A compound in solid form, its preparation method and uses

Abstract

This invention provides a solid form of a compound, its preparation method, and its uses, belonging to the field of medicinal chemistry. The solid form includes a cocrystal of the compound with cinnamamide, or a cocrystal with p-toluenesulfonic acid; or a tromethamine salt of the compound. The solid form of the compound exhibits good stability and solubility.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to Chinese application CN202011599361.4, filed with the China National Intellectual Property Administration on December 29, 2021, which is incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry, specifically relating to the solid form of a compound, its preparation method, and its uses. Background Technology

[0004] Lanifibranor (the compound shown in Formula I) is a small molecule agonist of panperoxisome proliferator-activated receptor (PanPPAR), primarily used to treat NASH (non-alcoholic fatty liver disease).

[0005] Compounds can exist in one or more crystalline forms. Crystalline forms can also exhibit different levels of stability, solubility, dissolution rate, and bioavailability. Drug solubility is one of many factors affecting drug absorption; drugs need suitable solubility in aqueous media to demonstrate optimal bioavailability and therapeutic effect. Typically, during drug product development, the most stable crystalline form of a drug product is selected based on the minimum probability of its conversion to another crystalline form and its higher chemical stability. To ensure the quality, safety, and efficacy of drug products, it is important to select crystalline forms that are stable, reproducible, and possess favorable physicochemical properties.

[0006] Currently, there is no existing technology that discloses the salt form or eutectic of Lanifibranor, and Lanifibranor is almost insoluble in water.

[0007] Therefore, in order to ensure the quality, safety and efficacy of pharmaceutical products, it is necessary to develop a solid form of Lanifibranor that is low in toxicity, stable and highly soluble. Summary of the Invention Invention Overview

[0009] The first objective of this invention is to provide a solid form comprising a eutectic or salt form of the compound shown in Formula I. The eutectic includes a eutectic selected from the compound shown in Formula I and cinnamamide, or a eutectic selected from the compound shown in Formula I and p-toluenesulfonic acid. The salt form may include an aminobutadiene triol salt of the compound shown in Formula I. The technical problem to be solved is to provide a solid form of Lanifibranor with good crystal stability and high solubility.

[0010]

[0011] A second objective of this invention is to provide a method for preparing the aforementioned solid form. This preparation method is simple to operate and has good reproducibility.

[0012] A third object of the present invention is to provide a pharmaceutical composition comprising the aforementioned solid form.

[0013] A fourth object of the present invention is to provide use of the aforementioned solid form or the aforementioned pharmaceutical composition. The aforementioned solid form or the aforementioned pharmaceutical composition has use in the preparation of a medicament for treating non-alcoholic fatty liver disease. Invention Details

[0015] To address the aforementioned problems, in a first aspect, the present invention provides a solid form.

[0016] A solid form comprising the eutectic or salt form of the compound shown in Formula I.

[0017]

[0018] The cocrystal includes a cocrystal of the compound shown in Formula I with cinnamamide, or a cocrystal of the compound shown in Formula I with p-toluenesulfonic acid.

[0019] The salt type may include the tromethamine salt of the compound shown in Formula I.

[0020] In the co-crystal of the compound shown in Formula I and cinnamamide, the molar ratio of the compound shown in Formula I to cinnamamide can be 1:1.

[0021] In the eutectic of the compound shown in Formula I and p-toluenesulfonic acid, the molar ratio of the compound shown in Formula I to p-toluenesulfonic acid can be 1:1.

[0022] In the tromethamine salt of the compound shown in Formula I, the molar ratio of the compound shown in Formula I to tromethamine can be 1:1.

[0023] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the cocrystal of the aforementioned compound of formula I and cinnamamide showed characteristic peaks at 2θ of 10.6±0.2°, 19.2±0.2°, 19.7±0.2°, 21.4±0.2°, 25.4±0.2°, 29.1±0.2° and 30.8±0.2°. In some embodiments, the powder X-ray diffraction pattern of the cocrystal of the compound of Formula I and cinnamamide has characteristic peaks at 2θ of 7.2±0.2°, 8.2±0.2°, 10.6±0.2°, 18.5±0.2°, 18.9±0.2°, 19.2±0.2°, 19.7±0.2°, 20.0±0.2°, 21.4±0.2°, 21.7±0.2°, 22.1±0.2°, 22.8±0.2°, 25.4±0.2°, 26.4±0.2°, 28.2±0.2°, 28.7±0.2°, 29.1±0.2°, and 30.8±0.2°. In some embodiments, the powder X-ray diffraction patterns of the cocrystal of the aforementioned compound of Formula I with cinnamamide show 2θ values ​​of 7.2±0.2°, 8.2±0.2°, 9.9±0.2°, 10.3±0.2°, 10.6±0.2°, 14.4±0.2°, 18.0±0.2°, 18.5±0.2°, 18.9±0.2°, 19.2±0.2°, 19.7±0.2°, 20.0±0.2°, 20.7±0.2°, and 21.4°. Characteristic peaks are observed at ±0.2°, 21.7±0.2°, 22.1±0.2°, 22.4±0.2°, 22.8±0.2°, 24.6±0.2°, 25.4±0.2°, 26.4±0.2°, 27.2±0.2°, 28.0±0.2°, 28.2±0.2°, 28.7±0.2°, 29.1±0.2°, 30.8±0.2°, 31.7±0.2°, 33.3±0.2°, and 36.1±0.2°.

[0024] The differential scanning calorimetry (DSC) spectrum of the cocrystal of the compound shown in Formula I and cinnamamide shows an endothermic peak at 152℃-158℃.

[0025] The thermogravimetric analysis (TGA) spectrum of the cocrystallization of the compound shown in Formula I with cinnamamide shows a weight loss of less than 0.50% in the temperature range of 30℃ to 120℃.

[0026] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the cocrystal of the aforementioned compound of formula I and p-toluenesulfonic acid exhibits characteristic peaks at 2θ of 7.9±0.2°, 11.8±0.2°, 16.4±0.2°, 19.3±0.2°, 19.5±0.2°, 20.6±0.2°, 21.8±0.2°, 23.6±0.2°, 25.0±0.2°, and 31.5±0.2°; or the X-ray powder diffraction pattern of the cocrystal of the aforementioned compound of formula I and p-toluenesulfonic acid exhibits characteristic peaks at 2θ of 6.2±0.2°. °, 7.9±0.2°, 11.8±0.2°, 12.3±0.2°, 12.5±0.2°, 15.8±0.2°, 16.4±0.2°, 19.3±0.2°, 19.5±0.2°, 20.6±0.2°, 21.8±0.2°, 23.3±0.2°, 23.6±0.2°, 25.0±0.2°, 25.5±0.2°, 26.4±0.2°, 27.4±0.2°, 27.7±0.2°, 31.5±0.2°, 32.9±0.2°, 3 Characteristic peaks are observed at 5.6±0.2° and 35.9±0.2°; or, in the X-ray powder diffraction pattern of the cocrystal of the compound shown in Formula I with p-toluenesulfonic acid, characteristic peaks are observed at 2θ of 6.2±0.2°, 7.9±0.2°, 10.3±0.2°, 11.8±0.2°, 12.3±0.2°, 12.5±0.2°, 15.4±0.2°, 15.8±0.2°, 16.4±0.2°, 18.8±0.2°, 19.3±0.2°, 19.5±0.2°, 20.6±0.2°, 21. Characteristic peaks are present at 8±0.2°, 23.3±0.2°, 23.6±0.2°, 24.6±0.2°, 25.0±0.2°, 25.5±0.2°, 26.4±0.2°, 26.8±0.2°, 27.4±0.2°, 27.7±0.2°, 29.0±0.2°, 29.3±0.2°, 30.4±0.2°, 31.5±0.2°, 32.9±0.2°, 34.7±0.2°, 35.6±0.2°, 35.9±0.2°, and 37.2±0.2°.

[0027] The differential scanning calorimetry (DSC) spectrum of the eutectic of the compound shown in Formula I and p-toluenesulfonic acid shows an endothermic peak at 166℃-172℃.

[0028] In the thermogravimetric analysis (TGA) spectrum of the cocrystal of the compound of Formula I and p-toluenesulfonic acid, the weight loss is less than 0.50% in the range of 30°C to 120°C. In some embodiments, in the TGA spectrum of the cocrystal of the compound of Formula I and p-toluenesulfonic acid, the weight loss is less than 0.30% in the range of 30°C to 120°C.

[0029] Using Cu-Kα radiation, the X-ray powder diffraction patterns of the tromethamine salts of the aforementioned compound of formula I show characteristic peaks at 2θ of 11.1±0.2°, 16.2±0.2°, 17.6±0.2°, 19.6±0.2°, 21.1±0.2°, 21.7±0.2°, 22.4±0.2°, and 24.8±±0.2°; or the X-ray powder diffraction patterns of the tromethamine salts of the aforementioned compound of formula I show characteristic peaks at 2θ of 9.8±0.2°, 11.1±0.2°, and 24.8±±0.2°. 12.6±0.2°, 16.2±0.2°, 16.5±0.2°, 17.2±0.2°, 17.6±0.2°, 18.6±0.2°, 19.0±0.2°, 19.6±0.2°, 21.1±0.2°, 21.7±0.2°, 22.4±0.2°, 23.3±0.2°, 23.6±0.2°, 24.8±0.2°, 25.8±0.2°, 26.2±0.2°, 26.4±0.2°, 26.8±0.2° and 3 A characteristic peak is present at 0.5±0.2°; or, in the X-ray powder diffraction pattern of the tromethamine salt of the compound shown in Formula I, a characteristic peak is present at 2θ of 7.4±0.2°, 9.8±0.2°, 11.1±0.2°, 12.6±0.2°, 12.9±0.2°, 14.3±0.2°, 15.1±0.2°, 16.2±0.2°, 16.5±0.2°, 17.2±0.2°, 17.6±0.2°, 18.6±0.2°, 19.0±0.2°, 19.6±0.2°. Characteristic peaks are present at 0.2°, 21.1±0.2°, 21.7±0.2°, 22.4±0.2°, 23.3±0.2°, 23.6±0.2°, 24.0±0.2°, 24.8±0.2°, 25.6±0.2°, 25.8±0.2°, 26.2±0.2°, 26.4±0.2°, 26.8±0.2°, 27.7±0.2°, 30.5±0.2°, 32.1±0.2°, 33.6±0.2°, and 35.5±0.2°.

[0030] The differential scanning calorimetry (DSC) spectrum of the aminobutadiene triol salt of the compound shown in Formula I has an endothermic peak at 146℃-152℃.

[0031] The thermogravimetric analysis (TGA) spectrum of the aminobutyrate salt of the compound shown in Formula I shows a weight loss of less than 0.50% in the range of 30–120 °C.

[0032] Secondly, the present invention provides a method for preparing the aforementioned solid form.

[0033] In some embodiments of the present invention, a method for preparing the aforementioned solid form includes: dissolving the compound shown in Formula I, along with cinnamamide, p-toluenesulfonic acid, or tromethamine, in an organic solvent; cooling to precipitate crystals; filtering; and drying to obtain the solid form. The organic solvent includes at least one selected from 1,4-dioxane, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, ethanol, acetone, butanone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether. In some preferred embodiments, the organic solvent is selected from at least one selected from ethanol, acetone, dimethyl carbonate, 1,4-dioxane, and ethyl acetate. In some embodiments, the organic solvent is a mixture of ethanol and acetone.

[0034] In some embodiments of the present invention, a method for preparing the aforementioned solid form includes: dissolving the compound shown in Formula I, and cinnamamide, p-toluenesulfonic acid, or tromethamine in a good solvent, then adding an antisolvent to precipitate crystals, filtering, and drying to obtain the solid form. The good solvent includes at least one selected from 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, acetone, butanone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether. The antisolvent includes at least one selected from trifluoroethanol, n-heptane, n-hexane, cyclohexane, and isopropyl ether. In some preferred embodiments, the good solvent is at least one selected from 1,4-dioxane, dimethyl carbonate, ethanol, and acetone. In some embodiments, the good solvent is a mixture of dimethyl carbonate and ethanol. In some embodiments, the good solvent is acetone. In some embodiments, the good solvent is a mixture of acetone and ethanol. In some preferred embodiments, the antisolvent is selected from at least one of trifluoroethanol, isopropyl ether, and n-heptane.

[0035] Filtration, drying, filtration, drying, filtration, drying. In some embodiments of the present invention, a method for preparing the aforementioned solid form includes: dissolving the compound shown in Formula I, and cinnamamide, p-toluenesulfonic acid, or tromethamine in an organic solvent, evaporating, and obtaining the solid form. The organic solvent includes at least one selected from 1,4-dioxane, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, acetone, butanone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether. In some preferred embodiments, the organic solvent is selected from at least one selected from dimethyl carbonate, 1,4-dioxane, and ethyl acetate.

[0036] The molar ratio of the compound shown in Formula I to cinnamamide can be 1:1 to 1:2.

[0037] The molar ratio of the compound shown in Formula I to p-toluenesulfonic acid can be 1:1 to 1:2.

[0038] The molar ratio of the compound shown in Formula I to tromethamine can be 1:1 to 1:2.

[0039] For each gram of the compound represented by Formula I, the amount of organic solvent used can be 1 ml-200 ml, or 1 ml-150 ml, or 1 ml-100 ml, or 1 ml-50 ml, or 1 ml-30 ml, or 1 ml-10 ml. In some embodiments, for each gram of the compound represented by Formula I, the amount of organic solvent used can be 5 ml-200 ml, or 5 ml-100 ml, or 5 ml-50 ml, or 5 ml-30 ml. In some embodiments, for each gram of the compound represented by Formula I, the amount of organic solvent used can be 1 ml, 3 ml, 5 ml, 8 ml, 10 ml, 15 ml, 20 ml, 25 ml, 40 ml, 60 ml, 80 ml, or 120 ml.

[0040] For each gram of the compound represented by Formula I, the amount of the good solvent may be 1 ml-200 ml, or 1 ml-150 ml, or 1 ml-100 ml, or 1 ml-50 ml, or 1 ml-30 ml, or 1 ml-10 ml. In some embodiments, for each gram of the compound represented by Formula I, the amount of the good solvent may be 5 ml-200 ml, or 5 ml-100 ml, or 5 ml-50 ml, or 5 ml-30 ml. In some embodiments, for each gram of the compound represented by Formula I, the amount of the good solvent may be 1 ml, 3 ml, 5 ml, 8 ml, 10 ml, 15 ml, 20 ml, 25 ml, 40 ml, 60 ml, 80 ml, or 120 ml.

[0041] For each gram of the compound represented by Formula I, the amount of the antisolvent can be 1 ml-300 ml, or 1 ml-200 ml, or 1 ml-150 ml, or 1 ml-100 ml, or 1 ml-50 ml, or 1 ml-30 ml, or 1 ml-10 ml. In some embodiments, for each gram of the compound represented by Formula I, the amount of the antisolvent can be 5 ml-300 ml, or 5 ml-200 ml, or 5 ml-100 ml, or 5 ml-50 ml, or 5 ml-30 ml. In some embodiments, for each gram of the compound represented by Formula I, the amount of the antisolvent can be 1 ml, 3 ml, 5 ml, 8 ml, 10 ml, 15 ml, 20 ml, 25 ml, 40 ml, 60 ml, 80 ml, 120 ml, 140 ml, 160 ml, 180 ml, 230 ml, 250 ml, or 280 ml.

[0042] The dissolution temperature in the organic solvent can be 20℃-70℃. In some embodiments, the dissolution temperature in the organic solvent is 40℃-60℃. In some embodiments, the dissolution temperature in the organic solvent is 30℃, 40℃, 50℃, 55℃, or 60℃.

[0043] The cooling can be to -10°C to 10°C. In some embodiments, the cooling is to -5°C to 5°C. In some embodiments, the cooling is to -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C.

[0044] The dissolution temperature in the good solvent can be 20℃-70℃. In some embodiments, the dissolution temperature in the good solvent is 40℃-60℃. In some embodiments, the dissolution temperature in the good solvent is 30℃, 40℃, 50℃, 55℃, or 60℃.

[0045] In the preparation method, heating of the system composed of the good solvent can be stopped before the step of adding the antisolvent; or during the step of adding the antisolvent to precipitate crystals, the system composed of the good solvent and the added antisolvent can be maintained at a temperature of 20℃-70℃ or 30℃, 40℃, 50℃, 55℃ or 60℃.

[0046] In the preparation method, in the process of adding an antisolvent to precipitate crystals, after the crystals precipitate and before filtration, the crystallization system can be cooled to room temperature before filtration.

[0047] Thirdly, the present invention provides a pharmaceutical composition.

[0048] A pharmaceutical composition comprising the aforementioned solid form and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises, based on the total weight of the composition, at least 0.5% to 10% of a cocrystal of the aforementioned compound of Formula I with cinnamamide or a tromethamine salt of the compound of Formula I. In some embodiments, based on the mass of the compound of Formula I, the cocrystal of the compound of Formula I with cinnamamide or the tromethamine salt of the compound of Formula I comprises at least 90%, at least 95%, or at least 97% of the compound of Formula I. In some embodiments, based on the mass of the compound of Formula I, the cocrystal of the compound of Formula I with cinnamamide or the tromethamine salt of the compound of Formula I comprises at least 0.5%, at least 5%, or at least 10% of the compound of Formula I.

[0049] Fourthly, the present invention provides the use of the aforementioned solid form or the aforementioned pharmaceutical composition.

[0050] Use of the aforementioned solid form or the aforementioned pharmaceutical composition in the preparation of a medicament for treating non-alcoholic fatty liver disease.

[0051] Beneficial effects

[0052] Compared with the prior art, one embodiment of the above technical solution has at least one of the following technical effects:

[0053] (1) The cocrystal of the compound shown in Formula I with cinnamamide did not undergo any change in crystal form under various influencing conditions, demonstrating good stability. The cocrystal of the compound shown in Formula I with p-toluenesulfonic acid and the tromethamine salt of the compound shown in Formula I were also stable under high temperature, light, and high temperature and high humidity conditions.

[0054] (2) The tromethamine salt of the compound shown in Formula I and the cocrystal of the compound shown in Formula I with cinnamonamide both have good solubility, which is beneficial to improving the bioavailability of the drug.

[0055] (3) The cocrystal of the compound shown in Formula I and cinnamamide has good solubility in a pH 6.8 buffer aqueous solution, which has unexpected technical effects.

[0056] (4) The aminobutane triol salt of the compound shown in Formula I has good crystal stability and good solubility in pH 6.8 buffer aqueous solution, which has unexpected technical effects.

[0057] (5) The compound shown in Formula I can form a eutectic with cinnamamide or p-toluenesulfonic acid. The compound shown in Formula I can form a salt form with tromethamine.

[0058] The compound shown cannot form eutectic or salt forms with most other ligands except for cinnamamide, p-toluenesulfonic acid, and tromethamine. Attached Figure Description

[0059] Figure 1 XRD pattern of the cocrystal of the compound shown in Formula I with cinnamamide.

[0060] Figure 2 DSC spectrum of the cocrystal of the compound shown in Formula I with cinnamamide.

[0061] Figure 3 TGA spectrum of the cocrystal of the compound shown in Formula I with cinnamamide.

[0062] Figure 4 XRD pattern of the cocrystal of the compound shown in Formula I with p-toluenesulfonic acid.

[0063] Figure 5DSC spectrum of the cocrystal of the compound shown in Formula I with p-toluenesulfonic acid.

[0064] Figure 6 TGA spectrum of the cocrystal of the compound shown in Formula I with p-toluenesulfonic acid.

[0065] Figure 7 XRD pattern of the aminobutadiene triol salt of the compound shown in Formula I.

[0066] Figure 8 DSC spectrum of the aminobutadiene triol salt of the compound shown in Formula I.

[0067] Figure 9 TGA spectrum of the aminobutadiene triol salt of the compound shown in Formula I.

[0068] Figure 10 The XRD pattern of crystal form A of the compound shown in Formula I.

[0069] Figure 11 The DSC spectrum of crystal form A of the compound shown in Formula I.

[0070] Figure 12 TGA spectrum of crystal form A of compound shown in Formula I.

[0071] Figure 13 The amorphous XRD pattern of the compound shown in Formula I.

[0072] Terminology Explanation

[0073] This invention is intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials described herein can be used to practice this invention. This invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0074] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0075] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0076] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS version of the periodic table and the 75th edition of the *Handbook of Chemistry and Physics*, 1994. Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0077] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0078] The term "eutectic" or "eutectic" refers to a substance composed of two or more phases; a phase refers to a substance that has the same composition, crystal structure, and properties.

[0079] The term "XRD pattern" refers to an X-ray powder diffraction pattern.

[0080] The term "substantially as shown" means that a substantially pure "crystal form" has 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 its peaks appearing in the given X-ray powder diffraction pattern. As the content of a certain crystal form in a sample gradually decreases, some diffraction peaks attributable to that crystal form in its X-ray powder diffraction pattern may decrease due to factors such as the instrument's detection sensitivity.

[0081] The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak in a set of diffraction peaks belonging to a certain crystal form, when the intensity of the first strongest peak is defined as 100%.

[0082] In the context of this invention, the diffraction angle 2θ (also known as 2theta or diffraction peak) values ​​in X-ray powder diffraction patterns are all expressed in degrees (°).

[0083] When referring to spectra and / or data in figures, the term "diffraction peak" refers to a feature that a person skilled in the art would not attribute to background noise.

[0084] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between different machines and between different samples. The experimental error or difference may be + / - 0.2 units, + / - 0.1 units, or + / - 0.05 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0085] The differential scanning calorimetry (DSC) curve of the crystal has experimental errors. The position and peak value of the endothermic peak may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

[0086] The thermogravimetric analysis (TGA) curves of the crystals are subject to experimental error. The endothermic curves or weight loss rates may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 0.004%, 0.003%, 0.002%, or 0.001%. Therefore, the thermogravimetric analysis curves or their weight loss rates cannot be considered absolute.

[0087] In the context of this invention, all figures disclosed herein are approximate values, regardless of whether the words "approximately" or "about" are used. The value of each figure may vary by + / -1%, + / -2%, or + / -5%, etc. When "approximately" is used to describe the 2θ (also known as 2theta or diffraction peak) value of an X-ray powder diffraction peak, "approximately" means that the 2θ value may vary by + / -0.2 units, + / -0.1 units, or + / -0.05 units.

[0088] The term "room temperature" refers to a temperature of approximately 20°C-35°C, approximately 23°C-28°C, or approximately 25°C.

[0089] The term "good solvent" can refer to a single solvent or a mixture of solvents, meaning that the sample's solubility in that single solvent or mixture of solvents is greater than 1 g / L, or greater than 2 g / L, or greater than 3 g / L, or greater than 4 g / L, or greater than 5 g / L, or greater than 6 g / L, or greater than 7 g / L, or greater than 8 g / L, or greater than 9 g / L, or greater than 10 g / L, or greater than 15 g / L, or greater than 20 g / L, or greater than 30 g / L, or greater than 40 g / L, or greater than 50 g / L, or greater than 60 g / L, or greater than 70 g / L, or greater than 80 g / L, or greater than 100 g / L.

[0090] The term "antisolvent" refers to a solvent that can promote supersaturation and / or crystallization of a solution. In some embodiments, the solubility of the sample in the antisolvent is less than 0.001 g / L, less than 0.1 g / L, less than 0.0 g / L, less than 0.3 g / L, less than 0.4 g / L, less than 0.5 g / L, less than 0.6 g / L, less than 0.7 g / L, less than 0.8 g / L, less than 1 g / L, less than 2 g / L, less than 3 g / L, less than 4 g / L, less than 5 g / L, less than 6 g / L, less than 7 g / L, less than 8 g / L, less than 9 g / L, or less than 10 g / L.

[0091] In some embodiments, the sample is more soluble in the good solvent than in the antisolvent; in some embodiments, the difference in solubility of the sample in the good solvent and the antisolvent is approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, the sample is more soluble in the good solvent than in the antisolvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0092] In this invention, μg / mL represents micrograms per milliliter, h represents hours, g represents grams, and ml represents milliliters.

[0093] The "crystal form" described in this invention can exist in a sample at concentrations ranging from 0.0001% to 100%. Therefore, any sample containing even trace amounts of the "crystal form" described in this invention, such as greater than 0.0001%, 0.001%, 0.001%, or 0.01%, should be understood as falling within the scope of protection of this invention. To describe the various parameters of the "crystal form" described in this invention more clearly, this invention characterizes and identifies the crystal form by testing various parameters on samples containing a substantially pure "crystal form."

[0094] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0095] In this invention, "RH" refers to relative humidity.

[0096] In this invention, the room temperature is in the range of 20℃-40℃. In some embodiments, the room temperature can be 20℃-35℃. In some embodiments, the room temperature can be 20℃-30℃. In some embodiments, the room temperature can be 20℃-25℃. Detailed Implementation

[0097] Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.

[0098] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0099] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0100] Test instruments and methods

[0101] (1) X-ray powder diffraction (XRD) studies

[0102] X-ray powder diffraction (XRD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transmission / reflection sample stage. The radiation source used was (Cu, kα, Kα1) 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage is set at 45KV and the current at 40mA. The X-ray beam divergence, i.e., the effective size of the X-ray confinement on the sample, is 10mm. A continuous θ-θ scanning mode is used to obtain an effective 2θ range of 3°–40°. An appropriate amount of sample is placed in the circular groove of the zero-background sample holder under ambient conditions (approximately 18℃–32℃), and gently pressed with a clean glass slide to obtain a flat surface. The zero-background sample holder is then fixed. A conventional XRPD pattern is generated within the 3–40° 2θ range using a scanning step size of 0.0168°. Data collection software is Data Collector, and data is analyzed and displayed using Data Viewer and HighScore Plus.

[0103] Under the above conditions, the crystal forms prepared in the examples were subjected to XRD detection.

[0104] (2) Differential Scanning Calorimetry (DSC) Analysis

[0105] DSC measurement at TA InstrumentsTM The Q2000 model uses a sealed disc apparatus. The sample (approximately 1–3 mg) is weighed in an aluminum disc, capped with a Tzero, and precisely recorded to the nearest hundredth of a milligram. The sample is then transferred to the instrument for measurement. The instrument is purged with nitrogen at 50 mL / min. Data are collected at a heating rate of 10 °C / min between 30 °C and 300 °C. A graph is plotted with the endothermic peak pointing downwards, and the data are analyzed and presented using TA Universal Analysis.

[0106] (3) Thermogravimetric analysis (TGA)

[0107] TGA measurements at TA Instruments TM The procedure is performed using a model Q500. The empty crucible is tare, and approximately 10 mg of solid sample is placed in the tare crucible and spread evenly. After the instrument stabilizes, data is collected and recorded at a heating rate of 10 °C / min between room temperature and 300 °C under nitrogen purging.

[0108] Example 1: Preparation of a cocrystal of the compound shown in Formula I and cinnamamide

[0109] 200 mg of the compound shown in Formula I and 70 mg of cinnamamide were dissolved in 5 mL of dimethyl carbonate at 50 °C. The solution was then cooled to 0 °C, precipitating a solid. The solid was filtered, dried, and yielded a cocrystal of 205 mg of the compound shown in Formula I and cinnamamide. The XRD, DSC, and TGA spectra were found to be similar to those of [other compounds]. Figure 1 , 2 It is basically the same as 3.

[0110] Example 2: Preparation of a cocrystal of the compound shown in Formula I and cinnamamide

[0111] 300 mg of the compound shown in Formula I and 98 mg of cinnamamide were dissolved in 7 mL of acetone at 50 °C. Heating was stopped, and the mixture was then added to 20 mL of n-heptane, causing a solid to precipitate. The solid was cooled to room temperature, filtered, and dried to obtain a cocrystal of 320 mg of the compound shown in Formula I and cinnamamide. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 1 , 2 It is basically the same as 3.

[0112] Example 3: Preparation of a cocrystal of the compound shown in Formula I and cinnamamide

[0113] 300 mg of the compound shown in Formula I and 98 mg of cinnamamide were dissolved in 7 mL of acetone at 50 °C, and then mixed with 20 mL of n-heptane. A solid precipitated (the system temperature was maintained at 50 °C during the addition of n-heptane and the precipitation of the solid). The mixture was then cooled to room temperature, filtered, and dried to obtain a cocrystal of 315 mg of the compound shown in Formula I and cinnamamide. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 1 , 2 It is basically the same as 3.

[0114] Example 4: Preparation of a cocrystal of the compound shown in Formula I and cinnamamide

[0115] 300 mg of the compound shown in Formula I and 98 mg of cinnamamide were dissolved in 7 mL of acetone at 50 °C. Heating was stopped, and the mixture was then mixed with 20 mL of trifluoroethanol, precipitating a solid. The solid was cooled to room temperature, filtered, and dried to obtain a cocrystal of 319 mg of the compound shown in Formula I and cinnamamide. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 1 , 2 It is basically the same as 3.

[0116] Example 5: Preparation of a cocrystal of the compound shown in Formula I and cinnamamide

[0117] 400 mg of the compound shown in Formula I and 150 mg of cinnamamide were dissolved in 5 mL of 1,4-dioxane at 40 °C, volatilized at room temperature, and dried to obtain a cocrystal of 460 mg of the compound shown in Formula I and cinnamamide. The XRD, DSC, and TGA spectra were found to be similar to those of [previous compounds]. Figure 1 , 2 It is basically the same as 3.

[0118] Example 6: Preparation of a cocrystal of the compound shown in Formula I and cinnamamide

[0119] 400 mg of the compound shown in Formula I and 150 mg of cinnamamide were dissolved in 5 mL of 1,4-dioxane at 30 °C, volatilized at room temperature, and dried to obtain a cocrystal of 457 mg of the compound shown in Formula I and cinnamamide. The XRD, DSC, and TGA spectra were found to be similar to those of [previous compounds]. Figure 1 , 2 It is basically the same as 3.

[0120] Example 7: Preparation of a eutectic of the compound shown in Formula I with p-toluenesulfonic acid

[0121] 100 mg of the compound shown in Formula I and 95 mg of p-toluenesulfonic acid were dissolved in 6 mL of ethyl acetate at 50 °C, evaporated at room temperature, and dried to obtain a cocrystal of 140 mg of the compound shown in Formula I and p-toluenesulfonic acid. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 4 ,5 It is basically the same as 6.

[0122] Example 8: Preparation of a co-crystal of the compound shown in Formula I and p-toluenesulfonic acid

[0123] 200 mg of the compound shown in Formula I and 190 mg of p-toluenesulfonic acid were dissolved in 5 mL of acetone at 55 °C. Heating was stopped, and the mixture was then mixed with 20 mL of n-heptane, causing a solid to precipitate. The mixture was cooled to room temperature, filtered, and dried to obtain 330 mg of a cocrystal of the compound shown in Formula I and p-toluenesulfonic acid. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 4 , 5 It is basically the same as 6.

[0124] Example 9: Preparation of a eutectic of the compound shown in Formula I and p-toluenesulfonic acid

[0125] 200 mg of the compound shown in Formula I and 190 mg of p-toluenesulfonic acid were dissolved in 5 mL of acetone at 55 °C, and then mixed with 20 mL of n-heptane. A solid precipitated (the system temperature was maintained at 55 °C during the addition of n-heptane and the precipitation of the solid). The mixture was cooled to room temperature, filtered, and dried to obtain 327 mg of a cocrystal of the compound shown in Formula I and p-toluenesulfonic acid. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 4 , 5 It is basically the same as 6.

[0126] Example 10: Preparation of a co-crystal of the compound shown in Formula I and p-toluenesulfonic acid

[0127] 200 mg of the compound shown in Formula I and 190 mg of p-toluenesulfonic acid were dissolved in 5 mL of acetone at 55 °C, and then mixed with 20 mL of trifluoroethanol. A solid precipitated (the system temperature was maintained at 55 °C during the addition of trifluoroethanol and the precipitation of the solid). The mixture was cooled to room temperature, filtered, and dried to obtain 329 mg of a cocrystal of the compound shown in Formula I and p-toluenesulfonic acid. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 4 , 5 It is basically the same as 6.

[0128] Example 11: Preparation of a co-crystal of the compound shown in Formula I and p-toluenesulfonic acid

[0129] 200 mg of the compound shown in Formula I and 190 mg of p-toluenesulfonic acid were dissolved in 10 mL of ethyl acetate at 60 °C, then cooled to -5 °C, precipitating a solid. The solid was filtered, dried, and yielded a cocrystal of 280 mg of the compound shown in Formula I and p-toluenesulfonic acid. The XRD, DSC, and TGA spectra were found to be similar to those of [previous compounds]. Figure 4 , 5 It is basically the same as 6.

[0130] Example 12: Preparation of the aminobutadiene triol salt of the compound shown in Formula I

[0131] 200 mg of the compound shown in Formula I and 62 mg of tromethamine were dissolved in a mixed solvent of 5 mL dimethyl carbonate and 5 mL ethanol at 50 °C. Heating was stopped, and the solution was then mixed with 30 mL isopropyl ether, precipitating a solid. The solution was cooled to room temperature, filtered, and dried to obtain 220 mg of the tromethamine salt of the compound shown in Formula I. Its XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 7 , 8 It is basically the same as 9.

[0132] Example 13: Preparation of the aminobutadiene triol salt of the compound shown in Formula I

[0133] 200 mg of the compound shown in Formula I and 62 mg of tromethamine were dissolved in a mixed solvent of 5 mL dimethyl carbonate and 5 mL ethanol at 50 °C. The solution was then mixed with 30 mL isopropyl ether, and a solid precipitated (the system temperature was maintained at 50 °C during the addition of isopropyl ether and the precipitation process). The mixture was cooled to room temperature, filtered, and dried to obtain 219 mg of the tromethamine salt of the compound shown in Formula I. Its XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 7 , 8 It is basically the same as 9.

[0134] Example 14: Preparation of the aminobutadiene triol salt of the compound shown in Formula I

[0135] 200 mg of the compound shown in Formula I and 62 mg of tromethamine were dissolved in a mixed solvent of 5 mL dimethyl carbonate and 5 mL ethanol at 50 °C. Heating was stopped, and the solution was then mixed with 30 mL trifluoroethanol, precipitating a solid. The solution was cooled to room temperature, filtered, and dried to obtain 221 mg of the tromethamine salt of the compound shown in Formula I. Its XRD, DSC, and TGA spectra were found to be similar to those of... Figure 7 , 8 It is basically the same as 9.

[0136] Example 15: Preparation of the aminobutadiene triol salt of the compound shown in Formula I

[0137] 100 mg of the compound shown in Formula I and 65 mg of tromethamine were dissolved in a mixed solvent of 5 mL acetone and 5 mL ethanol at 60 °C. The solution was then cooled to 0 °C, precipitating a solid. The solid was filtered, dried, and yielded 90 mg of the tromethamine salt of the compound shown in Formula I. The XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 7 , 8 It is basically the same as 9.

[0138] Example 16: Preparation of the aminobutanetriol salt of the compound shown in Formula I

[0139] At room temperature, 60 mg of the compound shown in Formula I and 40 mg of tromethamine were mixed with 3 mL of ethyl acetate, evaporated, and dried to obtain 65 mg of the tromethamine salt of the compound shown in Formula I. Its XRD, DSC, and TGA spectra were found to be similar to those of... Figure 7 , 8 It is basically the same as 9.

[0140] Example 17: Preparation of crystal form A of the compound shown in Formula I

[0141] 100 mg of the compound shown in Formula I was dissolved in 15 mL of methanol at 60 °C. The solution was then cooled to 0 °C, precipitating a solid. The solid was filtered, dried, and yielded 65 mg of the compound in Formula I, crystal form A. Its XRD, DSC, and TGA spectra were found to be similar to those of... Figure 10 , 11 It is basically the same as 12.

[0142] Example 18: Preparation of crystal form A of the compound shown in Formula I

[0143] 500 mg of the compound shown in Formula I was dissolved in 15 mL of acetone at 50 °C. Heating was stopped, and the solution was then mixed with 40 mL of trifluoroethanol, causing a solid to precipitate. The solution was cooled to room temperature, filtered, and dried to obtain 450 mg of the compound shown in Formula I, crystal form A. Its XRD, DSC, and TGA spectra were found to be similar to those of the compound shown in Formula I. Figure 10 , 11 It is basically the same as 12.

[0144] Example 19: Preparation of crystal form A of the compound shown in Formula I

[0145] 400 mg of the compound shown in Formula I was dissolved in 4 mL of 1,4-dioxane at 30 °C, then mixed with 40 mL of water, precipitating a solid. The solid was filtered, dried, and yielded 366 mg of the compound in Formula I, crystal form A. Its XRD, DSC, and TGA spectra were found to be similar to those of [other compounds]. Figure 10 , 11 It is basically the same as 12.

[0146] Example 20: Preparation of crystal form A of the compound shown in Formula I

[0147] 200 mg of the compound shown in Formula I was dissolved in 2 mL of tetrahydrofuran, evaporated at room temperature, and a solid precipitated. After drying, 180 mg of the compound shown in Formula I, crystal form A, was obtained. Its XRD, DSC, and TGA spectra were found to be similar to those of... Figure 10 , 11 It is basically the same as 12.

[0148] Example 21: Preparation of Amorphous Forms

[0149] 300 mg of the compound shown in Formula I was dissolved in 15 mL of acetone at room temperature, and the acetone was then rotary evaporated at 50 °C to obtain 260 mg of the amorphous compound shown in Formula I. Its XRD pattern was analyzed and found to be similar to... Figure 13 Basically the same.

[0150] Comparative Example 1: Ligand Screening (Method 1)

[0151] 0.2 mol of the compound shown in Formula I and 0.4 mol of the ligands described in Table 1 were dissolved in 6 mL of ethyl acetate at 50 °C, evaporated at room temperature, and dried to obtain solids. The results of determining whether the obtained solids formed salts or eutectic crystals are shown in Table 1.

[0152] Table 1: Ligand screening results (Method 1)

[0153]

[0154]

[0155] Results analysis: Using the method described in Comparative Example 1, the compound shown in Formula I can form a co-crystal with cinnamamide or p-toluenesulfonic acid, the compound shown in Formula I can form a salt form with tromethamine, and the compound shown in Formula I cannot form a co-crystal or salt form with other ligands in Table 1 except for cinnamamide, p-toluenesulfonic acid, and tromethamine.

[0156] Comparative Example 2: Ligand Screening (Method 2)

[0157] 0.2 mol of the compound shown in Formula I and 0.4 mol of the ligands listed in Table 2 were dissolved in 7 mL of acetone at 50 °C. Heating was stopped, and the mixture was then mixed with 20 mL of n-heptane. A solid precipitated, which was cooled to room temperature, filtered, and dried to obtain the product. The presence or absence of a salt or eutectic in the product was determined, and the results are shown in Table 2.

[0158] Table 2: Screening results of ligands (Method 2)

[0159] ligands Whether it becomes salt Whether it forms a eutectic benzamide no no Cinnamamide no yes Niacinamide no no propionamide no no Isoniazid no no Isonicotinic Acid no no Tromethamine yes no Urea no no 3-Aminopyridine no no Anhydrous oxalic acid no no Piperazine hexahydrate no no L-malic acid no no L-tartaric acid no no Anhydrous citric acid no no Cinnamon acid no no benzoic acid no no salicylic acid no no Sorbic acid no no Succinic acid no no p-Chlorobenzoic acid no no p-Toluenesulfonic acid no yes saccharin no no Isonicotinic acid no no adipic acid no no anthranilic acid no no Maleic acid no no

[0160] Results analysis: Using the method described in Comparative Example 2, the compound shown in Formula I can form a co-crystal with cinnamamide or p-toluenesulfonic acid, the compound shown in Formula I can form a salt form with tromethamine, and the compound shown in Formula I cannot form a co-crystal or salt form with other ligands in Table 2 except for cinnamamide, p-toluenesulfonic acid, and tromethamine.

[0161] Comparative Example 3: Ligand Screening (Method 3)

[0162] 0.2 mol of the compound shown in Formula I and 0.4 mol of the ligands listed in Table 3 were suspended in water and stirred for 12 hours. The mixture was then filtered and dried to obtain the product. The presence or absence of salt formation or eutectic formation of the obtained product was determined, and the results are shown in Table 3.

[0163] Table 3: Screening results of ligands (Method 3)

[0164] ligands Whether it becomes salt Whether it forms a eutectic L-glycine no no L-alanine no no L-methionine no no L-proline no no L-serine no no L-threonine no no L-cysteine no no L-Asparagine no no L-glutamine no no L-Lysine no no L-arginine no no L-histidine no no L-pyroglutamic acid no no DL-proline no no

[0165] Results analysis: Using the method described in Comparative Example 3, the compound shown in Formula I cannot form a eutectic or salt form with the ligands described in Table 3.

[0166] Comparative Example 4: Ligand Screening (Method 4)

[0167] 0.2 mol of the compound shown in Formula I and 0.4 mol of the ligands described in Table 3 were dissolved in 5 mL of dimethyl carbonate at 50 °C. The solution was cooled to 0 °C, and a solid precipitated. The solid was filtered, dried, and the product was obtained. The results of determining whether the product formed a salt or a eutectic are shown in Table 4.

[0168] Table 4: Screening results of ligands (Method 4)

[0169]

[0170]

[0171] Results analysis: Using the method described in Comparative Example 4, the compound shown in Formula I can form a co-crystal with cinnamamide or p-toluenesulfonic acid, the compound shown in Formula I can form a salt form with tromethamine, and the compound shown in Formula I cannot form a co-crystal or salt form with other ligands in Table 4 except for cinnamamide, p-toluenesulfonic acid, and tromethamine.

[0172] Example 22: Stability Study

[0173] According to the guidelines for drug formulation stability testing, experiments were conducted to investigate the influencing factors on the cocrystal of the compound shown in Formula I with cinnamamide, the cocrystal of the compound shown in Formula I with p-toluenesulfonic acid, the tromethamine salt of the compound shown in Formula I, crystal form A of the compound shown in Formula I, and the amorphous form of the compound shown in Formula I. These experiments included high temperature tests, high humidity tests, strong light irradiation, and high temperature and high humidity tests to investigate the effects on the stability of their crystal forms and salt forms.

[0174] High temperature test: Take an appropriate amount of the above eutectic, salt form, crystalline form or amorphous form, spread it evenly in a weighing bottle, and place it in a constant temperature oven at 60℃±5℃. Then, take about 20mg of the above sample at 0, 5 and 15 days respectively, and detect it by powder X-ray powder diffraction (XRD). The results are shown in Table 5.

[0175] High humidity test: Take an appropriate amount of the above eutectic, salt form, crystalline or amorphous material, spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber at 25℃ and RH 92.5±5%. Then, take about 20mg of the above sample at 0, 5 and 15 days respectively, and detect it by powder X-ray powder diffraction (XRD). The results are shown in Table 5.

[0176] Irradiation test: Take an appropriate amount of the above eutectic, salt form, crystalline form or amorphous form, spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber (25℃, RH 60%±5%) under visible light 4500Lux±500Lux (VIS) and ultraviolet light 1.7W*h / m2 (UV). Then, take about 20mg of the above sample at 0, 5 and 15 days respectively, and detect it by powder X-ray powder diffraction (XRD). The results are shown in Table 5.

[0177] High temperature and high humidity test: Take an appropriate amount of the above eutectic, salt form, crystalline or amorphous material, spread it evenly in a weighing bottle, and place it in a constant temperature and humidity chamber at 60℃ and RH 75%±5%. Then, take about 20mg of the above sample at 0, 5 and 15 days respectively, and detect it by powder X-ray powder diffraction (XRD). The results are shown in Table 5.

[0178] Table 5: Stability test results of the eutectic, crystal form, and salt form of the compounds shown in Formula I.

[0179]

[0180]

[0181] Results Analysis: The amorphous form of the compound shown in Formula I exhibits poor crystal stability under the influencing factor test conditions. The cocrystal of the compound shown in Formula I and cinnamamide shows no change in crystal form under all influencing factor conditions, demonstrating good stability. The cocrystal of the compound shown in Formula I and p-toluenesulfonic acid, as well as the tromethamine salt of the compound shown in Formula I, are also stable under high temperature, light, and high temperature and high humidity conditions.

[0182] Example 23: Solubility Test

[0183] In accordance with the current Chinese Pharmacopoeia guidelines for solubility testing, experiments were designed to measure the equilibrium solubility of crystal form A of the compound shown in Formula I, the cocrystal of the compound shown in Formula I and cinnamamide, the cocrystal of the compound shown in Formula I and p-toluenesulfonic acid, and the tromethamine salt of the compound shown in Formula I in a pH 6.8 buffer aqueous solution at 37°C. The results are shown in Table 6.

[0184] Table 6: Equilibrium solubility of the compound shown in Formula I with cinnamamide, p-toluenesulfonic acid, and tromethamine salt in pH 6.8 buffer aqueous solution.

[0185]

[0186] Results Analysis: The order of solubility of the cocrystals, crystal forms, and salt forms of the compound shown in Formula I in pH 6.8 buffer is as follows: tromethamine salt of the compound shown in Formula I > cocrystal of the compound shown in Formula I and cinnamamide > cocrystal of the compound shown in Formula I and p-toluenesulfonic acid. Calculated using the compound shown in Formula I, the solubility of the cocrystal of the compound shown in Formula I and cinnamamide is 3.2 times that of crystal form A of the compound shown in Formula I, and the solubility of the tromethamine salt of the compound shown in Formula I is more than 20 times that of crystal form A of the compound shown in Formula I, significantly improving solubility.

[0187] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A solid form comprising a eutectic or salt form of the compound of Formula I, wherein the eutectic is a eutectic of the compound of Formula I and cinnamamide; and the salt form is a tromethamine salt of the compound of Formula I. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the cocrystal of the compound shown in Formula I and cinnamamide exhibits characteristic peaks at 2θ of 10.6±0.2°, 19.2±0.2°, 19.7±0.2°, 21.4±0.2°, 25.4±0.2°, 29.1±0.2° and 30.8±0.2°. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the tromethamine salt of the compound shown in Formula I shows a 2θ of 11.1 ± 0.2°. Characteristic peaks are present at 16.2±0.2°, 17.6±0.2°, 19.6±0.2°, 21.1±0.2°, 21.7±0.2°, 22.4±0.2° and 24.8±0.2°.

2. In the solid form according to claim 1, the molar ratio of the compound of formula I to cinnamonamide in the eutectic of the compound of formula I and cinnamonamide is 1:1; Optionally, in the tromethamine salt of the compound shown in Formula I, the molar ratio of the compound shown in Formula I to tromethamine is 1:

1.

3. The solid form according to any one of claims 1-2, characterized in that, Using Cu-Kα radiation, the powder X-ray diffraction pattern of the cocrystal of the compound of Formula I and cinnamamide exhibits characteristic peaks at 2θ of 7.2±0.2°, 8.2±0.2°, 10.6±0.2°, 18.5±0.2°, 18.9±0.2°, 19.2±0.2°, 19.7±0.2°, 20.0±0.2°, 21.4±0.2°, 21.7±0.2°, 22.1±0.2°, 22.8±0.2°, 25.4±0.2°, 26.4±0.2°, 28.2±0.2°, 28.7±0.2°, 29.1±0.2°, and 30.8±0.2°.

4. The solid form according to any one of claims 1-2, characterized in that, Using Cu-Kα radiation, the powder X-ray diffraction patterns of the cocrystal of the compound of Formula I and cinnamamide were obtained at 2θ values ​​of 7.2±0.2°, 8.2±0.2°, 9.9±0.2°, 10.3±0.2°, 10.6±0.2°, 14.4±0.2°, 18.0±0.2°, 18.5±0.2°, 18.9±0.2°, 19.2±0.2°, 19.7±0.2°, 20.0±0.2°, 20.7±0.2°, and 21. Characteristic peaks are present at 4±0.2°, 21.7±0.2°, 22.1±0.2°, 22.4±0.2°, 22.8±0.2°, 24.6±0.2°, 25.4±0.2°, 26.4±0.2°, 27.2±0.2°, 28.0±0.2°, 28.2±0.2°, 28.7±0.2°, 29.1±0.2°, 30.8±0.2°, 31.7±0.2°, 33.3±0.2°, and 36.1±0.2°.

5. The solid form according to any one of claims 1-4, characterized in that, The differential scanning calorimetry spectrum of the cocrystal of the compound shown in Formula I and cinnamamide shows an endothermic peak at 152℃-158℃. Optionally, the differential scanning calorimeter of the compound shown in Formula I has an endothermic peak at 146℃-152℃.

6. The solid form according to any one of claims 1-5, characterized in that, The thermogravimetric analysis spectrum of the cocrystallization of the compound shown in Formula I with cinnamamide shows a weight loss of less than 0.50% in the range of 30℃ to 120℃. Optionally, in the thermogravimetric analysis (TGA) spectrum of the tromethamine salt of the compound shown in Formula I, the weight loss is less than 0.50% in the range of 30°C to 120°C.

7. The solid form according to any one of claims 1-2 and 5-6, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction patterns of the tromethamine salt of the compound shown in Formula I are as follows: at 2θ values ​​of 9.8±0.2°, 11.1±0.2°, 12.6±0.2°, 16.2±0.2°, 16.5±0.2°, 17.2±0.2°, 17.6±0.2°, 18.6±0.2°, 19.0±0.2°, 19.6±0.2°, 21.1±0.2°, 21.7±0.2°, 22.4±0.2°, and 23.3±0.2°. Characteristic peaks are present at 23.6±0.2°, 24.8±0.2°, 25.8±0.2°, 26.2±0.2°, 26.4±0.2°, 26.8±0.2° and 30.5±0.2°.

8. The solid form according to any one of claims 1-2 and 5-6, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction patterns of the tromethamine salt of the compound shown in Formula I at 2θ of 7.4±0.2°, 9.8±0.2°, 11.1±0.2°, 12.6±0.2°, and 12.9±0.2° are obtained. 14.3±0.2°，15.1±0.2°，16.2±0.2°，16.5±0.2°，17.2±0.2°，17.6±0.2°，18.6±0.2°，19.0±0.2°，19.6±0.2°， 21.1±0.2°，21.7±0.2°，22.4±0.2°，23.3±0.2°，23.6±0.2°，24.0±0.2°，24.8±0.2°，25.6±0.2°，25.8±0.2°， Characteristic peaks are present at 26.2±0.2°, 26.4±0.2°, 26.8±0.2°, 27.7±0.2°, 30.5±0.2°, 32.1±0.2°, 33.6±0.2° and 35.5±0.2°.

9. A method for preparing the solid form according to any one of claims 1-8, characterized in that, The method includes dissolving the compound shown in Formula I, and cinnamamide or tromethamine, in an organic solvent, cooling to precipitate crystals, filtering, and drying to obtain the solid form; or dissolving the compound shown in Formula I, and cinnamamide or tromethamine, in a good solvent, adding an antisolvent to precipitate crystals, filtering, and drying to obtain the solid form.

10. The preparation method according to claim 9, wherein, The organic solvent is selected from at least one of 1,4-dioxane, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, ethanol, acetone, butanone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether; and / or the good solvent is selected from at least one of 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, acetone, butanone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether; and / or the antisolvent is selected from at least one of trifluoroethanol, n-heptane, n-hexane, cyclohexane, and isopropyl ether.

11. The preparation method according to claim 9, wherein, The dissolution temperature in organic solvents is 20℃-70℃; optionally, the cooling is to -10℃ to 10℃; optionally, the dissolution temperature in good solvents is 20℃-70℃.

12. The preparation method according to any one of claims 9-10, wherein the molar ratio of the compound of formula I to cinnamamide or tromethamine is 1:1 to 1:2; optionally, for each gram of the compound of formula I, the amount of the organic solvent is 1 ml to 200 ml, or optionally, for each gram of the compound of formula I, the amount of the good solvent is 1 ml to 200 ml, and the amount of the antisolvent is 1 ml to 300 ml.

13. The preparation method according to any one of claims 10-12, wherein the organic solvent is selected from at least one of dimethyl carbonate, 1,4-dioxane and ethyl acetate; and / or the good solvent is selected from at least one of 1,4-dioxane, dimethyl carbonate, ethanol and acetone.

14. A pharmaceutical composition comprising the solid form of any one of claims 1-8, and a pharmaceutically acceptable excipient or carrier.

15. The pharmaceutical composition according to claim 14, wherein, based on the mass of the compound represented by Formula I, the eutectic of the compound represented by Formula I or the tromethamine salt of the compound represented by Formula I is at least 90% of the compound represented by Formula I.

16. Use of the solid form of any one of claims 1-8 or the pharmaceutical composition of claim 14 or 15 in the preparation of a medicament for treating non-alcoholic fatty liver disease.

Images