not detected in FaSSGF; the solubility of Type A hydrochloride in the three media at 24h was lower than that in 2h. The remaining solid of fumaric acid eutectic Type A in FaSSGF after 24h was still fumaric acid eutectic Type A, and the remaining solid of the other samples in the three biological media after 24h was free Type B. The pH of the solution of fumaric acid eutectic Type A, maleic acid eutectic Type B and hydrochloride Type A decreased after 24h in FaSSIF and FeSSIF, and the pH of the medium of the other samples did not change significantly after 24h.

表11生物介质中的动态溶解度测试

a标准曲线下限为0.1μg/mL
b根据标准曲线计算溶液中对应游离态的浓度Table 11 Dynamic solubility test in biological media

aThe 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

测试例4稳定性研究Test Example 4: Stability Study

对富马酸共晶Type A进行高温(60℃)、高湿(25℃/92.5％ RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)条件下的稳定性研究，分别于7天和15天取样进行XRPD和HPLC表征，结果如表12、表13和图90所示。XRPD结果显示，富马酸共晶Type A在高温、高湿、光照、加速条件下7天和15天均稳定，没有发生晶型转变，外观无显著变化。化学纯度方面，富马酸共晶Type A在所有测试条件均无显著变化。The stability of fumaric acid eutectic Type A was studied under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500Lux), and accelerated (40°C/75% RH) conditions. Samples were taken for XRPD and HPLC characterization at 7 days and 15 days, respectively. The results are shown in Table 12, Table 13 and Figure 90. The XRPD results show that fumaric acid eutectic Type A is stable under high temperature, high humidity, light, and accelerated conditions for 7 days and 15 days, without any crystal transformation and no significant change in appearance. In terms of chemical purity, fumaric acid eutectic Type A has no significant change under all test conditions.

表12稳定性研究结果
Table 12 Stability study results

表13富马酸共晶Type A稳定性样品的HPLC纯度分析结果

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

对富马酸共晶Type A的系统评估中，除了对样品进行基本表征和溶解度评估外，还考察了吸湿性和稳定性，评估结果显示：In the systematic evaluation of fumaric acid cocrystal Type A, in addition to basic characterization and solubility evaluation of the sample, the hygroscopicity and stability were also investigated. The evaluation results showed:

1)引湿性方面，富马酸共晶Type A几乎无引湿性。1) In terms of hygroscopicity, fumaric acid eutectic Type A is almost non-hygroscopic.

2)稳定性方面，富马酸共晶Type A在高温、高湿、光照、加速条件下7天和15天均没有发生晶型转变，外观和纯度也无显著变化。2) In terms of stability, fumaric acid eutectic Type A did not undergo crystal transformation under high temperature, high humidity, light and accelerated conditions for 7 days and 15 days, and there was no significant change in appearance and purity.

测试例5药代动力学实验Test Example 5 Pharmacokinetic Experiment

·溶媒是0.5％MC。比格犬禁食过夜，给药后4h喂食。n＝4，给药前称重，根据体重，计算给药量。给药剂量10mg/kg、30mg/kg；给药体积5mL/kg。采血时间点：给药前和给药后0.25h,0.5h,1h,2h,4h,6h,8h,10h,24h,48h,72h。The solvent was 0.5% MC. Beagles were fasted overnight and fed 4 hours after administration. n = 4, weighed before administration, and the dosage was calculated based on body weight. Dosage was 10 mg/kg, 30 mg/kg; administration volume was 5 mL/kg. Blood collection time points: before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h, 72 h after administration.

·经前肢静脉采血，每个样品采集约1mL，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆(离心条件，2200g，10分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。Blood was collected from the forelimb vein, about 1 mL per sample, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions, 2200g, 10 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.

·采用LC-MS/MS法测定比格犬血浆中目标分析物的浓度。通过不同时间点的血药浓度数据，运用Phoenix WinNonlin7.0计算药代动力学参数，提供AUC0-t、AUC0-∞、Cmax、Tmax、和T1/2等参数及其平均值和标准差。·LC-MS/MS was used to determine the concentration of the target analyte in beagle dog plasma. Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters based on the blood drug concentration data at different time points, providing parameters such as AUC 0-t , AUC 0-∞ , C max , T max , and T 1/2 and their mean and standard deviation.

以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims (10)

一种式I所示化合物药学上可接受的盐的盐型或共晶；
A salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I;
所述药学上可接受的盐的盐型或共晶为式Ⅰ化合物与酸或碱形成的盐型或共晶，优选式Ⅰ化合物与酸形成的盐型或共晶；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; 优选地，所述酸可以选自无机酸或有机酸，例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸，甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、3,5-二羟基苯甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、对羟基苯甲酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、L-酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、龙胆酸、反式乌头酸、半硫酸或硫氰酸，以及烟酰胺、1,4-苯二酚或双羟萘酸。作为实例，所述酸可以选自盐酸、氢溴酸、硫酸、富马酸、马来酸、酒石酸、3,5-二羟基苯甲酸、龙胆酸、对羟基苯甲酸、草酸、对甲苯磺酸和反式乌头酸中的一种；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; 优选地，所述碱可以选自无机碱，例如碱金属氢氧化物或碱土金属的氢氧化物，优选为氢氧化钠或氢氧化钾。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. 根据权利要求1所述的盐型或共晶，其特征在于，所述式Ⅰ化合物药学上可接受的盐的盐型选自其盐酸盐、氢溴酸盐、硫酸盐和对甲苯磺酸盐中的一种；The salt form or co-crystal according to claim 1, characterized in that the salt form of the pharmaceutically acceptable salt of the compound of formula I is selected from one of its hydrochloride, hydrobromide, sulfate and p-toluenesulfonate; 优选地，所述式Ⅰ化合物药学上可接受的盐的共晶选自其富马酸共晶、马来酸共晶、酒石酸共晶(L-酒石酸共晶)、3,5-二羟基苯甲酸共晶、龙胆酸共晶、对羟基苯甲酸共晶、草酸共晶和反式乌头酸共晶中的一种。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. 根据权利要求1或2所述的盐型或共晶，其特征在于，所述式Ⅰ化合物药学上可接受的盐的共晶是式Ⅰ化合物与富马酸形成的共晶，即式Ⅰ化合物富马酸共晶。The salt form or co-crystal according to claim 1 or 2 is 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, that is, the fumaric acid co-crystal of the compound of formula I. 根据权利要求1-3任一项所述的盐型或共晶，其特征在于，式I所示化合物药学上可接受的盐的盐型和/或共晶可以选自：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 can be selected from: 盐酸盐Type A；氢溴酸盐Type A、氢溴酸盐Type B、氢溴酸盐Type C、氢溴酸盐Type D、氢溴酸盐Type E；硫酸盐Type A；富马酸共晶Type A；马来酸共晶Type A、马来酸共晶Type B；酒石酸共晶Type A、酒石酸共晶Type B、酒石酸共晶Type C；3,5-二羟基苯甲酸共晶Type A、3,5-二羟基苯甲酸共晶Type B；龙胆酸共晶Type A；对羟基苯甲酸共晶Type A；草酸共晶Type A；对甲苯磺酸盐Type A；反式乌头酸共晶Type A、反式乌头酸共晶Type B；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; 一种式Ⅰ化合物的盐酸盐Type A，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.06±0.2°、18.80±0.2°、22.24±0.2°处具有特征峰；A hydrochloride Type A of a compound of formula I, wherein the hydrochloride Type A has characteristic peaks at 18.06±0.2°, 18.80±0.2°, and 22.24±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; 优选地，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.06±0.2°、18.80±0.2°、21.35±0.2°、22.24±0.2°、26.67±0.2°处具有特征峰；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°; 优选地，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.67±0.2°处具有特征峰； 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°; 优选地，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、30.19±0.2°处具有特征峰；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°; 优选地，所述盐酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-1所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°: 表1-1盐酸盐Type A的XRPD解析数据
Table 1-1 XRPD analysis data of hydrochloride Type A
优选地，所述盐酸盐Type A具有基本如图4所示的X射线粉末衍射图；Preferably, the hydrochloride salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 4; 优选地，所述盐酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度160.6℃附近出现吸热峰；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; 优选地，所述盐酸盐Type A具有基本如图5所示的DSC图；Preferably, the hydrochloride salt Type A has a DSC graph substantially as shown in Figure 5; 优选地，所述盐酸盐Type A的热重分析(TGA)显示在100℃至200℃区间内具有约4.6％的失重；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); 优选地，所述盐酸盐Type A具有基本如图5所示的TGA图；Preferably, the hydrochloride salt Type A has a TGA graph substantially as shown in Figure 5; 优选地，所述盐酸盐Type A为式Ⅰ化合物盐酸盐的无水物或水合物；Preferably, the hydrochloride Type A is an anhydrate or hydrate of the hydrochloride of the compound of formula I; 一种式Ⅰ化合物的氢溴酸盐Type A，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.95±0.2°、24.55±0.2°、25.08±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.95±0.2°、24.50±0.2°、24.55±0.2°、25.08±0.2°、26.77±0.2°处具有特征峰；Preferably, the hydrobromide 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°; 优选地，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.89±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.89±0.2°处具有特征峰；Preferably, 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°, 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°; 优选地，所述氢溴酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-2所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°: 表1-2氢溴酸盐Type A的XRPD解析数据

Table 1-2 XRPD analysis data of hydrobromide Type A

优选地，所述氢溴酸盐Type A具有基本如图9所示的X射线粉末衍射图；Preferably, the hydrobromide salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 9; 优选地，所述氢溴酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度90.1℃和/或183.7℃附近出现吸热峰，峰值温度128.2℃附近出现放热峰；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 when heated to a peak temperature of 128.2°C; 优选地，所述氢溴酸盐Type A具有基本如图10所示的DSC图；Preferably, the hydrobromide salt Type A has a DSC graph substantially as shown in Figure 10; 优选地，所述氢溴酸盐Type A的热重分析(TGA)显示在室温至150℃区间内具有约4.1％的失重；Preferably, the hydrobromide salt Type A has a weight loss of about 4.1% in the range of room temperature to 150°C as shown by thermogravimetric analysis (TGA); 优选地，所述氢溴酸盐Type A具有基本如图10所示的TGA图；Preferably, the hydrobromide salt Type A has a TGA graph substantially as shown in Figure 10; 优选地，所述氢溴酸盐Type A为式Ⅰ化合物氢溴酸盐的无水物或水合物；Preferably, the hydrobromide Type A is an anhydrate or hydrate of the hydrobromide of the compound of formula I; 一种式Ⅰ化合物的氢溴酸盐Type B，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.30±0.2°、25.23±0.2°、27.55±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在18.30±0.2°、21.54±0.2°、25.23±0.2°、27.41±0.2°、27.55±0.2°处具有特征峰；Preferably, 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°; 优选地，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.55±0.2°处具有特征峰；Preferably, 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°; 优选地，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.55±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-3所示的特征峰，其中所述2θ角度的误差范围为±0.20°：Preferably, the hydrobromide Type B uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks as shown in Table 1-3, wherein the error range of the 2θ angle is ±0.20°: 表1-3氢溴酸盐Type B的XRPD解析数据

Table 1-3 XRPD analysis data of hydrobromide Type B

优选地，所述氢溴酸盐Type B具有基本如图14所示的X射线粉末衍射图；Preferably, the hydrobromide salt Type B has an X-ray powder diffraction pattern substantially as shown in Figure 14; 优选地，所述氢溴酸盐Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度91.5℃附近出现吸热峰，峰值温度220.3℃附近出现放热峰；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; 优选地，所述氢溴酸盐Type B具有基本如图16所示的DSC图；Preferably, the hydrobromide salt Type B has a DSC graph substantially as shown in Figure 16; 优选地，所述氢溴酸盐Type B的热重分析(TGA)显示在室温至150℃区间内具有约3.3％的失重；Preferably, the hydrobromide salt Type B has a weight loss of about 3.3% in the range of room temperature to 150°C as shown by thermogravimetric analysis (TGA); 优选地，所述氢溴酸盐Type B具有基本如图16所示的TGA图；Preferably, the hydrobromide salt Type B has a TGA graph substantially as shown in Figure 16; 优选地，所述氢溴酸盐Type B为式Ⅰ化合物氢溴酸盐的无水物或水合物；Preferably, the hydrobromide Type B is an anhydrate or hydrate of the hydrobromide of the compound of formula I; 一种式Ⅰ化合物的氢溴酸盐Type C，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.09±0.2°、22.26±0.2°、26.56±0.2°处具有特征峰；A hydrobromide salt Type C of a compound of formula I, wherein the hydrobromide salt Type C uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 4.09±0.2°, 22.26±0.2°, and 26.56±0.2°; 优选地，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.09±0.2°、17.52±0.2°、21.25±0.2°、22.26±0.2°、26.56±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.56±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.56±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-4所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-4, wherein the error range of the 2θ angle is ±0.20°: 表1-4氢溴酸盐Type C的XRPD解析数据

Table 1-4 XRPD analysis data of hydrobromide Type C

优选地，所述氢溴酸盐Type C具有基本如图18所示的X射线粉末衍射图；Preferably, the hydrobromide salt Type C has an X-ray powder diffraction pattern substantially as shown in Figure 18; 优选地，所述氢溴酸盐Type C的差示扫描量热法(DSC)分析显示在加热至峰值温度90.4℃和/或177.6℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the hydrobromide Type C shows an endothermic peak when heated to a peak temperature of 90.4°C and/or 177.6°C; 优选地，所述氢溴酸盐Type C具有基本如图19所示的DSC图；Preferably, the hydrobromide salt Type C has a DSC graph substantially as shown in Figure 19; 优选地，所述氢溴酸盐Type C的热重分析(TGA)显示在室温至150℃区间内具有约2.2％的失重；Preferably, the hydrobromide salt Type C has a weight loss of about 2.2% in the range of room temperature to 150°C as shown by thermogravimetric analysis (TGA); 优选地，所述氢溴酸盐Type C具有基本如图19所示的TGA图；Preferably, the hydrobromide salt Type C has a TGA graph substantially as shown in Figure 19; 优选地，所述氢溴酸盐Type C为式Ⅰ化合物氢溴酸盐的无水物或水合物；Preferably, the hydrobromide Type C is an anhydrate or hydrate of the hydrobromide of the compound of formula I; 一种式Ⅰ化合物的氢溴酸盐Type D，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.72±0.2°、17.89±0.2°、28.71±0.2°处具有特征峰；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; 优选地，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在3.72±0.2°、17.89±0.2°、21.48±0.2°、25.08±0.2°、28.71±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.71±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.71±0.2°处具有特征峰；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°, 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°; 优选地，所述氢溴酸盐Type D使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-5所示的特征峰，其中所述2θ角度的误差范围为±0.20°：Preferably, 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°: 表1-5氢溴酸盐Type D的XRPD解析数据
Table 1-5 XRPD analysis data of hydrobromide Type D
优选地，所述氢溴酸盐Type D具有基本如图21所示的X射线粉末衍射图；Preferably, the hydrobromide salt Type D has an X-ray powder diffraction pattern substantially as shown in Figure 21; 一种式Ⅰ化合物的氢溴酸盐Type E，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.00±0.2°、21.46±0.2°、27.22±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.00±0.2°、21.46±0.2°、22.92±0.2°、27.22±0.2°、28.21±0.2°处具有特征峰；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°, 27.22±0.2°, and 28.21±0.2°; 优选地，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.21±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.14±0.2°处具有特征峰；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°; 优选地，所述氢溴酸盐Type E使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-6所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-6, wherein the error range of the 2θ angle is ±0.20°: 表1-6氢溴酸盐Type E的XRPD解析数据
Table 1-6 XRPD analysis data of hydrobromide Type E
优选地，所述氢溴酸盐Type E具有基本如图23所示的X射线粉末衍射图；Preferably, the hydrobromide salt Type E has an X-ray powder diffraction pattern substantially as shown in Figure 23; 优选地，所述氢溴酸盐Type E的差示扫描量热法(DSC)分析显示在加热至峰值温度199.5℃附近出现吸热峰；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; 优选地，所述氢溴酸盐Type E具有基本如图24所示的DSC图；Preferably, the hydrobromide salt Type E has a DSC graph substantially as shown in Figure 24; 优选地，所述氢溴酸盐Type E具有基本如图24所示的TGA图；Preferably, the hydrobromide salt Type E has a TGA graph substantially as shown in Figure 24; 优选地，所述氢溴酸盐Type E为式Ⅰ化合物氢溴酸盐的无水物；Preferably, the hydrobromide salt Type E is an anhydrate of the hydrobromide salt of the compound of formula I; 一种式Ⅰ化合物的硫酸盐Type A，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在25.10±0.2°、25.16±0.2°、29.63±0.2°处具有特征峰；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; 优选地，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.87±0.2°、25.10±0.2°、25.16±0.2°、29.70±0.2°、29.63±0.2°处具有特征峰；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°; 优选地，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.63±0.2°处具有特征峰；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°; 优选地，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.63±0.2°处具有特征峰；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°; 优选地，所述硫酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-7所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°: 表1-7硫酸盐Type A的XRPD解析数据
Table 1-7 XRPD analysis data of sulfate Type A
优选地，所述硫酸盐Type A具有基本如图26所示的X射线粉末衍射图；Preferably, the sulfate Type A has an X-ray powder diffraction pattern substantially as shown in Figure 26; 优选地，所述硫酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度81.1℃和/或156.9℃附近出现吸热峰；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; 优选地，所述硫酸盐Type A具有基本如图27所示的DSC图；Preferably, the sulfate Type A has a DSC graph substantially as shown in Figure 27; 优选地，所述硫酸盐Type A的热重分析(TGA)显示在室温至150℃区间内具有约6.2％的失重；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; 优选地，所述硫酸盐Type A具有基本如图27所示的TGA图；Preferably, the sulfate Type A has a TGA graph substantially as shown in Figure 27; 优选地，所述硫酸盐Type A为式Ⅰ化合物硫酸盐的水合物；Preferably, the sulfate Type A is a hydrate of the sulfate of the compound of formula I; 一种式Ⅰ化合物的富马酸共晶Type A，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.34±0.2°、24.09±0.2°、25.95±0.2°处具有特征峰；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°; 优选地，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在8.93±0.2°、17.34±0.2°、22.03±0.2°、24.09±0.2°、25.95±0.2°处具有特征峰；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°; 优选地，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、30.21±0.2°处具有特征峰；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°; 优选地，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、30.21±0.2°处具有特征峰；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°; 优选地，所述富马酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-8所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-8, wherein the error range of the 2θ angle is ±0.20°: 表1-8富马酸共晶Type A的XRPD解析数据

Table 1-8 XRPD analysis data of fumaric acid eutectic Type A

优选地，所述富马酸共晶Type A具有基本如图85所示的X射线粉末衍射图；Preferably, the fumaric acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 85; 优选地，所述富马酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度170.1℃附近出现吸热峰；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; 优选地，所述富马酸共晶Type A具有基本如图86所示的DSC图；Preferably, the fumaric acid cocrystal Type A has a DSC graph substantially as shown in Figure 86; 优选地，所述富马酸共晶Type A具有基本如图86所示的TGA图；Preferably, the fumaric acid cocrystal Type A has a TGA graph substantially as shown in Figure 86; 优选地，所述富马酸共晶Type A为式Ⅰ化合物富马酸共晶无水物；Preferably, the fumaric acid eutectic Type A is anhydrous fumaric acid eutectic of the compound of formula I; 一种式Ⅰ化合物的马来酸共晶Type A，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.58±0.2°、22.36±0.2°、25.31±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.58±0.2°、22.36±0.2°、22.73±0.2°、23.45±0.2°、25.31±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.28±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.28±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-9所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-9, wherein the error range of the 2θ angle is ±0.20°: 表1-9马来酸共晶Type A的XRPD解析数据

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

优选地，所述马来酸共晶Type A具有基本如图34所示的X射线粉末衍射图；Preferably, the maleic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 34; 优选地，所述马来酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度107.8℃、118.5℃和/或155.6℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of 107.8°C, 118.5°C and/or 155.6°C; 优选地，所述马来酸共晶Type A具有基本如图35所示的DSC图；Preferably, the maleic acid cocrystal Type A has a DSC graph substantially as shown in Figure 35; 优选地，所述马来酸共晶Type A的热重分析(TGA)显示在100℃至200℃区间内具有约11.4％的失重；Preferably, the thermogravimetric analysis (TGA) of the maleic acid eutectic Type A shows a weight loss of about 11.4% in the range of 100°C to 200°C; 优选地，所述马来酸共晶Type A具有基本如图35所示的TGA图；Preferably, the maleic acid cocrystal Type A has a TGA graph substantially as shown in Figure 35; 优选地，所述马来酸共晶Type A为式Ⅰ化合物马来酸共晶的无水物；Preferably, the maleic acid cocrystal Type A is an anhydrate of the maleic acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的马来酸共晶Type B，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在22.57±0.2°、25.78±0.2°、26.94±0.2°处具有特征峰；A maleic acid cocrystal Type B of a compound of formula I, wherein the maleic acid cocrystal Type B has characteristic peaks at 22.57±0.2°, 25.78±0.2°, and 26.94±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; 优选地，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.92±0.2°、22.57±0.2°、24.92±0.2°、25.78±0.2°、26.94±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.22±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.22±0.2°处具有特征峰；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°; 优选地，所述马来酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-10所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°: 表1-10马来酸共晶Type B的XRPD解析数据
Table 1-10 XRPD analysis data of maleic acid cocrystal Type B
优选地，所述马来酸共晶Type B具有基本如图37所示的X射线粉末衍射图；Preferably, the maleic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 37; 优选地，所述马来酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度127.3℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the maleic acid cocrystal Type B shows an endothermic peak when heated to a peak temperature of about 127.3°C; 优选地，所述马来酸共晶Type B具有基本如图38所示的DSC图；Preferably, the maleic acid eutectic Type B has a DSC graph substantially as shown in Figure 38; 优选地，所述马来酸共晶Type B的热重分析(TGA)显示在100℃至200℃区间内具有约19.5％的失重；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; 优选地，所述马来酸共晶Type B具有基本如图38所示的TGA图；Preferably, the maleic acid cocrystal Type B has a TGA graph substantially as shown in Figure 38; 优选地，所述马来酸共晶Type B为式Ⅰ化合物马来酸共晶的无水物；Preferably, the maleic acid cocrystal Type B is an anhydrate of the maleic acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的酒石酸共晶Type A，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.79±0.2°、25.43±0.2°、26.38±0.2°处具有特征峰；A tartaric acid cocrystal Type A of a compound of formula I, wherein the tartaric acid cocrystal Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 21.79±0.2°, 25.43±0.2°, and 26.38±0.2°; 优选地，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在13.38±0.2°、18.84±0.2°、21.79±0.2°、25.43±0.2°、26.38±0.2°处具有特征峰；Preferably, the tartaric acid eutectic 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°; 优选地，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.38±0.2°处具有特征峰；Preferably, the tartaric acid eutectic 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°; 优选地，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.85±0.2°处具有特征峰；Preferably, the tartaric acid eutectic 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°; 优选地，所述酒石酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-11所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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°: 表1-11酒石酸共晶Type A的XRPD解析数据
Table 1-11 XRPD analysis data of tartaric acid cocrystal Type A
优选地，所述酒石酸共晶Type A具有基本如图40所示的X射线粉末衍射图；Preferably, the tartaric acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 40; 优选地，所述酒石酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度87.5℃、102.6℃、135.7℃和/或187.5℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the tartaric acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of 87.5°C, 102.6°C, 135.7°C and/or 187.5°C; 优选地，所述酒石酸共晶Type A具有基本如图41所示的DSC图； Preferably, the tartaric acid cocrystal Type A has a DSC graph substantially as shown in Figure 41; 优选地，所述酒石酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约2.2％的失重；Preferably, the tartaric acid eutectic Type A has a weight loss of about 2.2% in the range of room temperature to 150°C by thermogravimetric analysis (TGA); 优选地，所述酒石酸共晶Type A具有基本如图41所示的TGA图；Preferably, the tartaric acid eutectic Type A has a TGA graph substantially as shown in Figure 41; 优选地，所述酒石酸共晶Type A为式Ⅰ化合物酒石酸共晶的无水物；Preferably, the tartaric acid cocrystal Type A is an anhydrate of the tartaric acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的酒石酸共晶Type B，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.03±0.2°、5.18±0.2°、20.30±0.2°处具有特征峰；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°; 优选地，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.03±0.2°、5.18±0.2°、5.53±0.2°、18.20±0.2°、20.30±0.2°处具有特征峰；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°; 优选地，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、20.30±0.2°处具有特征峰；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°; 优选地，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.04±0.2°处具有特征峰；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°; 优选地，所述酒石酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-12所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-12, wherein the error range of the 2θ angle is ±0.20°: 表1-12酒石酸共晶Type B的XRPD解析数据
Table 1-12 XRPD analysis data of tartaric acid cocrystal Type B
优选地，所述酒石酸共晶Type B具有基本如图44所示的X射线粉末衍射图；Preferably, the tartaric acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 44; 优选地，所述酒石酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度88.4℃和/或172.5℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the tartaric acid eutectic Type B shows an endothermic peak when heated to a peak temperature of 88.4°C and/or 172.5°C; 优选地，所述酒石酸共晶Type B具有基本如图45所示的DSC图；Preferably, the tartaric acid eutectic Type B has a DSC graph substantially as shown in Figure 45; 优选地，所述酒石酸共晶Type B的热重分析(TGA)显示在室温至150℃区间内具有约3.3％的失重；Preferably, the tartaric acid eutectic Type B has a weight loss of about 3.3% in the range of room temperature to 150°C by thermogravimetric analysis (TGA); 优选地，所述酒石酸共晶Type B具有基本如图45所示的TGA图；Preferably, the tartaric acid eutectic Type B has a TGA graph substantially as shown in Figure 45; 优选地，所述酒石酸共晶Type B为式Ⅰ化合物酒石酸共晶的无水物或水合物；Preferably, the tartaric acid cocrystal Type B is an anhydrate or a hydrate of the tartaric acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的酒石酸共晶Type C，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.85±0.2°、12.99±0.2°、21.27±0.2°处具有特征峰；A tartaric acid cocrystal Type C of a compound of formula I, wherein the tartaric acid cocrystal Type C uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 6.85±0.2°, 12.99±0.2°, and 21.27±0.2°; 优选地，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在6.73±0.2°、6.85±0.2°、12.19±0.2°、12.99±0.2°、21.27±0.2°处具有特征峰； 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°; 优选地，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.88±0.2°处具有特征峰；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°; 优选地，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、25.88±0.2°处具有特征峰；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°; 优选地，所述酒石酸共晶Type C使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-13所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-13, wherein the error range of the 2θ angle is ±0.20°: 表1-13酒石酸共晶Type C的XRPD解析数据
Table 1-13 XRPD analysis data of tartaric acid eutectic Type C
优选地，所述酒石酸共晶Type C具有基本如图49所示的X射线粉末衍射图；Preferably, the tartaric acid cocrystal Type C has an X-ray powder diffraction pattern substantially as shown in Figure 49; 优选地，所述酒石酸共晶Type C的差示扫描量热法(DSC)分析显示在加热至峰值温度87.4℃、113.2℃、137.2℃和/或189.5℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the tartaric acid eutectic Type C shows endothermic peaks when heated to peak temperatures of 87.4°C, 113.2°C, 137.2°C and/or 189.5°C; 优选地，所述酒石酸共晶Type C具有基本如图50所示的DSC图；Preferably, the tartaric acid eutectic Type C has a DSC graph substantially as shown in Figure 50; 优选地，所述酒石酸共晶Type C的热重分析(TGA)显示在室温至150℃区间内具有约1.9％的失重；Preferably, the tartaric acid eutectic Type C has a weight loss of about 1.9% in the range of room temperature to 150° C. by thermogravimetric analysis (TGA); 优选地，所述酒石酸共晶Type C具有基本如图50所示的TGA图；Preferably, the tartaric acid eutectic Type C has a TGA graph substantially as shown in Figure 50; 优选地，所述酒石酸共晶Type C为式Ⅰ化合物酒石酸共晶的无水物或水合物；Preferably, the tartaric acid cocrystal Type C is an anhydrate or a hydrate of the tartaric acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的3,5-二羟基苯甲酸共晶Type A，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.19±0.2°、22.92±0.2°、27.49±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.80±0.2°、19.23±0.2°、21.19±0.2°、22.92±0.2°、27.49±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.49±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.49±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-14所示的特征峰，其中所述2θ角度的误差范围为±0.20°： 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°: 表1-14 3,5-二羟基苯甲酸共晶Type A的XRPD解析数据
Table 1-14 XRPD analysis data of 3,5-dihydroxybenzoic acid cocrystal Type A
优选地，所述3,5-二羟基苯甲酸共晶Type A具有基本如图52所示的X射线粉末衍射图；Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 52; 优选地，所述3,5-二羟基苯甲酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度203.1℃附近出现吸热峰；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; 优选地，所述3,5-二羟基苯甲酸共晶Type A具有基本如图53所示的DSC图；Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A has a DSC graph substantially as shown in Figure 53; 优选地，所述3,5-二羟基苯甲酸共晶Type A具有基本如图53所示的TGA图；Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type A has a TGA graph substantially as shown in Figure 53; 优选地，所述3,5-二羟基苯甲酸共晶Type A为式Ⅰ化合物3,5-二羟基苯甲酸共晶的无水物；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; 一种式Ⅰ化合物的3,5-二羟基苯甲酸共晶Type B，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.10±0.2°、23.47±0.2°、28.05±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.10±0.2°、17.40±0.2°、21.79±0.2°、23.47±0.2°、28.05±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.31±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.31±0.2°处具有特征峰；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°; 优选地，所述3,5-二羟基苯甲酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-15所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-15, wherein the error range of the 2θ angle is ±0.20°: 表1-15 3,5-二羟基苯甲酸共晶Type B的XRPD解析数据

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

优选地，所述3,5-二羟基苯甲酸共晶Type B具有基本如图55所示的X射线粉末衍射图；Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 55; 优选地，所述3,5-二羟基苯甲酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度170.5和/或203.6℃附近出现吸热峰，峰值温度172.5℃附近出现放热峰；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; 优选地，所述3,5-二羟基苯甲酸共晶Type B具有基本如图56所示的DSC图；Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B has a DSC graph substantially as shown in Figure 56; 优选地，所述3,5-二羟基苯甲酸共晶Type B的热重分析(TGA)显示在室温至200℃区间内具有约0.2％的失重；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; 优选地，所述3,5-二羟基苯甲酸共晶Type B具有基本如图56所示的TGA图；Preferably, the 3,5-dihydroxybenzoic acid cocrystal Type B has a TGA graph substantially as shown in Figure 56; 优选地，所述3,5-二羟基苯甲酸共晶Type B为式Ⅰ化合物3,5-二羟基苯甲酸共晶的无水物；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; 一种式Ⅰ化合物的龙胆酸共晶Type A，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在19.29±0.2°、23.45±0.2°、27.47±0.2°处具有特征峰；A gentisic acid cocrystal Type A of a compound of formula I, wherein the gentisic acid cocrystal Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 19.29±0.2°, 23.45±0.2°, and 27.47±0.2°; 优选地，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在15.03±0.2°、19.29±0.2°、23.45±0.2°、27.47±0.2°、27.80±0.2°处具有特征峰；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°; 优选地，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.80±0.2°处具有特征峰；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°; 优选地，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.39±0.2°处具有特征峰；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°; 优选地，所述龙胆酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-16所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-16, wherein the error range of the 2θ angle is ±0.20°: 表1-16龙胆酸共晶Type A的XRPD解析数据

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

优选地，所述龙胆酸共晶Type A具有基本如图58所示的X射线粉末衍射图；Preferably, the gentisic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 58; 优选地，所述龙胆酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度166.7℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the gentisic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of 166.7°C; 优选地，所述龙胆酸共晶Type A具有基本如图59所示的DSC图；Preferably, the gentisic acid cocrystal Type A has a DSC graph substantially as shown in Figure 59; 优选地，所述龙胆酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约0.2％的失重；Preferably, the thermogravimetric analysis (TGA) of the gentisic acid cocrystal Type A shows a weight loss of about 0.2% in the range of room temperature to 150°C; 优选地，所述龙胆酸共晶Type A具有基本如图59所示的TGA图；Preferably, the gentisic acid cocrystal Type A has a TGA graph substantially as shown in Figure 59; 优选地，所述龙胆酸共晶Type A为式Ⅰ化合物龙胆酸共晶的无水物；Preferably, the gentisic acid cocrystal Type A is an anhydrate of the gentisic acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的对羟基苯甲酸共晶Type A，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.93±0.2°、24.77±0.2°、26.85±0.2°处具有特征峰；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°; 优选地，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在21.68±0.2°、21.93±0.2°、23.43±0.2°、24.77±0.2°、26.85±0.2°处具有特征峰；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°; 优选地，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.85±0.2°处具有特征峰；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°; 优选地，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.85±0.2°处具有特征峰；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°; 优选地，所述对羟基苯甲酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-17所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-17, wherein the error range of the 2θ angle is ±0.20°: 表1-17对羟基苯甲酸共晶Type A的XRPD解析数据
Table 1-17 XRPD analysis data of p-hydroxybenzoic acid cocrystal Type A
优选地，所述对羟基苯甲酸共晶Type A具有基本如图61所示的X射线粉末衍射图；Preferably, the p-hydroxybenzoic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 61; 优选地，所述对羟基苯甲酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度124.4℃附近出现吸热峰；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; 优选地，所述对羟基苯甲酸共晶Type A具有基本如图62所示的DSC图；Preferably, the p-hydroxybenzoic acid cocrystal Type A has a DSC graph substantially as shown in Figure 62; 优选地，所述对羟基苯甲酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约0.1％的失重；Preferably, the thermogravimetric analysis (TGA) of the p-hydroxybenzoic acid cocrystal Type A shows a weight loss of about 0.1% in the range of room temperature to 150°C; 优选地，所述对羟基苯甲酸共晶Type A具有基本如图62所示的TGA图；Preferably, the p-hydroxybenzoic acid cocrystal Type A has a TGA graph substantially as shown in Figure 62; 优选地，所述对羟基苯甲酸共晶Type A为式Ⅰ化合物对羟基苯甲酸共晶的无水物；Preferably, the p-hydroxybenzoic acid cocrystal Type A is an anhydrate of the p-hydroxybenzoic acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的草酸共晶Type A，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.64±0.2°、26.69±0.2°、27.96±0.2°处具有特征峰；An oxalic acid cocrystal Type A of a compound of formula I, wherein the oxalic acid cocrystal Type A uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 16.64±0.2°, 26.69±0.2°, and 27.96±0.2°; 优选地，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在16.64±0.2°、17.01±0.2°、20.96±0.2°、26.69±0.2°、27.96±0.2°处具有特征峰；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°; 优选地，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.04±0.2°处具有特征峰；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°; 优选地，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、29.04±0.2°处具有特征峰；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°; 优选地，所述草酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-18所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-18, wherein the error range of the 2θ angle is ±0.20°: 表1-18草酸共晶Type A的XRPD解析数据
Table 1-18 XRPD analysis data of oxalic acid cocrystal Type A
优选地，所述草酸共晶Type A具有基本如图64所示的X射线粉末衍射图；Preferably, the oxalic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 64; 优选地，所述草酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度105.0℃、160.7℃和/或203.7℃附近出现吸热峰；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; 优选地，所述草酸共晶Type A具有基本如图65所示的DSC图；Preferably, the oxalic acid eutectic Type A has a DSC graph substantially as shown in Figure 65; 优选地，所述草酸共晶Type A的热重分析(TGA)显示在室温至150℃区间内具有约0.8％的失重，和/或在150℃至250℃区间内具有约9.0％的失重；Preferably, the thermogravimetric analysis (TGA) of the oxalic acid eutectic 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; 优选地，所述草酸共晶Type A具有基本如图65所示的TGA图； Preferably, the oxalic acid cocrystal Type A has a TGA graph substantially as shown in Figure 65; 优选地，所述草酸共晶Type A为式Ⅰ化合物草酸共晶的无水物；Preferably, the oxalic acid cocrystal Type A is an anhydrate of the oxalic acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的对甲苯磺酸盐Type A，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.36±0.2°、21.93±0.2°、24.55±0.2°处具有特征峰；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°; 优选地，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.36±0.2°、21.93±0.2°、23.49±0.2°、24.55±0.2°、25.82±0.2°处具有特征峰；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°; 优选地，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、28.77±0.2°处具有特征峰；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°; 优选地，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、31.20±0.2°处具有特征峰；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°; 优选地，所述对甲苯磺酸盐Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-19所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-19, wherein the error range of the 2θ angle is ±0.20°: 表1-19对甲苯磺酸盐Type A的XRPD解析数据
Table 1-19 XRPD analysis data of p-toluenesulfonate Type A
优选地，所述对甲苯磺酸盐Type A具有基本如图67所示的X射线粉末衍射图；Preferably, the p-toluenesulfonate salt Type A has an X-ray powder diffraction pattern substantially as shown in Figure 67; 优选地，所述对甲苯磺酸盐Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度127.7℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the p-toluenesulfonate salt Type A shows an endothermic peak when heated to a peak temperature of approximately 127.7°C; 优选地，所述对甲苯磺酸盐Type A具有基本如图68所示的DSC图；Preferably, the p-toluenesulfonate salt Type A has a DSC graph substantially as shown in Figure 68; 优选地，所述对甲苯磺酸盐Type A具有基本如图68所示的TGA图；Preferably, the p-toluenesulfonate salt Type A has a TGA graph substantially as shown in Figure 68; 优选地，所述对甲苯磺酸盐Type A为式Ⅰ化合物对甲苯磺酸盐的无水物；Preferably, the p-toluenesulfonate salt Type A is an anhydrous form of the p-toluenesulfonate salt of the compound of formula I; 一种式Ⅰ化合物的反式乌头酸共晶Type A，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.44±0.2°、22.73±0.2°、23.54±0.2°处具有特征峰；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 has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 17.44±0.2°, 22.73±0.2°, and 23.54±0.2°; 优选地，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在17.21±0.2°、17.44±0.2°、22.73±0.2°、23.54±0.2°、24.32±0.2°处具有特征峰；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°; 优选地，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、26.28±0.2°处具有特征峰； 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°; 优选地，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.98±0.2°处具有特征峰；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°; 优选地，所述反式乌头酸共晶Type A使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-20所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-20, wherein the error range of the 2θ angle is ±0.20°: 表1-20反式乌头酸共晶Type A的XRPD解析数据
Table 1-20 XRPD analysis data of trans-aconitic acid cocrystal Type A
优选地，所述反式乌头酸共晶Type A具有基本如图70所示的X射线粉末衍射图；Preferably, the trans-aconitic acid cocrystal Type A has an X-ray powder diffraction pattern substantially as shown in Figure 70; 优选地，所述反式乌头酸共晶Type A的差示扫描量热法(DSC)分析显示在加热至峰值温度55.6℃、104.9℃、114.9℃、129.9℃、136.1℃和/或149.9℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the trans-aconitic acid cocrystal Type A shows an endothermic peak when heated to a peak temperature of 55.6°C, 104.9°C, 114.9°C, 129.9°C, 136.1°C and/or 149.9°C; 优选地，所述反式乌头酸共晶Type A具有基本如图71所示的DSC图；Preferably, the trans-aconitic acid cocrystal Type A has a DSC graph substantially as shown in Figure 71; 优选地，所述反式乌头酸共晶Type A的热重分析(TGA)显示在室温至120℃区间内具有约5.7％的失重；Preferably, the thermogravimetric analysis (TGA) of the trans-aconitic acid cocrystal Type A shows a weight loss of about 5.7% in the range of room temperature to 120°C; 优选地，所述反式乌头酸共晶Type A具有基本如图71所示的TGA图；Preferably, the trans-aconitic acid cocrystal Type A has a TGA graph substantially as shown in Figure 71; 优选地，所述反式乌头酸共晶Type A为式Ⅰ化合物反式乌头酸共晶的乙醇溶剂合物；Preferably, the trans-aconitic acid cocrystal Type A is an ethanol solvate of the trans-aconitic acid cocrystal of the compound of formula I; 一种式Ⅰ化合物的反式乌头酸共晶Type B，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在11.69±0.2°、17.09±0.2°、23.47±0.2°处具有特征峰；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°; 优选地，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在8.29±0.2°、11.69±0.2°、17.09±0.2°、23.47±0.2°、26.28±0.2°处具有特征峰；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°; 优选地，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.90±0.2°处具有特征峰；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°; 优选地，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在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°、27.90±0.2°处具有特征峰；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°; 优选地，所述反式乌头酸共晶Type B使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射具有如表1-21所示的特征峰，其中所述2θ角度的误差范围为±0.20°：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 Table 1-21, wherein the error range of the 2θ angle is ±0.20°: 表1-21反式乌头酸共晶Type B的XRPD解析数据
Table 1-21 XRPD analysis data of trans-aconitic acid cocrystal Type B
优选地，所述反式乌头酸共晶Type B具有基本如图75所示的X射线粉末衍射图；Preferably, the trans-aconitic acid cocrystal Type B has an X-ray powder diffraction pattern substantially as shown in Figure 75; 优选地，所述反式乌头酸共晶Type B的差示扫描量热法(DSC)分析显示在加热至峰值温度78.3℃、106.5℃、118.0℃、137.1℃和/或148.0℃附近出现吸热峰；Preferably, differential scanning calorimetry (DSC) analysis of the trans-aconitic acid cocrystal Type B shows an endothermic peak when heated to a peak temperature of 78.3°C, 106.5°C, 118.0°C, 137.1°C and/or 148.0°C; 优选地，所述反式乌头酸共晶Type B具有基本如图76所示的DSC图；Preferably, the trans-aconitic acid cocrystal Type B has a DSC graph substantially as shown in Figure 76; 优选地，所述反式乌头酸共晶Type B的热重分析(TGA)显示在室温至120℃区间内具有约3.0％的失重；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; 优选地，所述反式乌头酸共晶Type B具有基本如图76所示的TGA图；Preferably, the trans-aconitic acid cocrystal Type B has a TGA graph substantially as shown in Figure 76; 优选地，所述反式乌头酸共晶Type B为式Ⅰ化合物反式乌头酸共晶的水合物。Preferably, the trans-aconitic acid cocrystal Type B is a hydrate of the trans-aconitic acid cocrystal of the compound of formula I. 权利要求1-4任一项所述盐型或共晶的制备方法，所述制备方法包括将式Ⅰ化合物与所述酸或碱反应，制备得到式Ⅰ化合物药学上可接受的盐的盐型或共晶；A method for preparing a salt form or co-crystal according to any one of claims 1 to 4, comprising reacting a compound of formula I with the acid or base to prepare a salt form or co-crystal of a pharmaceutically acceptable salt of the compound of formula I; 优选地，所述制备方法包括将式Ⅰ化合物与所述酸或碱在溶剂中反应，制备得到式I化合物药学上可接受的盐的盐型或共晶；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; 优选地，所述式Ⅰ化合物与所述酸或碱的摩尔比可以为1:0.2～1:3，1:0.8～1:1.5，优选为1:0.5～1:1.5，更优选为1:0.6～1:1.3。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. 根据权利要求5所述的制备方法，其特征在于，包括以下步骤：The preparation method according to claim 5, characterized in that it comprises the following steps: 将式I所示化合物与所述酸溶于有机溶剂中，搅拌，得到所述盐型或共晶；Dissolving the compound represented by formula I and the acid in an organic solvent and stirring to obtain the salt form or co-crystal; 和/或，将式I所示化合物与所述酸溶于有机溶剂中，搅拌，析晶，得到所述盐型或共晶；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; 和/或，将式I所示化合物与所述酸溶于有机溶剂中，搅拌，析晶，挥发，得到所述盐型或共晶；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; 和/或，将式I所示化合物与所述酸溶于有机溶剂中，搅拌，析晶，反滴，得到所述盐型或共晶；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; 优选地，所述有机溶剂选自甲醇、乙醇、丙酮、乙酸乙酯、正庚烷、甲基叔丁基醚、乙二醇甲醚、二甲基亚砜、二氯甲烷、四氢呋喃中的至少一种；优选乙酸乙酯、乙醇、正庚烷、甲醇、甲基叔丁基醚、丙酮中的至少一种；例如选自乙酸乙酯、乙醇/正庚烷(1/9，v/v)、甲醇/MTBE(1/9，v/v)或丙酮/MTBE(1/9，v/v)；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); 优选地，式I所示化合物与所述酸的摩尔比可以为1:(0.2-3)，1:(0.5-1.5)，例如1:(0.6-1.3)，如1:0.6、1:1、1:1.1、1:1；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; 优选地，式I所示化合物与所述有机溶剂的质量体积比可以为(10-50)mg:1mL，例如(20-40)mg:1mL；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; 优选地，所述反滴是将反应溶液滴加到反溶剂中；所述反溶剂可以选自正庚烷或甲基叔丁基醚中的至少一种。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. 一种药物组合物，包含权利要求1-4任一项所述盐型或共晶中的至少一种，以及任选存在的药学上可接受的辅料。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. 一种制剂，包含权利要求1-4任一项所述盐型或共晶中的至少一种，以及任选存在的药学上可接受 的辅料。A preparation comprising at least one of the salt forms or cocrystals according to any one of claims 1 to 4, and optionally a pharmaceutically acceptable of auxiliary materials. 权利要求1-4任一项所述盐型或共晶或权利要求7所述药物组合物在制备用于抑制电压门控型钠通道的药物中的用途；Use of the salt form or cocrystal 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; 优选地，所述电压门控型钠通道是NaV1.8。Preferably, the voltage-gated sodium channel is NaV1.8. 权利要求1-4任一项所述盐型或共晶或权利要求7所述药物组合物在制备用于治疗和/或预防和/或减轻和/或缓解疾病的药物中的用途，所述疾病优选为疼痛、咳嗽；Use of the salt form or cocrystal 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; 优选地，所述疾病选自慢性疼痛、肠痛、神经性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原发性疼痛、手术后疼痛、内脏痛、多发性硬化症、夏-马-图三氏综合症、失禁和心律失常；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; 优选地，所述肠痛选自炎性肠病疼痛、克罗恩病疼痛和间质性膀胱炎疼痛；Preferably, the intestinal pain is selected from inflammatory bowel disease pain, Crohn's disease pain and interstitial cystitis pain; 优选地，所述神经性疼痛选自疱疹后神经痛、糖尿病性神经痛、HIV相关性感觉神经病、三叉神经痛、口灼伤综合症、截肢术后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、Morto神经瘤、神经挤压损伤、脊管狭窄、腕管综合症、神经根痛、坐骨神经痛、神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合症、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、脊髓损伤后疼痛、原发性小纤维神经病、原发性感觉神经病和三叉自主神经性头痛；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; 优选地，所述肌肉骨骼痛选自骨关节炎疼痛、背痛、冷痛、烧伤疼痛和牙痛；Preferably, the musculoskeletal pain is selected from osteoarthritis pain, back pain, cold pain, burn pain and toothache; 优选地，所述炎性疼痛选自类风湿性关节炎疼痛和外阴痛；Preferably, the inflammatory pain is selected from rheumatoid arthritis pain and vulvar pain; 优选地，所述原发性疼痛选自纤维肌痛。 Preferably, the primary pain is selected from fibromyalgia.
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CN112479996A (en) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 Pyridine oxynitride and preparation method and application thereof
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