WO2024255833A1 - Co-crystal of pyridine oxynitride and fumaric acid, composition comprising same, use thereof and preparation method therefor - Google Patents

Abstract

Disclosed in the present invention are a co-crystal of a compound represented by formula (I) and fumaric acid, a pharmaceutical composition and a use thereof. Specifically, disclosed in the present invention is a co-crystal formed by a compound represented by formula (I) and fumaric acid in a molar ratio of 1:0.4-0.6, wherein the structure of the co-crystal is as shown in formula (II); and the present invention further relates to a preparation method for the co-crystal of the compound represented by formula (I) and the fumaric acid.

Description

Co-crystal of pyridine nitrogen oxide and fumaric acid, composition, use and preparation method thereof

This application requires:

The priority of the prior application, patent application number 202310705175.1, filed with the State Intellectual Property Office of China on June 14, 2023, entitled “Co-crystals of pyridine nitrogen oxides and fumaric acid, compositions, uses and preparation methods thereof”;

The priority of the prior application, patent application number 2024107508051, filed with the State Intellectual Property Office of China on June 11, 2024, entitled “Co-crystals of pyridine nitrogen oxides and fumaric acid, compositions, uses and preparation methods thereof”;

The entirety of said prior application is incorporated into the present application by reference.

Technical Field

The present invention relates to a co-crystal of a compound of formula (I) and fumaric acid, a pharmaceutical composition containing the same, and an application of the co-crystal as a voltage-gated sodium channels (NaV) blocker.

Background Art

An application with application number PCT/CN2020/114700 (application date September 11, 2020, patent application publication WO2021047622A1) provides a NaV1.8 blocker, whose structure is shown in formula (I).

The industry is looking forward to providing solid forms of pharmaceuticals with excellent physical or chemical properties.

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.

Summary of the invention

First aspect

The present invention provides a co-crystal of a compound of formula (I) and fumaric acid, wherein the co-crystal is formed by a non-covalent bond between the compound of formula (I) and fumaric acid in a molar ratio of 1:(0.4-0.6), and the molar ratio is preferably 1:(0.45-0.55) or 1:(0.48-0.51);

In some embodiments of the present invention, the co-crystal is formed by non-covalent bonding of the compound of formula (I) and fumaric acid at a molar ratio of 1:0.5.

In some embodiments of the present invention, the co-crystal of the compound of formula (I) and fumaric acid is co-crystal A, and the X-ray powder diffraction pattern of co-crystal A has characteristic diffraction peaks at the following 2θ angles:

8.93±0.2°, 17.34±0.2°, 22.03±0.2°, 22.46±0.2°, 24.09±0.2°, 25.95±0.2°, 30.21±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the co-crystal A further comprises the following one, two or more 2θ angles: Characteristic diffraction peaks: 14.99±0.2°, 16.86±0.2°, 17.65±0.2°, 18.00±0.2°, 18.61±0.2°, 19.35±0.2°, 21.27±0.2°, 26.40±0.2°, 27.02±0.2°, 27.90±0.2°, 28.62±0.2°, 28.83±0.2°, 29.22±0.2°, 31.07±0.2°.

In some embodiments of the present invention, the co-crystal A has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the cocrystal A is shown in Table 1 below.

Table 1

In some embodiments of the present invention, the co-crystal of the compound of formula (I) and fumaric acid is co-crystal B, and the X-ray powder diffraction pattern of co-crystal B has characteristic diffraction peaks at the following 2θ angles:

8.99±0.2°, 22.65±0.2°, 25.00±0.2°, 25.29±0.2°, 27.12±0.2°, 28.54±0.2°, 29.30±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the cocrystal B further includes the following one, two or more characteristic diffraction peaks at 2θ angles:

13.51±0.2°, 20.28±0.2°, 23.70±0.2°, 28.81±0.2°, 30.70±0.2°, 31.47±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the co-crystal B has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the cocrystal B is shown in Table 2 below.

Table 2

In another aspect of the present invention, the co-crystal of the compound of formula (I) and fumaric acid is co-crystal C, and the X-ray powder diffraction pattern of co-crystal C has characteristic diffraction peaks at the following 2θ angles:

9.28±0.2°, 23.06±0.2°, 25.35±0.2°, 27.49±0.2°, 27.7±0.2°, 28.46±0.2°, 29.32±0.2°, 29.67±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the cocrystal C further includes the following one, two or more characteristic diffraction peaks at 2θ angles:

17.29±0.2°, 17.6±0.2°, 22.14±0.2°, 23.31±0.2°, 31.9±0.2°.

In some embodiments of the present invention, the X-ray powder diffraction pattern of the co-crystal C has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .

In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the cocrystal C is shown in Table 3 below.

Table 3

In some embodiments of the present invention, the co-crystal of the compound of formula (I) and fumaric acid is a single crystal of the triclinic system, the space group is P-1, and the unit cell parameters are: α=96.640(5)°, β=97.063(6)°, γ=92.579(6)°.

In some embodiments of the present invention, the unit cell volume of the single crystal is The number of asymmetric units in the unit cell is Z = 2.

In some embodiments of the present invention, the single crystal has a three-dimensional structural ellipsoid diagram as shown in FIG. 1 .

In some embodiments of the present invention, the single crystal has a unit cell stacking projection diagram along the b-axis direction as shown in FIG. 2 .

In some embodiments of the present invention, the atomic coordinates and isotropic temperature factor of the single crystal are shown in Table 4 below.

Table 4

In some embodiments of the present invention, the bond length of the single crystal is and bond angles (°) are shown in Table 5 below.

Table 5

In some embodiments of the present invention, the twist angle (°) of the single crystal is shown in Table 6 below.

Table 6

In some embodiments of the present invention, the hydrogen bond list of the co-single crystal ( °) are shown in Table 7 below.

Table 7

Second aspect

The present invention also provides a pharmaceutical composition, comprising a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid, such as co-crystal A, co-crystal B, co-crystal C, or a single crystal.

In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

The third aspect

The present invention also provides the use of a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to inhibit voltage-gated sodium channels.

In some embodiments of the present invention, the voltage-gated sodium channel is Nav1.8.

The fourth aspect

The present invention also provides the use of a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent and/or alleviate and/or relieve a disease, wherein the disease is preferably pain or cough.

In some embodiments of the invention, the disease is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and cardiac arrhythmia.

Fifth Aspect

The present invention also provides a method for preparing the above co-crystal, the preparation method comprising the following steps:

The free compound of formula (I) and fumaric acid are mixed in a solvent, stirred, filtered, and dried under vacuum at room temperature to obtain the co-crystal.

The preparation method-1 of the above-mentioned co-crystal A comprises the following steps:

The free compound of formula (I) and a certain amount of fumaric acid are mixed in solvent-1, stirred and then a certain amount of fumaric acid is added, the stirring is continued, the mixture is filtered and dried under vacuum at room temperature to obtain the cocrystal A.

In some embodiments of the present invention, in the preparation method-1 of co-crystal A:

Solvent-1 is selected from a mixed solvent of ethanol and n-heptane, a mixed solvent of n-propanol and n-heptane, a mixed solvent of acetone and n-heptane, and a mixed solvent of 2-methyltetrahydrofuran and n-heptane; preferably, it is a mixed solvent of ethanol and n-heptane in a volume ratio of 2:3;

And/or, the molar ratio of the free compound of formula (I) to fumaric acid is 1:0.4-1.0, preferably 1:0.5.

In some embodiments of the present invention, the preparation method 1 of co-crystal A is specifically as follows:

5.000 g of free compound of formula (I) and 324.8 mg of fumaric acid were mixed in 100 mL of ethanol/n-heptane (2/3, v/v), stirred at 50°C for 2 hours, and then 975.0 mg of fumaric acid was added. The mixture was stirred for 1 hour, filtered, and then dried in vacuo at room temperature for 1 day to obtain 4.769 g of fumaric acid cocrystal A of compound of formula (I).

The preparation method 2 of the above-mentioned co-crystal A comprises the following steps:

The free compound of formula (I) and fumaric acid are mixed in solvent-2, stirred at room temperature, filtered, and vacuum dried to obtain a mixed product;

The mixed product was added into solvent-3, stirred at room temperature, filtered, and dried in vacuo to obtain the co-crystal A.

In some embodiments of the present invention, in the preparation method-2 of co-crystal A:

Solvent-2 is selected from ethyl acetate;

and/or, solvent-3 is selected from methanol;

And/or, the molar ratio of the free compound of formula (I) to fumaric acid is 1:0.4-1.0, preferably 1:0.5.

In some embodiments of the present invention, the preparation method 2 of cocrystal A is specifically as follows:

5.000 g of the free compound of formula (I) and 1.301 g of fumaric acid were mixed in 160 mL of ethyl acetate, stirred at room temperature for 2 hours, filtered, and then dried in vacuum at room temperature for 1 day to obtain fumaric acid co-crystal A of the compound of formula (I) mixed with fumaric acid; the above product was added to 25 mL of methanol, stirred at room temperature for 1 day, filtered, and then dried in vacuum at 40°C for 1 day to obtain the co-crystal A.

The preparation method-1 of the above-mentioned co-crystal B comprises the following steps:

The co-crystal A was added into the solvent-4, stirred at room temperature, filtered, and dried in vacuo to obtain the co-crystal B.

In some embodiments of the present invention, in the preparation method-1 of co-crystal B:

Solvent-4 is selected from acetone.

In some embodiments of the present invention, the preparation method 1 of cocrystal B is specifically as follows:

4.769 g of the above co-crystal A was added to 30 mL of acetone, stirred at room temperature for 1 day, filtered, and then vacuum dried at 40° C. for 1 day to obtain the co-crystal B.

The preparation method 2 of the above-mentioned co-crystal B comprises the following steps:

Dissolve the free form of the compound of formula (I) or the crystalline form A of the compound of formula (I) and fumaric acid in solvent-5 respectively, add the solvent-5 solution of fumaric acid to the solvent-5 solution of the free form of the compound of formula (I) in portions, and optionally add seed crystals during the adding process;

Then add solvent-6, stir, cool, stir, filter, and obtain the co-crystal B.

In some embodiments of the present invention, in the preparation method-2 of co-crystal B:

Solvent-5 is selected from n-propanol and ethanol;

and/or, solvent-6 is selected from n-heptane;

and/or, cooling is 0-10°C for 5h;

and/or, the amount of seed crystal added is 0.5%-0.7%;

and/or, the temperature for dissolving, adding in portions, and stirring is 50-60°C or 45-55°C;

And/or, the molar ratio of the free compound of formula (I) to fumaric acid is 1:0.4-1.0, preferably 1:0.5.

The preparation method of the above-mentioned co-crystal C comprises the following steps:

The co-crystal B is added to the solvent-7, and the solvent-8 is gradually added dropwise, and the mixture is stirred at room temperature and/or allowed to stand in a refrigerator and/or allowed to stand in an open container for evaporation until a solid is precipitated, and the mixture is centrifuged to obtain the co-crystal C.

In some embodiments of the present invention, in the method for preparing co-crystal C:

Solvent-7 is selected from cyclohexane;

And/or, solvent-8 is selected from tetrahydrofuran.

In some embodiments of the present invention, the preparation method of co-crystal C is specifically as follows:

20 mg of co-crystal B was added to cyclohexane, and tetrahydrofuran was gradually added dropwise. The mixture was stirred at room temperature and/or allowed to stand in a refrigerator and/or allowed to stand in an open container for evaporation until a solid was precipitated. The mixture was centrifuged to obtain the co-crystal C.

The method for preparing the single crystal comprises the following steps:

1) Weigh a certain amount of cocrystal B into a vial, add solvent-9, seal with a parafilm, and pierce a hole with a needle;

2) Add water to the large bottle.

3) Put the small bottle into the large bottle, seal it, and place it in a refrigerator at 0-5°C to obtain the above-mentioned single crystal.

In some embodiments of the present invention, solvent-9 is selected from methanol.

In some embodiments of the present invention, the amount of cocrystal B is 10 mg;

And/or, the amount of methanol used is 0.5 mL.

Beneficial Effects

The present invention provides a co-crystal of a compound of formula (I) and fumaric acid, including co-crystal A, co-crystal B, co-crystal C, and a single crystal. The co-crystal has good stability in different solvents and has good stability under high temperature, high humidity, light and accelerated conditions.

Definition and Description

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by ordinary technicians in the field to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety. Any methods and materials similar or identical to those described in the present invention may be used in the present invention, but the present invention describes preferred methods, equipment and materials.

"API" or "free state" refers to the free base form of the compound represented by formula (I).

"Eutectoid" 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.

As used herein, the term "the molar ratio of the compound of formula (I) and fumaric acid is approximately 1:0.5" means that the compound of formula (I) and fumaric acid co-crystal has a stoichiometric ratio of about 1:0.5 of the compound of formula (I): fumaric acid; for example, 1:(0.4-0.6), 1:(0.45-0.55), 1:(0.48-0.51) or 1:0.5.

"Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts of compounds. The crystalline form of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.

"Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances. The amorphous form of a substance can be obtained by many methods known in the art. This method includes, but is not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion technology, etc.

"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, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"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.

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

Crystalline or amorphous forms can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

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

Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (usually α-Al ₂ O ₃ ) as a function of temperature by continuous heating or cooling under program control. The height of the melting peak of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values of DSC spectra may vary slightly between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, the melting peak has an error tolerance of ±3°C.

Glass transition refers to the transition between the highly elastic state and the glassy state of an amorphous material, which is an inherent property of the material; its corresponding transition temperature is the glass transition temperature (Tg), which is an important physical property of an amorphous material. However, the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details, etc. According to the instrument conditions used in the test of the present invention, the glass transition temperature has an error tolerance of ±3°C.

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

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

Thermogravimetric analysis (TGA) is a technique for measuring the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of crystal water or crystallization solvent in the crystals. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. According to the instrument conditions used in the test of the present invention, the mass change has an error tolerance of ±0.3%.

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

In the context of the present invention, 2θ values in X-ray powder diffraction patterns are given in degrees (°).

When referring to a spectrum and/or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.

The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or the DSC pattern or the TGA results are shown in the pattern thereof.

"Substantially pure" means that one crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms, and the percentage of the other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

“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%.

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

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

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an ellipsoid diagram of the three-dimensional structure of a single crystal of a eutectic body according to an embodiment of the present invention;

FIG2 is a unit cell stacking projection diagram of a single crystal of a eutectic along the b-axis direction according to an embodiment of the present invention;

FIG3 is an XRPD diagram of a free state of a compound of formula (I) according to an embodiment of the present invention;

FIG4 is a DSC and TGA diagram of the free state of the compound of formula (I) according to an embodiment of the present invention;

FIG5 is an NMR diagram of the free state of the compound of formula (I) according to an embodiment of the present invention;

FIG6 is an XRPD diagram of co-crystal A according to an embodiment of the present invention;

FIG7 is a DSC and TGA graph of co-crystal A according to an embodiment of the present invention;

FIG8 is a comparison of NMR of (a) and free state of co-crystal A according to an embodiment of the present invention; (b) NMR graph;

FIG9 is (a) a DVS curve of co-crystal A according to an embodiment of the present invention; (b) a comparison diagram of XRPD of the sample before and after the DVS test;

FIG10 is an XRPD pattern of co-crystal B according to an embodiment of the present invention;

FIG11 is a DSC and TGA graph of co-crystal B according to an embodiment of the present invention;

FIG12 is a comparison of NMR of (a) and free state of co-crystal B according to an embodiment of the present invention; (b) NMR graph;

FIG13 is (a) a DVS curve of co-crystal B according to an embodiment of the present invention; (b) a comparison diagram of XRPD of the sample before and after the DVS test;

FIG14 is an XRPD pattern of co-crystal C according to an embodiment of the present invention;

FIG15 is a DSC and TGA graph of co-crystal C according to an embodiment of the present invention;

FIG16 is a NMR comparison diagram of (a) co-crystal C and co-crystal A according to an embodiment of the present invention; (b) NMR diagram;

FIG17 is an XRPD diagram of the stability study of co-crystal A according to an embodiment of the present invention;

FIG. 18 is an XRPD pattern of a stability study of co-crystal B according to an embodiment of the present invention.

DETAILED DESCRIPTION

The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

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

General analysis methods:

1. Nuclear magnetic resonance analysis ( ¹ H NMR)

Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and analyzed by NMR on Bruker AVANCE NEO 400 (Bruker, GER).

2. X-ray powder diffraction (XRPD)

The solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2θ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds. The test method was Cu target Kα1 radiation, voltage 40kV, current 40mA, and the sample pan was a zero background sample pan.

3. Thermogravimetric analysis (TGA)

The model of the thermogravimetric analyzer is TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.

4. Differential Scanning Calorimetry (DSC)

The model of the differential scanning calorimeter was TA Discovery 250 (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. The nitrogen purge rate in the furnace was 50 mL/min.

5. Dynamic moisture adsorption and desorption analysis (DVS)

Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode with a humidity change of 0%-95%-0%. 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, or each gradient maintained for up to 180 minutes. After the test was completed, the sample was analyzed by XRPD to confirm whether the solid morphology had changed.

6. High Performance Liquid Chromatography (HPLC)

The HPLC model was Waters Acquity Arc (Waters, US), and the test conditions were shown in Table 8.

Table 8 HPLC test conditions

7. Single crystal diffraction experiment

Determined according to the first method of 0451 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, test conditions: MoKα radiation, Scanning, CMOS detector, data collection temperature: -103.15°C, data collection range (θ): 1.04-26.39°.

Instrument: Single crystal X-ray diffractometer;

Model: D8 Venture

Manufacturer: Bruker

General test methods:

1. Stability study

About 15 mg of sample was weighed and placed in a weighing bottle, and placed under high temperature (60°C), high humidity (25°C/92.5% RH), light (25°C/4500Lux), and acceleration (40°C/75% RH), and samples were taken for XRPD characterization and HPLC testing after 7 days and 15 days.

2. Biological media and water solubility test

The preparation process of the biological medium is shown in the table. Samples of different crystal forms were added to the biological medium and water and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5h, 2h and 24h, respectively. The sampled solutions were filtered with a 0.22μm water filter membrane. Some samples with higher concentrations were appropriately diluted with diluents. 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 free raw material and the dilution multiple. In addition, the pH value of the supernatant after 24h was tested, and the remaining solid was tested by XRPD.

Table 9 Preparation process of biological medium

DETAILED DESCRIPTION

The starting materials of the free compound of formula (I) used in the following examples can be prepared according to the prior art. For example, they can be prepared according to the method described in patent application publication WO2021047622A1, but the starting materials are not limiting conditions for preparing the co-crystals of the present invention.

The XRPD results (Figure 3) of the free state of the compound of formula (I) show that it is a solid with good crystallinity. The TGA results (Figure 4) show that the free state has a weight loss of 0.8% during heating to 150°C, and decomposition may occur above 300°C. The DSC results (Figure 4) show that the free state has an endothermic signal at about 94°C and a melting endothermic peak at about 150°C. No obvious residual organic solvent signal peak is found in the NMR results (Figure 5), and the NMR results are used as a reference for subsequent comparison.

Example 1 Preparation Example 1 of Fumaric Acid Cocrystal A of Compound of Formula (I)

5.000 g of free compound of formula (I) and 324.8 mg of fumaric acid were mixed in 100 mL of ethanol/n-heptane (2/3, v/v), stirred at 50°C for 2 hours, and then 975.0 mg of fumaric acid was added. The mixture was stirred for 1 hour, filtered, and then dried in vacuo at room temperature for 1 day to obtain 4.769 g of fumaric acid cocrystal A of compound of formula (I).

Example 2 Preparation Example 2 of Fumaric Acid Cocrystal A of Compound of Formula (I)

5.000 g of free compound of formula (I) and 1.301 g of fumaric acid were mixed in 160 mL of ethyl acetate, stirred at room temperature for 2 hours, filtered, and then dried in vacuum at room temperature for 1 day to obtain 5.409 g of fumaric acid co-crystal A of compound of formula (I) mixed with fumaric acid; the above product was added to 25 mL of methanol, stirred at room temperature for 1 day, filtered, and then dried in vacuum at 40°C for 1 day to obtain 4.012 g of fumaric acid co-crystal A of compound of formula (I).

XRPD results (Figure 6) show that cocrystal A is a solid with good crystallinity. TGA results (Figure 7) show that cocrystal A has almost no weight loss during heating to 150°C, and may decompose above 225°C. DSC results (Figure 7) show that cocrystal A has a melting endothermic peak at 170°C. NMR results (Figure 8) show that the integral of the peak corresponding to the free state of the sample is consistent with the API, and the active hydrogen of fumaric acid can be seen around 13.1ppm, and the characteristic signal peak of fumaric acid can be seen around 6.6ppm. From the integral value, it can be obtained that the molar ratio of the API and fumaric acid is approximately 1:0.5; no obvious residual organic solvent signal peak is observed. DVS results (Figure 9) show that cocrystal A gains 0.03% at 80%RH, 0.05% at 95%RH, and 0.03% at 0%RH during the adsorption process, indicating that cocrystal A is not hygroscopic. There is no significant change in XRPD of cocrystal A after DVS test. In summary, eutectic A is anhydrous and non-hygroscopic.

Example 3 Preparation Example 1 of Fumaric Acid Cocrystal B of Compound of Formula (I)

4.769 g of fumaric acid co-crystal A of the compound of formula (I) prepared in any one of Example 1 or Example 2 of the present invention was added to 30 mL of acetone, stirred at room temperature for 1 day, filtered, and then vacuum dried at 40°C for 1 day to obtain 4.275 g of fumaric acid co-crystal B of the compound of formula (I).

The XRPD results (Figure 10) show that cocrystal B is a solid with good crystallinity. The TGA results (Figure 11) show that cocrystal B has almost no weight loss during heating to 150°C, and may decompose above 225°C. The DSC results (Figure 11) show that cocrystal B has a melting endothermic peak at 169°C. The NMR results (Figure 12) show that the integral of the peak corresponding to the free state of the sample is consistent with the API, and the active hydrogen of fumaric acid can be seen around 13.1ppm, and the characteristic signal peak of fumaric acid can be seen around 6.6ppm. From the integral value, it can be obtained that the molar ratio of the API and fumaric acid is approximately 1:0.5; no obvious residual organic solvent signal peak is observed. The DVS results (Figure 13) show that cocrystal B gains 0.02% at 80%RH, 0.05% at 95%RH, and 0.01% at 0%RH during the adsorption process, indicating that cocrystal B is not hygroscopic. There is no significant change in the XRPD of cocrystal B after the DVS test. In summary, eutectic B is an anhydrous crystalline form and has no hygroscopicity.

Example 4 Preparation of Fumaric Acid Cocrystal C of Compound of Formula (I)

Take a cyclohexane solution containing about 20 mg of the fumaric acid cocrystal B of the compound of formula (I) prepared in Example 3 of the present invention, gradually add tetrahydrofuran until solid precipitates, or the total volume of the solution is close to 10 mL, or the total volume of tetrahydrofuran reaches 10 times that of cyclohexane, and then stir at room temperature for 1 hour. If there is not enough solid precipitation, continue stirring at room temperature for 2 days. The system with no sufficient solid precipitation is placed in a 4°C or -15°C refrigerator. After cooling, the system with no sufficient solid precipitation is left to volatilize in the open at room temperature. During the experiment, except for the volatilization experiment, the system with sufficient solid precipitation was centrifuged, and the solid fumaric acid cocrystal C of the compound of formula (I) was vacuum dried at room temperature.

XRPD results (Figure 14) show that cocrystal C is a solid with good crystallinity. TGA results (Figure 15) show that cocrystal C loses 0.1% of its weight when heated to 150°C, and may decompose above 225°C. DSC results (Figure 15) show that cocrystal C has endothermic and exothermic signals at 162°C and 164°C, and a melting endothermic peak at around 170°C. NMR results (Figure 16) show that the NMR peak shift of this sample is consistent with that of cocrystal A, and the integral of the corresponding free state peak is consistent with the API. The active hydrogen of fumaric acid can be seen around 13.1ppm, and the characteristic signal peak of fumaric acid can be seen around 6.6ppm. From the integral value, it can be obtained that the molar ratio of the API and fumaric acid is approximately 1:0.5; no obvious residual organic solvent signal peak is observed. In summary, cocrystal C is anhydrous crystalline.

Example 5 Solubility Stability Test

The results of the solution stability study of the free state in different solvents at 55 and 75°C are shown in Table 10. The free state solutions of ethanol, 2-methyltetrahydrofuran and acetone are stable at 55 and 75°C within 24 hours.

Table 10

The results of the solution stability study of cocrystal A in different solvents at 55 and 75°C are shown in Table 11. The ethanol, n-propanol, isopropanol, acetone and tetrahydrofuran solutions of cocrystal A remain stable at 55°C for at least 24 hours. The ethanol, n-propanol and isopropanol solutions of cocrystal A remain stable at 75°C for at least 24 hours.

Table 11

The results of the solution stability study of co-crystal B in different solvents at 55 and 75°C are shown in Table 12. The ethanol, 2-methyltetrahydrofuran and acetone solutions of co-crystal B remained stable at 55 and 75°C for at least 24 h.

Table 12

Example 6 Stability Study

The stability of the compound of formula (I) fumaric acid co-crystal A and co-crystal B 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 HPLC testing and XRPD characterization at 7 days and 15 days, respectively. The results are shown in Tables 13 to 15, Figures 17 and 18. The XRPD results show that co-crystal A and co-crystal B are stable under high temperature, high humidity, light, and accelerated conditions for 7 days and 15 days, and no crystal transformation occurs, and the appearance does not change significantly. The HPLC results show that the chemical purity of co-crystal A and co-crystal B does not change significantly after being placed under the above conditions for 7 days and 15 days.

Table 13 Stability study results

Table 14 HPLC purity analysis results of cocrystal A stability samples

Table 15 HPLC purity analysis results of cocrystal B stability samples

Example 7 Preparation Example 2 of Fumaric Acid Cocrystal B of Compound of Formula (I)

10g of the free state was dissolved in 6.5V n-propanol at 50-60°C, 1.1eq. of fumaric acid was dissolved in 8V n-propanol at 50-60°C, and the mixture was kept at 50-60°C. 0.25eq. of fumaric acid in n-propanol was added to the n-propanol solution of the free state, 0.7% of seed was added, and the mixture was stirred at 50-60°C for 20h. 0.85eq. of fumaric acid in n-propanol was added dropwise to the n-propanol solution of the free state, and the mixture was stirred at 50-60°C for 20h. 14.5V of n-heptane was added dropwise for 4h, and the mixture was stirred at 50-60°C for 5h. The mixture was cooled to 0-10°C for 5h, and the mixture was stirred for 18h. The mixture was filtered, and the NMR free state: fumaric acid = 1: 0.48 to obtain 9.7g of solid, with a content of 87.6%, a purity of 99.1%, a yield of 85.0%, and a mother liquor loss of 2.7%.

Example 8 Preparation Example 3 of Fumaric Acid Cocrystal B of Compound of Formula (I)

10g of free state was dissolved in 5V ethanol at 50-60℃, 1.1eq. of fumaric acid was dissolved in 6V ethanol at 50-60℃, and the temperature was kept at 50-60℃. 0.25eq. of fumaric acid in ethanol solution was added to the ethanol solution of the free state, 0.7% of seed was added, and the mixture was stirred at 50-60℃ for 20h. 0.85eq. of fumaric acid in ethanol solution was added dropwise to the ethanol solution of the free state, and the mixture was stirred at 50-60℃ for 20h. 11V of n-heptane was added dropwise for 4h, and the mixture was stirred at 50-60℃ for 5h. The mixture was cooled to 0-10℃ for 5h, and the mixture was stirred for 18h. The mixture was filtered, and the NMR free state: fumaric acid = 1: 0.48 to obtain 10.3g of solid, with a content of 88.3%, a purity of 99.1%, a yield of 91.0%, and a mother liquor loss of 3.7%.

Example 9 Preparation Example 4 of Fumaric Acid Cocrystal B of Compound of Formula (I)

20g of free state was dissolved in 5V ethanol at 50-60℃, 0.277eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60℃, maintained at 50-60℃, added to the ethanol solution of the free state, 0.5% of seed was added, and stirred at 50-60℃ for 2h. 0.277eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60℃, maintained at 50-60℃, added to the ethanol solution of the free state, and stirred at 50-60℃ for 18h. 16V of n-heptane was added dropwise for 4h, and stirred at 50-60℃ for 5h. The temperature was lowered to 0-10℃ for 5h, and stirring was continued for 10h. Filtered, the wet product had a free state NMR: fumaric acid = 1:0.5, and 19.5g of product was obtained after drying, with a crude yield of 86.6%.

Example 10 Preparation Example 5 of Fumaric Acid Cocrystal B of Compound of Formula (I)

106.1g of free state was dissolved in 5.1V ethanol at 50-60℃, 0.277eq. of fumaric acid was dissolved in 1.8V ethanol (1.5V for dissolution, 0.3V for rinsing pipeline) at 50-60℃, maintained at 50-60℃, added to the ethanol solution of the free state, added with seed crystals, stirred at 50-60℃ for 4h, 0.277eq. of fumaric acid was dissolved in 1.8V ethanol at 50-60℃, maintained at 50-60℃, added to the ethanol solution of the free state, stirred at 50-60℃ for 3h, 9.9V of n-heptane was added dropwise for 8h, stirred at 50-60℃ for 8h, cooled to 0-10℃ for 4h, stirred for 3h, filtered, and the wet product had a free state NMR of fumaric acid = 1:0.49. After drying, 107g of product was obtained with a yield of 88.4%.

Example 11 Preparation Example 6 of Fumaric Acid Cocrystal B of Compound of Formula (I)

1907g of free state was dissolved in 5.5V ethanol at 50-60℃, 0.287eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60℃, maintained at 50-60℃, added to the ethanol solution of the free state, solid precipitated, which was a mixed crystal of co-crystal A and co-crystal B, added the seed of co-crystal B, stirred at 50-60℃ for 1 hour, sampled, and the measured result was a mixed crystal of co-crystal A and co-crystal B, continued stirring at 50-60℃ for 18h, sampled and hot filtered, the crystal form was co-crystal Body B, 0.287eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60℃, maintained at 50-60℃, added to the free ethanol solution for 3h, maintained at 50-60℃ and stirred for 3h, 10.5V n-heptane was added dropwise for 8h, stirred at 50-60℃ for 8h, cooled to 0-10℃ for 3h, stirred for 4h, filtered, the wet product had the correct XRPD crystal form, and 1.96kg of product was obtained after sieving, with a content of 87.5% and a yield of 89.8%.

Example 12 Preparation Example 7 of Fumaric Acid Cocrystal B of Compound of Formula (I)

10g free II was dissolved in 5.5V ethanol at 45-55℃, 0.277eq. fumaric acid was dissolved in 1.5V EtOH at 45-55℃, maintained at 45-55℃, added to the ethanol solution of free II, 1% seed was added, and stirred at 45-55℃ for 2h. 0.277eq. fumaric acid was dissolved in 1.5V EtOH at 45-55℃, maintained at 45-55℃, added to the ethanol solution of free II for 1h, maintained at 50-60℃ and stirred for 18h, 10V n-heptane was added dropwise for 3h, and stirred at 45-55℃ for 1h. The temperature was cooled to 0-10℃ after 1h, and the mixture was filtered. XRPD of the wet product showed the correct crystal form.

The free state II can be obtained according to the preparation method of the crystalline form A of the compound of formula (I) disclosed in patent application publication TW202300147A.

Example 13 Preparation of single crystal of fumaric acid co-crystal of compound of formula (I)

1. Weigh about 10 mg of cocrystal B into a 4 ml glass vial, add 0.5 ml of methanol, dissolve, seal with parafilm, and pierce a hole with a needle;

2. Add about 4 ml of water to the 20 ml bottle;

3. Put the small bottle into the large bottle, seal it, and place it in a refrigerator at 0-5℃.

The single crystal is a triclinic single crystal with a space group of P-1 and unit cell parameters of: α＝96.640(5)°，β＝97.063(6)°，γ＝92.579(6)°. Unit cell volume The number of asymmetric units in the unit cell is Z = 2.

The single crystal has a three-dimensional structure ellipsoid diagram as shown in FIG1 , and a unit cell stacking projection diagram along the b-axis direction as shown in FIG2 .

The atomic coordinates and isotropic temperature factor of the single crystal are shown in Table 4. The bond angles (°) are shown in Table 5, the torsion angles (°) are shown in Table 6, and the hydrogen bond list ( °) as shown in Table 7.

Example 14 Pharmacokinetic Experiment

The solvent was 0.5% MC. Beagles were fasted overnight and fed 4 hours after administration. n = 4, weighed before administration, and the dosage was calculated based on body weight. Dosage was 10 mg/kg, 30 mg/kg; administration volume was 5 mL/kg. Blood collection time points: before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, 48 h, 72 h after administration.

Blood was collected from the forelimb vein, about 1 mL per sample, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions, 2200g, 10 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.

·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.

The results of pharmacokinetic experiments show that the fumaric acid cocrystal B of the compound of formula (I) has excellent pharmacokinetic properties.

In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (10)

A co-crystal of a compound of formula (I) and fumaric acid, characterized in that the co-crystal is formed by a non-covalent bond between the compound of formula (I) and fumaric acid in a molar ratio of 1:(0.4-0.6);
The co-crystal according to claim 1, characterized in that the co-crystal is co-crystal A, and the X-ray powder diffraction pattern of the co-crystal A has characteristic diffraction peaks at the following 2θ angles: 8.93±0.2°, 17.34±0.2°, 22.03±0.2°, 22.46±0.2°, 24.09±0.2°, 25.95±0.2°, 30.21±0.2°; Preferably, the X-ray powder diffraction pattern of the cocrystal A further comprises the following one, two or more characteristic diffraction peaks at 2θ angles: 14.99±0.2°, 16.86±0.2°, 17.65±0.2°, 18.00±0.2°, 18.61±0.2°, 19.35±0.2°, 21.27±0.2°, 26.40±0.2°, 27.02±0.2°, 27.90±0.2°, 28.62±0.2°, 28.83±0.2°, 29.22±0.2°, 31.07±0.2°; Preferably, the co-crystal A has an X-ray powder diffraction pattern substantially as shown in Figure 6. The co-crystal according to claim 1, characterized in that the co-crystal is co-crystal B, and the X-ray powder diffraction pattern of the co-crystal B has characteristic diffraction peaks at the following 2θ angles: 8.99±0.2°, 22.65±0.2°, 25.00±0.2°, 25.29±0.2°, 27.12±0.2°, 28.54±0.2°, 29.30±0.2°; Preferably, the X-ray powder diffraction pattern of the cocrystal B further comprises the following one, two or more characteristic diffraction peaks at 2θ angles: 13.51±0.2°, 20.28±0.2°, 23.70±0.2°, 28.81±0.2°, 30.70±0.2°, 31.47±0.2°; Preferably, the X-ray powder diffraction pattern of the co-crystal B has an X-ray powder diffraction pattern substantially as shown in FIG. 10 . The co-crystal according to claim 1, characterized in that the co-crystal is co-crystal C, and the X-ray powder diffraction pattern of the co-crystal C has characteristic diffraction peaks at the following 2θ angles: 9.28±0.2°, 23.06±0.2°, 25.35±0.2°, 27.49±0.2°, 27.7±0.2°, 28.46±0.2°, 29.32±0.2°, 29.67±0.2°; Preferably, the X-ray powder diffraction pattern of the cocrystal C further comprises the following one, two or more characteristic diffraction peaks at 2θ angles: 17.29±0.2°, 17.6±0.2°, 22.14±0.2°, 23.31±0.2°, 31.9±0.2°; Preferably, the X-ray powder diffraction pattern of the co-crystal C has an X-ray powder diffraction pattern substantially as shown in Figure 14. The eutectic substance according to claim 1, characterized in that the eutectic substance is a single crystal of the triclinic system, the space group is P-1, and the unit cell parameters are: β=97.063(6)°, γ=92.579(6)°; Preferably, the unit cell volume of the single crystal The number of asymmetric units in the unit cell is Z = 2; Preferably, the single crystal has a three-dimensional structural ellipsoid diagram as shown in FIG1 ; Preferably, the single crystal has a unit cell stacking projection diagram along the b-axis direction as shown in FIG. 2 . A pharmaceutical composition comprising the co-crystal according to any one of claims 1 to 5, such as co-crystal A, co-crystal B, co-crystal C, or a single crystal. Use of the co-crystal according to any one of claims 1 to 5 (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) or the pharmaceutical composition according to claim 6 in the preparation of a drug for inhibiting voltage-gated sodium channels; Preferably, the voltage-gated sodium channel is Nav1.8. Use of the co-crystal according to any one of claims 1 to 5 (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) or the pharmaceutical composition according to claim 6 in the preparation of a drug, wherein the drug is used to treat and/or prevent and/or alleviate and/or relieve a disease, wherein the disease is preferably pain or cough. The use according to claim 8, characterized in that 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 method for preparing the co-crystal according to any one of claims 1 to 5, comprising the following steps: The free compound of formula (I) and fumaric acid are mixed in a solvent, stirred, filtered, and dried under vacuum at room temperature to obtain the co-crystal.