Resmetirom crystal form and its preparation method and use

Abstract

The present invention relates to a new crystalline form of Resmetirom (referred to as "Compound I") and its preparation method, a pharmaceutical composition containing this crystalline form, and the use of this crystalline form in the preparation of THR-β selective agonist drugs and drugs for the treatment of NASH and HeFH. The crystalline form of Compound I provided by this invention has one or more improved properties compared to the prior art, solves problems existing in the prior art, and is of great value to the optimization and development of drugs containing Compound I. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of crystal chemistry, and more particularly to a crystal form of Resmetirom, a preparation method thereof, and uses thereof. Background Art

[0002] Heterozygous familial hypercholesterolemia (HeFH) is the most severe of lipid metabolism diseases and can lead to a variety of life-threatening cardiovascular complications. Non-alcoholic steatohepatitis (NASH) is a serious liver disease characterized by fatty degeneration with inflammation and liver cell damage. Resmetirom, a selective agonist of the thyroid hormone receptor THR-β, can improve the symptoms of NASH and HeFH by lowering low-density lipoprotein cholesterol, triglycerides, and liver fat levels, and stimulating liver mitochondrial biogenesis in NASH individuals. Resmetirom has achieved positive results in Phase II clinical trials for NASH and HeFH.

[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-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (hereinafter referred to as "Compound I"), and its structural formula is as follows:

[0004]

[0005] A crystal is a solid formed by the three-dimensional, orderly arrangement of compound molecules within a microstructure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted. APIs with different crystalline forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the drug's clinical efficacy to a certain extent. In particular, for some poorly soluble oral solid or semisolid dosage forms, the crystalline form is crucial to product performance. Furthermore, the physicochemical properties of the crystalline form are crucial to the production process. Therefore, polymorphism is an important aspect of pharmaceutical research and drug quality control. US9266861B2 discloses a hydrate, anhydrous crystalline Form I, a methyl isobutyl ketone solvate, and a dimethylacetamide solvate of Compound I. According to the ICH regulations for the classification of residual solvents, methyl isobutyl ketone and dimethylacetamide are both Class II solvents, which are severely toxic and restricted in use and are not suitable for pharmaceutical use. US9266861B2 discloses that the purity of the hydrate of Compound I is only 96.4% (HPLC). The high impurity content thereof may cause variations in the appearance of the drug, affect the stability of the drug, and increase toxic side effects.

[0006] WO2020010068A1 discloses various salt forms such as calcium salt, magnesium salt, sodium salt, potassium salt, ethanolamine salt of compound I. At the same time, it discloses 27 free state crystal forms of compound I, including various solvate crystal forms (such as methanol solvate, acetone solvate, tetrahydrofuran solvate, methyl isobutyl ketone solvate, acetonitrile solvate, dimethyl sulfoxide solvate, dimethylacetamide solvate) and multiple desolvate crystal forms. According to the contents disclosed in WO2020010068A1 and the experimental studies conducted by the inventors of the present application, Form A is the same crystal form as Form I disclosed in US9266861B2, and the hygroscopicity of desolvate crystal form F is large, and desolvate crystal forms S+T, Form V, Form W, and Form Z are all mixed crystals composed of non-single crystal forms.

[0007] Form I is a known solid form of Compound I with relatively good properties, but Form I must be prepared from specific starting materials, such as methyl isobutyl ketone solvate and dimethylacetamide solvate. The inventors of the present application repeated the preparation method disclosed in US Pat. No. 9,266,861B2 to obtain Form I and characterized the properties of Form I. The results showed that Form I had low solubility, poor grinding stability, and was mostly amorphous after grinding. It also had poor compressibility and extremely poor fluidity. Therefore, there is still a need in the art to develop a single crystalline form of Compound I with high solubility, good physicochemical stability, safety, non-toxicity, and good physicochemical properties for the development of drugs containing Compound I.

[0008] The inventors of the present application conducted extensive experimental research on Compound I in an attempt to obtain a more pharmaceutically suitable crystalline form. Over 300 experiments were conducted, but most of the results were solvates of Compound I, such as methanol solvate, acetone solvate, tetrahydrofuran solvate, chlorobenzene solvate, toluene solvate, and cyclohexanone solvate. The inventors of the present application discovered that Compound I readily combines with solvents to form solvates, making it extremely difficult to obtain a stable, non-solvated single crystalline form.

[0009] The inventors of the present application unexpectedly discovered that the Compound I crystalline form CSVI provided by the present invention has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability. In particular, it has high solubility, good physicochemical stability, good mechanical stability, low hygroscopicity, good fluidity, good compressibility, low adhesion, and good formulation stability. This solves the problems existing in the prior art and is of great significance to the development of drugs containing Compound I. Summary of the Invention

[0010] The present invention provides a new crystal form of Compound I, a preparation method thereof, and a pharmaceutical composition comprising the new crystal form.

[0011] According to the purpose of the present invention, the present invention provides a crystalline form CSVI of Compound I (hereinafter referred to as "crystalline form CSVI").

[0012] On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 9.6°±0.2°, 10.1°±0.2°, and 18.9°±0.2°.

[0013] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 11.6°±0.2°, 19.5°±0.2°, and 23.3°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at three of the diffraction angles 2θ of 11.6°±0.2°, 19.5°±0.2°, and 23.3°±0.2°.

[0014] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at one, two, or three of the diffraction angles 2θ of 13.7°±0.2°, 20.6°±0.2°, and 31.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at three of the diffraction angles 2θ of 13.7°±0.2°, 20.6°±0.2°, and 31.9°±0.2°.

[0015] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVI has characteristic peaks at at least three of the diffraction angle 2θ values ​​of 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°, 16.2°±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 31.1°±0.2°.

[0016] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of Form CSVI is substantially as follows Figure 1 shown.

[0017] In a non-limiting manner, the thermogravimetric analysis diagram of the crystalline form CSVI is substantially as follows Figure 2 As shown, it has a mass loss of about 0.2% when heated to 250°C.

[0018] Without limitation, the crystalline form CSVI has a weight gain of 0.07% when absorbing moisture under the conditions of 25°C / 80% RH, which is no or almost no hygroscopicity. Its DVS diagram is basically as follows: Figure 3 shown.

[0019] Without limitation, the crystalline form CSVI is an anhydrous crystalline form.

[0020] On the other hand, the present invention also provides a method for preparing the crystalline form CSVI, characterized in that the preparation method comprises:

[0021] (1) suspending compound I in a nitrile or a mixed solvent of nitrile and water, stirring, separating the solid and drying to obtain crystalline form CSVI; or

[0022] (2) Compound I is dissolved in a mixed solvent of nitriles and water or a mixed solvent of nitriles and alcohols, filtered, and the obtained filtrate is cooled and stirred to obtain a solid, which is separated and dried to obtain crystalline form CSVI.

[0023] Furthermore, the nitrile in method (1) is preferably acetonitrile, and the volume ratio of acetonitrile to water in the mixed solvent is preferably 95:5; the nitrile in method (2) is preferably acetonitrile, and the alcohol is preferably isopropanol, and the volume ratio of acetonitrile to water in the mixed solvent is preferably 95:5, and the volume ratio of acetonitrile to isopropanol is preferably 1:1.

[0024] Furthermore, the stirring temperature in method (1) is preferably -20°C-76°C, more preferably -20°C-30°C; the drying temperature is preferably 10°C-70°C, more preferably 10°C-40°C.

[0025] Furthermore, in method (2), the dissolving temperature is preferably 40°C-76°C; the cooling temperature is preferably -20°C-5°C, more preferably -20°C; and the drying temperature is preferably 10°C-70°C, more preferably 10°C-40°C.

[0026] According to the purpose of the present invention, the crystal form CSVI of the present invention is used to prepare other crystal forms or salts of Compound I.

[0027] According to the purpose of the present invention, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline CSVI and a pharmaceutically acceptable excipient.

[0028] Furthermore, the present invention provides a use of the crystalline CSVI in the preparation of a THR-β selective agonist pharmaceutical preparation.

[0029] Furthermore, the present invention provides a use of the crystalline CSVI in the preparation of pharmaceutical preparations for treating NASH and HeFH.

[0030] The crystalline form CSVI provided by the present invention has the following advantages:

[0031] (1) Compared with the prior art, the crystalline form CSVI provided by the present invention has higher solubility. In particular, in SGF, the solubility of the crystalline form CSVI is approximately twice that of the prior art crystalline form I.

[0032] Compound I is a poorly water-soluble drug. The crystalline form of CSVI provided by the present invention has higher solubility, which helps improve drug absorption in the human body and enhances bioavailability. Furthermore, this higher solubility allows for a lower drug dosage while maintaining efficacy, thereby reducing side effects and improving drug safety.

[0033] (2) Compared with the prior art, the crystalline form CSVI provided by the present invention has lower hygroscopicity. Test results show that the weight gain of the prior art crystalline form I upon hygroscopicity is approximately twice that of the crystalline form CSVI of the present invention upon hygroscopicity.

[0034] On the one hand, high hygroscopicity can easily cause chemical degradation and crystal transformation of APIs, directly affecting their physicochemical stability. Furthermore, high hygroscopicity can reduce the flowability of APIs, thus affecting their processing.

[0035] On the other hand, highly hygroscopic drugs require low humidity during production and storage, placing higher demands on production and incurring high costs. More importantly, high hygroscopicity can easily cause changes in the content of the active ingredient in the drug, affecting its quality.

[0036] (3) Compared with the prior art, the crystalline CSVI provided by the present invention has superior compressibility. The improved compressibility of crystalline CSVI can effectively improve problems such as substandard hardness / friability and tablet cracking during tableting, making the formulation process more reliable, improving product appearance, and enhancing product quality and production efficiency.

[0037] (4) Compared with the prior art, the crystalline form CSVI provided by the present invention has lower adhesion. Adhesion evaluation results show that the adhesion of the prior art crystalline form I is 5 times that of the crystalline form CSVI. The superior adhesion performance effectively reduces the agglomeration of the API, effectively improves or avoids the phenomena of sticking to the wheel and the punch caused by dry granulation and tablet compression, facilitates the dispersion of the raw materials and their mixing with the excipients, improves the mixing uniformity during material mixing, and ultimately improves product quality.

[0038] (5) The crystalline CSVI API and preparation provided by the present invention have good physicochemical stability. When the crystalline CSVI API was placed in an open or closed container at 25°C / 60% RH, the crystal form did not change for at least 6 months, and the chemical purity was above 99.7%. The purity remained substantially unchanged during storage. After the crystalline CSVI was mixed with excipients to form a pharmaceutical preparation, it was placed at 25°C / 60% RH for at least 3 months without changing the crystal form. The purity remained substantially unchanged during storage. This indicates that the crystalline CSVI API and preparation have good long-term stability, which is beneficial for drug storage.

[0039] Furthermore, the crystalline CSVI API maintained its crystal form unchanged for at least six months when stored in both open and closed containers at 40°C / 75% RH, maintaining a chemical purity exceeding 99.7%. This purity remained essentially unchanged during storage. When the crystalline CSVI was mixed with excipients to form a pharmaceutical preparation, it remained unchanged for at least three months at 40°C / 75% RH. This indicates that the crystalline CSVI API and preparation exhibited excellent stability under accelerated conditions. The stability of APIs and preparations under accelerated conditions is crucial for pharmaceuticals. High temperatures and high humidity, caused by seasonal variations, regional climate variations, and environmental factors, can affect the storage, transportation, and production of APIs. Therefore, the stability of APIs under accelerated conditions is crucial for pharmaceuticals. The enhanced stability of the crystalline CSVI API and preparation under these harsh conditions helps prevent the effects of crystal transformation or purity loss during storage, which can impact drug quality.

[0040] (6) The crystalline CSVI provided by the present invention has good mechanical stability. The crystal form of the crystalline CSVI API does not change after grinding. During the formulation process, APIs often need to be ground and pulverized. Good physical stability can reduce the risk of API crystallinity reduction and crystal transformation during the formulation process. The crystalline CSVI API has good physical stability under different pressures, which is beneficial for maintaining crystal stability during the tableting process.

[0041] The excellent physical and chemical stability of the API crystal form ensures that the drug will not undergo crystal transformation and is essentially free of impurities during production and storage. The excellent physical and chemical stability of the CSVI crystal form ensures consistent and controllable quality of the API and drug product, minimizing changes in drug quality, bioavailability, and toxic side effects caused by changes in crystal form or impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 XRPD pattern of the crystalline form CSVI obtained in Example 1

[0043] Figure 2 TGA diagram of the crystal form CSVI obtained in Example 1

[0044] Figure 3 DVS diagram of the crystal form CSVI obtained in Example 1

[0045] Figure 4 XRPD comparison chart of the crystalline form CSVI obtained in Example 1 before and after DVS (from top to bottom: before DVS, after DVS)

[0046] Figure 5 XRPD pattern of the crystalline form CSVI obtained in Example 2

[0047] Figure 6 XRPD comparison of CSVI before and after storage under different conditions (from top to bottom: before storage, storage at 25°C / 60% RH with open lid for 6 months, storage at 40°C / 75% RH with open lid for 6 months)

[0048] Figure 7 XRPD comparison of CSVI before and after storage under different conditions (from top to bottom: before storage, closed storage at 25°C / 60% RH for 6 months, closed storage at 40°C / 75% RH for 6 months)

[0049] Figure 8 XRPD comparison charts of CSVI under different pressure conditions (from top to bottom: 14KN, 7KN, 3KN, before tableting)

[0050] Figure 9 XRPD comparison chart of crystalline CSVI before and after formulation (from top to bottom: blank tablet, after formulation process, crystalline CSVI)

[0051] Figure 10 XRPD comparison of crystalline CSVI preparations before and after closed storage (from top to bottom: initial, 25°C / 60% RH for 3 months, 40°C / 75% RH for 3 months) DETAILED DESCRIPTION

[0052] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0053] The abbreviations used in the present invention are explained as follows:

[0054] XRPD: X-ray powder diffraction

[0055] TGA: Thermogravimetric analysis

[0056] DVS: Dynamic Water Sorption

[0057] 1 H NMR: liquid hydrogen nuclear magnetic spectroscopy

[0058] HPLC: High Performance Liquid Chromatography

[0059] BCS: Biopharmaceutics Classification System

[0060] RH: relative humidity

[0061] ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

[0062] Instruments and methods used to collect data:

[0063] The X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0064] X-ray source: Cu, Kα

[0065] Kα1 1.5406; Kα2 1.54439

[0066] Kα2 / Kα1 intensity ratio: 0.50

[0067] Voltage: 30 kilovolts (kV)

[0068] Current: 10 milliamperes (mA)

[0069] Scanning range (2θ): from 3.0 to 40.0 degrees

[0070] The thermogravimetric analysis (TGA) graphs of the present invention were collected on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:

[0071] Scan rate: 10℃ / min

[0072] Shielding gas: N2

[0073] The dynamic moisture sorption (DVS) graphs described herein were collected using an Intrinsic dynamic moisture sorption instrument manufactured by SMS (Surface Measurement Systems Ltd.). The instrument control software was DVS-Intrinsic control software. The method parameters for the dynamic moisture sorption instrument were as follows:

[0074] Temperature: 25℃

[0075] Carrier gas, flow rate: N2, 200 ml / min

[0076] Relative humidity range: 0%RH-95%RH

[0077] H NMR data ( 1 H NMR spectra were obtained on a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg / mL solution.

[0078] The test parameters for the detection of related substances in the present invention are shown in Table 1:

[0079] Table 1

[0080]

[0081]

[0082] The test parameters of the solubility of the present invention are shown in Table 2:

[0083] Table 2

[0084]

[0085]

[0086] In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

[0087] The separation is accomplished by 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 solids settle to the bottom of the centrifuge tube.

[0088] The drying process is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably from room temperature to about 80°C, or to 60°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven.

[0089] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0090] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0091] In some embodiments, the crystalline form CSVI of the present invention is pure and substantially free of any other crystalline form. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of any other crystalline form, particularly less than 10% (by weight) of any other crystalline form, more particularly less than 5% (by weight) of any other crystalline form, and even more particularly less than 1% (by weight) of any other crystalline form.

[0092] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0093] Unless otherwise specified, the following examples are all operated at room temperature, which is not a specific temperature value but refers to a temperature range of 10-30°C.

[0094] According to the present invention, the compound I and / or its salt as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I and / or its salt as a raw material is in solid form.

[0095] Compound I and / or its salt used in the following examples may be a solid / crystal form disclosed in the prior art, for example, prepared according to the method described in WO2020010068A1. DETAILED DESCRIPTION

[0097] Example 1-2 Preparation method of crystal form CSVI

[0098] Example 1

[0099] 1.5801 g of Compound I solid was weighed into a glass bottle, 25 mL of acetonitrile was added thereto, and the mixture was stirred at room temperature for 4 days, then filtered and separated. The obtained solid was dried under forced air at 40° C. for 15.5 h to obtain the crystalline form CSVI of the present invention.

[0100] The XRPD pattern of CSVI is as follows: Figure 1 The XRPD data are shown in Table 3.

[0101] TGA of CSVI Figure 2 As shown, heating to 250°C results in a mass loss of approximately 0.2%.

[0102] The NMR data of crystal form CSVI are: 1 H NMR (400MHz, DMSO-d6) δ 13.28 (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).

[0103] The DVS diagram of crystal form CSVI is as follows Figure 3 As shown in FIG. 1 , the weight gain due to moisture absorption under the conditions of 25°C / 80%RH is 0.07%, which is no or almost no hygroscopicity.

[0104] The XRPD comparison of CSVI before and after DVS is shown in the figure below: Figure 4 As shown, the results show that the crystal form remains unchanged before and after DVS.

[0105] Table 3

[0106] Diffraction angle 2θ d value strength% 6.49 13.62 2.06 9.57 9.25 65.84 10.11 8.75 100.00 11.58 7.65 7.89 12.77 6.93 0.88 13.68 6.48 3.39 13.98 6.33 0.91 14.75 6.00 2.41 16.19 5.48 4.32 17.64 5.03 1.13 18.10 4.90 2.23 18.94 4.68 10.63 19.50 4.55 19.67 19.81 4.48 4.75 20.33 4.37 1.63 20.61 4.31 7.02 21.62 4.11 2.74 21.86 4.07 2.96 22.66 3.92 4.89 22.91 3.88 2.66 23.29 3.82 8.60 23.72 3.75 1.44 24.14 3.69 0.98 24.80 3.59 3.03 24.98 3.57 4.96 25.69 3.47 1.87 26.12 3.41 3.40

[0107] 26.75 3.33 4.17 27.31 3.27 2.57 27.57 3.24 1.94 28.01 3.19 1.85 29.19 3.06 1.72 29.79 3.00 2.09 31.13 2.87 1.30 31.90 2.81 4.91 32.68 2.74 1.98 33.48 2.68 1.87 33.77 2.65 1.24 34.37 2.61 1.29 35.45 2.53 1.92 36.44 2.47 1.70 38.27 2.35 1.43 39.14 2.30 3.36

[0108] Example 2

[0109] 22.0 mg of Compound I solid was weighed into a glass bottle, 2.0 mL of a mixed solvent of acetonitrile and water (95:5, V:V) was added thereto, dissolved at 50°C, filtered, and the filtrate was stirred at -20°C for 4 h to precipitate a solid, which was centrifuged. The obtained solid was vacuum dried at 25°C for 2 h to obtain the crystalline form CSVI of the present invention.

[0110] The XRPD pattern of CSVI is as follows: Figure 5 The XRPD data are shown in Table 4.

[0111] Table 4

[0112] Diffraction angle 2θ d value strength% 6.48 13.65 9.15 9.55 9.26 51.51 10.09 8.76 100.00 11.56 7.65 10.22 13.00 6.81 1.45 13.67 6.48 6.38 13.97 6.34 1.56 14.71 6.02 2.42 16.18 5.48 9.37 17.61 5.04 0.98 18.11 4.90 1.81

[0113] 18.93 4.69 22.10 19.49 4.56 18.39 19.82 4.48 2.83 20.61 4.31 4.81 21.61 4.11 3.08 21.84 4.07 7.91 22.64 3.93 4.23 22.88 3.89 3.26 23.27 3.82 12.36 24.97 3.57 3.66 25.62 3.48 1.81 26.11 3.41 3.28 26.73 3.34 3.74 27.28 3.27 2.52 27.59 3.23 2.25 27.96 3.19 5.37 29.20 3.06 1.70 29.76 3.00 1.82 31.13 2.87 3.79 31.91 2.81 5.06 32.69 2.74 2.33 33.43 2.68 3.01 34.36 2.61 2.57 35.41 2.53 1.64 36.43 2.47 1.33 38.18 2.36 1.33 39.15 2.30 2.37

[0114] Example 3 Solubility of Form CSVI and Form I of the Prior Art

[0115] When conducting drug solubility testing to predict in vivo performance, it's crucial to closely mimic in vivo conditions. For oral medications, using SGF (simulated gastric fluid) can mimic in vivo conditions and predict the effects of food intake. Solubility measurements in this medium more closely resemble solubility in the human body.

[0116] About 15 mg of the crystalline form CSVI of the present invention was dispersed in 2.0 mL of SGF (simulated gastric fluid), and the solution was equilibrated at 37° C. for 1 hour. The concentration (mg / mL) of the sample in the solution was measured by HPLC. The results are shown in Table 5.

[0117] Table 5

[0118]

[0119]

[0120] Note: The solubility data of the prior art crystalline form I is cited from WO2020010068A1.

[0121] The results show that the solubility of the crystalline form CSVI after equilibration in SGF for 1 hour is higher, which is about twice the solubility of the crystalline form I in the prior art.

[0122] Example 4 Hygroscopicity of Form CSVI and Form I of the Prior Art

[0123] Appropriate amounts of the crystalline form CSVI of the present invention and the crystalline form I of the prior art were weighed, and their hygroscopicity was tested using a DVS instrument. The relative humidity was cycled from 0% to 95% and then to 0%, and the mass change at each humidity was recorded.

[0124] The crystal form CSVI of the present invention is Figure 3 As shown, the XRPD patterns before and after DVS testing are as follows Figure 4 shown.

[0125] Experimental results show that the hygroscopic weight gain of Form CSVI at 25°C / 80% RH is 0.07%, while that of Form I at 25°C / 80% RH is 0.13%. The hygroscopic weight gain of Form I in the prior art is approximately twice that of Form CSVI in this application.

[0126] Example 5 Physicochemical Stability of Crystalline Form CSVI

[0127] An appropriate amount of the crystalline form CSVI prepared by the present invention was weighed and placed under 25°C / 60% RH and 40°C / 75% RH conditions, respectively. The purity and crystalline form were determined by HPLC and XRPD. The results are shown in Table 6, and the XRPD comparison is shown in Figure 6. Figure 6 and Figure 7 shown.

[0128] Table 6

[0129] Placement conditions Placement time Crystal form purity Start —— CSVI 99.73％ 25℃ / 60%RH open 6 months CSVI 99.73％ 40℃ / 75%RH open 6 months CSVI 99.73％ 25℃ / 60%RH closed 6 months CSVI 99.74％ 40℃ / 75%RH closed 6 months CSVI 99.73％

[0130] The results showed that crystalline CSVI was stable for at least six months at 25°C / 60% RH and 40°C / 75% RH in both open and closed conditions. This suggests that crystalline CSVI maintains good stability under both long-term and accelerated conditions.

[0131] Example 6 Mechanical Stability of Crystalline Form CSVI

[0132] Pressure stability:

[0133] The tablets were pressed using an ENERPAC manual tablet press. A Φ6 mm round flat punch was selected, and about 20 mg of crystalline CSVI was added. The tablets were pressed under different pressures. XRPD tests were performed before and after tableting. The test results are shown in Table 7. Figure 8 shown.

[0134] Table 7

[0135]

[0136] The results show that the crystalline form CSVI has good stability under different pressures.

[0137] Grinding stability:

[0138] An appropriate amount of the crystalline form CSVI of the present invention was placed in a mortar and manually ground for 5 minutes. The crystalline form CSVI did not change before and after grinding.

[0139] Example 7 Flowability of Form CSVI and Form I of the Prior Art

[0140] During the preparation process, the compressibility index is usually used to evaluate the fluidity of powders or particles. The determination method is to gently put a certain amount of powder into a measuring cylinder and measure the volume before tapping; use the tapping method to make the powder in the most compact state, and measure the volume after tapping; calculate the bulk density ρ0 and the tapped density ρ f According to the formula c=(ρ f -ρ0) / ρ f Calculate the compressibility coefficient.

[0141] The definition standard of powder flowability by compressibility coefficient refers to ICH Q4B Appendix 13, see Table 8 for details.

[0142] Table 8

[0143] Compressibility coefficient (%) Liquidity ≦10 Excellent 11-15 good 16-20 generally 21-25 Acceptable 26-31 Difference 32-37 Very poor >38 Extremely poor

[0144] The experimental results show that the fluidity of the prior art crystal form I is extremely poor, and the fluidity of the crystal form CSVI of the present application is better than that of the prior art crystal form I.

[0145] Example 8 Compressibility of Form CSVI and Form I of the Prior Art

[0146] Tablets were compressed using an ENERPAC manual tablet press. A 6 mm Φ round flat punch was used, and 80 mg of both the prior art Form I and the present invention Form CSVI were added. Round tablets were pressed using a 10 kN pressure and allowed to stand at room temperature for 24 hours. After complete elastic recovery, the tablets were measured for diameter (D) and thickness (L) using a vernier caliper. The radial crushing force (hardness, H) was measured using a tablet hardness tester. The tensile strength of the powders was calculated using the formula T = 2H / πDL. The results are shown in Table 9.

[0147] Table 9

[0148] Crystal form Thickness (mm) Diameter (mm) Hardness (N) Tensile strength (MPa) Prior art crystal form I 2.12 6.06 7.4 0.37 Crystal form CSVI 2.05 6.06 13.4 0.69

[0149] The results show that compared with the existing crystal form I, the crystal form CSVI has better compressibility.

[0150] Example 9 Adhesion of Form CSVI to Form I of the Prior Art

[0151] Approximately 30 mg of each of Form CSVI and Form I from the prior art were added to a circular flat punch with a diameter of 8 mm. Tablets were compressed using an ENERPAC manual tablet press at a pressure of 10 kN. The tablets were held for approximately half a minute. The amount of powder adsorbed by the punch was measured, and the maximum and average amounts of powder adsorbed during the compression process were recorded. Detailed experimental results are shown in Table 10.

[0152] Table 10

[0153] Crystal form Maximum adhesion amount (mg) Average adhesion amount (mg) Prior art crystal form I 0.30 0.25 Crystal form CSVI 0.10 0.05

[0154] The experimental results show that the average adhesion amount of the prior art crystal form I is 5 times that of the crystal form CSVI, and the adhesion of the crystal form CSVI is better than that of the prior art crystal form I.

[0155] Example 10 Preparation of Crystalline Form CSVI

[0156] The formulation formula and preparation process of crystalline CSVI are shown in Table 11 and Table 12 respectively. Figure 9The results show that the crystal form of CSVI remains unchanged before and after preparation.

[0157] Table 11

[0158]

[0159] Table 12

[0160]

[0161] Example 11 Formulation Stability of Crystalline Form CSVI

[0162] The crystalline CSVI preparation was packaged in an HDPE bottle and 1 g of desiccant was added. The preparation was placed under the conditions of 25°C / 60% RH and 40°C / 75% RH and samples were taken to detect the crystal form and impurities. The stability of the crystalline CSVI preparation was investigated. The results are shown in Table 13. The XRPD patterns of the crystalline CSVI preparation before and after placement are shown in Table 13. Figure 10 shown.

[0163] Table 13

[0164] Placement conditions Purity change (%) Crystal form Starting preparation sample N / A Crystal form CSVI Place in a closed container at 25℃ / 60%RH with 1g of desiccant for 1 month 0.08％ Crystal form CSVI Place in a closed container at 40℃ / 75%RH with 1g of desiccant for 1 month 0.05％ Crystal form CSVI Place in a closed container at 25℃ / 60%RH with 1g of desiccant for 3 months 0.03％ Crystal form CSVI Place in a closed container at 40℃ / 75%RH with 1g of desiccant for 3 months 0.03％ Crystal form CSVI

[0165] The results showed that the crystalline CSVI preparation could remain stable for at least 3 months under 25°C / 60% RH and 40°C / 75% RH conditions without significant changes in purity.

[0166] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. Compound I The crystalline form CSVI is characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.6°±0.2°, 10.1°±0.2°, 18.9°±0.2°, 11.6°±0.2°, 19.5°±0.2°, 23.3°±0.2°, 13.7°±0.2°, 20.6°±0.2°, and 31.9°±0.2°.

2. The crystalline form CSVI according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

3. A method for preparing the crystalline form CSVI according to claim 1, characterized in that: The method is: Compound I was suspended and stirred in acetonitrile, or a mixed solvent of acetonitrile and water in a volume ratio of 95:5, and the solid was separated and dried to obtain the crystalline form CSVI.

4. The preparation method according to claim 3, characterized in that The stirring temperature is -20°C-30°C, and the drying temperature is 10°C-40°C.

5. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CSVI according to claim 1 and a pharmaceutically acceptable excipient.

6. Use of the crystalline form CSVI according to claim 1 in the preparation of THR-β selective agonist drugs.

7. Use of the crystalline form CSVI according to claim 1 in the preparation of a drug for treating NASH and HeFH.

Images