Crystals of thyroid hormone beta receptor agonists, their preparation method and use

Abstract

The present invention provides a crystal of a thyroid hormone β-receptor agonist, a method for preparing the same, and uses thereof. The crystal is essentially non-hygroscopic and has a relatively small crystal particle size and a relatively large specific surface area of ​​the drug, which can improve the dissolution rate of the drug, which is beneficial for drug absorption and improves bioavailability.

Description

Detailed Description of the Invention

[0001] [Field] The present disclosure relates to the pharmaceutical field, in particular to crystals of thyroid hormone beta receptor agonists, methods for preparing said crystals, pharmaceutical compositions containing said crystals, and uses thereof. [background] The compound of formula I (molecular formula C 28 H 32 ClO5P, with a molecular weight of 514.98 and a CAS Registry Number of 852948-13-1, is a cyclic phosphonate compound. It selectively activates THR-β, controls the expression of downstream genes such as CYP7A and SREBP-1c, effectively promotes the decomposition of fatty acids, stimulates mitochondrial biogenesis, reduces the levels of low-density lipoprotein and triglyceride, reduces lipotoxicity, improves liver function and reduces fatty liver, making it a highly effective and less toxic candidate drug for non-alcoholic steatohepatitis (NASH) as a novel oral thyroid hormone beta receptor agonist (THR-beta agonist).

[0002] [ka]

[0003] However, when amorphous compounds are used in the preparation of pharmaceuticals, they have problems such as low stability and high hygroscopicity.Currently, the preparation methods of the crystals of compounds disclosed in the art have problems such as low reproducibility, and many preparation methods also require the addition of seed crystals in the preparation method, which makes the preparation process very complicated.Therefore, it is necessary to develop the crystals of the compound of formula I with higher efficacy, and the preparation method of the compound of formula I with higher reproducibility and simpler process.

[0004] [overview] Therefore, the objective of the present disclosure is to provide a crystal of the compound of formula I, which is essentially non-hygroscopic, has a relatively small crystal grain size and a relatively large specific surface area of ​​the drug, thereby improving the dissolution rate of the drug, which is beneficial for the absorption of the drug, and improves the bioavailability. The crystal of the compound of formula I provided in the present disclosure may be simply referred to as crystalline form I of the compound of formula I in the present disclosure.

[0005] The present disclosure relates to a crystalline compound of formula I having, in an X-ray powder diffraction pattern, diffraction peaks at 2θ angles of 12.124±1, 15.483±1, 16.38±1, 16.666±1, 19.089±1, 20.415±1, and 20.821±1 using Cu-Kα radiation.

[0006] [ka]

[0007] More preferably, the crystals of the present disclosure have diffraction peaks at 2θ angles of 7.951±1, 12.124±1, 13.555±1, 15.483±1, 16.017±1, 16.38±1, 16.666±1, 19.089±1, 20.415±1, 20.821±1, 21.764±1, 22.34±1, 22.628±1, 24.055±1, and 26.426±1 using Cu-Kα radiation in an X-ray powder diffraction pattern.

[0008] Specifically, the X-ray powder diffraction pattern at 2θ angles using Cu-Kα radiation of crystalline Form I of the compound of formula I provided in this disclosure has d spacings (Å) as shown in Table 1.

[0009] Table 1. Spacing of characteristic peaks in the X-ray powder diffraction pattern for crystalline form I of the compound of formula I

[0010] [Table 1]

[0011] More preferably, the crystalline form I of the compound of formula I provided in this disclosure has an X-ray powder diffraction pattern at 2θ angles using Cu-Kα radiation as shown in FIG.

[0012] Crystalline Form I of the compound of formula I provided in the present disclosure has an endothermic peak at 111.92° C. as a result of thermal analysis using differential scanning calorimetry (DSC).

[0013] The present disclosure relates to (1) dissolving an amorphous compound of formula I in a first solvent and precipitating a solvate of the compound of formula I; (2) dissolving, pulping and / or crystallizing the solvate obtained in step (1) in a second solvent to obtain crystals.

[0014] The present disclosure also provides (1) dissolving an amorphous compound of formula I in a first solvent and precipitating a solvate of the compound of formula I; (2) pulping the solvate obtained in step (1) to obtain crystals.

[0015] In the preparation method of the present disclosure, the first solvent is selected from the group consisting of C1-C4 lower alcohols such as methanol, ethanol, or isopropanol; C3-C6 lower ketones such as acetone or butanone; acetonitrile; methyl tert-butyl ether; diisopropyl ether; C5-C8 linear and branched alkanes such as n-hexane; C5-C8 cycloalkanes; and mixtures of any two or more thereof, preferably, the first solvent is methyl tert-butyl ether and / or ethanol, more preferably, the first solvent is methyl tert-butyl ether.

[0016] In the preparation method of the present disclosure, preferably, the amorphous compound of formula I is dissolved in a first solvent followed by stirring and filtration and / or drying of the precipitated solvate of compound of formula I.

[0017] In the preparation method of the present disclosure, the second solvent is selected from the group consisting of C1-C4 lower alcohols such as methanol, ethanol, or isopropanol; C3-C6 lower ketones such as acetone or butanone; and mixtures of any two or more thereof, preferably, the second solvent is selected from the group consisting of methanol, ethanol, acetone, isopropanol, and mixtures of any two or more thereof, more preferably, the second solvent is ethanol.

[0018] In the preparation method of the present disclosure, preferably, pulping and / or crystallization is carried out in a third solvent. Pulping may be performed by directly pulping the solvate obtained in step (1), or by dissolving the solvate obtained in step (1) in a second solvent, and the crystals are obtained by pulping and / or crystallization. The third solvent may be selected as a solvent that is poorly soluble in the crystals, preferably water, ethanol, or a mixture of ethanol and water. Pulping may be performed under negative pressure and / or stirring, and / or crystallization may be performed under stirring to promote precipitation of the crystals. Preferably, concentration may be performed under reduced pressure before crystallization. Crystallization may be followed by further pulping to improve the purity of the product obtained. This step may be repeated multiple times until the purity of the product reaches an ideal level. The preparation method of the present disclosure may further include a step of filtering, washing, and / or drying the crude crystalline product obtained.

[0019] The present disclosure also relates to a pharmaceutical composition comprising crystalline Form I of the compound of formula I, and optionally, a pharma- ceutically acceptable formulation additive. The crystalline Form I of the compound of formula I according to the present disclosure may be made into a pharmaceutical composition together with one or more pharma- ceutically acceptable carriers, formulation additives, or diluents. The pharmaceutical composition may be a solid oral formulation, a liquid oral formulation, an injection, or the like.

[0020] The crystalline form I of the compound of formula I provided in the present disclosure can selectively activate THR-β, control downstream gene expression such as CYP7A, SREBP-1c, effectively promote the decomposition of fatty acids, stimulate mitochondrial biogenesis, and reduce the levels of low-density lipoprotein and triglyceride, thereby reducing lipotoxicity, improving liver function, and reducing fatty liver. The crystalline form I can be used as an active ingredient for preparing a therapeutic drug for non-alcoholic steatohepatitis (NASH) and the like. The crystalline form I of the compound of formula I provided in the present disclosure has a relatively small crystal grain size and a relatively large specific surface area of ​​the drug, which can improve the dissolution rate of the drug, which is more beneficial for the absorption of the drug and improves its bioavailability. Therefore, the present disclosure also relates to the use of the crystalline form I of the compound of formula I or a pharmaceutical composition comprising the crystalline form I of the compound of formula I in preparing a therapeutic drug for treating non-alcoholic steatohepatitis. [Brief description of the drawings]

[0021] Specific embodiments of the present disclosure are described in conjunction with the following drawings. [Figure 1] FIG. 1 is an X-ray powder diffraction (PXRD) pattern for crystalline Form I of the compound of formula I according to the present disclosure. [Diagram 2] FIG. 2 is a differential scanning calorimetry (DSC) chart for crystalline Form I of the compound of formula I according to the present disclosure. [Diagram 3] FIG. 3 is an infrared absorption spectrum for crystalline Form I of the compound of formula I according to the present disclosure. [Figure 4] FIG. 4 is an ultraviolet absorption spectrum for crystalline Form I of the compound of formula I according to the present disclosure. [Diagram 5] FIG. 5 is a Raman spectrum for crystalline Form I of the compound of formula I according to the present disclosure. [Figure 6] FIG. 6 is a diagram showing the particle size selection of the crystals obtained in Example 1. [Figure 7] FIG. 7 is a DVS diagram of the crystals obtained in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] [Detailed Description of the Invention] The present disclosure will be further described below with reference to examples. The following examples are merely illustrative and do not limit the present disclosure. Various improvements made by those skilled in the art according to the teachings of the present disclosure shall fall within the scope of protection of the claims of the present disclosure.

[0023] The differential scanning calorimetry (DSC) conditions for the crystalline form I of the compound of formula I used in this disclosure are heating rate: 10°C / min, heating range: 0-300°C, pressure: 1013 Mbar, pressure rise rate: left: 20 ml / min, right: 100 ml / min. The instrument used is a differential scanning calorimeter / DSC1.

[0024] The X-ray powder diffraction (XRPD) pattern of the crystalline form I of the compound of formula I according to the present disclosure is analyzed using an X-ray powder diffractometer / D8 ADVANCE with X-ray source: Cu, voltage: 40KV, current: 40mA, scan range: 3-40°, scan width: 0.02°, and retention time of each width: 0.1 seconds.

[0025] The infrared absorption spectrum conditions of the crystalline form I of the compound of formula I used in this disclosure are: Instrument model: Frontier Fourier transform infrared spectrometer (FX057), potassium bromide tablet method, wavelength interval: 400-4000 cm -1 , and resolution: 4.0cm -1 , is.

[0026] The ultraviolet absorption spectrum conditions of the crystalline form I of the compound of formula I used in this disclosure are: Instrument model: Lambda 365 UV-visible spectrophotometer (FX058), wavelength interval: 200-800 cm -1 , scanning speed: 480 nm / min, slit width: 2 nm, and light speed mode: double light speed.

[0027] The Raman spectroscopic conditions for the crystalline form I of the compound of formula I used in this disclosure are: instrument model: DXR2xi dispersive laser confocal Raman microspectrometer, and excitation wavelength: 532 nm.

[0028] The thermogravimetric analysis (TGA) conditions for crystalline Form I of compound of formula I used in the present disclosure are: Instrument name / model: Thermogravimetric analyzer / TGA / DSC2, Heating range: 25-500°C, Heating rate: 10°C / min, Pressure: 1013 Mbar, and Pressure rise rate: 20 ml / min.

[0029] The particle size conditions of the crystalline form I of the compound of formula I used in the present disclosure are: detection instrument name / model: micrometer particle size analyzer / MS3000, test method: dry method, sample injection rate: 50%, air pressure: 2.5 bar, slit width: 2.0 mm, refractive index: 1.52, absorption coefficient: 0.1, shading: 0.5%-6%, background measurement time: 10 seconds, and sample measurement time: 10 seconds.

[0030] Example 1: Preparation of crystalline form I of the compound of formula I A 10 g sample of the amorphous compound of formula I was taken and dissolved in 100 ml of methyl tert-butyl ether (MTBE) at room temperature, stirred for 5 hours, filtered and dried to obtain the MTBE solvate of compound of formula I for subsequent experiments.

[0031] 8 g of MTBE solvate of compound of formula I was weighed, dissolved in anhydrous ethyl alcohol, and concentrated to about 24 g under reduced pressure at 25-35° C. The resultant was transferred to a 250 ml single-hole eggplant bottle. 16-20 ml of water was added dropwise with stirring. After the dropwise addition, the resultant was stirred under negative pressure for 1-2 hours. After the solid precipitated, about 100 ml of water was added dropwise. The resultant was stirred under negative pressure for 12-20 hours, filtered and dried to obtain crystalline form I of compound of formula I of the present disclosure. The yield was 7.12 g, and the yield was 89.0%.

[0032] The measured melting point of crystalline form I was 107.2-109.7°C. Figure 1 and Table 2 are X-ray powder diffraction (PXRD) patterns and data for crystalline form I of the compound of formula I according to the present disclosure. Figure 2 is a differential scanning calorimetry (DSC) spectrum for crystalline form I of the compound of formula I according to the present disclosure. Figure 3 and Table 3 are infrared absorption spectra and data for crystalline form I of the compound of formula I according to the present disclosure. Figure 4 and Table 4 are ultraviolet absorption spectra and data for crystalline form I of the compound of formula I according to the present disclosure. Figure 5 is a Raman spectrum for crystalline form I of the compound of formula I according to the present disclosure.

[0033] Table 2. Powder diffraction data for crystalline form I

[0034] [Table 2]

[0035] Table 3. Infrared absorption spectroscopic characteristics for crystalline form I

[0036] [Table 3]

[0037] Table 4. Absorption peaks and analysis of the ultraviolet spectrum for crystalline form I

[0038] [Table 4]

[0039] Example 2: Preparation of crystalline form I of the compound of formula I 8g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed, pulped with a mixture of 8ml of anhydrous ethyl alcohol and 80ml of water for 20 hours, filtered and dried to obtain the product, which was found to be crystalline form I upon inspection. The yield was 7.20g, and the yield was 90.0%.

[0040] Example 3: Preparation of crystalline form I of the compound of formula I 8 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed out, dissolved in anhydrous ethyl alcohol, and concentrated under reduced pressure at 25-35°C to obtain about 24 g of the resultant product. The resultant product was transferred to a 250 ml single-hole eggplant-shaped bottle. 16-20 ml of water was added dropwise while stirring. After the dropwise addition, the resultant product was stirred for 1-2 hours to precipitate a large amount of solid. 100 ml of water was added, stirred for 10-20 hours, filtered and dried to obtain the product. Upon inspection, the product was crystalline form I. The amount of the product was 7.25 g, and the yield was 90.6%.

[0041] Example 4: Preparation of Crystalline Form I of the Compound of Formula I 8 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed out, dissolved in anhydrous ethyl alcohol, and concentrated under reduced pressure at 25-35°C to obtain about 24 g of the resultant product. The resultant product was transferred to a dropping funnel. The resultant product was added dropwise to a single-neck flask containing 100 ml of water. After the dropwise addition, the resultant product was continuously stirred for 12-20 hours, filtered and dried to obtain the product. Upon inspection, the product was crystalline form I. The amount of the product was 6.9 g, and the yield was 86.3%.

[0042] Example 5: Preparation of Crystalline Form I of the Compound of Formula I Approximately 6 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed out, dissolved in 50-60 ml of ethanol, and concentrated to dryness under reduced pressure. 10 ml of ethanol was added and stirred for about 30 minutes to precipitate a solid. 30 ml of water was added to the solid, stirred for 30-60 minutes, and water was replenished for 30 minutes. The resultant was stirred overnight at room temperature, filtered, washed, and dried to obtain the product. Upon inspection, the product was crystalline form I. The amount of the product was 4.98 g, and the yield was 83.0%.

[0043] Example 6: Preparation of Crystalline Form I of the Compound of Formula I About 3.71 g of the MTBE solvate of compound of formula I obtained in Example 1 was weighed and pulped with a mixture of 20 ml of water and 10 ml of absolute ethyl alcohol under negative pressure for about 1 hour. 10 ml of water was added and stirred continuously under negative pressure for 1 hour. About 60 ml of water was added. The resultant was stirred overnight at room temperature and normal pressure, filtered, washed and dried to obtain the product. Upon testing, the product was crystalline form I. The yield was 3.23 g and the yield was 87.1%.

[0044] Example 7: Preparation of crystalline form I of the compound of formula I Approximately 2 g of the MTBE solvate of compound of formula I obtained in Example 1 was weighed and dissolved in 4 ml of anhydrous ethyl alcohol. 1.5 ml of water was added to the resulting mixture and stirred at room temperature. After 1 hour, 0.5 ml of water was added and stirred continuously for 1 hour. A solid precipitated. 20 ml of water was added and stirred continuously for 12-20 hours. The resulting material was filtered, washed and dried to obtain the product. Upon testing, the product was crystalline form I. The amount of the product was 1.73 g, and the yield was 86.6%.

[0045] Example 8: Preparation of Crystalline Form I of the Compound of Formula I About 0.5g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved in 2.5ml of anhydrous ethyl alcohol. 47.5ml of water was added, pulped, and stirred for 12-20 hours. The resultant was filtered, washed, and dried to obtain the product. Upon inspection, the product was found to be crystalline form I. The amount of the product was 0.41g, and the yield was 82.0%.

[0046] Example 9: Preparation of Crystalline Form I of the Compound of Formula I Approximately 3 g of the MTBE solvate of compound of formula I obtained in Example 1 was weighed and dissolved in 20-30 ml of ethanol. The resulting mixture was concentrated to dryness under reduced pressure. 6 ml of ethanol was added and stirred for about 30 minutes. A solid precipitated. The solid was taken out and dissolved in 4 ml of ethanol. 25 ml of water was added and pulped for 20 hours. The resulting product was filtered, washed and dried to obtain the product. Upon testing, the product was crystalline form I. The amount of production was 2.6 g, and the yield was 86.7%.

[0047] Example 10: Preparation of crystalline form I of the compound of formula I 1 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved in 20-30 ml of methanol. The resulting mixture was concentrated to dryness under reduced pressure. The solid was dissolved in about 2-3 ml of methanol. About 1 ml of water was added for crystallization. After dropwise addition, the mixture was stirred for 1 hour. Then, 1 ml of water was added dropwise and stirred for 1 hour. 10 ml of water was added and stirred at room temperature overnight. The resulting product was filtered, washed and dried to obtain the product. Upon testing, the product was crystalline form I. The amount of production was 0.7 g, and the yield was 70.0%.

[0048] Example 11: Preparation of Crystalline Form I of the Compound of Formula I 1 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved in about 20 ml of acetone. The resulting mixture was concentrated to dryness under reduced pressure. The solid was dissolved in about 6 ml of acetone. 4 ml of water was added dropwise, stirred for about 30 minutes to precipitate, and filtered to obtain a solid. The solid was dissolved in 4 ml of ethanol. 4 ml of water was added to pulp and stirred for 1 hour. 20 ml of water was added and stirred for 12 to 20 hours. Upon inspection, the product was crystalline form I. The amount of production was 0.81 g, and the yield was 81.0%.

[0049] Example 12: Preparation of crystalline form I of the compound of formula I 3 g of the MTBE solvate of compound of formula I obtained in Example 1 was weighed and dissolved in 30 ml of isopropanol. The resulting mixture was concentrated to dryness under reduced pressure. To crystallize, 10 ml of isopropanol was added and about 4 ml of water was added dropwise. After the dropwise addition, stirring was continued for 1 hour. 20 ml of water was added and pulped for 12-20 hours. After filtration, a solid was obtained. The solid was dissolved in 6 ml of ethanol. 40 ml of water was added and pulped for 12-20 hours. The resultant was filtered, washed and dried to obtain the product. Upon testing, the product was crystalline form I. The amount of product was 2.3 g and the yield was 77.0%.

[0050] Example 13: Preparation of crystalline form I of the compound of formula I 10 g of an amorphous sample of the compound of formula I was dissolved in 30 ml of ethanol. The resulting mixture was stirred at room temperature for 12 hours to allow the solid to precipitate. The EtOH solvate of the compound of formula I was obtained.

[0051] Approximately 5 g of the EtOH solvate of the compound of formula I was weighed and pulped with 40 ml of water under negative pressure at room temperature. 5 ml of water was added every 2 hours. According to the decreasing trend of water and the stirring conditions, an appropriate amount of water was added and stirred for about 6 to 7 hours. The resultant was filtered and washed with water to obtain a solid. The solid was dissolved in 40 ml of water and 4 ml of absolute ethyl alcohol. The mixture was stirred overnight at room temperature and normal pressure. The resultant was filtered, washed and dried to obtain the product. Upon inspection, the product was crystalline form I. The amount of production was 4.3 g, and the yield was 86.0%.

[0052] Example 14: Particle size study of crystalline form I of the compound of formula I The crystals obtained in Example 1 were subjected to a particle size test according to the above conditions. The results are shown in Table 5.

[0053] Table 5. Particle size analysis of crystalline form I

[0054] [Table 5]

[0055] Figure 6 is a particle size selection diagram of the crystals obtained in Example 1. As can be seen from Figure 6, the crystalline form I of the compound of formula I has a relatively small crystal particle size and a large specific surface area, which can improve the dissolution rate of the drug, which can be beneficial for the absorption of the drug, and can improve the bioavailability. Figure 6 also shows that the crystalline form I is almost normally distributed, has a uniform particle size distribution, and has good uniformity.

[0056] Example 15: Hygroscopicity test for crystalline form I of the compound of formula I About 28 mg of the crystals obtained in Example 1 was taken, and the hygroscopicity of the crystals was measured using a dynamic hygroscopicity measuring device according to the above conditions. The results are shown in Table 6.

[0057] Table 6. Hygroscopicity analysis of crystalline form I

[0058] [Table 6]

[0059] The DVS diagram of the crystals obtained in Example 1 is shown in Figure 7. The weight gain of crystalline form I was within 0.2% at a relative humidity of 80%. According to the guideline for drug hygroscopicity in Appendix XIXJ of the Chinese Pharmacopoeia 2015 Edition, crystalline form I was non-hygroscopic or nearly non-hygroscopic.

[0060] Comparative Example 1: Preparation of other crystalline forms of the compound of formula I 1 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved in 30 ml of n-heptane. The resulting mixture was concentrated under reduced pressure. About 1 ml of water was added to induce crystallization. After the dropwise addition of water, stirring was continued for 1 hour. 1 ml of water was continuously added dropwise. Stirring was continued for 1 hour. 10 ml of water was added and stirring was continued overnight at room temperature. Upon inspection, crystals of the compound of formula I were not obtained by this method.

[0061] Although the present disclosure has been described to some extent, it is apparent that suitable modifications can be made under various conditions without departing from the spirit and scope of the present disclosure. The present disclosure is not limited to the described embodiments, but should be understood to fall within the scope of the claims, including equivalent replacements of each element.

Claims

1. A crystalline compound of formula I having diffraction peaks at 2θ angles of 12.124±0.2, 15.483±0.2, 16.38±0.2, 16.666±0.2, 19.089±0.2, 20.415±0.2, and 20.821±0.2 using Cu-Kα radiation in an X-ray powder diffraction pattern. 【Chemistry 1】

2. 2. The crystal of claim 1, having diffraction peaks at 2θ angles of 7.951±0.2, 12.124±0.2, 13.555±0.2, 15.483±0.2, 16.017±0.2, 16.38±0.2, 16.666±0.2, 19.089±0.2, 20.415±0.2, 20.821±0.2, 21.764±0.2, 22.34±0.2, 22.628±0.2, 24.055±0.2, and 26.426±0.2 using Cu-Kα radiation in an X-ray powder diffraction pattern.

3. The crystal according to claim 1 or 2, which has an endothermic peak at 111.92°C as a result of thermal analysis using differential scanning calorimetry.

4. A method for preparing the crystal according to any one of claims 1 to 3, comprising the steps of: (1) dissolving an amorphous compound of formula I in a first solvent and precipitating a solvate of said compound of formula I; (2) dissolving, pulping, and / or crystallizing the solvate obtained in step (1) in a second solvent to obtain the crystals; The first solvent is １ -C ４ Lower alcohols; C ３ -C ６ Lower ketones; acetonitrile; methyl tert-butyl ether; diisopropyl ether; C ５ -C ８ Linear and branched alkanes; C ５ -C ８ cycloalkanes; and mixtures of any two or more thereof, The second solvent is １ -C ４ Lower alcohols; C ３ -C ６ lower ketones; and mixtures of any two or more thereof.

5. A method for preparing the crystal according to any one of claims 1 to 3, comprising the steps of: (1) dissolving an amorphous compound of formula I in a first solvent and precipitating a solvate of said compound of formula I; (2) pulping the solvate obtained in step (1) to obtain the crystals; The first solvent is １ -C ４ Lower alcohols; C ３ -C ６ Lower ketones; acetonitrile; methyl tert-butyl ether; diisopropyl ether; C ５ -C ８ Linear and branched alkanes; C ５ -C ８ cycloalkanes; and mixtures of any two or more thereof.

6. 6. The process according to claim 4 or 5, wherein the pulping and / or crystallization is carried out in a third solvent.

7. The preparation method according to any one of claims 4 to 6, wherein the pulping is carried out under negative pressure and / or under stirring and / or the crystallization is carried out under stirring.

8. The process according to claim 4, wherein the concentration is carried out under reduced pressure prior to said crystallization.

9. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 3, and optionally a pharma- ceutically acceptable formulation additive.

10. Use of the crystal according to any one of claims 1 to 3, or the pharmaceutical composition according to claim 9, in the preparation of a therapeutic agent for treating non-alcoholic steatohepatitis.

11. The crystal according to claim 1 or 2, having an X-ray powder diffraction pattern at 2θ angles using Cu-Kα radiation as shown in FIG.

12. The method of claim 4, wherein the first solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, butanone, acetonitrile, methyl tert-butyl ether, diisopropyl ether, n-hexane, and a mixture of two or more thereof.

13. The method of claim 4, wherein the second solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, butanone, and a mixture of any two or more thereof.

14. The method of claim 5, wherein the first solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, butanone, acetonitrile, methyl tert-butyl ether, diisopropyl ether, n-hexane, and a mixture of any two or more thereof.

15. The method of claim 6, wherein the third solvent is water, ethanol, or a mixture of ethanol and water.

16. The method of claim 8, further comprising pulping after the crystallization.

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