Resmetirom crystal forms, preparation method therefor and use thereof

Abstract

Provided in the present invention are a plurality of cocrystal forms of Resmetirom and isonicotinamide, a pharmaceutical composition containing the crystal forms, and the use of the crystal forms in the preparation of drugs for treating THR-β-mediated diseases.

Description

Resmetirom crystal forms and preparation method and use thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a co-crystal crystal form of resmetirom and isocyanamide, a preparation method thereof and use thereof. BACKGROUND

[0002] On March 15, 2024, resmetirom (trade name: Rezdiffra, English name, Resmetirom) became the first new drug approved by FDA for the treatment of metabolic dysfunction-related fatty liver (MASH), used for the treatment of non-alcoholic steatohepatitis in adult patients with non-cirrhotic liver fibrosis. The drug is a thyroid hormone receptor-beta (THR-beta) agonist developed by Madrigal Pharmaceuticals, and its core mechanism of action is the activation of THR-beta in the liver. Thyroid hormones play a key role in regulating metabolism, improving insulin sensitivity, and reducing blood lipid levels. By selectively activating THR-beta, resmetirom can promote the metabolism of fatty acids in the liver, reduce the accumulation of fat in the liver, and reduce inflammation and fibrosis in the liver, bringing hope to MASH patients.

[0003] The chemical name of resmetirom is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, and the Chinese name is resmetirom, and the structural formula is as follows:

[0004] Crystal form is a solid in which the molecules of a compound are arranged in a three-dimensional order in the microstructure to form a crystal lattice. The phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of a drug. Because of the difference in physical and chemical properties, different crystal forms of a drug may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to some extent. Especially for poorly soluble solid drugs, the influence of crystal form will be greater. Therefore, drug crystal form is an important content of drug research and an important content of drug quality control.

[0005] Therefore, it is still of great social significance to continue to develop high-quality crystal forms of resmetirom, improve drug quality, promote the listing of generic drugs, and increase the accessibility of clinical drugs. SUMMARY

[0006] The present application provides a plurality of co-crystal structures of resmetirom and isonicotinamide, and the obtained co-crystals have good solubility, hygroscopicity, stability and other physicochemical properties, and are suitable for drug development.

[0007] In a first aspect, the present application provides a co-crystal of a compound of formula (I) and isonicotinamide,

[0008] In certain embodiments of the present application, the molar ratio of the compound of formula (I) to isonicotinamide is 1 : 1.

[0009] The present application provides a co-crystal Q1 of a compound of formula (I) and isonicotinamide, wherein the molar ratio of the compound of formula (I) to isonicotinamide is 1 : 1,

[0010] characterized in that the X-ray powder diffraction pattern is obtained using Cu-K α radiation and further comprising characteristic peaks at two or more of 2-theta values 12.78, 14.75, 16.24, 17.71, 18.57, 23.62, 24.01, 27.99, 30.29, with a range of error of ±0.2° in the 2-theta values.

[0011] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that the X-ray powder diffraction pattern is obtained using Cu-Kα radiation and further comprising characteristic peaks at two or more of 2-theta values 11.41, 15.61, 19.13, 20.05, 22.46, 24.74, 26.88, 27.23, 29.51, 31.19, 32.86, 36.56, with a range of error of ±0.2° in the 2-theta values.

[0012] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that the X-ray powder diffraction pattern is obtained using Cu-Kα radiation and further comprising characteristic peaks at two or more of 2-theta values 11.41, 15.61, 19.13, 20.05, 22.46, 24.74, 26.88, 27.23, 29.51, 31.19, 32.86, 36.56, with a range of error of ±0.2° in the 2-theta values.

[0013] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that the X-ray powder diffraction pattern is substantially as depicted in Figure la.

[0014] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that the TGA-DSC pattern thereof shows an endothermic peak between about 103°C and 140°C, accompanied by a weight loss of about 11% to 12%; and an endothermic peak between about 190°C and 205°C, accompanied by a weight loss of about 21% to 22%.

[0015] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that its DSC pattern shows an endothermic peak at about 103°C; an endothermic peak at about 191°C; and its TGA pattern shows a weight loss of about 11-12% at 31-159°C, and a weight loss of about 21-22% at 159-286°C.

[0016] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that its TGA pattern is substantially as shown in Figure 1b; and its DSC is substantially as shown in Figure 1c.

[0017] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that the co-crystal Q1 is a tetrahydrofuran solvate.

[0018] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that the co-crystal Q1 is a tetrahydrofuran solvate, wherein the molar ratio of the compound of formula (I) to isonicotinamide to tetrahydrofuran is 1:1.

[0019] In certain embodiments of the present application, the co-crystal Q1 of the compound of formula (I) and isonicotinamide is characterized in that its X-ray powder diffraction pattern has the data shown in Table 1 below:

[0020] Table 1: XRPD diffraction peak analysis data of co-crystal Q1

[0021] The present application provides a co-crystal Q2 of the compound of formula (I) and isonicotinamide, wherein the molar ratio of the compound of formula (I) to isonicotinamide is 1:1, which is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 9.79, 14.73 using Cu-Kα radiation, with a 2θ error range of ±0.2°.

[0022] In certain embodiments of the present application, the co-crystal Q2 of the compound of formula (I) and isonicotinamide is characterized in that its X-ray powder diffraction pattern further has characteristic peaks at one or more of 2θ values of 16.90, 19.69, 21.15, 21.86, 25.30, 30.79, 34.87 using Cu-Kα radiation, with a 2θ error range of ±0.2°.

[0023] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized by an X-ray powder diffractogram further comprising one or more peaks at 2-theta values of 13.36, 16.25, 20.30, 20.82, 22.13, 24.70, 28.90, 29.76 using Cu-Ka radiation, with a 2-theta error range of + / - 0.2°.

[0024] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized by an X-ray powder diffractogram substantially as depicted in Figure 2a.

[0025] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized by a TGA-DSC pattern showing an endothermic peak between about 106°C and 145°C with about 7% to 8% weight loss; an endothermic peak between about 183°C and 190°C with about 18% to 19% weight loss.

[0026] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized by a DSC pattern showing an endothermic peak at about 106°C and an endothermic peak at about 183°C; and a TGA pattern showing about 7% to 8% weight loss between about 102°C and 158°C; about 18% to 19% weight loss between about 155°C and 225°C;

[0027] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized by a TGA pattern substantially as depicted in Figure 2b; and a DSC substantially as depicted in Figure 2c.

[0028] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized in that said co-crystal Q2 is a 1,2-ethanediol dimethyl ether solvate.

[0029] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is a 1,2-ethanediol dimethyl ether solvate, wherein the molar ratio of the compound of formula (I) to isonicotinamide to 1,2-ethanediol dimethyl ether is 1:0.5.

[0030] In certain embodiments of the present application, said co-crystal Q2 of the compound of formula (I) with isonicotinamide is characterized by an X-ray powder diffractogram having data as shown in Table 2 below:

[0031] Table 2: XRPD diffraction peak resolution data for co-crystal Q2

[0032] The present application provides a co-crystal Q3 of a compound of formula (I) and isonicotinamide, wherein the molar ratio of the compound of formula (I) to isonicotinamide is 1:1, characterized by an X-ray powder diffraction pattern using Cu-Ka radiation having characteristic peaks at 2-theta values of 9.83, 11.17, 14.81, 24.89, 25.63, with a 2-theta error range of ±0.2°.

[0033] In certain embodiments of the present application, the co-crystal Q3 of a compound of formula (I) and isonicotinamide is characterized by an X-ray powder diffraction pattern using Cu-Ka radiation further having characteristic peaks at one or more of 2-theta values of 11.91, 12.91, 15.77, 17.12, 17.97, 20.04, 20.85, 23.55, 27.64, 30.01, with a 2-theta error range of ±0.2°.

[0034] In certain embodiments of the present application, the co-crystal Q3 of a compound of formula (I) and isonicotinamide is characterized by an X-ray powder diffraction pattern using Cu-Ka radiation further having characteristic peaks at one or more of 2-theta values of 4.89, 7.88, 11.53, 13.71, 22.57, 22.98, 24.09, 26.50, 31.34, 35.16, with a 2-theta error range of ±0.2°.

[0035] In certain embodiments of the present application, the co-crystal Q3 of a compound of formula (I) and isonicotinamide is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 3a.

[0036] In certain embodiments of the present application, the co-crystal Q3 of a compound of formula (I) and isonicotinamide is characterized by a TGA pattern showing a weight loss of about 21% at 131-212°C; a DSC pattern showing an endothermic peak at about 132°C, an exothermic peak at about 136°C; an endothermic peak at about 181°C; an endothermic peak at about 203°C; an endothermic peak at about 314°C.

[0037] In certain embodiments of the present application, the co-crystal Q3 of a compound of formula (I) and isonicotinamide is characterized by a TGA pattern substantially as shown in Figure 3b; a DSC substantially as shown in Figure 3c.

[0038] In certain embodiments of the present application, the co-crystal Q3 of a compound of formula (I) and isonicotinamide is characterized in that said Q3 is a single crystal having unit cell parameters of a = 9. 1 (1) A, b = 11. 1 (1) A, c = 25. 1 (1) A, a = 90°, b = 99. 3 (2) °, g = 90°, and a unit cell volume of V = 2753 (3) A3.

[0039] In some embodiments of the present application, the co-crystal Q3 of the compound of formula (I) and isonicotinamide is characterized by an X-ray powder diffraction pattern as shown in Table 3 below:

[0040] Table 3 XRPD diffraction peak analysis data of co-crystal Q3

[0041] In some embodiments of the present application, the unit cell parameters of the co-crystal Q3 are shown in Table 4, which contains 2 risutimib and 2 isonicotinamide molecules in the minimum asymmetric unit, and each unit cell contains 2 minimum asymmetric units.

[0042] Table 4 Single crystal structure data and unit cell parameters of co-crystal Q3

[0043] In a second aspect, the present application provides a pharmaceutical preparation comprising any one or more of the co-crystals of the compound of formula (I) and isonicotinamide selected from the first aspect, and the preparation further comprises one or more pharmaceutically acceptable excipients, which can be any dosage form pharmaceutically acceptable. The pharmaceutically acceptable excipient is a substance that is nontoxic, compatible with the active ingredient, and otherwise biologically suitable for use in the body. The selection of a particular excipient will depend on the mode of administration or the type and state of the disease for which the particular patient is being treated. Examples of the pharmaceutically acceptable excipients include, but are not limited to, solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.

[0044] In a third aspect, the present application provides the use of any one or more of the co-crystals of the compound of formula (I) and isonicotinamide selected from the first aspect in the preparation of a medicament for treating a disease mediated by thyroid hormone receptor β.

[0045] In some embodiments of the present application, the disease mediated by thyroid hormone receptor β is preferably metabolic disease, hyperlipidemia, hypercholesterolemia, diabetes and its complications, liver steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer.

[0046] In some embodiments of the present application, the disease mediated by thyroid hormone receptor β is preferably obesity, non-alcoholic steatohepatitis, hypercholesterolemia, atherosclerosis.

[0047] In a fourth aspect, the present application provides a method for treating a disease mediated by thyroid hormone receptor β, comprising administering to a subject an effective therapeutic amount of any one or more crystal forms of the co-crystal of the compound of formula (I) and isonicotinamide or a pharmaceutical preparation thereof according to the first aspect.

[0048] In some embodiments of the present application, the disease mediated by thyroid hormone receptor β is preferably a metabolic disease, hyperlipidemia, hypercholesterolemia, diabetes and its complications, liver steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer.

[0049] In some embodiments of the present application, the disease mediated by thyroid hormone receptor β is preferably obesity, non-alcoholic steatohepatitis, hypercholesterolemia, atherosclerosis.

[0050] In a fifth aspect, the present application provides a method for preparing the co-crystal Q3 of the compound of formula (I) and isonicotinamide, characterized in that it comprises the following preparation steps:

[0051] The compound of formula (I) and a certain amount of isonicotinamide are added to a halogenated solvent and stirred for a certain period of time to obtain the co-crystal Q3.

[0052] In some embodiments of the present application, the reaction conditions in the preparation step further comprise one or more of the following:

[0053] (a) the molar ratio of the compound of formula (I) to isonicotinamide is 1:0.9-1.1, preferably 1:1;

[0054] (b) the halogenated solvent is selected from dichloromethane, trichloromethane;

[0055] (c) the stirring time is 1-10 days, preferably 4-6 days, preferably 5 days.

[0056] In a fifth aspect, the present application provides a method for preparing the co-crystal Q3 of the compound of formula (I) and isonicotinamide, characterized in that it comprises the following preparation steps:

[0057] The co-crystal Q2 of the compound of formula (I) and isonicotinamide is mixed with a halogenated solvent and stirred for a certain period of time to obtain the co-crystal Q3.

[0058] In some embodiments of the present application, the halogenated solvent is selected from dichloromethane, trichloromethane.

[0059] In some embodiments of the present application, the co-crystal Q2 of the compound of formula (I) and isonicotinamide is prepared by the following method:

[0060] The compound of formula (I) is added to a certain amount of isonicotinamide in 1,2-ethyleneglycol dimethyl ether, heated to dissolution, filtered to obtain the filtrate, slowly cooled to room temperature to crystallize, to obtain co-crystal Q2.

[0061] In certain embodiments of the present application, the reaction conditions in the preparation step further comprise one or more of the following:

[0062] (a) the molar ratio of the compound of formula (I) to isonicotinamide is 1 : 0.9-1.1, preferably 1 : 1;

[0063] (b) the heating temperature is 60-100°C, preferably 80°C

[0064] (c) the stirring time is 1-10 days, preferably 4-6 days, preferably 5 days.

[0065] Explanation and definition

[0066] In the present application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for better understanding of the present application, the definitions of some terms are provided below. When the definitions of the terms provided in the present application are inconsistent with the meanings commonly understood by one of ordinary skill in the art, the definitions and explanations of the terms provided in the present application shall prevail.

[0067] Herein, unless otherwise stated, all numerical values are modified by the term "about", wherein the term "about" means within ±20% of a given value or range. For example, the numerical value "10" encompasses a range of "8-12"; the numerical range "10-20" encompasses a range of "8-24".

[0068] The term "therapeutically effective amount" means an amount of a compound of the present application or a pharmaceutically acceptable salt thereof that is sufficient to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It will be recognized by those skilled in the art that the total daily usage of the compounds of the formula (I) or a pharmaceutically acceptable salt thereof and the compositions of the application will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0069] In the present application, the co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) in a fixed stoichiometric ratio in the same crystal lattice through non-covalent bond interactions such as hydrogen bond, van der Waals force, π-π stacking, halogen bond, etc. The co-crystal can improve the physicochemical properties of the drug without affecting the internal structure of the drug, and it makes the API more diversified and can improve many physicochemical properties of the drug. The drug co-crystal is a new solid form that can improve the physicochemical properties of the active pharmaceutical ingredient, and has certain advantages compared with single-component and compound drugs, and is a potential new drug development technology.

[0070] It is well known in the art that X-ray powder diffraction patterns have one or more measurement errors due to slight changes in measurement conditions, and the structure of the crystalline, crystal or crystal form disclosed or claimed in the present application can exhibit similar but not exactly the same analytical characteristics within a reasonable error range according to test conditions, purity, equipment and other common variables known to those skilled in the art. For example, the diffraction angle (2θ) in powder X-ray powder diffraction usually produces an error within the range of ±0.20°, so the present application not only includes crystalline with exactly the same diffraction angle in powder X-ray powder diffraction, but also includes crystalline with the same diffraction angle within the error range of ±0.20°. The crystalline form of the compound of formula (I) in the present application is not limited to crystals with the same X-ray powder diffraction pattern as shown in the accompanying drawings, and any crystal with substantially the same X-ray powder diffraction pattern as shown in the accompanying drawings belongs to the scope of the present application.

[0071] It should be understood that different types of equipment or different test conditions can give slightly different DSC patterns and endothermic transition temperature readings. DSC data can reflect changes in the morphology of the substance, and the endothermic peak can indicate that the substance has undergone dehydration or desolvation, or has undergone crystallization, or has undergone melting, etc.; when reflecting the melting state, the corresponding temperature is generally understood as the melting point of the substance. This value will be affected by the purity of the compound, the sample weight, the heating rate, the particle size and the calibration and maintenance of the test equipment. Those skilled in the art can understand that the temperature at which a substance changes from a solid state to a liquid state is usually a temperature range, not a fixed point value, so whether the onset or peak or left limit-right limit or other reasonable values can be used to characterize the temperature corresponding to the endothermic peak or the melting point of the substance. The maximum endothermic transition temperature of the crystal form can be within ±5.0°C, preferably within ±2.0°C, of the specific values disclosed above.

[0072] The present application also uses thermal gravimetric analysis (TGA) to analyze the relationship between the degree of decomposition or sublimation, evaporation of the crystal form (loss of weight) and temperature. It should be understood that the same crystal form is affected by sample purity, particle size, different types of equipment, different testing methods, etc. There is a certain error in the obtained numerical value. The temperature at which the crystal form decomposes or sublimates, evaporates can be within ±5.0℃ of the specific values disclosed above, for example, within ±2.0℃.

[0073] The "stability" of the crystal form includes "chemical stability" and / or "physical stability". "Chemical stability" refers to the degree of degradation reaction of the crystal form under certain temperature, humidity, light conditions. "Chemical stability" reflects the stability of the crystal form under storage conditions. "Physical stability" refers to the degree of solid form conversion of the crystal form under certain conditions, such as high temperature, high humidity, grinding, tabletting, desolvation, adsorption of solvent. Therefore, "stability" can reflect the stability of the crystal form to some extent during the use of preparations and the like.

[0074] Regarding the definition of hygroscopicity characteristics and hygroscopic weight gain (Guidelines for Drug Hygroscopicity Test in Chinese Pharmacopoeia 2020 Edition 9103):

[0075] Deliquescence: Absorbing enough moisture to form a liquid;

[0076] Extremely hygroscopic: hygroscopic weight gain is not less than 15.0%;

[0077] Hygroscopic: hygroscopic weight gain is less than 15.0% but not less than 2.0%;

[0078] Slightly hygroscopic: hygroscopic weight gain is less than 2.0% but not less than 0.2%;

[0079] No or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%.

[0080] Hygroscopicity directly affects the physical and chemical stability of the drug. High hygroscopicity can easily cause chemical degradation and crystal form conversion. In addition, high hygroscopicity will reduce the flowability of the drug, thereby affecting the processing technology of the drug. Not only that, high hygroscopicity of the drug needs to maintain low humidity during production and storage, which puts higher requirements on production and requires high cost. More importantly, high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.

[0081] The transformation of crystal form can cause the change of drug absorption, and affect the bioavailability. The change of bioavailability can cause the change of drug efficacy or induce toxic side effects. Good stability can ensure that no impurities are generated during storage. The crystal form has good physical and chemical stability, which ensures the quality of raw materials and preparations to be consistent and controllable, and maximally reduces the change of drug quality caused by crystal form change or impurity generation.

[0082] In the present application, the "stirring" is completed by using the conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100-300 rpm.

[0083] The "drying" can be carried out at room temperature or at a higher temperature. The drying temperature is room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. The drying is carried out in a fume hood, a forced air oven or a vacuum oven. The crystalline structure of the present application can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, conversion from another phase solid state, crystallization from supercritical fluid and jet spray, etc. The technique of crystallization or recrystallization of the crystalline structure from a solvent mixture includes solvent evaporation, reduction of the temperature of the solvent mixture, seeding of the super-saturated solvent mixture of the molecule and / or salt, freeze-drying of the solvent mixture, addition of an anti-solvent to the solvent mixture, etc.

[0084] In the present application, the compound of formula (I), the API, and the raw material of the compound of formula (I) all refer to the same substance, i.e. 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. It can be obtained by the preparation method described in Example 1.

[0085] In the present application, the solvate (including hydrate) generally refers to the case that solvent molecules enter the crystal lattice. According to the form of the force between the solvent and the main body of the compound after the solvent enters the crystal lattice, the solvate is divided into independent site type, channel type and complex type. The case that the solvent molecules remain on the surface of the crystal form does not belong to the category of solvate.

[0086] The independent site type solvate (also known as cavity type solvate) microstructure features (i.e. the form of intermolecular physical interaction in the single crystal structure): the solvent molecules in the crystal lattice only interact with the drug compound molecules; and there is no direct interaction between the solvent molecules. The type can be determined by combining the characteristics of various analysis spectra; the DSC / TGA spectrum of the independent site solvate has the following morphological characteristics: a: the desolvation peak of the DSC spectrum is "relatively sharp"; b: the mass loss process of the TGA spectrum is "relatively fast"; c: the desolvation temperature point has little to do with the boiling point of the solvent molecules; at the same time, the hydrogen bond interaction between the solvent molecules and the host compound molecules plays a key role in maintaining the stability of the entire crystal cell structure. Therefore, during the desolvation process of this type of solvate, the original crystal cell structure will generally collapse to form amorphous or undergo crystal transformation.

[0087] The channel type solvate microstructure features: the solvent molecules exist in the tunnels of the crystal cell, and the solvent molecules interact with each other along a certain direction to form a chain-shaped arrangement to form an independent "channel" structure; this channel type structure can be dynamically "closed" and "opened" with changes in external temperature / humidity, and when the solvent channel is in the open state, the channel can adsorb or remove excess solvent; the DSC / TGA spectrum of the channel type solvate has the following morphological characteristics: a: the desolvation peak of the DSC spectrum is relatively wide (bulging type); b: the desolvation process of the TGA spectrum is "slow"; c: the initial desolvation temperature point is lower than the boiling point of the solvent; in this type of solvate, the solvent molecules are filled in the cavity of the crystal under the action of van der Waals force and do not participate in the construction of the crystal cell network, so the solvent content has little effect on the crystal cell structure, i.e. the XRD spectrum changes little during the desolvation process.

[0088] The ion type solvate microstructure features: the solvent molecules form a complex with the metal cations through hydrogen bonding. The ion type solvate contains metal ions, and the DSC / TGA generally has a high desolvation temperature, the dehydration endothermic peak on the DSC is obvious, and the desolvation temperature range on the TGA is relatively narrow, and the crystal structure changes after desolvation. The same solvate molecule can have two or more types. BRIEF DESCRIPTION OF DRAWINGS

[0089] Figure 1a is an XRPD diffraction pattern of the co-crystal Q1 formed by the compound of formula (I) and isonicotinamide.

[0090] Figure 1b is a TGA spectrum of the co-crystal Q1 formed by the compound of formula (I) and isonicotinamide.

[0091] Figure 1c is a DSC spectrum of the co-crystal Q1 formed by the compound of formula (I) and isonicotinamide.

[0092] Figure 1d is an H-NMR spectrum of the co-crystal Q1 formed by the compound of formula (I) and isonicotinamide. 1 H-NMR spectrum.

[0093] Figure 2a XRPD diffractogram of co-crystal Q2 of compound of formula (I) with isonicotinamide.

[0094] Figure 2b TGA profile of co-crystal Q2 of compound of formula (I) with isonicotinamide.

[0095] Figure 2c DSC profile of co-crystal Q2 of compound of formula (I) with isonicotinamide.

[0096] Figure 2d H-NMR profile of co-crystal Q2 of compound of formula (I) with isonicotinamide. 1 H-NMR profile.

[0097] Figure 3a XRPD diffractogram of co-crystal Q3 of compound of formula (I) with isonicotinamide.

[0098] Figure 3b TGA profile of co-crystal Q3 of compound of formula (I) with isonicotinamide.

[0099] Figure 3c DSC profile of co-crystal Q3 of compound of formula (I) with isonicotinamide.

[0100] Figure 3d H-NMR profile of co-crystal Q3 of compound of formula (I) with isonicotinamide. 1 H-NMR profile.

[0101] Figure 3e Single crystal stereoview of co-crystal Q3 of compound of formula (I) with isonicotinamide.

[0102] Figure 3f DVS profile of co-crystal Q3 of compound of formula (I) with isonicotinamide. DETAILED DESCRIPTION

[0103] The present application is described in detail below by way of examples, but it is not meant to be limited by any of the examples. Any technical solutions achieved based on the above description of the present application are within the scope of the present application. The materials used in the experiments and the experimental methods are described generally and / or specifically in the present application; unless otherwise specified, "room temperature" as described in the present application has the common meaning in the art, specifically 15-35°C, preferably 20-30°C, and more preferably 20-25°C.

[0104] Instruments and analytical methods used in the present application

[0105] (1) X-ray powder diffraction (XRPD)

[0106] The solid sample was analyzed by X-ray powder diffractometer (X'Pert PRO), and the fine powder of the test sample was taken in an appropriate amount, placed in the groove of the sample holder, and pressed into a flat and dense plane with a glass sheet. The XRPD measurement parameters are shown in the following table:

[0107] XRPD test parameters

[0108] (2) Thermal Gravimetric Analysis (TGA)

[0109] Thermal gravimetric analysis of solids was performed using a TA Instrument Thermal Gravimetric Analyzer. Approximately 1-5 mg of sample was placed in an unskinned aluminum sample pan and heated according to the parameters listed in the table below. Data was analyzed using TRIOS.

[0110] TGA Method Parameters

[0111] (3) Differential Scanning Calorimetry (DSC)

[0112] DSC analysis of solids was performed using a TA Instrument Differential Scanning Calorimeter. Approximately 1-3 mg of sample was accurately weighed into a pierced aluminum sample pan and heated according to the parameters listed in the table below. Data was analyzed using TA Universal Analysis.

[0113] DSC Method Parameters

[0114] Thermal gravimetric-differential scanning calorimetry coupled analysis of solids was performed using a Mettler Toledo simultaneous thermal analyzer. A small scoop of test article was placed into a crucible and spread evenly, weighed, and heated according to the parameters listed in the table below. Data was analyzed using STARe.

[0115] TGA-DSC Method Parameters

[0116] (4) Dynamic Vapor Sorption (DVS)

[0117] Determination of hygroscopicity of samples was performed using a DVS Intrinsic Dynamic Vapor Sorption instrument. The sample was placed in an unskinned sample basket and the instrument automatically weighed. The sample was analyzed according to the parameters in the table below.

[0118] DVS Method Parameters

[0119] (5) Proton Nuclear Magnetic Resonance (1H-NMR) 1 H-NMR)

[0120] NMR was measured using a Bruker AVANCE NEO 400 NMR instrument. The solvent used was deuterated dimethyl sulfoxide (DMSO-d6).

[0121] (6) Micro-crystal electron diffraction (MicroED)

[0122] MicroED analysis method parameters

[0123] The compound of formula (I) raw material and isonicotinamide are both commercially available.

[0124] Preparation of the compound of formula (I) and isonicotinamide co-crystal of Example 1

[0125] (1) Preparation of co-crystal Q1

[0126] 40.0 mg of resmetirom and 11.2 mg of isonicotinamide were weighed into a sample bottle, 1 mL of tetrahydrofuran was added to stir to obtain a suspension, and the suspension was stirred and pulped at room temperature for 5 days. The obtained solid was characterized by XRPD, TGA-DSC and 1H-NMR tests, and the solid was co-crystal Q1, the XRPD spectrum of which was substantially as shown in Figure 1a. The TGA and DSC spectra are shown in Figures 1b and 1c. 1 The 1H-NMR spectrum is shown in Figure 1d.

[0127] According to the XRPD, TGA-DSC and 1 1H-NMR, Q1 was determined to be a tetrahydrofuran solvate of isonicotinamide co-crystal, and the ratio of resmetirom-isonicotinamide to tetrahydrofuran was 1:1.

[0128] (2) Preparation of co-crystal Q2

[0129] 40.0 mg of resmetirom and 11.2 mg of isonicotinamide were weighed into a sample bottle, 1 mL of 1,2-ethyleneglycol dimethyl ether was added, and the temperature was raised to 80°C to dissolve, then filtered to obtain a filtrate, and the temperature was slowly lowered to room temperature to crystallize. The obtained solid was characterized by XRPD, TGA-DSC and 1 1H-NMR tests, and the solid was co-crystal Q2, the XRPD spectrum of which was substantially as shown in Figure 2a.

[0130] The TGA and DSC spectra are shown in Figures 2b and 2c. 1 The 1H-NMR spectrum is shown in Figure 2d.

[0131] According to the XRPD, TGA-DSC and 1 1H-NMR, Q3 was determined to be a 1,2-ethyleneglycol dimethyl ether solvate of isonicotinamide co-crystal, and the ratio of resmetirom-isonicotinamide to 1,2-ethyleneglycol dimethyl ether was 1:0.5.

[0132] (3) Preparation of co-crystal Q3

[0133] Method one:

[0134] Take 40.0 mg of resmetirom and 11.2 mg of isonicotinamide into a sample bottle, add 1 mL of dichloromethane to stir to obtain a suspension, and stir and beat the suspension at room temperature for 5 days. The obtained solid is characterized by XRPD, TGA-DSC, 1H-NMR and MicroED tests, and the solid is co-crystal Q3, and the XRPD spectrum thereof is substantially as shown in FIG. 3a.

[0135] The TGA and DSC spectra are shown in FIG. 3b and FIG. 3c. 1 The H-NMR spectrum is shown in FIG. 3d.

[0136] Method two:

[0137] Take about 50 mg of co-crystal Q2 into a sample bottle, add 1 mL of dichloromethane to stir to obtain a suspension, and stir and beat the suspension at room temperature for 5 days. The obtained solid is characterized by XRPD test, and the solid is co-crystal Q3. A small amount of co-crystal powder sample is tested by MicroED to test the single crystal structure.

[0138] The single crystal stereoscopic structure ellipsoid diagram is shown in FIG. 3e.

[0139] Effect test of the co-crystal of the compound of formula (I) and isonicotinamide

[0140] Test example 1 hygroscopicity experiment

[0141] According to the “Guiding principles for drug hygroscopicity test” in the 2020 edition of Chinese Pharmacopoeia, the moisture adsorption / desorption data of the co-crystal Q3 formed by the compound of formula (I) and isonicotinamide are tested. The DVS curve of the co-crystal Q3 is shown in FIG. 3f, and the hygroscopicity data is shown in Table 5. The XRPD of the remaining solid after the DVS test shows that the co-crystal Q3 has not changed, as shown in the figure.

[0142] Table 5 Hygroscopicity of co-crystal Q3

[0143] Test example 2 influence factor experiment

[0144] According to the “Guiding principles for stability test of raw materials and preparations” in the 2020 edition of Chinese Pharmacopoeia, the stability of the co-crystal Q3 formed by the compound of formula (I) and isonicotinamide under different temperatures and humidities is investigated. The purity is tested by HPLC on the 0th day, 5th day and 10th day, and the crystal form is tested by XRPD, and the experimental results are shown in Table 6.

[0145] Table 6 Influence factor test of co-crystal Q3

[0146] Conclusion: Under the conditions of high temperature, high humidity and light, the co-crystal Q3 does not change in crystal form, and the purity is basically unchanged. The physical and chemical properties of the co-crystal Q3 are stable.

[0147] Test Example 3 Solubility Experiment

[0148] At 37℃, a certain amount of co-crystal Q3 formed by the compound of formula (I) and isonicotinamide was dispersed in buffer solutions with different pH to prepare suspensions, and the content of the sample in the solution (mg / mL) was tested by high performance liquid chromatography, and the results are shown in Table 7.

[0149] Table 7 Equilibrium solubility of different crystal forms in buffer solutions with different pH

[0150] Conclusion: The solubility of co-crystal Q3 increases with the increase of pH.

Claims

1. A co-crystal of a compound of formula (I) ###0001### (I) with isonicotinamide, ###0002### 2. A co-crystal of the compound of formula (I) according to claim 1 with isonicotinamide, characterized by, The molar ratio of the compound of formula (I) to isonicotinamide is 1:

1.

3. A co-crystal of a compound of formula (I) and isonicotinamide Q1, wherein the molar ratio of the compound of formula (I) and isonicotinamide is 1 : 1, ###0002### characterized in that The X-ray powder diffraction pattern thereof has characteristic peaks at 2-theta values of 9.22, 13.86, 16.52, 20.66, 21.29, 22.93, with a 2-theta error range of ±0.2°, using Cu-Ka radiation; Preferably, the co-crystal Q1 is characterized in that the X-ray powder diffraction pattern thereof further has one or more characteristic peaks at 2-theta values of 12.78, 14.75, 16.24, 17.71, 18.57, 23.62, 24.01, 27.99, 30.29, with a 2-theta error range of ±0.2°, using Cu-Ka radiation; Preferably, the co-crystal Q1 is characterized in that the X-ray powder diffraction pattern thereof further has one or more characteristic peaks at 2-theta values of 11.41, 15.61, 19.13, 20.05, 22.46, 24.74, 26.88, 27.23, 29.51, 31.19, 32.86, 36.56, with a 2-theta error range of ±0.2°, using Cu-Ka radiation; Preferably, the co-crystal Q1 has the XRPD diffraction peak resolution data as shown in Table 1 below: Table 1 Preferably, the co-crystal Q1 is characterized in that the X-ray powder diffraction pattern thereof is substantially as shown in Figure 1a, using Cu-Ka radiation.

4. A co-crystal Ql of the compound of formula (I) according to claim 3 with isonicotinamide, characterized by, The DSC pattern thereof shows an endothermic peak at about 103°C; an endothermic peak at about 191°C; and the TGA pattern thereof shows a weight loss of about 11%-12% at 31°C-159°C, and a weight loss of about 21%-22% at 159°C-286°C; Preferably, the co-crystal Q1 is characterized in that the TGA pattern thereof is substantially as shown in Figure 1b; and the DSC is substantially as shown in Figure 1c.

5. A co-crystal Ql of a compound of formula (I) according to claim 3 or 4 with isonicotinamide, characterized by, The co-crystal Q1 is a tetrahydrofuran solvate; Preferably, the co-crystal Q1 is a tetrahydrofuran solvate, wherein the molar ratio of the compound of formula (I)-isonicotinamide to tetrahydrofuran is 1:

1.

6. A co-crystal of a compound of formula (I) Q2 with isonicotinamide, wherein, The molar ratio of the compound of formula (I) to isonicotinamide is 1 :1, The X-ray powder diffraction pattern thereof has characteristic peaks at 2-theta values of 9.79, 14.73, with a 2-theta error range of ±0.2°, using Cu-Ka radiation; Preferably, the co-crystal Q2 is characterized in that the X-ray powder diffraction pattern thereof further has one or more characteristic peaks at 2-theta values of 16.90, 19.69, 21.15, 21.86, 25.30, 30.79, 34.87, with a 2-theta error range of ±0.2°, using Cu-Ka radiation; Preferably, the co-crystal Q2 is characterized in that the X-ray powder diffraction pattern thereof further has one or more characteristic peaks at 2-theta values of 13.36, 16.25, 20.30, 20.82, 22.13, 24.70, 28.90, 29.76, with a 2-theta error range of ±0.2°, using Cu-Ka radiation; Preferably, the co-crystal Q2 has the XRPD diffraction peak resolution data as shown in Table 2 below: Table 2 Preferably, said co-crystal Q2 is characterized in that its X-ray powder diffraction pattern is substantially as shown in Figure 2a using Cu-Ka radiation.

7. A co-crystal Q2 of the compound of formula (I) according to claim 6 with isonicotinamide, characterized by, Its DSC pattern shows an endothermic peak at about 106°C, an endothermic peak at about 183°C; its TGA pattern shows a weight loss of about 7-8% at about 102-158°C; a weight loss of about 18-19% at about 155-225°C; Preferably, said co-crystal Q1 is characterized in that its TGA pattern is substantially as shown in Figure 2b; its DSC pattern is substantially as shown in Figure 2c.

8. A co-crystal Q2 of a compound of formula (I) according to claim 6 or 7 with isonicotinamide, characterized by, Said co-crystal Q2 is a 1,2-ethanediol dimethyl ether solvate; Preferably, said co-crystal Q2 is a 1,2-ethanediol dimethyl ether solvate, wherein the molar ratio of the compound of formula (I)-isonicotinamide to 1,2-ethanediol dimethyl ether is 1:0.

5.

9. A co-crystal of a compound of formula (I) with isonicotinamide Q3, wherein the molar ratio of the compound of formula (I) to isonicotinamide is 1 : 1, ###00003### characterized in that using Cu-Ka radiation, its X-ray powder diffraction pattern has characteristic peaks at 2Q values of 9.83, 11.17, 14.81, 24.89, 25.63, with a 2Q error range of ±0.2°; Preferably, said co-crystal Q3 is characterized in that, using Cu-Ka radiation, its X-ray powder diffraction pattern further has characteristic peaks at one or more of 2Q values of 11.91, 12.91, 15.77, 17.12, 17.97, 20.04, 20.85, 23.55, 27.64, 30.01, with a 2Q error range of ±0.2°; Preferably, said co-crystal Q3 is characterized in that, using Cu-Ka radiation, its X-ray powder diffraction pattern further has characteristic peaks at one or more of 2Q values of 4.89, 7.88, 11.53, 13.71, 22.57, 22.98, 24.09, 26.50, 31.34, 35.16, with a 2Q error range of ±0.2°; Preferably, said co-crystal Q3 has the XRPD diffraction peak resolution data as shown in Table 3 below: Table 3 Preferably, said co-crystal Q3 is characterized in that, using Cu-Ka radiation, its X-ray powder diffraction pattern is substantially as shown in Figure 3a.

10. A co-crystal Q3 of the compound of formula (I) according to claim 9 with isonicotinamide, characterized by, its TGA pattern shows a weight loss of about 21% at 131-212°C; its DSC pattern shows an endothermic peak at about 132°C, an exothermic peak at about 136°C; an endothermic peak at about 181°C; an endothermic peak at about 203°C; an endothermic peak at about 314°C; Preferably, its TGA pattern is substantially as shown in Figure 3b; Preferably, its DSC pattern is substantially as shown in Figure 3c.

11. A co-crystal Q3 of a compound of formula (I) according to claim 9 or 10 with isonicotinamide, characterized by, The Q3 is a single crystal, belongs to monoclinic system, space group is P21 (no. 4), and the cell parameter is axis length Axis angle α = 90°, β = 99.3 (2) °, γ = 90°, and the cell volume is 12. A pharmaceutical preparation comprising the co-crystal of the compound of formula (I) and isonicotinamide according to any one of claims 1-11, and any one or more pharmaceutically acceptable carriers.

13. Use of the co-crystal of the compound of formula (I) and isonicotinamide according to claim 1 or 2, the co-crystal Q1 according to any one of claims 3-5, the co-crystal Q2 according to any one of claims 6-8, the co-crystal Q3 according to any one of claims 9-11 in the preparation of a medicament for treating a disease mediated by thyroid hormone receptor beta. Preferably, the thyroid hormone receptor beta mediated disease is preferably metabolic disease, hyperlipidemia, hypercholesterolemia, diabetes and its complications, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer; Preferably, the thyroid hormone receptor beta mediated disease is preferably obesity, non-alcoholic steatohepatitis, hypercholesterolemia, atherosclerosis.

14. A process for the preparation of a co-crystal Q3 of a compound of formula (I) according to any one of claims 9 to 11 with isonicotinamide, characterized in that, The preparation process comprises the following steps: The compound of formula (I) and a certain amount of isonicotinamide are added into a halogenated solvent and stirred, and the co-crystal Q3 is obtained after stirring for a certain period of time.

15. The production method according to claim 14, wherein The reaction conditions in the preparation process further comprise one or more of the following: (a) the molar ratio of the compound of formula (I) to isonicotinamide is 1:0.9-1.1, preferably 1:1; (b) the halogenated solvent is selected from dichloromethane, trichloromethane.

16. A process for the preparation of a co-crystal Q3 of a compound of formula (I) according to any one of claims 9 to 11 with isonicotinamide, characterized in that, The preparation process comprises the following steps: The co-crystal Q2 formed by the compound of formula (I) and isonicotinamide is mixed with a halogenated solvent and stirred, and the co-crystal Q3 is obtained after stirring for a certain period of time; Preferably, the halogenated solvent is selected from dichloromethane, trichloromethane.

17. The production method according to claim 16, wherein The co-crystal Q2 formed by the compound of formula (I) and isonicotinamide is prepared by the following method: The compound of formula (I) and a certain amount of isonicotinamide are added into 1,2-ethyleneglycol dimethyl ether, heated to dissolve, filtered to obtain a filtrate, slowly cooled to room temperature to crystallize, and the co-crystal Q2 is obtained.

18. The production method according to claim 17, wherein The conditions in the preparation process of Q2 further comprise one or more of the following: (a) the molar ratio of the compound of formula (I) to isonicotinamide is 1:0.9-1.1, preferably 1:1; (b) the heating temperature is 60-100°C, preferably 80°C.

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