Co-crystal of pyridine oxynitride and fumaric acid as well as composition, application and preparation method of co-crystal

Abstract

The invention discloses a eutectic of a compound as shown in a formula (I) and fumaric acid, a pharmaceutical composition and application of the eutectic. Specifically, the invention discloses a eutectic formed by a compound shown as a formula (I) and fumaric acid in a molar ratio of 1: 0.4-0.6, and the structure of the eutectic is shown as a formula (II), the invention also relates to a preparation method of the eutecticum of the compound as shown in the formula (I) and fumaric acid.

Description

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

[0001] This application requires the following:

[0002] Priority to 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 thereof, uses and preparation methods thereof”;

[0003] Priority to 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 thereof, uses and preparation methods”;

[0004] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0005] The present invention relates to a co-crystal of a compound of formula (I) and fumaric acid, a pharmaceutical composition containing the co-crystal, and an application of the co-crystal as a voltage-gated sodium channel (NaV) blocker. Background Art

[0006] The application with application number PCT / CN2020 / 114700 (application date is September 11, 2020, patent application publication WO2021047622A1) provides a NaV1.8 blocker, whose structure is shown in formula (I).

[0007] The industry expects to provide solid forms of pharmaceuticals with excellent physical or chemical properties.

[0008] Pharmaceutical cocrystals are crystals formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a specific ratio. The formation of cocrystals can improve a drug's physicochemical properties and enhance its clinical therapeutic effects, while also enriching its crystalline forms. However, the development of pharmaceutical cocrystals is challenging, requiring in-depth research and evaluation of cocrystal ligand selection, preparation processes, and physical property characterization.

[0009] Summary of the Invention

[0010] First aspect

[0011] 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), preferably 1:(0.45-0.55) or 1:(0.48-0.51);

[0012] 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.

[0013] 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:

[0014] 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°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the cocrystal A further includes one, two or more of the following 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°, and 31.07±0.2°.

[0016] In some embodiments of the present invention, the co-crystal A has an X-ray powder diffraction pattern substantially as shown in FIG6 .

[0017] 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.

[0018] Table 1

[0019] 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 the co-crystal B has characteristic diffraction peaks at the following 2θ angles:

[0020] 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°.

[0021] In some embodiments of the present invention, the X-ray powder diffraction pattern of the cocrystal B further includes one, two or more of the following characteristic diffraction peaks at 2θ angles:

[0022] 13.51±0.2°, 20.28±0.2°, 23.70±0.2°, 28.81±0.2°, 30.70±0.2°, 31.47±0.2°.

[0023] 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 FIG10 .

[0024] 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.

[0025] Table 2

[0026] 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 the co-crystal C has characteristic diffraction peaks at the following 2θ angles:

[0027] 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°.

[0028] In some embodiments of the present invention, the X-ray powder diffraction pattern of the cocrystal C further includes one, two or more of the following characteristic diffraction peaks at 2θ angles:

[0029] 17.29±0.2°, 17.6±0.2°, 22.14±0.2°, 23.31±0.2°, 31.9±0.2°.

[0030] 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 FIG14 .

[0031] In some embodiments of the present invention, the X-ray powder diffraction pattern analysis data of the cocrystal C are shown in Table 3 below.

[0032] Table 3

[0033] 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, with a space group of P-1 and unit cell parameters of: α=96.640(5)°, β=97.063(6)°, γ=92.579(6)°.

[0034] 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.

[0035] In some embodiments of the present invention, the single crystal has a three-dimensional structural ellipsoidal diagram as shown in FIG1 .

[0036] In some embodiments of the present invention, the single crystal has a unit cell stacking projection diagram along the b-axis as shown in FIG2 .

[0037] In some embodiments of the present invention, the atomic coordinates and isotropic temperature factor of the single crystal are shown in Table 4 below.

[0038] Table 4

[0039] In some embodiments of the present invention, the bond length of the single crystal is The bond angles (°) are shown in Table 5 below.

[0040] Table 5

[0041] In some embodiments of the present invention, the twist angle (°) of the single crystal is shown in Table 6 below.

[0042] Table 6

[0043] In some embodiments of the present invention, the hydrogen bond list of the co-single crystal ( °) are shown in Table 7 below.

[0044] Table 7

[0045] Second aspect

[0046] 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.

[0047] In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0048] The third aspect

[0049] The present invention also provides the use of a co-crystal (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) of any of the above-mentioned compounds of formula (I) and fumaric acid or the above-mentioned pharmaceutical composition in the preparation of a drug for inhibiting voltage-gated sodium channels.

[0050] In some embodiments of the present invention, the voltage-gated sodium channel is Nav1.8.

[0051] The fourth aspect

[0052] The present invention also provides the use of a co-crystal (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) of any of the above-mentioned compounds of formula (I) and fumaric acid or the above-mentioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to treat and / or prevent and / or alleviate and / or relieve a disease, wherein the disease is preferably pain or cough.

[0053] 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.

[0054] The fifth aspect

[0055] The present invention also provides a method for preparing the above-mentioned co-crystal, which comprises the following steps:

[0056] 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.

[0057] The preparation method 1 of the above-mentioned co-crystal A comprises the following steps:

[0058] 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 mixture is stirred continuously, filtered, and dried in vacuo at room temperature to obtain the cocrystal A.

[0059] In some embodiments of the present invention, in the preparation method 1 of cocrystal A:

[0060] 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;

[0061] 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.

[0062] In some embodiments of the present invention, the preparation method 1 of cocrystal A is specifically as follows:

[0063] 5.000 g of the 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). After stirring at 50°C for 2 hours, 975.0 mg of fumaric acid was added, and stirring was continued for 1 hour. The mixture was filtered and then dried in vacuo at room temperature for 1 day to obtain 4.769 g of fumaric acid cocrystal A of the compound of formula (I).

[0064] The preparation method 2 of the above-mentioned cocrystal A comprises the following steps:

[0065] The free compound of formula (I) and fumaric acid were mixed in solvent-2, stirred at room temperature, filtered, and vacuum dried to obtain a mixed product;

[0066] The mixed product was added to solvent-3, stirred at room temperature, filtered, and vacuum dried to obtain the cocrystal A.

[0067] In some embodiments of the present invention, in the preparation method 2 of co-crystal A:

[0068] Solvent-2 is selected from ethyl acetate;

[0069] and / or, solvent-3 is selected from methanol;

[0070] 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.

[0071] In some embodiments of the present invention, the preparation method 2 of cocrystal A is specifically as follows:

[0072] 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 vacuum-dried at room temperature for 1 day to obtain fumaric acid cocrystal 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 vacuum-dried at 40°C for 1 day to obtain the cocrystal A.

[0073] The preparation method 1 of the above-mentioned co-crystal B comprises the following steps:

[0074] Co-crystal A was added to solvent-4, stirred at room temperature, filtered, and dried in vacuo to obtain the co-crystal B.

[0075] In some embodiments of the present invention, in the preparation method 1 of co-crystal B:

[0076] Solvent-4 is selected from acetone.

[0077] In some embodiments of the present invention, the preparation method 1 of cocrystal B is specifically as follows:

[0078] 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.

[0079] The preparation method 2 of the above-mentioned co-crystal B comprises the following steps:

[0080] 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 fumaric acid solution in solvent-5 to the free form of the compound of formula (I) in solvent-5 in portions. Optionally, seed crystals may be added during the addition process.

[0081] Then, solvent-6 was added, stirred, cooled, stirred, and filtered to obtain the co-crystal B.

[0082] In some embodiments of the present invention, in the preparation method 2 of co-crystal B:

[0083] Solvent-5 is selected from n-propanol and ethanol;

[0084] and / or, solvent-6 is selected from n-heptane;

[0085] and / or, cooling by 0-10°C for 5 hours;

[0086] and / or, the amount of seed crystal added is 0.5%-0.7%;

[0087] and / or, the temperature for dissolving, adding in portions, and stirring is 50-60°C or 45-55°C;

[0088] 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.

[0089] The preparation method of the above-mentioned co-crystal C comprises the following steps:

[0090] Co-crystal B is added to solvent-7, and solvent-8 is gradually added dropwise. 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 precipitates. The mixture is centrifuged to obtain the co-crystal C.

[0091] In some embodiments of the present invention, in the method for preparing cocrystal C:

[0092] Solvent-7 is selected from cyclohexane;

[0093] And / or, solvent-8 is selected from tetrahydrofuran.

[0094] In some embodiments of the present invention, the preparation method of cocrystal C is specifically as follows:

[0095] 20 mg of cocrystal 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 precipitated. The mixture was centrifuged to obtain the cocrystal C.

[0096] The method for preparing the above-mentioned single crystal comprises the following steps:

[0097] 1) Weigh a certain amount of cocrystal B into a vial, add solvent-9, seal with parafilm, and pierce a hole with a needle;

[0098] 2) Add water to the large bottle,

[0099] 3) Place the small bottle in a large bottle, seal it, and place it in a refrigerator at 0-5°C to obtain the above-mentioned single crystal.

[0100] In some embodiments of the present invention, solvent-9 is selected from methanol.

[0101] In some embodiments of the present invention, the amount of cocrystal B is 10 mg;

[0102] And / or, the amount of methanol used is 0.5 mL. Beneficial effects

[0103] The present invention provides co-crystals of a compound of formula (I) and fumaric acid, including co-crystal A, co-crystal B, co-crystal C, and single crystals. The co-crystals have good stability in different solvents and have good stability under high temperature, high humidity, light, and accelerated conditions.

[0104] Definition and Description

[0105] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications to which this invention pertains are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

[0106] "API" or "free state" refers to the free base form of the compound represented by formula (I).

[0107] "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 salts) and at least two of the components are solid at room temperature.

[0108] 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 compound of formula (I): fumaric acid of approximately 1:0.5; for example, 1:(0.4-0.6), 1:(0.45-0.55), 1:(0.48-0.51) or 1:0.5.

[0109] "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, and hydrates of salts of a compound. Crystalline forms of a substance can be obtained by a number of 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-crystallizing countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0110] "Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity, characterized by a diffuse, unsharp X-ray powder diffraction pattern. Amorphous is a special physical form of solid matter, and its locally ordered structure suggests that it is inextricably linked to crystalline forms. Amorphous forms of substances can be obtained by a variety of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques.

[0111] "Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0112] "Anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0113] "Solvate" refers to a crystal having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, wherein the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. A hydrate may or may not have other solvents other than water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice.

[0114] 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, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0115] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. According to the instrument conditions used in the test of the present invention, the diffraction peak has an error tolerance of ±0.2°.

[0116] Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The height of the melting peak of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in the test of the present invention, the melting peak has an error tolerance of ±3°C.

[0117] The glass transition, the transition between a highly elastic and glassy states, is an inherent property of amorphous materials. The corresponding transition temperature, the glass transition temperature (Tg), is a key physical property of amorphous materials. The glass transition is a phenomenon related to molecular motion. Therefore, the Tg depends primarily on the structure of the material and is relatively insensitive to experimental details. Due to the instrumentation used in the present test, the Tg has an error tolerance of ±3°C.

[0118] Differential scanning calorimetry (DSC) can also be used to detect and analyze whether there is crystal transformation or mixed crystal phenomenon.

[0119] Solids with the same chemical composition often form isomers, or variants, with different crystal structures under different thermodynamic conditions. This phenomenon is called polymorphism or polyphasic phenomenon. When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will undergo significant changes. When the temperature of the crystal transformation is within the measurable range, this transformation process can be observed on the differential scanning calorimetry (DSC) graph, which is characterized by having an exothermic peak reflecting this transformation process and two or more endothermic peaks, which are respectively characteristic endothermic peaks of the different crystal forms before and after the transformation. The crystalline form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.

[0120] Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or solvent in the crystals. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and samples. Based on the instrumentation used in the present test, the mass change has an error tolerance of ±0.3%.

[0121] The moisture adsorption / desorption isotherm (DVS) is a method that measures the adsorption and desorption behavior of water by measuring the weight change of a solid under various relative humidity conditions.

[0122] In the context of the present invention, the 2θ values ​​in the X-ray powder diffraction pattern are all in degrees (°).

[0123] When referring to a spectrum and / or data appearing in a graph, a "peak" refers to a feature that can be identified by one skilled in the art and is not attributable to background noise.

[0124] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or TGA results are shown in its pattern.

[0125] "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%.

[0126] "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%.

[0127] “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%.

[0128] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0129] 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

[0130] FIG1 is an ellipsoidal diagram of the three-dimensional structure of a single crystal of a eutectic according to an embodiment of the present invention;

[0131] FIG2 is a unit cell stacking projection diagram along the b-axis of a single crystal of a eutectic according to an embodiment of the present invention;

[0132] FIG3 is an XRPD diagram of the free state of the compound of formula (I) according to an embodiment of the present invention;

[0133] 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;

[0134] FIG5 is an NMR diagram of the free state of the compound of formula (I) according to an embodiment of the present invention;

[0135] FIG6 is an XRPD pattern of co-crystal A according to an embodiment of the present invention;

[0136] FIG7 is a DSC and TGA diagram of co-crystal A according to an embodiment of the present invention;

[0137] FIG8 is a comparison of NMR images of (a) and the free state of cocrystal A according to an embodiment of the present invention; (b) NMR image;

[0138] FIG9 is (a) a DVS curve of co-crystal A according to an embodiment of the present invention; (b) a comparison of XRPD images of the sample before and after the DVS test;

[0139] Figure 10 is an XRPD pattern of co-crystal B according to an embodiment of the present invention;

[0140] FIG11 is a DSC and TGA graph of co-crystal B according to an embodiment of the present invention;

[0141] FIG12 is a comparison of NMR images of (a) and the free state of cocrystal B according to an embodiment of the present invention; (b) NMR image;

[0142] FIG13 is (a) a DVS curve of co-crystal B according to an embodiment of the present invention; (b) a comparison of XRPD images of the sample before and after the DVS test;

[0143] FIG14 is an XRPD pattern of co-crystal C according to an embodiment of the present invention;

[0144] FIG15 is a DSC and TGA graph of co-crystal C according to an embodiment of the present invention;

[0145] FIG16 is a comparison of (a) NMR images of co-crystal C and co-crystal A according to an embodiment of the present invention; (b) NMR image;

[0146] FIG17 is an XRPD pattern of a stability study of co-crystal A according to an embodiment of the present invention;

[0147] FIG18 is an XRPD pattern of a stability study of co-crystal B according to an example of the present invention. DETAILED DESCRIPTION

[0148] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 encompassed within the scope of protection that the present invention is intended to protect.

[0149] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0150] General analytical methods:

[0151] 1. NMR analysis ( 1 H NMR)

[0152] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE NEO 400 (Bruker, Germany).

[0153] 2. X-ray powder diffraction (XRPD)

[0154] The solid samples obtained in the experiment were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, GER). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 seconds. The test method used Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[0155] 3. Thermogravimetric analysis (TGA)

[0156] The thermogravimetric analyzer (TA Discovery 550, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0157] 4. Differential Scanning Calorimetry (DSC)

[0158] The differential scanning calorimeter was a TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0159] 5. Dynamic moisture adsorption and desorption analysis (DVS)

[0160] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient mode with humidity changes from 0% to 95% to 0%, with each gradient increasing by 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per gradient. After the test, the sample was analyzed by XRPD to confirm any changes in the solid form.

[0161] 6. High Performance Liquid Chromatography (HPLC)

[0162] The HPLC model was Waters Acquity Arc (Waters, US), and the test conditions were shown in Table 8.

[0163] Table 8 HPLC test conditions

[0164] 7. Single crystal diffraction experiment

[0165] 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°.

[0166] Instrument: Single crystal X-ray diffractometer;

[0167] Model: D8 Venture

[0168] Manufacturer: Bruker

[0169] General test methods:

[0170] 1. Stability study

[0171] About 15 mg of sample was weighed and placed in a weighing bottle, which was then placed under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated conditions (40°C / 75% RH). Samples were taken on the 7th and 15th days for XRPD characterization and HPLC testing.

[0172] 2. Biological media and water solubility test

[0173] The preparation process of the biological medium is shown in the table. Samples of different crystalline forms were added to the biological medium and water and shaken at 37°C for 24 hours. Samples were taken at 0.5, 2, and 24 hours. The sampled solutions were filtered through a 0.22 μm water filter. Some samples with higher concentrations were appropriately diluted with diluent. 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-form material, and the dilution factor. In addition, the pH value of the supernatant after 24 hours was measured, and the remaining solid was analyzed by XRPD.

[0174] Table 9 Preparation process of biological medium

[0175] DETAILED DESCRIPTION

[0176] The starting materials of the free form of the compound of formula (I) used in the following examples can be prepared according to existing techniques. 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.

[0177] The XRPD results (Figure 3) of the free form of the compound of formula (I) show that it is a well-crystalline solid. TGA results (Figure 4) show that the free form loses 0.8% weight upon heating to 150°C, and decomposition may occur above 300°C. DSC results (Figure 4) show that the free form exhibits an endothermic signal at approximately 94°C and a melting endothermic peak at approximately 150°C. NMR results (Figure 5) show no obvious residual organic solvent signal peaks, and these NMR results are provided as a reference for subsequent comparisons.

[0178] Example 1 Preparation Example 1 of Fumaric Acid Cocrystal A of Compound of Formula (I)

[0179] 5.000 g of the 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). After stirring at 50°C for 2 hours, 975.0 mg of fumaric acid was added, and stirring was continued for 1 hour. The mixture was filtered and then dried in vacuo at room temperature for 1 day to obtain 4.769 g of fumaric acid cocrystal A of the compound of formula (I).

[0180] Example 2 Preparation Example 2 of Fumaric Acid Cocrystal A of Compound of Formula (I)

[0181] 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 5.409 g of fumaric acid cocrystal 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 4.012 g of fumaric acid cocrystal A of the compound of formula (I).

[0182] XRPD results (Figure 6) show that cocrystal A is a well-crystalline solid. TGA results (Figure 7) show that cocrystal A shows little weight loss upon heating to 150°C, but decomposition may occur above 225°C. DSC results (Figure 7) reveal a melting endotherm at 170°C for cocrystal A. NMR results (Figure 8) show that the integration of the peaks corresponding to the free form of this sample is consistent with that of the API. The active hydrogen of fumaric acid is visible at around 13.1 ppm, and a characteristic fumaric acid peak is observed at around 6.6 ppm. The integrated values ​​indicate that the molar ratio of API to fumaric acid is approximately 1:0.5. No significant residual organic solvent peaks are observed. DVS results (Figure 9) show that cocrystal A gained 0.03% weight at 80% RH, 0.05% weight at 95% RH, and 0.03% weight at 0% RH during adsorption, indicating that cocrystal A is non-hygroscopic. The XRPD pattern of cocrystal A showed no significant changes after DVS analysis. In summary, eutectic A is an anhydrous crystalline form and has no hygroscopicity.

[0183] Example 3 Preparation Example 1 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0184] 4.769 g of the fumaric acid cocrystal A of the compound of formula (I) prepared in either 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 the fumaric acid cocrystal B of the compound of formula (I).

[0185] XRPD results (Figure 10) show that cocrystal B is a well-crystalline solid. TGA results (Figure 11) show that cocrystal B shows little weight loss upon heating to 150°C, but decomposition may occur above 225°C. DSC results (Figure 11) reveal a melting endotherm at 169°C for cocrystal B. NMR results (Figure 12) show that the integration of the peaks corresponding to the free form of this sample is consistent with that of the API. The active hydrogen of fumaric acid is visible around 13.1 ppm, and a characteristic fumaric acid signal peak is observed around 6.6 ppm. The integrated values ​​indicate that the molar ratio of API to fumaric acid is approximately 1:0.5. No significant residual organic solvent signal peaks are observed. DVS results (Figure 13) show that cocrystal B gained 0.02% weight at 80% RH, 0.05% weight at 95% RH, and 0.01% weight at 0% RH during adsorption, indicating that cocrystal B is non-hygroscopic. The XRPD pattern of cocrystal B showed no significant changes after DVS analysis. In summary, eutectic B is an anhydrous crystalline form and has no hygroscopicity.

[0186] Example 4 Preparation of Fumaric Acid Cocrystal C of Compound of Formula (I)

[0187] 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, and gradually add tetrahydrofuran dropwise 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 sufficient solid precipitates, continue stirring at room temperature for 2 days. The system with still insufficient solid precipitation is placed in a 4°C or -15°C refrigerator. After cooling, the system with insufficient solid precipitation is left to evaporate in the open air at room temperature. During the experiment, except for the volatilization experiment, the system with sufficient solid precipitation was centrifuged, and the solid was vacuum-dried at room temperature to obtain the fumaric acid cocrystal C of the compound of formula (I).

[0188] XRPD results (Figure 14) indicate that cocrystal C is a well-crystalline solid. TGA results (Figure 15) show that cocrystal C loses 0.1% weight upon heating to 150°C, and decomposition may occur above 225°C. DSC results (Figure 15) reveal endothermic and exothermic signals at 162°C and 164°C, with a melting endothermic peak at approximately 170°C. NMR results (Figure 16) show that the NMR peak shifts for this sample are consistent with those of cocrystal A. The integration of the corresponding free phase peaks is consistent with the API, with the active hydrogen of fumaric acid visible around 13.1 ppm and a characteristic fumaric acid peak around 6.6 ppm. The integrated values ​​indicate that the molar ratio of API to fumaric acid is approximately 1:0.5. No significant residual organic solvent peaks are observed. In summary, cocrystal C is an anhydrous crystalline form.

[0189] Example 5 Solubility Stability Test

[0190] 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 in ethanol, 2-methyltetrahydrofuran and acetone were stable at 55 and 75 °C for 24 h.

[0191] Table 10

[0192] The results of the solution stability study of cocrystal A in different solvents at 55 and 75°C are shown in Table 11. Solutions of cocrystal A in ethanol, n-propanol, isopropanol, acetone, and tetrahydrofuran remained stable at 55°C for at least 24 hours. Solutions of cocrystal A in ethanol, n-propanol, and isopropanol remained stable at 75°C for at least 24 hours.

[0193] Table 11

[0194] The results of the solution stability study of cocrystal B in different solvents at 55 and 75°C are shown in Table 12. Solutions of cocrystal B in ethanol, 2-methyltetrahydrofuran, and acetone remained stable at 55 and 75°C for at least 24 h.

[0195] Table 12

[0196] Example 6 Stability Study

[0197] Stability studies were conducted on fumaric acid cocrystals A and B of the compound of formula (I) under conditions of high temperature (60°C), high humidity (25°C / 92.5% RH), illumination (25°C / 4500 Lux), and accelerated storage (40°C / 75% RH). Samples were taken for HPLC analysis and XRPD characterization after 7 and 15 days, respectively. The results are shown in Tables 13 to 15, Figures 17, and 18. XRPD results showed that cocrystals A and B were stable under the conditions of high temperature, high humidity, illumination, and accelerated storage for 7 and 15 days, with no crystal transformation and no significant change in appearance. HPLC results showed that the chemical purity of cocrystals A and B remained unchanged after 7 and 15 days under the above conditions.

[0198] Table 13 Stability study results

[0199] Table 14 HPLC purity analysis results of cocrystal A stability samples

[0200] Table 15 HPLC purity analysis results of cocrystal B stability samples

[0201] Example 7 Preparation Example 2 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0202] 10g free state was dissolved in 6.5V n-propanol at 50-60°C, 1.1eq. fumaric acid was dissolved in 8V n-propanol at 50-60°C, maintained 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% seed crystals were 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 stirring was continued at 50-60°C for 20h. 14.5V of n-heptane was added dropwise over 4h, and the mixture was stirred at 50-60°C for 5h. The mixture was cooled to 0-10°C for 5h, and stirring was continued for 18h. The mixture was filtered, and the NMR analysis showed that the free state: fumaric acid = 1:0.48 to give 9.7g of solid, content: 87.6%, purity: 99.1%, yield: 85.0%, and mother liquor loss was 2.7%.

[0203] Example 8 Preparation Example 3 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0204] 10g of the free state was dissolved in 5V ethanol at 50-60°C, 1.1eq. of fumaric acid was dissolved in 6V ethanol at 50-60°C, and the mixture was kept at 50-60°C. 0.25eq. of fumaric acid in ethanol was added to the free state ethanol solution, 0.7% seed crystals were added, and the mixture was stirred at 50-60°C for 20h. 0.85eq. of fumaric acid in ethanol was added dropwise to the free state ethanol solution, and the mixture was continued to be stirred at 50-60°C for 20h. 11V 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 stirred for 18h. The mixture was filtered, and the NMR analysis showed that the free state: fumaric acid = 1:0.48 to give 10.3g of solid, content: 88.3%, purity: 99.1%, yield: 91.0%, and mother liquor loss of 3.7%.

[0205] Example 9 Preparation Example 4 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0206] 20g of the free state was dissolved in 5V ethanol at 50-60°C, 0.277eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60°C, maintained at 50-60°C, and added to the ethanol solution of the free state, 0.5% seed crystals were added, and the mixture was stirred at 50-60°C for 2h. 0.277eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60°C, maintained at 50-60°C, and added to the ethanol solution of the free state, and the mixture was stirred at 50-60°C for 18h. 16V of n-heptane was added dropwise over 4h, and the mixture was stirred at 50-60°C for 5h. The mixture was cooled to 0-10°C for 5h, and stirred for 10h. The mixture was filtered, and the wet product had a free state: fumaric acid NMR ratio of 1:0.5. After drying, 19.5g of the product was obtained, and the crude yield was 86.6%.

[0207] Example 10 Preparation Example 5 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0208] 106.1g of the free state was dissolved in 5.1V ethanol at 50-60°C, 0.277eq. of fumaric acid was dissolved in 1.8V ethanol (1.5V dissolved, 0.3V rinsed pipe) at 50-60°C, maintained at 50-60°C, added to the ethanol solution of the free state, seed crystals were added, and stirred at 50-60°C for 4h. 0.277eq. of fumaric acid was dissolved in 1.8V ethanol at 50-60°C, maintained at 50-60°C, added to the ethanol solution of the free state, and stirred at 50-60°C for 3h. 9.9V of n-heptane was added dropwise for 8h, stirred at 50-60°C for 8h, cooled to 0-10°C for 4h, and continued to stir for 3h. The product was filtered, and the wet product had a free state NMR of fumaric acid = 1:0.49. After drying, 107g of the product was obtained with a yield of 88.4%.

[0209] Example 11 Preparation Example 6 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0210] 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℃, and the mixture was added to the ethanol solution of the free state at 50-60℃. Solids precipitated as mixed crystals of eutectic A and eutectic B. Seed crystals of eutectic B were added, and the mixture was stirred at 50-60℃ for 1 hour. Samples were taken, and the measured results were mixed crystals of eutectic A and eutectic B. Stirring was continued at 50-60℃ for 18h. The sample was hot filtered and the crystal form was eutectic. For body B, 0.287 eq. of fumaric acid was dissolved in 1.5V ethanol at 50-60°C, maintained at 50-60°C, and added to the free ethanol solution for 3 hours, maintained at 50-60°C and stirred for 3 hours, 10.5V n-heptane was added dropwise for 8 hours, stirred at 50-60°C for 8 hours, cooled to 0-10°C for 3 hours, and stirred for 4 hours. The wet product had the correct XRPD crystal form, and 1.96 kg of product was obtained after sieving, with a content of 87.5% and a yield of 89.8%.

[0211] Example 12 Preparation Example 7 of Fumaric Acid Cocrystal B of Compound of Formula (I)

[0212] 10 g of free form II was dissolved in 5.5 V ethanol at 45-55°C, 0.277 eq. of fumaric acid was dissolved in 1.5 V EtOH at 45-55°C, maintained at 45-55°C, and added to the ethanol solution of free form II. 1% seed crystals were added, and the mixture was stirred at 45-55°C for 2 h. 0.277 eq. of fumaric acid was dissolved in 1.5 V EtOH at 45-55°C, maintained at 45-55°C, and added to the ethanol solution of free form II for 1 h. The mixture was stirred at 50-60°C for 18 h. 10 V of n-heptane was added dropwise over 3 h, and the mixture was stirred at 45-55°C for 1 h. The temperature was lowered to 0-10°C after 1 h, and stirring was continued for 2 h. The mixture was filtered, and XRPD of the wet product showed the correct crystal form.

[0213] The free form 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.

[0214] Example 13 Preparation of Fumaric Acid Cocrystal Single Crystal of Compound of Formula (I)

[0215] 1. Weigh approximately 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;

[0216] 2. Add about 4 ml of water to the 20 ml bottle;

[0217] 3. Place the small bottle in a large bottle, seal it, and place it in a refrigerator at 0-5°C.

[0218] 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.

[0219] The single crystal has a three-dimensional structural ellipsoid diagram as shown in FIG1 , and a unit cell stacking projection diagram along the b-axis direction as shown in FIG2 .

[0220] The atomic coordinates and isotropic temperature factors 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.

[0221] Example 14 Pharmacokinetic Experiment

[0222] The vehicle was 0.5% MC. Beagle dogs were fasted overnight and fed 4 hours after dosing. N = 4 dogs. Weigh before dosing, and the dose was calculated based on body weight. Doses were 10 mg / kg and 30 mg / kg; the dosing volume was 5 mL / kg. Blood was collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24, 48, and 72 hours after dosing.

[0223] Blood samples were collected from the forelimb vein, approximately 1 mL per sample, anticoagulated with sodium heparin, placed on ice, and centrifuged within 1 hour to separate plasma (2200 g, 10 minutes, 2-8°C). Plasma samples were stored at -80°C until analysis.

[0224] · LC-MS / MS was used to determine the concentration of the target analyte in beagle dog plasma. The pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 based on the plasma concentration data at different time points, providing the AUC 0-t , AUC 0-∞ 、C max 、T max , and T 1 / 2 Parameters and their means and standard deviations.

[0225] The results of the pharmacokinetic experiments showed that the fumaric acid cocrystal B of the compound of formula (I) had excellent pharmacokinetic properties.

[0226] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean 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 can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0227] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A co-crystal of a compound of formula (I) and fumaric acid, characterized in that: The co-crystal is formed by non-covalent bonding of the compound of formula (I) and fumaric acid in a molar ratio of 1:(0.4-0.6); 2. The eutectic substance 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.

3. The eutectic substance 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 .

4. The eutectic substance 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.

5. The eutectic substance according to claim 1, characterized in that The eutectic 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 .

6. 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 single crystal.

7. 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.

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 for treating and / or preventing and / or alleviating and / or relieving a disease, wherein the disease is preferably pain or cough.

9. 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 cardiac arrhythmia.

10. A method for preparing a 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.

Images