Crystalline form of resmetirom, preparation method therefor, and use thereof

Abstract

To provide a new crystal form of lesmerome having improved characteristics and a method for preparing the same.SOLUTION: Crystalline form CSVI having an XRPD pattern as shown in the Figure is obtained by a process comprising: (1) adding Compound I below to a nitrile or a solvent mixture of nitrile and water, stirring, separating and drying to obtain Form CSVI; or (2) dissolving Compound I below in a solvent mixture of nitrile and water or a solvent mixture of nitrile and alcohol, filtering, cooling and stirring the filtrate to obtain a solid, separating and drying to obtain Form CSVI.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (Technical field) The present invention relates to the field of chemical crystallography, and in particular to novel crystalline forms of resmetirom, their preparation. Law and use. [Background technology]

[0002] Heterozygous familial hypercholesterolemia (HeFH) is a condition that causes a variety of life-threatening cardiovascular It is the most serious lipid metabolism disorder that can lead to complications. Hepatic steroidogenesis (SH) is a severe liver disease with steatosis associated with inflammation and hepatocellular injury. As a selective agonist of the hormone receptor THR-β, resmetirom inhibits the activity of low-density lipoprotein Reduces levels of cholesterol, triglycerides, and liver fat in individuals with NASH It is thought to improve the symptoms of NASH and HeFH by stimulating hepatic mitochondrial biogenesis in Resmetirom has shown positive results in phase 2 trials for NASH and HeFH. Achieve sexuality.

[0003] The chemical name of resmetirom is 2-(3,5-dichloro-4-((5-isopropyl-6 -oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-di 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile ( Compound I) and its structure is as follows: [ka]

[0004] Crystalline morphology is a state in which the components are arranged in a highly ordered microstructure that extends in all directions. Polymorphism is the ability of a compound to exist in more than one crystalline form. A compound may exist in one or more crystalline forms, but their existence and The properties cannot be predicted with certainty. Different crystalline forms of drug substance have different physicochemical properties. This can affect the drug's dissolution and absorption in vivo and affect the clinical In particular, some poorly soluble oral solids In solid or semi-solid dosage forms, the crystalline form can be important to the performance of the formulation. The physiochemical properties of the forms are very important for the manufacturing process. , an important part of drug research and drug quality control. Compound I hydrate, anhydrous form I, The dimethyl isobutyl ketone solvate and the dimethyl acetamide solvate are disclosed in the prior art U.S. According to the ICH guidelines for classification of solvents, For example, methyl isobutyl ketone and dimethylacetamide are both Class II solvents. Its use is restricted, it is highly toxic and not suitable for medicinal purposes. 861B2 discloses that the purity of Compound I hydrate is only 96.4% (HPLC). High impurity content can cause changes in the appearance of the drug, affecting its stability, Increased toxicity and side effects.

[0005] Calcium, magnesium, sodium, potassium salts, and ethanolamine Various crystalline forms of Compound I, including salts, are disclosed in WO2020010068A1 At the same time, various solvates (methanol solvate, acetone solvate, tetrahydrofuran solvate, solvate, methyl isobutyl ketone solvate, acetonitrile solvate, dimethyl sulfoxide methoxide solvate, dimethylacetamide solvate, etc.) and several desolvates Twenty-seven free crystalline forms of Compound I were also disclosed. According to the experimental research of the inventors of the present disclosure, the results disclosed in US9266861B2 Form A and Form I are the same crystalline form, and the desolvated form F is highly hygroscopic and desolvated. Solvate Forms S+T, V, W, and Z are all non-single crystalline forms. It is a mixture composed of

[0006] Crystalline Form I is a known solid form of Compound I with better properties, but from specific starting materials such as isobutyl ketone solvate and dimethylacetamide solvate The inventors of the present disclosure have prepared the The preparation process was repeated to obtain crystalline form I, which was further characterized. Low solubility of Form I, poor grinding stability since most of Form I transforms into amorphous form after grinding This indicates that the material has low compressibility and very low flowability. High solubility, good physicochemical stability, safety and non-toxicity, and good physicochemical properties A single crystalline form of Compound I having the desired properties is still needed for the development of drugs containing Compound I. It has been done.

[0007] The inventors of the present disclosure have conducted numerous experimental studies on Compound I and have demonstrated its suitability for medicinal use. More than 300 experiments have been carried out, but most is a methanol solvate, acetone solvate, tetrahydrofuran solvate, chlorobenzene solvates of Compound I, such as toluene solvate, cyclohexanone solvate, The inventors of the present disclosure have found that Compound I is highly susceptible to combining with solvents to form solvates. However, it has been found that it is very difficult to obtain a stable, non-solvated single crystalline form.

[0008] The inventors of the present disclosure have surprisingly found that the solubility, hygroscopicity, purification ability, stability, adhesiveness, A few properties such as compressibility, flowability, in vitro and in vivo dissolution, and bioavailability We have discovered a crystalline form of Compound I, CSVI, which has advantages in at least one aspect. In particular, The crystalline form of Compound I of the present disclosure has high solubility, good physicochemical stability, and good mechanical stability. Good flowability, good compressibility, low adhesion, and good formulation stability. Which advantages it has, which solves the problems existing in the prior art, and which are useful for the preparation of drugs containing Compound I It is very important for development. Summary of the Invention

[0009] The present disclosure relates to novel crystalline forms of Compound I, methods for their preparation, and pharmaceutical compositions containing the crystalline forms. The present invention provides a composition.

[0010] For purposes of this disclosure, crystalline form CSVI of Compound I (hereinafter referred to as Form CSVI) is provided.

[0011] In one embodiment provided herein, the X-ray powder diffraction pattern of crystalline form CSVI is CuK 9.6°±0.2°, 10.1°±0.2°, and 18.9°± It contains a characteristic peak at a 2θ value of 0.2°.

[0012] Furthermore, the X-ray powder diffraction pattern of the crystalline form CSVI was obtained using CuKα radiation. 1 at 2θ values ​​of 1.6°±0.2°, 19.5°±0.2°, and 23.3°±0.2° Preferably, the X-ray powder diffraction pattern of Form CSVI contains one, two, or three characteristic peaks. The fold pattern is 11.6°±0.2° and 19.5°±0.2° using CuKα radiation. , and a characteristic peak at a 2θ value of 23.3°±0.2°.

[0013] Furthermore, the X-ray powder diffraction pattern of the crystalline form CSVI was obtained using CuKα radiation. at 2θ values ​​of 3.7°±0.2°, 20.6°±0.2°, and 31.9°±0.2°. Preferably, the X-ray powder diffraction pattern of Form CSVI contains one, two, or three characteristic peaks. The fold pattern is 13.7°±0.2° and 20.6°±0.2° using CuKα radiation. , and a characteristic peak at a 2θ value of 31.9°±0.2°.

[0014] In another aspect provided herein, the X-ray powder diffraction pattern of crystalline form CSVI is Using uKα radiation, 9.6°±0.2°, 10.1°±0.2°, 11.6°±0. 2°, 18.9°±0.2°, 19.5°±0.2°, 23.3°±0.2°, 13.7 °±0.2°, 20.6°±0.2°, 31.9°±0.2°, 6.5°±0.2°, 1 6.2°±0.2°, 21.9°±0.2°, 24.1°±0.2°, 24.8°±0. 2°, 25.7°±0.2°, 26.7°±0.2°, 27.3°±0.2° and 31 It contains at least three characteristic peaks at 2θ values ​​of 0.1°±0.2°.

[0015] Without implying any limitation, the X-ray powder diffraction pattern of crystalline form CSVI is substantially As shown in Figure 1.

[0016] Although not limited to this, the thermogravimetric analysis (TGA) curve of the crystalline form CSVI is 2, which is substantially as shown in FIG. 2, and which has a 0.2% weight loss when heated to 250° C. Indicates a decrease.

[0017] Without implying any limitation, the weight gain of crystalline form CSVI at 25°C / 80%RH The crystalline form CSVI is non-hygroscopic or almost non-hygroscopic. The dynamic vapor sorption (DVS) plot for Form CSVI is substantially as shown in Figure 3. This is as expected.

[0018] Without being limited thereto, the crystalline form CSVI is an anhydrous form.

[0019] In accordance with the purposes of the present disclosure, there is also provided a process for preparing Form CSVI. teeth:

[0020] Method (1): Compound I is added to a nitrile or a solvent mixture of a nitrile and water, and the mixture is stirred. , separating and drying to obtain form CSVI; or

[0021] Method (2): Compound I is dissolved in a solvent mixture of nitrile and water or a solvent of nitrile and alcohol. The mixture is dissolved, filtered, and the filtrate is cooled and stirred to obtain a solid, which is separated and dried to obtain Form CS. Get VI.

[0022] Furthermore, in the method (1), the nitrile is preferably acetonitrile, and the solvent The volume ratio of acetonitrile to water in the mixture is preferably 95:5; in method (2), The nitrile is preferably acetonitrile and the alcohol is preferably isopropyl alcohol. propanol, and the volume ratio of acetonitrile to water in the solvent mixture is preferably 95:5 and the volume ratio of acetonitrile to isopropanol in the solvent mixture is preferably 1:1 is.

[0023] Furthermore, in the method (1), the stirring temperature is preferably −20° C. to 76° C., more preferably The drying temperature is preferably from -20°C to 30°C, and the drying temperature is preferably from 10°C to 70°C, and The temperature is preferably 10°C to 40°C.

[0024] Furthermore, in the method (1), the dissolution temperature is preferably 40°C to 76°C, The cooling temperature is preferably −20° C. to 5° C., more preferably −20° C. The drying temperature is preferably 10°C to 70°C, and more preferably 10°C to 40°C.

[0025] For purposes of this disclosure, the present disclosure also provides methods for preparing other crystalline forms or salts of Compound I. This provides the use of the CSVI format.

[0026] In accordance with the object of the present disclosure, there is provided a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of crystalline Form CSVI and pharmaceutically acceptable excipients.

[0027] Further, for purposes of this disclosure, crystalline form CSVI is a THR-β selective agonist drug. can be used to prepare

[0028] The crystalline form CSVI of the present disclosure has the following advantages:

[0029] (1) Compared with the prior art, the crystalline form CSVI has higher solubility, especially SGF In the present invention, the solubility of CSVI form is approximately twice that of form I in the prior art.

[0030] Compound I is a poorly water-soluble drug. The crystalline form of CSVI drug substance provided by the present disclosure Higher solubility is useful for improving the in vivo absorption and bioavailability of drugs. In addition, the higher solubility allows for a higher drug dose without affecting efficacy. It is possible to reduce the side effects of drugs and improve drug safety. Improve.

[0031] (2) Compared with the prior art, the crystalline form CSVI has lower hygroscopicity. The test results show that , the weight gain of crystalline form I in the prior art is about twice that of crystalline form CSVI. This indicates that...

[0032] In one aspect, low hygroscopicity tends to cause chemical decomposition and polymorphic transformations, This directly affects the physicochemical stability of the drug substance. In addition, low hygroscopicity can affect the flowability of the drug substance. This reduces the activity of the drug substance, thereby affecting its processing.

[0033] In another aspect, poorly hygroscopic drug substances require a low humidity environment during manufacturing and storage, More importantly, low moisture absorption means lower production costs. The content of the active pharmaceutical ingredient in the formulation may vary, thus affecting the quality of the formulation. High potential.

[0034] (3) Compared with the prior art, the crystalline form CSVI of the present disclosure has better compressibility. Hardness / friability testing and tablet cracking issues are avoided due to better compressibility.

[0035] (4) Compared with the prior art, the crystalline form CSVI of the present disclosure exhibits low adhesiveness. The evaluation results show that the amount of adhesion of crystalline form I in the prior art is five times that of crystalline form CSVI. Low adhesion reduces clumping of the drug substance and aids in roller adhesion during dry granulation and compression processes. It can effectively improve the adhesion of the drug substance and excipients to the tooling. This contributes to improving the dispersion of the materials and the mixing uniformity of the materials, ultimately improving the product quality.

[0036] (5) The CSVI drug substance of the present disclosure has good physicochemical stability. 25°C / 60%RH When stored in an open sealed package under the conditions below, the crystalline form of the CSVI drug substance remains at least Unchanged for 6 months. Chemical purity is greater than 99.7% and remains virtually unchanged during storage. The crystalline form CSVI is mixed with excipients to form a product, which is then stored at 25°C / 60% RH. After storage under these conditions, the crystalline state of the CSVI product remains unchanged for at least 3 months. The chemical purity remains substantially unchanged during storage. These results confirm the effectiveness of crystalline form C. The SVI drug substance has good stability under long-term conditions both by itself and in the formulation, and This indicates that it is useful for storing things.

[0037] On the other hand, the crystalline state of the CSVI drug substance is maintained at 40°C / 75%RH after opening and sealing the package. When stored in a sealed container, it remains unchanged for at least 6 months. Its chemical purity is greater than 99.7%. It remains substantially unchanged during storage. The crystalline form CSVI is mixed with excipients to form a formulation. After storage at 40°C / 75%RH, the crystalline form of the CSVI formulation was slightly crystalline. Chemical purity remains substantially unchanged during storage. These results demonstrate that the crystalline form of the CSVI drug substance, both by itself and in the formulation, performs well under accelerated conditions. Good stability under accelerated conditions is crucial for drug development. Drug substances and drug products are subject to the effects of seasons, local climates, and other factors during storage, transportation, and manufacturing processes. Due to the difference in the environment, the product is exposed to high temperature and humidity conditions. Therefore, it has good stability under accelerated conditions. The crystalline form of the CSVI drug substance is very important for drug development. It has good stability under stress conditions both in the formulation and in the crystalline transformation or drug storage. This is beneficial in avoiding the impact on drug quality due to a decrease in purity during storage.

[0038] (6) The crystalline form CSVI of the present disclosure has good physical stability under mechanical forces. The crystalline form of CSVI remains unchanged after milling. Milling and grinding are often performed in pharmaceutical manufacturing processes. Good physical stability of the drug substance is required to prevent crystallization during the drug manufacturing process. The risk of deterioration and crystal transformation can be reduced. It has good physical stability under force, which helps keep the crystalline form unchanged during the tableting process. It is beneficial to

[0039] The good physical and chemical stability of the drug substance prevents crystal changes during manufacturing and storage. The crystalline form CSVI has good physical and chemical properties. Stability ensures consistent and controllable quality of drug substance and drug product, preventing crystal transformation or impurities This minimizes changes in quality, bioavailability, and toxicity due to product formation. [Brief explanation of the drawings]

[0040] [Figure 1] FIG. 1 shows the XRPD pattern of crystalline form CSVI according to Example 1.

[0041] [Figure 2] FIG. 2 shows the TGA curve of the crystalline form CSVI according to Example 1.

[0042] [Figure 3] FIG. 3 shows the DVS plot of crystalline form CSVI according to Example 1.

[0043] [Figure 4] 4 shows an XRPD pattern overlay of crystalline form CSVI after the round bottom of the DVS test according to Example 1 (top: DVS round bottom, bottom: after DVS).

[0044] [Figure 5] FIG. 5 shows the XRPD pattern of crystalline form CSVI according to Example 2.

[0045] [Figure 6] Figure 6 shows the XRPD pattern overlay of crystalline form CSVI before and after storage under different conditions (top to bottom: initial, 25 °C / 60% RH, 6 months, open package, 40 °C / 75% RH, 6 months, open package).

[0046] [Figure 7] Figure 7 shows the XRPD pattern overlay of crystalline form CSVI before and after storage under different conditions (top to bottom: initial, 25 °C / 60% RH, sealed packaging for 6 months, 40 °C / 75% RH, sealed packaging for 6 months).

[0047] [Figure 8] Figure 8 shows the XRPD pattern overlay of crystalline form CSVI with different pressure conditions (top to bottom: 14 kN, 7 kN, 3 kN, initial).

[0048] [Figure 9] FIG. 9 shows an XRPD pattern overlay of crystalline form CSVI before and after the formulation process (top to bottom: blank tablet, after the formulation process, crystalline form CSVI).

[0049] [Figure 10] FIG. 10 shows XRPD pattern overlays of crystalline form CSVI formulations before and after storage under sealed conditions (top to bottom: initial, 25° C. / 60% RH for 3 months, 40° C. / 75% RH for 3 months). DETAILED DESCRIPTION OF THE INVENTION

[0050] The present disclosure is further illustrated by the following examples which describe in detail the preparation and use of the crystalline forms of the present disclosure. Modifications in materials and methods may be accomplished without departing from the scope of the present disclosure. It will be clear to one skilled in the art that this can be achieved.

[0051] Abbreviations used in this disclosure are explained as follows: XRPD: X-ray powder diffraction TGA: Thermogravimetric analysis DVS: Dynamic Vapor Sorption 1 H NMR: proton nuclear magnetic resonance HPLC: High-performance liquid chromatography BCS: Biopharmaceutic Classification System RH: Relative humidity ICH: International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use

[0052] Equipment and methods used to collect data:

[0053] X-ray powder diffraction patterns in this disclosure were obtained using a Bruker D2 PHASER X-ray powder diffraction The X-ray powder diffraction parameters for the present disclosure were as follows: X-ray source: Cu, Kα Kα1(Å):1.5406;Kα2(Å):1.54439 Kα2 / Kα1 intensity ratio: 0.50 Voltage: 30 (kV) Current: 10(mA) Scanning range (2θ): 3.0 degrees to 40.0 degrees

[0054] The thermogravimetric analysis (TGA) data in this disclosure was obtained using a TA Q500. The parameters of the disclosed TGA method are as follows: Heating rate: 10℃ / min Purge gas: N2

[0055] Dynamic Vapor Sorption (DVS) is a surface measurement system (SMS). The measurements were taken via the in-house DVS instrument (Stems Ltd.). The instrument control software was DVS-Intrinsic control software. Typical for DVS testing. The parameters are: Temperature: 25℃ Gas and flow rate: N2, 200mL / min RH range: 0%RH~95%RH

[0056] Proton nuclear magnetic resonance spectrum data ( 1 H NMR) on a Bruker Avance II The data were collected from a DMX 400 MHz NMR spectrometer. 1-5 mg of sample was weighed and 0. Dissolve in 5 mL of deuterated dimethyl sulfoxide to obtain a solution with a concentration of 2-10 mg / mL. Ta.

[0057] The parameters for related substance detection in this disclosure are shown in Table 1.

[0058] [Table 1]

[0059] The parameters for solubility detection in this disclosure are shown in Table 2.

[0060] [Table 2]

[0061] In this disclosure, the term "stirring" refers to using conventional methods such as magnetic stirring or mechanical stirring. The stirring speed is 50 to 1800 r / min. Preferably, the magnetic stirring speed is 30 The speed of the mechanical stirring is 100-300 r / min.

[0062] The "separation" may be carried out using conventional methods in the art such as centrifugation or filtration. The operation of "centrifugation" is as follows: the sample to be separated is centrifuged. The mixture was then centrifuged at a speed of 10,000 rpm until all the solids had settled to the bottom of the tube. Separate.

[0063] The "drying" may be performed by any method known in the art, such as vacuum drying, blast drying, or free air drying. This can be achieved by using conventional methods. The drying temperature may be room temperature or higher. Preferably, the drying temperature is from room temperature to about 60°C, or 50°C, or 40°C. Drying can be done in a fume hood, forced air or air dryer, or overnight. This is accomplished in a flow oven or vacuum oven.

[0064] The "characteristic peak" refers to a typical diffraction peak used to distinguish crystals, Typically, one can have a deviation of ±0.2° using CuKα radiation.

[0065] In the present disclosure, a "crystal" or "crystalline form" refers to a crystal having an X-ray diffraction pattern shown herein. Those skilled in the art will recognize that X-ray powder diffraction patterns are useful for determining the crystal or crystalline form of a compound. It can be seen that the results depend on the conditions of the instrument, the sample preparation, and the purity of the sample. The relative intensities of the diffraction peaks in the diffraction pattern may also vary depending on the experimental conditions; Therefore, the order of the diffraction peak intensity cannot be considered the only or decisive factor. In this case, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals. The diffraction peak intensities shown herein are exemplary and do not necessarily represent identical diffraction peak intensities. Therefore, the crystalline forms of the present disclosure do not necessarily correspond entirely to the examples shown herein. It will be understood by those skilled in the art that the X-ray diffraction patterns need not be identical. Any crystalline form having an X-ray diffraction pattern with the same or similar characteristic peaks is considered to be a crystal form of the present disclosure. Those skilled in the art will be able to interpret the patterns shown in this disclosure as patterns of unknown crystalline forms. Compared with turns, do these two groups of patterns reflect the same or different crystal morphologies? It is possible to identify whether

[0066] In some embodiments, the crystalline form CSVI of the present disclosure is pure and does not contain any other In the present invention, the term "substantially free" means that the When used to describe a crystalline form, the inclusion of other crystalline forms in the novel crystalline form an amount of less than 20% (w / w), particularly less than 10% (w / w), more particularly less than 5% (w / w); More specifically, it means that the concentration is less than 1% (w / w).

[0067] In this disclosure, the term "about" when referring to a measurable value such as weight, time, temperature, etc. Includes variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount It means to do.

[0068] Unless otherwise noted, the following examples were carried out at room temperature. The temperature range is 10 to 30°C.

[0069] According to the present disclosure, Compound I used as a raw material is in the form of a solid (crystalline or amorphous) These include, but are not limited to, liquids, semi-solids, waxes, oils, liquid crystalline forms or solutions. Preferably, the compound I used as a starting material is a solid. [Example]

[0070] The raw materials of Compound I used in the following examples are disclosed in the prior art, for example, WO20200100 68A1.

[0071] Example 1-2: Preparation of crystalline form CSVI

[0072] Example 1 1.5801 g of compound I was weighed into a glass bottle, followed by the addition of 25 mL of acetonitrile. The mixture was then stirred at room temperature for 4 days. The resulting solid was separated by filtration, and the resulting solid was The solid was blast dried at 40° C. for 15.5 hours to obtain crystalline form CSVI of the present disclosure.

[0073] The XRPD pattern of crystalline form CSVI is substantially as shown in Figure 1. The data are listed in Table 3.

[0074] The TGA curve of the crystalline form CSVI is substantially as shown in Figure 2, and when heated to 250°C, When the temperature is increased, the weight loss is about 0.2%.

[0075] The crystal form of CSVI 1 H NMR data is 1 H NMR (400 MHz, DM SO-d6)δ13.28(s, 1H), 12.23(s, 1H), 7.79(s, 2H ), 7.44(d, J = 0.8Hz, 1H), 3.04(dq, J=13.5, 6. 8Hz, 1H), 1.20 (d, J = 6.9Hz, 6H).

[0076] The DVS plot of crystalline form CSVI is substantially as shown in Figure 3, and is The weight gain rate of crystalline form CSVI at 0% RH was 0.07%. indicates non-hygroscopic or nearly non-hygroscopic.

[0077] As shown in Figure 4, the XRPD patterns of the crystalline form CSVI before and after the DVS test are Ray has shown that the crystalline form of CSVI does not change after DVS testing.

[0078] [Table 3] JPEG2026016692000006.jpg166168

[0079] Example 2 22.0 mg of Compound I was weighed into a glass vial, followed by 2.0 mL of acetonitrile and water. A mixture of the solvents (95:5, V:V) was added, and then the mixture was dissolved at 50°C and filtered. The solution was stirred at -20°C for 4 hours. The obtained solid was separated by filtration, and then the obtained solid was Drying under vacuum at 25°C for 2 hours gave the crystalline form CSVI of the present disclosure.

[0080] The XRPD pattern of crystalline form CSVI is substantially as shown in Figure 5. The data are listed in Table 4.

[0081] [Table 4] JPEG2026016692000008.jpg66169

[0082] Example 3: Solubility of crystalline form CSVI and crystalline form I in the prior art When solubility tests are used to predict the in vivo performance of drugs, in vivo conditions must be simulated. It is important to simulate as closely as possible. Simulated Gastric Fluid (SGF) can be used to simulate in vivo conditions and predict the effects of feeding Thus, the solubility in this medium is closer to that in vivo.

[0083] 15 mg of crystalline form CSVI was suspended in 2.0 mL of SGF. Equilibrated at 37°C for 1 hour. After the addition, the concentration of the saturated solution was measured by HPLC. The results are shown in Table 5.

[0084] [Table 5]

[0085] The results show that the crystalline form CSVI has higher solubility after one equilibration in SGF, resulting in The solubility of crystalline form CSVI is shown to be approximately twice that of Form I in the prior art.

[0086] Example 4: Hygroscopicity of crystalline form CSVI and crystalline form I in the prior art Dynamic vapor sorption (DVS) analyzer was applied to analyze the crystal morphology CSVI and The hygroscopicity of crystalline Form I was evaluated using appropriate amounts. The weight gain at each relative humidity was measured in the range of 0 to 95%. RH cycles were recorded.

[0087] The DVS plot for crystalline form CSVI is substantially as shown in Figure 3. The XRPD pattern overlay before and after the DVS test of CSVI is essentially as shown in Figure 4. It is.

[0088] The results show that the weight gain of the crystalline form CSVI at 25°C / 80%RH is 0.07%. The weight gain of crystalline form I in the prior art at 25°C / 80%RH is 0.13%. The weight gain of crystalline form I in the prior art is about 2 times that of crystalline form CSVI. It's double.

[0089] Example 5: Physical and chemical stability of crystalline form CSVI An appropriate amount of crystalline form CSVI was added to the sol at 25°C / 60% RH and 40°C / 75% RH. The crystal morphology and chemical purity were determined by XRPD and HPLC, respectively. The results are shown in Table 6, and the XRPD overlays are shown in Figures 6 and 7. show.

[0090] [Table 6]

[0091] The results show that the crystal form CSVI in the open and sealed packages was stored at 25°C / 60% RH and 4 It has been shown to be stable for at least 6 months at 0°C / 75% RH. Crystal form: CSVI has good stability both long-term and under accelerated conditions.

[0092] Example 6: Physical stability of crystalline form CSVI against mechanical forces Pressure Stability An ENERPAC manual tablet press was used for compression. 20 mg of crystalline form CSVI was compressed into a 6 mm diameter tablet press. The crystal morphology before and after tableting was measured using X-ray diffraction (XRD) and X-ray diffraction (XRD) at different pressures. The results are shown in Table 7. XRPD of crystalline form CSVI before and after tableting The pattern overlay is shown in Figure 8.

[0093] [Table 7]

[0094] The results show that the crystalline form CSVI has good stability under different pressures.

[0095] Grinding Stability A solid sample of crystalline form CSVI was manually ground in a mortar for 5 minutes. It remained stable before and after grinding.

[0096] Example 7: Flowability of crystalline form CSVI and crystalline form I in the prior art The compressibility index is typically used to evaluate the flowability of powders or granules during formulation processes. The compressibility index test method was to add a certain amount of powder to a measuring cylinder and record the bulk volume. The powder was then tapped to form the most compact mass and the tapped volume was recorded. Calculate the density (ρ0) and tap density (ρf) and calculate the compressibility index c = (ρf-ρ0) / ρf Therefore, the calculation was carried out. Flowability criteria according to ICH Q4B Annex 13 are shown in Table 8.

[0097] [Table 8]

[0098] The results show that the flowability of crystalline form I in the prior art is very poor. The liquidity of SVI is superior to that of Type I in the prior art.

[0099] Example 8: Compressibility of crystalline form CSVI and crystalline form I in the prior art An ENERPAC manual tablet press was used for compression. Prior art crystalline forms CSVI and 80 mg of Form I was weighed and added to a Φ6 mm round tool die and manually compressed at 10 KN. Then, the specimen was stored at room temperature for 24 hours until complete elastic recovery. The diameter (D) and thickness (L) were measured. The hardness (H) was tested using an intelligent tablet hardness tester. The tensile strength at the end of the test piece was calculated using the following formula: T = 2H / πDL. The higher the degree, the better the compressibility. The results are shown in Table 9.

[0100] [Table 9]

[0101] The results show that crystalline form CSVI has better compaction properties compared to crystalline form I in the prior art. Indicates that it has a certain quality.

[0102] Example 9: Adhesion of crystalline form CSVI and crystalline form I in the prior art 30 mg of the prior art crystalline form CSVI and crystalline form I were weighed and then placed in a Φ8 mm round The punch was then weighed and pressed into the tool die at 10 KN and held for 30 seconds. The amount of material adhering to the punch during compression was calculated. The maximum and average amounts of material adhering to the punch during compression were recorded. Detailed experimental results are shown in Table 10.

[0103] [Table 10]

[0104] The test results showed that the amount of crystalline form I attached to the punch in the prior art was comparable to that of crystalline form CSVI. The adhesion of CSVI is superior to that of the prior art crystalline forms.

[0105] Example 10: Preparation of CSVI formulation The formulation and preparation process of crystalline form CSVI are shown in Tables 11 and 12, respectively. XRPD overlays of the samples before and after formulation are shown in Figure 9. The results show that It was shown that the crystal form CSVI remained stable.

[0106] [Table 11]

[0107] [Table 12]

[0108] Example 11: Stability of Crystalline Form CSVI in Formulations Crystalline form CSVI tablets were packed in HDPE bottles with 1g of desiccant and stored at 25℃ / 60 The crystal morphology and impurities of the sample were analyzed. The stability of the CSVI formulation was confirmed by the test. The results are shown in Table 13. An XRPD overlay of the morphology CSVI formulation is shown in FIG.

[0109] [Table 13]

[0110] The results show that the crystalline CSVI formulation exhibited at least It also shows that the stability can be maintained for 3 months.

[0111] The above examples are merely intended to illustrate the technical concepts and features of the present disclosure, and are not intended to be limiting unless otherwise specified. is intended to enable any person skilled in the art to understand and practice the present disclosure. and should not be concluded to limit the scope of protection of the present disclosure. Any equivalent variations or modifications should be covered by the protection scope of this disclosure.

Claims

1. Crystalline form CSVI of Compound I, having an X-ray powder diffraction pattern containing characteristic peaks at 2θ values ​​of 9.6°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 18.9°±0.2°, 20.6°±0.2°, and 31.9°±0.2° using CuKα radiation. 【Chemistry 1】

2. 2. The crystalline form CSVI of compound I of claim 1, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2θ values ​​of 11.6°±0.2°, 19.5°±0.2°, and 23.3±0.2° using CuKα radiation.

3. 10. A method for preparing crystalline form CSVI of Compound I according to claim 1, comprising: (1) adding Compound I to a nitrile or a solvent mixture of nitrile and water, stirring, separating, and drying to obtain crystalline form CSVI; or (2) dissolving Compound I in a solvent mixture of nitrile and water or a solvent mixture of nitrile and alcohol, filtering, cooling the filtrate, stirring to obtain a solid, isolating and drying to obtain crystalline form CSVI.

4. In the method (1), the nitrile is acetonitrile, and the volume ratio of acetonitrile to water in the solvent mixture is 95:5; 4. The method according to claim 3, wherein in the method (2), the nitrile is acetonitrile, the alcohol is isopropanol, the volume ratio of acetonitrile to water in the solvent mixture is 95:5, and the volume ratio of acetonitrile to isopropanol in the solvent mixture is 1:

1.

5. In the method (1), the stirring temperature is −20° C. to 76° C., and the drying temperature is 10° C. to 70° C.; The method according to claim 3, wherein in the method (2), the dissolving temperature is 40°C to 76°C, the cooling temperature is -20°C to 5°C, and the drying temperature is 10°C to 70°C.

6. In the method (1), the stirring temperature is −20° C. to 30° C., and the drying temperature is 10° C. to 40° C.; The method according to claim 5, wherein in the method (2), the cooling temperature is −20° C. and the drying temperature is 10° C. to 40° C.

7. 10. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form CSVI of Compound I of claim 1 and a pharmaceutically acceptable excipient.

8. A method for preparing a THR-β selective agonist drug, comprising using crystalline form CSVI of compound I of claim 1.

9. 10. A method for preparing a medicament for treating NASH and HeFH, comprising using crystalline form CSVI of compound I of claim 1.

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