WO2024255834A1 - Forme saline et co-cristal de pyridine-n-oxyde, son procédé de préparation et son utilisation - Google Patents

Forme saline et co-cristal de pyridine-n-oxyde, son procédé de préparation et son utilisation 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

La présente invention concerne une forme saline ou un co-cristal d'un sel pharmaceutiquement acceptable d'un composé tel que représenté par la formule (I) et son procédé de préparation. La forme saline ou le co-cristal a un bon effet d'inhibition d'un canal sodique sensible à la tension, a une bonne stabilité, peut satisfaire l'exigence de développement de préparations pharmaceutiques cliniques, et a une valeur d'application clinique très importante.
PCT/CN2024/099160 2023-06-14 2024-06-14 Forme saline et co-cristal de pyridine-n-oxyde, son procédé de préparation et son utilisation Ceased WO2024255834A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019014352A1 (fr) * 2017-07-11 2019-01-17 Vertex Pharmaceuticals Incorporated Carboxamides utilisés en tant qu'inhibiteurs des canaux sodiques
CN112479996A (zh) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2022188872A1 (fr) * 2021-03-11 2022-09-15 上海济煜医药科技有限公司 Forme cristalline d'un composé d'oxyde d'azote de pyridine et son utilisation
WO2023232117A1 (fr) * 2022-06-02 2023-12-07 上海济煜医药科技有限公司 Procédé de préparation d'un composé d'oxynitrure de pyridine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019014352A1 (fr) * 2017-07-11 2019-01-17 Vertex Pharmaceuticals Incorporated Carboxamides utilisés en tant qu'inhibiteurs des canaux sodiques
CN112479996A (zh) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2022188872A1 (fr) * 2021-03-11 2022-09-15 上海济煜医药科技有限公司 Forme cristalline d'un composé d'oxyde d'azote de pyridine et son utilisation
WO2023232117A1 (fr) * 2022-06-02 2023-12-07 上海济煜医药科技有限公司 Procédé de préparation d'un composé d'oxynitrure de pyridine

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