Crystal forms of resminostat compounds and methods of preparation and use thereof

Abstract

The present application relates to a crystal form of formula (I) and a preparation method thereof, a pharmaceutical composition containing the crystal form, and the use of the crystal form in the preparation of a drug for treating a disease related to a selective beta (THR-beta) agonist. The new crystal form of formula (I) provided by the present application has important value for the development of the compound of resmetirom.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to the crystal form of resmetiro compound, its preparation method, and its uses. Background Technology

[0002] NASH is a progressive chronic liver disease caused by metabolic disorders such as obesity and diabetes. It can lead to liver inflammation and fibrosis, eventually progressing to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. If not controlled in time, it will seriously threaten the patient's life. NASH has become a major global public health challenge. It is estimated that there are currently about 1 billion adults worldwide with NASH, accounting for about 13% of the total population.

[0003] Resmetiro is a thyroid hormone receptor β (THR-β) agonist. On March 14, 2024, the U.S. Food and Drug Administration (FDA) approved it as the first drug for the treatment of liver fibrosis caused by non-cirrhotic non-alcoholic steatohepatitis (NASH). Resmetiro is highly selective, playing a central role in the liver by activating β receptors in hepatocytes. It regulates lipid metabolism, lowering LDL-C, triglycerides, and atherogenic lipoproteins. It is inactive with THR-α receptors, thus not affecting bone or cardiac parameters, and does not affect other hormones in the thyroid hormone pathway. Therefore, impaired thyroid function, such as decreased serum thyroid hormone levels, is often observed in NASH. Resmetiro reduces liver fat by stimulating the degradation and oxidation of fatty acids.

[0004] The chemical name of resimetiro is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyrido[1,2-d]pyrimidin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile, and its specific chemical structure is as follows:

[0005]

[0006] Crystal form refers to the solid state of a compound's solid molecules, which are arranged in a long-range ordered lattice within a three-dimensional microscopic structure. Drug polymorphism refers to the phenomenon where solid drug molecules exist in two or more different crystal forms. Because different crystal forms have different physicochemical properties, different crystal forms of solid drug molecules may exhibit different dissolution and absorption rates in vivo, thus affecting the clinical efficacy and safety of the drug to some extent. This is especially true for poorly soluble solid drugs, where crystal form has a greater impact on bioavailability. Therefore, drug crystal form is a crucial aspect of solid-state drug research and development, and also an important component of drug quality control.

[0007] Existing patent CN105008335B discloses a crystal form I of resimetidine, its dihydrate, and various solvates. The preparation of crystal form I involves multiple steps and is complex, which is not conducive to industrial development; the purity of the dihydrate is only 96.4%, with a high impurity content; and the solvates are also unsuitable for pharmaceutical use due to the presence of organic solvents.

[0008] In summary, there is an urgent need in this field for a new crystal form of resimetidine that simultaneously possesses good solubility, good stability, and is suitable for industrial production, so as to meet the requirements of drug bioavailability, suitability for industrial development, and comprehensive performance in all aspects that meet the requirements for pharmaceutical development. Summary of the Invention

[0009] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a crystal form of resmetiro compound to solve the problems in the prior art. At the same time, this invention will also provide a method for preparing the crystal form of resmetiro compound.

[0010] To achieve the above objectives and other related objectives,

[0011] In a first aspect, the present invention provides a crystal form of compound I according to the purpose of the invention.

[0012] Furthermore, the present invention provides that the crystal form of compound I can be crystal form DCIII (hereinafter referred to as crystal form DCIII).

[0013] Furthermore, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least one characteristic peak among the diffraction angles 2theta of 5.0°±0.2°, 6.3°±0.2°, and 7.7°±0.2°.

[0014] Preferably, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least two characteristic peaks in the diffraction angle 2theta values ​​of 5.0°±0.2°, 6.3°±0.2°, and 7.7°±0.2°.

[0015] Preferably, the crystal form DCIII is irradiated using Cu-Ka radiation, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2theta of 5.0°±0.2°, 6.3°±0.2° and 7.7°±0.2°.

[0016] Furthermore, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least one characteristic peak among the diffraction angles 2theta of 10.1°±0.2°, 12.1°±0.2°, and 14.3°±0.2°;

[0017] Preferably, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least two characteristic peaks in the diffraction angle 2theta values ​​of 10.1°±0.2°, 12.1°±0.2°, and 14.3°±0.2°.

[0018] Preferably, the crystal form DCIII is irradiated using Cu-Ka radiation, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2theta of 10.1°±0.2°, 12.1°±0.2° and 14.3°±0.2°.

[0019] Furthermore, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least one characteristic peak among the diffraction angles 2theta of 21.9°±0.2°, 22.8°±0.2°, and 23.6°±0.2°;

[0020] Preferably, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least two characteristic peaks in the diffraction angle 2theta values ​​of 21.9°±0.2°, 22.8°±0.2°, and 23.6°±0.2°.

[0021] Preferably, its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2theta of 21.9°±0.2°, 22.8°±0.2° and 23.6°±0.2°.

[0022] Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the DCIII crystal form exhibits characteristic peaks at one, two, or three of the following diffraction angles with a 2θ value of 10.1°±0.2°, 12.1°±0.2°, and 14.3°±0.2°; preferably, the X-ray powder diffraction of the DCIII crystal form exhibits characteristic peaks at three of the following diffraction angles with a 2θ value of 10.1°±0.2°, 12.1°±0.2°, and 14.3°±0.2°.

[0023] Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the DCIII crystal form exhibits characteristic peaks at one, two, or three of the following diffraction angles with 2θ values: 21.9°±0.2°, 22.8°±0.2°, and 23.6°±0.2°; preferably, the X-ray powder diffraction of the DCIII crystal form exhibits characteristic peaks at three of the following diffraction angles with 2θ values: 21.9°±0.2°, 22.8°±0.2°, and 23.6°±0.2°.

[0024] On the other hand, using Cu-Ka radiation, the X-ray powder diffraction of the DCIII crystal form exhibits characteristic peaks at diffraction angles of 2θ values ​​of 5.0°±0.2°, 6.3°±0.2°, 7.7°±0.2°, 10.1°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 21.9°±0.2°, 22.8°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 25.3°±0.2°, and 26.5°±0.2°, at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve locations.

[0025] Non-limiting, the X-ray powder diffraction pattern of crystalline DCIII is basically as follows Figure 1 As shown.

[0026] Non-limiting, the DCIII crystal form begins to show an endothermic peak around 331 degrees Celsius, and the differential scanning calorimetry (DSC) chromatogram is basically as follows. Figure 2 As shown.

[0027] A second aspect of the present invention provides a method for preparing the crystal form DCIII, the method comprising: dissolving compound I in an organic solvent, shaking thoroughly and recrystallizing, separating and collecting the solid to obtain the crystal form.

[0028] Further, the organic solvent is an alkane solvent or an ether solvent; preferably, the alkane solvent is cumene, and the ether solvent is methyl tert-butyl ether.

[0029] Furthermore, the selected recrystallization temperature is -20℃ to 60℃; preferably, the selected recrystallization temperature is 0℃ to 25℃.

[0030] A third aspect of the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of crystalline DCIII and a pharmaceutically acceptable carrier or excipient.

[0031] A fourth aspect of the invention provides the use of crystalline DCIII in the preparation of medicaments for treating diseases associated with selective β (THR-β) agonists.

[0032] Furthermore, the use of the crystal form of compound I in the preparation of drugs for treating NASH.

[0033] As described above, the crystal forms of resmetrol compounds, their preparation methods, and uses of the present invention have the following beneficial effects: The different crystal forms of resmetrol provided by the present invention have advantages in terms of physicochemical properties, formulation processing performance, and bioavailability. For example, they have advantages in at least one aspect of melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in vivo and in vitro dissolution, and bioavailability, providing better options for the development of drugs containing resmetrol, which is of great significance. Attached Figure Description

[0034] Figure 1 The image shows the XRPD diagram of the crystal form DCIII obtained according to Example 1a.

[0035] Figure 2 The image shows the DSC diagram of crystal form DCIII obtained according to Example 1a.

[0036] Figure 3 This is a comparison image of XRPD before and after grinding of the DCIII crystal form.

[0037] Figure 4 XRPD comparison images of DCIII crystal form before and after one week of exposure to different ambient humidity levels. Detailed Implementation

[0038] The present invention will be described in detail below with reference to the embodiments, which describe in detail the methods for preparing and using the crystal forms of the present invention. It will be apparent to those skilled in the art that many modifications to both the materials and methods can be made without departing from the scope of the present invention.

[0039] The X-ray powder street pattern disclosed in this invention, and those substantially the same, also fall within the scope of this invention.

[0040] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0041] In this invention, the "stirring" is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm. Magnetic stirring is preferably performed at 300-900 rpm, and mechanical stirring is preferably performed at 100-300 rpm.

[0042] The "separation" is accomplished using conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all the solid settles to the bottom of the centrifuge tube.

[0043] The "drying" can be carried out at room temperature or higher. The drying temperature is from room temperature to about 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. Drying is carried out in a fume hood, forced-air oven, or vacuum oven.

[0044] In this invention, "crystal" or "polymorphic" refers to a solid confirmed by X-ray powder diffraction (XPD) characterization. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray powder diffraction patterns typically vary with different instrument conditions. It should be particularly noted that the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions; therefore, the order of diffraction peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystal. The diffraction peak intensities shown in this invention are illustrative rather than for absolute comparison. Furthermore, experimental errors in diffraction peak positions are typically 5% or less, and these positional errors should also be taken into account, generally allowing for ±0.2%. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in diffraction peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention need not be completely identical to the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern with the same or similar characteristic peaks as those in these patterns is within the scope of the present invention.

[0045] Those skilled in the art can compare the X-ray powder diffraction pattern listed in this invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

[0046] In some embodiments, the DCIII crystal form of the present invention is pure and substantially free of any other crystal form. In this invention, "substantially free" when referring to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, particularly less than 10% (by weight) of other crystal forms, more specifically less than 5% (by weight) of other crystal forms, and even more specifically less than 1% (by weight) of other crystal forms.

[0047] In this invention, the term "about" when used to refer to a measurable value, such as mass, time, temperature, etc., means that it can fluctuate within a certain range around a specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0048] XRPD: X-ray powder diffraction.

[0049] DSC: Differential Scan Calorimetry.

[0050] Instruments and methods used for data acquisition: The X-ray powder diffraction pattern described in this invention was acquired using a Bruker D2PHASER X-ray powder diffractometer.

[0051] The parameters of the X-ray powder diffraction method described in this invention are as follows: X-ray source: Cu Ka; Ka1 (A): 1.54060; Ka2 (A): 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kV; current: 10 mA; scanning range: from 3.0 to 40.0 degrees.

[0052] The differential scanning calorimetry (DSC) images described in this invention are acquired on a Mettler DSC3. The method parameters for differential scanning calorimetry (DSC) are as follows: scan rate: 10℃ / min; protective gas: nitrogen.

[0053] Unless otherwise specified, the following examples are all operated at room temperature. "Room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

[0054] According to the present invention, the compound I and / or its salt as raw materials include, but are not limited to, solid forms (crystalline or amorphous), oily forms, liquid forms, and solutions. Preferably, the compound I and / or its salt as raw materials are in solid form.

[0055] The resimetidine used in the following examples was purchased externally.

[0056] Example 1

[0057] Preparation method of crystal form DCIII

[0058] A certain amount of compound I was weighed and added to a glass bottle. A certain volume of ether or alkane solvent was added at room temperature and the mixture was shaken thoroughly. The bottle was placed on a magnetic stirrer and recrystallized at a certain temperature. After centrifugation and vacuum drying overnight, the solid was removed and XRPD was tested to obtain crystal form DCIII. The selected solvents and recrystallization temperatures in specific examples are shown in the table below:

[0059]

[0060]

[0061] The XRPD pattern of the DCIII crystal form obtained in Example 1a is shown below. Figure 1 As shown in Table 1, the XRPD data is as follows.

[0062] The DSC diagram of the DCIII crystal form obtained in Example 1a is shown below. Figure 2 As shown.

[0063] Table 1

[0064]

[0065]

[0066] Example 2

[0067] Dynamic solubility of crystal form DCIII

[0068] When conducting drug solubility tests to predict drug performance in vivo, it is important to simulate in vivo conditions as closely as possible. For oral medications, SGF (simulating gastric juice), FaSSIF (simulating intestinal juice under fasting conditions), FeSSIF (simulating intestinal juice under eating conditions), or buffers with different pH values ​​can simulate in vivo conditions and predict the effects of eating. Solubility tested in such media is closer to solubility in the human body environment.

[0069] Approximately 20 mg each of the present invention's crystal form DCIII and the prior art's crystal form A were suspended in 1.5 mL of SGF, 1.5 mL of FeSSIF, 1.5 mL of FaSSIF, and 1.5 mL of water to prepare suspensions. After equilibration for 1 hour, 4 hours, and 24 hours, the content (mg / mL) of the sample in the solution was tested by high performance liquid chromatography.

[0070] Example 3

[0071] Packaging stability of crystalline DCIII

[0072] Weigh approximately 5 mg of the crystalline form DCIII prepared in this invention, seal it in an aluminum foil bag, and then place it under conditions of 25℃ / 60%RH, 40℃ / 75%RH, and 60℃ / 75%RH respectively, and determine the crystal form using XRPD.

[0073] Example 4

[0074] Mechanical stability of DCIII crystal form

[0075] The DCIII crystal form was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The XRPD comparison before and after grinding is shown below. Figure 3 The image shows a comparison of XRPD before and after grinding of the DCIII crystal form (the top image is before grinding, and the bottom image is after grinding).

[0076] The results show that the crystal form of DCIII in this invention remains unchanged after grinding, and no significant decrease in crystallinity was observed, which indicates that the crystal form DCIII has good mechanical stability.

[0077] Example 5

[0078] Humidity stability of crystal form DCIII

[0079] Weigh about 5 mg of the crystalline form DCIII prepared in this invention and expose it to open conditions of RT / 22.5%RH, RT / 43%RH and RT / 75%RH for one week respectively. Then, determine the crystalline form using XRPD.

[0080] XRPD comparison images of the present invention's DCIII crystal form before and after one week of exposure under different environmental humidity conditions are shown below. Figure 4 As shown, XRPD comparison images of crystal form DCIII before and after placement under different humidity levels (from top to bottom: sample before placement; RT / 22.5%RH for one week; RT / 45%RH for one week; RT / 75%RH for one week).

[0081] The results show that the crystal form of DCIII of the present invention is stable and unchanged after being exposed to different environmental humidity conditions for one week, which indicates that the crystal form DCIII has good humidity stability and can be stably stored at different humidity levels at room temperature.

[0082] Example 6

[0083] Hygroscopicity of crystal form DCIII

[0084] Approximately 20 mg of the DCIII crystal form of this invention was weighed and placed at 25±1℃ and 80% relative humidity for 24 hours. The mass of the sample before and after the event was recorded. The specific results are shown in the table below.

[0085] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition, General Chapter 9103, Guidelines for Hygroscopicity Tests of Drugs, Experimental Conditions: 25±1℃, 80% Relative Humidity):

[0086] Deliquescence: Absorbs sufficient water to form a liquid.

[0087] Extremely hygroscopic: The weight gain due to moisture absorption is no less than 15.0%.

[0088] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15.0% but not less than 2.0%.

[0089] Slightly hygroscopic: Moisture absorption weight gain is less than 2.0% but not less than 0.2%.

[0090] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0091] Example 7

[0092] Intrinsic dissolution rate of crystal form DCIII

[0093] Weigh approximately 100 mg of the present invention's crystalline form DCIII, pour it into the inherent dissolution mold, and apply a pressure of 5 kN for 1 minute to prepare a solution with a surface area of ​​0.5 cm². 2The thin sheet is transferred to a dissolution apparatus to test the inherent dissolution rate.

[0094] Example 8

[0095] Fluidity of DCIII crystal form

[0096] During the preparation process, the compressibility index or Carr index can usually be used to evaluate the flowability of powders or particles. The measurement method is as follows: a certain amount of crystal form DCIII powder is loaded into a measuring cylinder and the volume before compaction is measured; the powder is brought to its most compacted state by tapping and the volume after compaction is measured; the loose density P0 and the tapped density Pr are calculated; the compressibility index is calculated according to the formula c = (Pr - P0) / Pr.

[0097] The compressibility coefficient is used to define the flowability of powders, as referenced in the USP standard. <1174> See Table 2 for details.

[0098] Table 2

[0099] Compressibility factor (%) Flowability ≦10 Excellent 11-15 Good 16-20 Fair 21-25 Acceptable 26-31 Poor 32-37 Very poor >38 Extremely poor

[0100] Example 9

[0101] Adhesion of crystalline DCIII

[0102] Approximately 30 mg of crystalline DCIII was added to an 8 mm circular flat punch and tableted using a pressure of 10 kN. After tableting, the tablet was held for about half a minute, and the amount of powder adsorbed by the punch was weighed. After pressing twice in this manner, the final cumulative amount of powder adsorbed by the punch, the highest amount of powder adsorbed during the pressing process, and the average amount of powder adsorbed were recorded.

[0103] Example 10

[0104] Formulation preparation of crystalline DCIII

[0105] Tablets: Take an appropriate amount of crystalline DCIII, mix it evenly with the excipients, roll it into thin tablets and crush it into granules, mix it evenly with the added excipients, and press it into shape using a suitable mold.

[0106] Capsules: Take an appropriate amount of crystalline DCIII, mix it evenly with the excipients, roll it into thin sheets and crush it into granules, mix it evenly with the added excipients, and fill it into capsules of appropriate size.

[0107] Example 11

[0108] Stability of crystalline DCIII formulations

[0109] The crystalline DCIII formulation was packaged in HDPE bottles and placed under conditions of 25℃ / 60%RH and 40℃ / 75%RH. Samples were taken to test the crystal form and impurities, and the formulation stability of crystalline DCIII was investigated.

[0110] Example 12

[0111] In vitro dissolution of crystalline DCIII formulation

[0112] For formulations containing crystalline DCIII, the in vitro dissolution was tested, and the dissolution rate was determined according to the Chinese Pharmacopoeia 2020 edition 0931 Dissolution and Release Determination Method.

[0113] In summary, the different crystal forms of compound I provided by this invention have advantages in terms of physicochemical properties, formulation processing performance, and bioavailability. For example, they have advantages in at least one aspect of melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in vitro and in vivo dissolution, and bioavailability. This provides a better option for the development of drugs containing compound I and is of great significance. Therefore, this invention effectively overcomes the various shortcomings of the prior art and has high industrial application value.

[0114] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. Crystal form of the compound shown in formula (I): Preferably, the crystal form is DCIII, the crystal form of compound I.

2. The crystal form according to claim 1, characterized in that, The DCIII crystal form was subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern showed at least one characteristic peak in the diffraction angle 2theta values ​​of 5.0°±0.2°, 6.3°±0.2°, and 7.7°±0.2°. Preferably, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least two characteristic peaks in the diffraction angle 2theta values ​​of 5.0°±0.2°, 6.3°±0.2°, and 7.7°±0.2°. Preferably, the crystal form DCIII is irradiated using Cu-Ka radiation, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2theta of 5.0°±0.2°, 6.3°±0.2° and 7.7°±0.2°.

3. The crystal form according to claim 1, characterized in that, The DCIII crystal form was subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern showed at least one characteristic peak among the diffraction angles 2theta of 10.1°±0.2°, 12.1°±0.2°, and 14.3°±0.2°. Preferably, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least two characteristic peaks in the diffraction angle 2theta values ​​of 10.1°±0.2°, 12.1°±0.2°, and 14.3°±0.2°. Preferably, the crystal form DCIII is irradiated using Cu-Ka radiation, and its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2theta of 10.1°±0.2°, 12.1°±0.2° and 14.3°±0.2°.

4. The crystal form according to claim 1, characterized in that, The DCIII crystal form was subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern showed at least one characteristic peak among the diffraction angles 2theta of 21.9°±0.2°, 22.8°±0.2°, and 23.6°±0.2°. Preferably, the crystal form DCIII is subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern has at least two characteristic peaks in the diffraction angle 2theta values ​​of 21.9°±0.2°, 22.8°±0.2°, and 23.6°±0.2°. Preferably, its X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2theta of 21.9°±0.2°, 22.8°±0.2° and 23.6°±0.2°.

5. The crystal form according to claim 1, characterized in that, The DCIII crystal form was subjected to Cu-Ka radiation, and its X-ray powder diffraction pattern showed at least one characteristic peak among the diffraction angles 2θ values ​​of 5.0°±0.2°, 6.3°±0.2°, 7.7°±0.2°, 10.1°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 21.9°±0.2°, 22.8°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 25.3°±0.2°, and 26.5°±0.2°.

6. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the DCIII crystal form is basically shown in Figure 1; the differential scanning calorimetry (DSC) pattern of the DCIII crystal form is basically shown in Figure 2.

7. A method for preparing the crystal form of compound I according to any one of claims 1 to 6, characterized in that, include: Compound I was dissolved in an organic solvent, shaken thoroughly, and recrystallized. The solid was then separated and collected to obtain the crystal form.

8. The preparation method according to claim 7, characterized in that, The organic solvent is an alkane solvent or an ether solvent; Preferably, the alkane solvent is cumene, and the ether solvent is methyl tert-butyl ether; The selected recrystallization temperature is -20℃ to 60℃; preferably, the selected recrystallization temperature is 0℃ to 25℃.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: The crystal form of compound I according to claims 1-8; and Pharmaceutically acceptable carriers or excipients.

10. Use of the crystal form of compound I according to claims 1 to 8 in the preparation of a THR-β agonist drug; preferably, use of the crystal form of compound I in the preparation of a drug for treating NASH.

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