WO2021063367A1 - 一种Resmetirom晶型及其制备方法和用途 - Google Patents

一种Resmetirom晶型及其制备方法和用途 Download PDF

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WO2021063367A1
WO2021063367A1 PCT/CN2020/118953 CN2020118953W WO2021063367A1 WO 2021063367 A1 WO2021063367 A1 WO 2021063367A1 CN 2020118953 W CN2020118953 W CN 2020118953W WO 2021063367 A1 WO2021063367 A1 WO 2021063367A1
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csi
crystal form
crystalline
preparation
ray powder
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PCT/CN2020/118953
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French (fr)
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陈敏华
常幸娟
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苏州科睿思制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of Resmetirom and its preparation method and use.
  • Heterozygous familial hypercholesterolemia is the most serious type of lipid metabolism diseases, which can lead to various life-threatening cardiovascular complications.
  • Non-alcoholic steatohepatitis is a serious liver disease that is accompanied by steatosis with inflammation and liver cell damage.
  • THR- ⁇ thyroid hormone receptor
  • Resmetirom can stimulate liver mitochondrial biosynthesis in individuals with NASH by reducing low-density lipoprotein cholesterol, triglycerides, and liver fat levels, thereby improving the symptoms of NASH and HeFH. Resmetirom has achieved positive results in phase II clinical trials of NASH and HeFH.
  • the crystal form is a solid in which the compound molecules 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 the drug. Because of different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, the crystal form of a drug must be an important content of drug research and also an important content of drug quality control.
  • US9266861B2 discloses compound I hydrate, anhydrous form I, methyl isobutyl ketone solvate, and dimethylacetamide solvate.
  • Methyl isobutyl ketone and dimethylacetamide are toxic organic solvents and are not suitable for medicinal use.
  • the crystal form I must be prepared by hydrate, methyl isobutyl ketone solvate or dimethyl acetamide solvate. It starts to melt at about 321°C and contains no solvent, which is safer than other crystal forms. It is a solid form of Compound I suitable for pharmaceutical development. The inventor of the present application repeated the preparation method disclosed in US9266861B2 to obtain crystal form I and characterize the properties of crystal form I.
  • the inventor of the present application conducted a large number of experimental studies on Compound I in an attempt to obtain a more suitable crystalline form for medicinal use, and conducted more than 300 experiments, but most of the obtained were Compound I solvates.
  • Compound I solvates For example, methanol solvate, acetone solvate, tetrahydrofuran solvate, chlorobenzene solvate, toluene solvate, cyclohexanone solvate, etc.
  • the inventor of the present application has paid a lot of creative work in order to obtain the crystal form CSI of the present invention.
  • the crystal form CSI has advantages in physical and chemical properties, preparation processing performance, and bioavailability, such as melting point, solubility, moisture absorption, purification, and stability.
  • advantages in at least one of properties, adhesion, compressibility, fluidity, dissolution in vivo and in vitro, and bioavailability especially good physical and chemical stability, low moisture absorption, good thermodynamic stability, and good grinding stability .
  • Good fluidity, low adhesion, good compressibility it provides a new and better choice for the development of drugs containing compound I, which is of very important significance.
  • the main purpose of the present invention is to provide a new crystal form of Compound I and its preparation method and application.
  • the present invention provides a crystalline form of Compound I (hereinafter referred to as "crystalline form CSI").
  • the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at diffraction angle 2 ⁇ values of 5.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 26.5° ⁇ 0.2.
  • the X-ray powder diffraction of the crystal form CSI has a diffraction angle 2 ⁇ value of 14.4° ⁇ 0.2°, 25.1° ⁇ 0.2°, 29.2° ⁇ 0.2° at 1 or 2 positions , Or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystal form CSI has characteristic peaks at 3 of the diffraction angles 2 ⁇ of 14.4° ⁇ 0.2°, 25.1° ⁇ 0.2°, 29.2° ⁇ 0.2° .
  • the X-ray powder diffraction of the crystal form CSI has a diffraction angle of 12.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 26.3° ⁇ 0.2°, or 2 positions. , Or 3 characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at 3 of the diffraction angles 2 ⁇ of 12.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, 26.3° ⁇ 0.2° .
  • the X-ray powder diffraction of the crystal form CSI has a diffraction angle 2 ⁇ value of 5.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 26.5° ⁇ 0.2, 14.4° ⁇ 0.2°, 25.1 ° ⁇ 0.2° ⁇ 29.2° ⁇ 0.2° ⁇ 12.5° ⁇ 0.2° ⁇ 26.3° ⁇ 0.2° ⁇ 13.0° ⁇ 0.2° ⁇ 17.6° ⁇ 0.2°any 3 places, or 4 places, or 5 places, or 6 There are characteristic peaks at, or 7, or 8, or 9, or 10.
  • the X-ray powder diffraction of the crystal form CSI has a diffraction angle 2 ⁇ value of 5.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 26.6° ⁇ 0.2, 14.5° ⁇ 0.2°, 25.1 ° ⁇ 0.2° ⁇ 29.3° ⁇ 0.2° ⁇ 12.5° ⁇ 0.2° ⁇ 26.3° ⁇ 0.2° ⁇ 13.0° ⁇ 0.2° ⁇ 17.6° ⁇ 0.2°any 3 places, or 4 places, or 5 places, or 6 There are characteristic peaks at, or 7, or 8, or 9, or 10.
  • the X-ray powder diffraction pattern of the crystalline form CSI is basically as shown in FIG. 1.
  • the X-ray powder diffraction pattern of the crystalline form CSI is basically as shown in FIG. 2.
  • the X-ray powder diffraction pattern of the crystalline form CSI is basically as shown in FIG. 3.
  • the crystalline form CSI has an endothermic peak near 96°C, and an exothermic peak begins to appear near 149°C.
  • This exothermic peak is a transition exothermic peak, and an endothermic peak begins to appear near 335°C.
  • the heat peak is the melting endothermic peak.
  • the differential scanning calorimetry diagram is basically shown in Figure 4.
  • the crystalline CSI heated to 150° C. has a weight loss of about 7.6%
  • the thermogravimetric analysis chart is basically as shown in FIG. 5.
  • the present invention also provides a preparation method of the crystal form CSI, and the preparation method includes:
  • the suspension stirring time in the method (1) is preferably greater than 12h, the stirring temperature is preferably 5-50°C, and the drying temperature is preferably 20-30°C; the alcohol in the method (2) is preferably isopropanol The volatilization temperature is preferably 20-50°C.
  • the crystalline CSI has low hygroscopicity.
  • the test results show that the weight gain of the crystalline CSI under the condition of 30%-80% RH is 0.13%, which means it has no or almost no hygroscopicity.
  • the hygroscopicity directly affects the physical and chemical stability of the drug, and the high hygroscopicity can easily cause chemical degradation and crystal transformation.
  • high hygroscopicity will reduce the fluidity of the drug, thereby affecting the processing technology of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during the production and storage process, which puts forward higher requirements on production and requires high costs.
  • high hygroscopicity can easily cause changes in the content of active ingredients in the drug, which affects the quality of the drug.
  • the low hygroscopicity crystal type is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystalline CSI bulk drug provided by the present invention has good physical, chemical and mechanical stability.
  • the crystal form of the CSI bulk drug has been stored for at least 3 months under 25°C/60%RH (relative humidity) open and 25°C/60%RH closed conditions.
  • the crystal form has not changed, and the chemical purity is above 99.7%.
  • the storage process The medium purity remained basically unchanged.
  • the crystal form of CSI bulk drug has not changed after being placed under 40°C/75%RH open and 40°C/75%RH closed conditions for at least 3 months.
  • the crystal form has not changed for at least one month under 60°C/75%RH closed conditions.
  • the chemical purity is above 99.7%, and the purity remains basically unchanged during storage. It shows that the crystalline CSI bulk drug has good stability under accelerated conditions and harsh conditions. Seasonal differences, climate differences in different regions and weather factors brought about high temperature and high humidity conditions will affect the storage, transportation, and production of APIs. Therefore, the stability of the bulk drug under accelerated conditions and harsh conditions is very important for the drug.
  • the crystalline CSI bulk drug has good stability under harsh conditions, which is beneficial to avoid the impact of deviation from the storage conditions on the label on the quality of the drug.
  • the crystalline CSI has good mechanical stability.
  • the crystalline CSI bulk drug has good physical stability after grinding. The preparation process often requires the grinding and pulverization of the drug substance, and good physical stability can reduce the risk of crystallinity change and crystal transformation of the drug substance in the preparation process. Under different pressures, the crystalline CSI bulk drug has good physical stability, which is conducive to maintaining the stability of the crystalline form during the preparation and tableting process.
  • Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and minimizing changes in drug quality, bioavailability, and even toxic side effects caused by changes in crystal form or impurities. .
  • the crystal form CSI provided by the present invention has better stability at room temperature.
  • the crystal form CSI and the prior art crystal form I are suspended and stirred in a solvent to obtain crystal form CSI, indicating that the crystal form CSI has better stability.
  • the stability of the drug is very important, especially to maintain good stability during the effective period of the market, to reduce the dissolution rate and bioavailability of the drug due to the change of the crystal form of the drug, to ensure the efficacy and safety of the drug, and to prevent the drug
  • the occurrence of adverse reactions is of great significance.
  • the crystal type CSI provided by the present invention has better compressibility.
  • the good compressibility of crystalline CSI can effectively improve the hardness/fragility unqualified, chipping and other problems in the tableting process, making the formulation process more reliable, improving the appearance of the product, and improving the quality of the product.
  • the better compressibility can also increase the tableting speed and thus the production efficiency, and at the same time can reduce the cost of auxiliary materials used to improve the compressibility.
  • the crystalline CSI provided by the present invention has better fluidity.
  • the fluidity evaluation results show that the fluidity of the crystalline CSI is significantly better than that of the prior art. Better fluidity can avoid clogging of production equipment and improve production efficiency; the better fluidity of crystalline CSI ensures the uniformity of formulation and content uniformity, reduces the weight difference of formulations, and improves product quality.
  • the crystalline CSI provided by the present invention has better adhesion.
  • the adhesion evaluation results show that the average adsorption capacity of crystal form CSI is much lower than that of crystal form I.
  • the better adhesion of crystalline CSI can effectively improve or avoid sticky wheels and sticking caused by dry granulation and tablet compression, which is beneficial to improve product appearance and weight differences.
  • the better adhesion of crystalline CSI can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and the mixing with other auxiliary materials, and increase the uniformity of the mixing of materials and the final product. The content uniformity.
  • the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline CSI and a pharmaceutically acceptable carrier or adjuvant.
  • crystal form CSI provided by the present invention in the preparation of THR- ⁇ selective agonist drugs.
  • crystal form CSI provided by the present invention in the preparation of drugs for the treatment of NASH and HeFH.
  • the “stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50-1800 revolutions per minute, wherein the magnetic stirring is preferably 300-900 revolutions per minute, and the mechanical stirring is preferably 100- 300 revolutions per minute.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: place the sample to be separated in a centrifuge tube and centrifuge at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "drying" can be performed at room temperature or higher.
  • the drying temperature is from room temperature to about 60°C. Drying is carried out in a fume hood, blast oven or vacuum oven.
  • volatization is accomplished by conventional methods in the art. For example, slow volatilization is to seal the container with a sealing film, pierce a hole, and evaporate at rest; rapid volatilization is to leave the container open to volatilize.
  • crystal or “polymorph” refers to a solid confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction pattern usually varies with the test conditions and parameters of the instrument, and the type of the instrument.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the order of the diffraction peak intensities cannot be the only or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals.
  • the intensity of the diffraction peaks shown in the present invention is illustrative rather than used for absolute comparison.
  • the experimental error of the position of the diffraction peak is usually 5% or less, and the error of these positions should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall angle of the diffraction peak will be shifted, and a certain shift is usually allowed.
  • the X-ray powder diffraction pattern of the protected crystal form of the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the embodiment referred to here, and any characteristic peaks in these patterns are the same. Or similar crystal forms of X-ray powder diffraction patterns are within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form of CSI of the present invention is pure, and substantially no other crystalline forms are mixed.
  • substantially no when used to refer to a new crystal form means that this crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less. Other crystal forms that are less than 5% by weight, and even other crystal forms that are less than 1% by weight.
  • Figure 1 is an XRPD diagram of the crystal form CSI obtained according to Example 1
  • Figure 2 is an XRPD diagram of the crystal form CSI obtained according to Example 2
  • Figure 3 is an XRPD image (transmission mode) of the crystal form CSI obtained according to Example 2
  • Figure 4 is a DSC chart of the crystal form CSI obtained according to Example 2.
  • Figure 5 is a TGA diagram of the crystal form CSI obtained according to Example 2.
  • Figure 6 is the XRPD diagram of crystalline form CSI and crystalline form I before and after suspension and stirring in n-butanol/water (95:5) system (from top to bottom: initial, after suspension and stirring, crystalline form CSI)
  • Figure 7 XRPD comparison of crystalline CSI before and after closed storage at 25°C/60%RH, 40°C/75%RH and 60°C/75%RH (from top to bottom: before placement, 25°C/60%RH placement 3 months, 40°C/75%RH storage for 3 months, 60°C/75%RH storage for 1 month)
  • Fig. 8 XRPD comparison chart of crystalline CSI before and after opening at 25°C/60%RH and 40°C/75%RH (from top to bottom: before placing, 25°C/60%RH for 3 months, 40°C/ 75%RH for 3 months)
  • Figure 9 is a comparison diagram of XRPD before and after polishing of crystalline CSI (top: before polishing; bottom: after polishing)
  • Figure 10 is the XRPD comparison diagram of Form I before and after grinding (upper: before grinding; lower: after grinding)
  • Figure 11 is the DVS diagram of crystalline CSI
  • Figure 12 is the XRPD diagram of crystalline CSI before and after DVS test (top: before DVS; bottom: after DVS)
  • Figure 13 is the XRPD diagram of crystalline CSI before and after the tableting test (top: before tableting; bottom: after tableting)
  • the X-ray powder diffraction pattern described in Example 1 of the present invention was collected on a Bruker D8 X-ray powder diffractometer.
  • the parameters of the X-ray powder diffraction method described in the present invention are as follows:
  • the X-ray powder diffraction patterns described in other embodiments of the present invention are collected on a Bruker D2PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction are as follows:
  • the X-ray powder diffraction pattern (transmission mode) of Example 2 of the present invention was collected on a PANalytical X'Pert 3 XRPD powder diffractometer.
  • the method parameters of the X-ray powder diffraction (transmission mode) of Example 2 are as follows:
  • the differential scanning calorimetry (DSC) chart of the present invention was collected on TA Q2000.
  • the method parameters of the DSC are as follows:
  • thermogravimetric analysis (TGA) chart of the present invention is collected on TA Q500.
  • the method parameters of the TGA are as follows:
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS Company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • Proton nuclear magnetic resonance data ( 1 H NMR) was collected from Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and make a 2-10 mg/mL solution.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • 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.
  • the compound I and/or its salt as a raw material are in solid form.
  • the compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2007009913A1.
  • the XRPD diagram of the crystal form CSI obtained in this embodiment is shown in FIG. 1, and the XRPD data is shown in Table 2.
  • the XRPD data (reflection mode) of the crystalline CSI is shown in Table 3, and the XRPD pattern (reflection mode) is shown in Figure 2.
  • the XRPD data (transmission mode) of the crystalline CSI is shown in Table 4, and the XRPD pattern (transmission mode) is shown in Figure 3.
  • DSC is shown in Figure 4, there is an endothermic peak near 96°C, and an exothermic peak begins to appear near 149°C.
  • This exothermic peak is the exothermic peak of crystal transition, and the endothermic peak begins to appear near 335°C.
  • the peak is the melting endothermic peak.
  • the TGA shown in Figure 5 has a mass loss of about 7.6% when heated to 150°C.
  • Placement conditions Set time Crystal form purity Start —— Crystal CSI 99.80 25°C/60%RH (closed) 3 months Crystal CSI 99.78 25°C/60%RH (open) 3 months Crystal CSI 99.79 40°C/75%RH (closed) 3 months Crystal CSI 99.78 40°C/75%RH (open) 3 months Crystal CSI 99.77 60°C/75%RH (closed) 1 month Crystal CSI 99.76
  • the crystalline CSI can be stable for at least 3 months under 25°C/60%RH and 40°C/75%RH open and closed conditions, and at least 1 month under 60°C/75%RH closed conditions. It can be seen that the crystalline CSI can maintain good stability under long-term, accelerated and severe conditions.
  • the crystalline form CSI and the crystalline form I were placed in a mortar, manually ground for 5 minutes, and XRPD tests were performed before and after the grinding.
  • the test results are shown in Table 7, and the XRPD comparison diagrams are shown in Figs. 9 and 10, respectively.
  • moisture-absorbing weight gain is not less than 15.0%
  • moisture absorption weight gain is less than 15.0% but not less than 2.0%
  • moisture absorption weight gain is less than 2.0% but not less than 0.2%
  • weight gain is less than 0.2%
  • the Compressibility index or Carr Index can usually be used to evaluate the fluidity of the powder or intermediate particles.
  • the fluidity test results show that the fluidity of the crystal form CSI is significantly better than that of the crystal form I.
  • Example 8 Compressibility of crystalline CSI
  • ENERPAC manual tablet press for tableting.
  • choose ⁇ 6mm round flat punch add 80mg crystal form CSI and crystal form I respectively, and press 10kN pressure to make round tablets, and leave them at room temperature for 24h until they are fully elastic.
  • a tablet hardness tester was used to test its radial crushing force (hardness, H).
  • Table 11 and Table 12 below, and the XRPD patterns of the crystal form CSI before and after tableting are shown in Figure 13.
  • the crystal form CSI has better compressibility, and the crystal form of the crystal form CSI remains unchanged before and after compression.
  • Better compressibility can effectively improve the hardness/fragility unqualified, chipping and other problems during the tableting process, making the process more robust, improving product appearance, and improving product quality; good compressibility can increase the tableting speed.
  • Improve production efficiency; in addition, the crystal form with good compressibility improves the feasibility of the process of direct compression and reduces the cost of research and development and production.

Abstract

Resmetirom（称为"化合物I"）的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备THR-β选择性激动剂药物和治疗NASH和HeFH药物中的用途。化合物I的晶型比现有技术具有一种或多种改进的性质，对未来该药物的优化和开发具有重要价值。

Description

一种Resmetirom晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及Resmetirom的晶型及其制备方法和用途。
背景技术
杂合性家族性高胆固醇血症(HeFH)是脂质代谢疾病中最严重的一种，可导致各种危及生命的心血管疾病并发症。非酒精性脂肪性肝炎(NASH)是一种严重的肝脏疾病，伴随有炎症及肝细胞损伤的脂肪变性现象。Resmetirom作为一种甲状腺激素受体THR-β选择性激动剂，可通过降低低密度脂蛋白胆固醇、甘油三酯、肝脏脂肪水平，刺激NASH个体中肝脏线粒体生物合成，进而改善NASH和HeFH的症状。Resmetirom在NASH和HeFH的临床II期试验中取得了积极的成果。
Resmetirom的化学名称为2-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2020118953-appb-000001
晶型是化合物分子在微观结构中三维有序排列而形成晶格的固体，药物多晶型现象是指药物存在两种或两种以上的不同晶型。因为理化性质不同，药物的不同晶型可能在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效和安全性。特别是对难溶性固体药物，晶型的影响会更大。因此，药物晶型必然是药物研究的重要内容，也是药物质量控制的重要内容。
US9266861B2中公开了化合物I的水合物、无水晶型I、甲基异丁酮溶剂合物、二甲基乙酰胺溶剂合物。甲基异丁酮和二甲基乙酰胺是有毒的有机溶剂，不适合药用。晶型I须通过水合物、甲基异丁酮溶剂合物或二甲基乙酰胺溶剂合物制备，其在约321℃时开始融化，且不含溶剂，相对于其他晶型安全性好，是适合药用开发的化合物I固体形态。本申请发明人重复US9266861B2公开的制备方法得到晶型I并对晶型I的性质进行表征，结果显示：晶型I的制备方法复杂，需由特定的起始物料制备，如甲基异丁酮溶剂合物、二甲基乙酰胺溶剂合物。晶型I的研磨稳定性差，研磨后大部分转变为无定型，且晶型I的流动性和可压性较差。因此，本领域仍然需要开发一种易于制备且稳定性好、安全无毒、理化性质好的化合物I结晶形式，以用于含化合物I的药物开发。
为克服现有技术的缺点，本申请发明人对化合物I进行了大量实验研究试图得到更适合药用的晶型，进行了300多个实验，但得到的大部分均是化合物I溶剂合物，例如甲醇溶剂合物、丙酮溶剂合物、四氢呋喃溶剂合物、氯苯溶剂合物、甲苯溶剂合物、环己酮溶剂合 物等。本申请发明人为了得到本发明晶型CSI付出了大量创造性劳动，其中晶型CSI在理化性质，制剂加工性能及生物利用度等方面具有优势，例如在熔点，溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是物理化学稳定性好，引湿性低，热力学稳定性好，研磨稳定性好，流动性好，黏附性低，可压性好，为含化合物I的药物开发提供了新的更好的选择，具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物I的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物I的晶型CSI(以下称作“晶型CSI”)。
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为5.8°±0.2°、11.7°±0.2°、26.5°±0.2处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为14.4°±0.2°、25.1°±0.2°、29.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射在衍射角2θ为14.4°±0.2°、25.1°±0.2°、29.2°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为12.5°±0.2°、13.0°±0.2°、26.3°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射在衍射角2θ为12.5°±0.2°、13.0°±0.2°、26.3°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为5.8°±0.2°、11.7°±0.2°、26.5°±0.2、14.4°±0.2°、25.1°±0.2°、29.2°±0.2°、12.5°±0.2°、26.3°±0.2°、13.0°±0.2°、17.6°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为5.8°±0.2°、11.7°±0.2°、26.6°±0.2、14.5°±0.2°、25.1°±0.2°、29.3°±0.2°、12.5°±0.2°、26.3°±0.2°、13.0°±0.2°、17.6°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处有特征峰。
非限制性地，晶型CSI的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSI的X射线粉末衍射图基本如图2所示。
非限制性地，晶型CSI的X射线粉末衍射图基本如图3所示。
非限制性地，晶型CSI在96℃附近存在吸热峰，在149℃附近开始出现放热峰，该放热峰为转晶放热峰，在335℃附近开始出现吸热峰，该吸热峰为熔化吸热峰。差示扫描量热分析图基本如图4所示。
非限制性地，晶型CSI加热至150℃具有约7.6％的失重，热重分析图基本如图5所示。
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括:
(1)将化合物I在水中悬浮搅拌，将得到的悬浊液分离得到固体并干燥得到晶型CSI；或
(2)将化合物I溶于醇类和水的混合溶剂中，过滤后将所得澄清溶液静置挥发得到晶型 CSI。
进一步地，方法(1)中所述悬浮搅拌时间优选大于12h，所述搅拌温度优选5-50℃，所述干燥温度优选20-30℃；方法(2)中所述醇类优选异丙醇，所述挥发温度优选20-50℃。
本发明提供的晶型CSI具有以下有益效果：
(1)晶型CSI具有低的引湿性。测试结果表明，晶型CSI在30％-80％RH条件下引湿性增重为0.13％，属于无或几乎无引湿性。
引湿性直接影响药物的物理化学稳定性，引湿性高易引起化学降解和晶型转变。此外，引湿性高会降低药物的流动性，从而影响药物的加工工艺。不仅如此，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。低引湿性晶型对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(2)本发明提供的晶型CSI原料药具有良好的物理化学和机械稳定性。晶型CSI原料药在25℃/60％RH(相对湿度)敞口、25℃/60％RH闭口条件下放置至少3个月晶型未发生变化，且化学纯度均在99.7％以上，储存过程中纯度基本保持不变。
晶型CSI原料药在40℃/75％RH敞口、40℃/75％RH闭口条件下放置至少3个月晶型未发生变化，在60℃/75％RH闭口条件至少一个月未发生变化，且化学纯度均在99.7％以上，储存过程中纯度基本保持不变。说明晶型CSI原料药在加速条件及严苛的条件下也具有很好的稳定性。季节差异、不同地区气候差异和天气因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。因此，原料药在加速条件及严苛条件下的稳定性对于药物至关重要。晶型CSI原料药在苛刻的条件下具有较好的稳定性，有利于避免偏离标签上的贮藏条件对药物质量的影响。
同时，晶型CSI具有良好的机械稳定性。晶型CSI原料药研磨后具有良好的物理稳定性。制剂加工过程中常需要原料药的研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药晶型结晶度改变和转晶的风险。在不同压力下，晶型CSI原料药均具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
晶型的转变会导致药物的吸收发生变化，影响生物利用度，甚至引起药物的毒副作用。良好的化学稳定性可以确保在储存过程中基本没有杂质产生。晶型CSI具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，最大程度地减少药物由于晶型改变或杂质产生引起的药物质量变化，生物利用度改变，甚至引起药物的毒副作用。
(3)与现有技术相比，室温条件下，本发明提供的晶型CSI具有更好的稳定性。非限制性地，本发明提供的一个具体实施例中，将晶型CSI和现有技术晶型I在溶剂中混悬搅拌，均得到晶型CSI，说明晶型CSI具有更好的稳定性。
药物的稳定性是至关重要的，尤其在市售有效期内保持较好的稳定性，减少药物由于晶型变化而导致药物溶出速率及生物利用度改变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。
(4)与现有技术相比，本发明提供的晶型CSI具有更优的可压性。晶型CSI好的可压性可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可靠，改 善产品外观，提升产品质量。更优的可压性亦可提升压片速度进而提升生产效率，同时可减少用于改善可压性的辅料的成本支出。
(5)与现有技术相比，本发明提供的晶型CSI具有更好的流动性。流动性评价结果表明，晶型CSI流动性明显优于现有技术。更好的流动性可以避免堵塞生产设备，提升生产效率；晶型CSI更好的流动性能保证制剂的混合均匀度及含量均匀度、降低制剂的重量差异，提升产品质量。
(6)与现有技术相比，本发明提供的晶型CSI具有更优的黏附性。黏附性评价结果表明，晶型CSI的平均吸附量远低于晶型I的平均吸附量。晶型CSI更优的黏附性可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型CSI更优的黏附性还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品的含量均匀度。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI及药学上可接受的载体或辅料。
进一步地，本发明提供的晶型CSI在制备THR-β选择性激动剂药物中的用途。
更进一步地，本发明提供的晶型CSI在制备治疗NASH和HeFH药物中的用途。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
所述“干燥”可以在室温或更高的温度下进行。干燥温度为室温到约60℃。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的固体。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线粉末衍射图通常会随着仪器测试条件和参数、仪器型号的不同而有所改变。特别需要指出的是，X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度的顺序不能作为唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。另外，衍射峰位置的实验误差通常在5％或更少，这些位置的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成衍射峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSI是纯的，基本没有混合任何其他晶型。本发明中， “基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
附图说明
图1为根据实施例1所得晶型CSI的XRPD图
图2为根据实施例2所得晶型CSI的XRPD图
图3为根据实施例2所得晶型CSI的XRPD图(透射模式)
图4为根据实施例2所得晶型CSI的DSC图
图5为根据实施例2所得晶型CSI的TGA图
图6为晶型CSI和晶型I在正丁醇/水(95:5)体系混悬搅拌前后的XRPD图(从上至下依次为：起始，混悬搅拌后，晶型CSI)
图7晶型CSI在25℃/60％RH、40℃/75％RH和60℃/75％RH闭口放置前后XRPD对比图(从上至下依次为：放置前，25℃/60％RH放置3个月，40℃/75％RH放置3个月，60℃/75％RH放置1个月)
图8晶型CSI在25℃/60％RH和40℃/75％RH开口放置前后XRPD对比图(从上至下依次为：放置前，25℃/60％RH放置3个月，40℃/75％RH放置3个月)
图9为晶型CSI研磨前后XRPD对比图(上：研磨前；下：研磨后)
图10为晶型I研磨前后XRPD对比图(上：研磨前；下：研磨后)
图11为晶型CSI的DVS图
图12为晶型CSI在DVS测试前后的XRPD图(上：DVS前；下：DVS后)
图13为晶型CSI在压片测试前后的XRPD图(上：压片前；下：压片后)
具体实施方式
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
HPLC：高效液相色谱
采集数据所用的仪器及方法：
本发明实施例1所述的X射线粉末衍射图在Bruker D8的X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2020118953-appb-000002
1.54060；Kα2
Figure PCTCN2020118953-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：40仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自4.0至40.0度
本发明其他实施例所述的X射线粉末衍射图在Bruker D2PHASER X射线粉末衍射仪上采集。所述X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2020118953-appb-000004
1.54060；Kα2
Figure PCTCN2020118953-appb-000005
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围(2θ)：自3.0至40.0度
本发明所述实施例2的X射线粉末衍射图(透射模式)在PANalytical X’Pert 3XRPD粉末衍射仪上采集。所述实施例2的X射线粉末衍射(透射模式)的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2020118953-appb-000006
1.540598；Kα2
Figure PCTCN2020118953-appb-000007
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围(2θ)：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。所述的DSC的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q500上采集。所述的TGA的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明所述的测试纯度的UPLC方法参数如表1所示：
表1
Figure PCTCN2020118953-appb-000008
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是特定的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述化合物I和/或其盐包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I和/或其盐为固体形式。
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2007009913A1文献所记载的方法制备获得。
具体实施方式
实施例1：晶型CSI的制备方法
称取12.1mg化合物I，向其中加入3mL异丙醇/水(9:1,v/v)，在50℃加热溶解固体，过滤得到澄清溶液，将得到的澄清溶液在室温挥发得到本发明的晶型CSI。
本实施例所得晶型CSI的XRPD图如图1所示，XRPD数据如表2所示。
表2
衍射角2θ d值 强度％
5.80 15.24 66.05
10.03 8.82 34.99
11.65 7.59 100.00
13.67 6.48 7.49
14.42 6.14 57.18
15.49 5.72 14.62
16.51 5.37 11.82
17.59 5.04 14.63
21.03 4.22 12.24
22.44 3.96 8.26
22.93 3.88 9.56
24.35 3.65 13.07
25.06 3.55 97.67
26.10 3.41 21.19
26.53 3.36 92.70
27.36 3.26 27.45
28.18 3.17 19.92
28.55 3.13 12.20
29.18 3.06 84.79
29.93 2.99 10.23
30.89 2.89 7.77
32.31 2.77 24.85
33.68 2.66 27.08
35.45 2.53 19.91
37.28 2.41 4.09
38.28 2.35 4.07
实施例2：晶型CSI的制备方法
称取173.4mg化合物I，向其加入4mL水，室温搅拌15h，然后升温至40℃继续搅拌7h。将得到的悬浊液离心，分离固体并在25℃真空干燥1h，得到晶型CSI。
晶型CSI的XRPD数据(反射模式)如表3所示，XRPD图(反射模式)如图2所示。
晶型CSI的XRPD数据(透射模式)如表4所示，XRPD图(透射模式)如图3所示。
DSC如图4所示，在96℃附近存在吸热峰，在149℃附近开始出现放热峰，该放热峰为转晶放热峰，在335℃附近开始出现吸热峰，该吸热峰为熔化吸热峰。
TGA如图5所示，加热至150℃具有约7.6％质量损失。
晶型CSI的核磁数据为： 1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),12.24(s,1H),7.78(s,2H),7.45(s,1H),3.05(m,1H),1.20(d,J＝6.9Hz,6H)。
表3
衍射角2θ d值 强度％
5.83 15.16 90.20
10.08 8.77 1.03
10.97 8.07 1.58
11.69 7.57 100.00
12.48 7.09 4.95
13.03 6.79 4.57
14.51 6.10 21.13
15.43 5.74 1.91
15.92 5.57 2.21
16.58 5.35 2.03
17.17 5.16 3.90
17.57 5.05 8.47
18.34 4.84 1.42
19.90 4.46 0.99
21.17 4.20 1.29
22.53 3.95 3.41
23.04 3.86 5.59
24.47 3.64 2.51
25.14 3.54 16.08
26.29 3.39 8.78
26.62 3.35 11.80
27.47 3.25 4.04
28.23 3.16 4.37
29.24 3.05 9.17
33.37 2.69 3.17
35.61 2.52 1.74
37.06 2.43 0.83
表4
衍射角2θ d值 强度％
5.83 15.16 100.00
9.13 9.69 14.73
10.09 8.76 12.75
10.98 8.06 23.21
11.69 7.57 63.30
12.06 7.34 9.83
12.50 7.08 26.88
13.03 6.80 19.58
14.53 6.09 59.51
15.44 5.74 18.34
15.88 5.58 11.55
16.59 5.34 12.03
17.18 5.16 20.70
17.63 5.03 11.27
18.20 4.87 20.12
18.37 4.83 22.16
19.21 4.62 3.91
22.54 3.95 42.65
23.14 3.84 30.90
24.44 3.64 20.80
25.17 3.54 79.10
26.29 3.39 91.51
26.66 3.34 52.14
27.44 3.25 26.81
28.31 3.15 9.85
29.33 3.05 29.64
30.25 2.95 5.49
31.60 2.83 3.96
33.43 2.68 35.91
37.24 2.41 4.92
39.03 2.31 5.52
实施例3 晶型CSI的稳定性
将各约20mg晶型CSI和晶型I样品，加入0.5mL表5所示的相应溶剂中配成悬浊液，于室温搅拌特定时间后测样，结果如表7所示。正丁醇/水(v/v,95:5)体系中搅拌前后XRPD对比图如图6所示。
表5
起始物料 溶剂(v/v) 搅拌时间 晶型
晶型CSI+晶型I 丁酮/水(95:5) 23小时 晶型CSI
晶型CSI+晶型I 正丁醇/水(95:5) 3天 晶型CSI
结果表明在室温条件下，晶型CSI在丁酮/水(v/v,95:5)和正丁醇/水(v/v,95:5)体系中比晶型I稳定。
实施例4 晶型CSI的物理化学稳定性
称取适量本发明制备得到的晶型CSI分别放置在25℃/60％RH、40℃/75％RH以及 60℃/75％RH条件下，采用UPLC和XRPD测定纯度与晶型。结果如表6所示，闭口和开口放置的XRPD对比图分别如图7和图8所示。
表6
放置条件 放置时间 晶型 纯度
起始 —— 晶型CSI 99.80
25℃/60％RH(闭口) 3个月 晶型CSI 99.78
25℃/60％RH(开口) 3个月 晶型CSI 99.79
40℃/75％RH(闭口) 3个月 晶型CSI 99.78
40℃/75％RH(开口) 3个月 晶型CSI 99.77
60℃/75％RH(闭口) 1个月 晶型CSI 99.76
结果表明，晶型CSI在25℃/60％RH以及40℃/75％RH开口和闭口条件下至少可稳定3个月，在60℃/75％RH闭口条件下至少可稳定1个月。可见，晶型CSI在长期、加速和严苛的条件下均可保持良好的稳定性。
实施例5 晶型CSI的机械稳定性
将晶型CSI及晶型I置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，测试结果如表7所示，XRPD对比图分别如图9和图10所示。
表7
研磨前 研磨后
晶型CSI 晶型CSI
晶型I 大部分转变为无定型
结果表明，与晶型I相比，晶型CSI具有更好的机械稳定性。
实施例6 晶型CSI的引湿性
取适量晶型CSI采用DVS测试其引湿性。结果如表8所示。晶型CSI的DVS图如图11所示，DVS前后XRPD叠图如图12所示。
表8
起始晶型 30％-80％RH的增重 DVS后晶型
晶型CSI 0.13％ 晶型CSI
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度，欧洲药典第九版5.11中对引湿性的界定与中国药典一致)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15.0％
有引湿性：引湿增重小于15.0％但不小于2.0％
略有引湿性：引湿增重小于2.0％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，晶型CSI在DVS前后晶型不变，在30％-80％RH条件下增重0.13％，属于无或几乎无引湿性。
实施例7 晶型CSI的流动性
制剂工艺过程中，通常可采用可压性系数(Compressibility index)或卡尔系数(Carr Index)来评价粉体或中间体颗粒的流动性，测定方法为将一定量的粉体轻轻装入量筒后测量振实前体积；采用轻敲法使粉体处于最紧状态，测量振实后体积；计算松密度ρ 0与振实密度ρ f；根据公式c＝(ρ f－ρ 0)/ρ f计算可压性系数。
可压性系数对粉体流动性的界定标准参考ICH Q4B附录13，详见表9。
表9
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型CSI和晶型I的流动性评价结果见表10。
表10
晶型 松密度(ρ 0,g/mL) 振实密度(ρ f,g/mL) 可压性指数(％) 流动性
晶型I 0.2169 0.3471 38 极差
晶型CSI 0.3653 0.4600 21 可接受
流动性测试结果表明晶型CSI的流动性明显优于晶型I。
实施例8 晶型CSI的可压性
采用ENERPAC手动压片机进行压片，压片时，选择Φ6mm圆形平冲，分别加入80mg晶型CSI、晶型I，采用10kN的压力压制成圆形片剂，室温放置24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。结果如下表11和表12所示，晶型CSI压片前后的XRPD图如图13所示。
表11
Figure PCTCN2020118953-appb-000009
表12
Figure PCTCN2020118953-appb-000010
结果表明，相比晶型I，晶型CSI具有更优的可压性，且晶型CSI在压片前后晶型保持不变。更优的可压性可以有效改善压片过程中的硬度/脆碎度不合格、裂片等问题，使工艺更为稳健，改善产品外观，提升产品质量；可压性好可提升压片速度，提高生产效率；另外，可压性好的晶型，其直接压片的工艺可行性提高，降低了研发和生产的成本。
实施例9 晶型CSI的黏附性
分别将约30mg晶型CSI和晶型I的API加入到8mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续进行数次压制后，记录冲头累计的最终黏附量、压制过程中的最高黏附量和平均黏附量。实验结果见表13。
表13
晶型 平均吸附量(mg)
晶型I 0.25
晶型CSI 0.20
实验结果表明，晶型CSI的黏附性优于晶型I。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (11)

  1. 一种Resmetirom的晶型CSI，其特征在于使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为5.8°±0.2°、11.7°±0.2°、26.5°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CSI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为14.4°±0.2°、25.1°±0.2°、29.2°±0.2°中的1处或2处或3处具有特征峰。
  3. 根据权利要求1所述的晶型CSI，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为12.5°±0.2°、13.0°±0.2°、26.3°±0.2°中的1处或2处或3处具有特征峰。
  4. 根据权利要求1所述的晶型CSI，其特征在于使用Cu-Kα辐射，其X射线粉末衍射图如图2所示。
  5. 根据权利要求1所述的晶型CSI，其特征在于使用Cu-Kα辐射，其X射线粉末衍射图如图3所示。
  6. 一种权利要求1所述的晶型CSI的制备方法，其特征在于，所述方法为：
    (1)将Resmetirom在水中悬浮搅拌，将得到的悬浊液分离得到固体并干燥得到晶型CSI；或
    (2)将Resmetirom溶于醇类和水的混合溶剂中，过滤后将所得澄清溶液静置挥发得到晶型CSI。
  7. 根据权利要求6所述的制备方法，方法(1)中所述悬浮搅拌时间大于12h；方法(2)中所述醇类为异丙醇。
  8. 根据权利要求6所述的制备方法，方法(1)中所述搅拌温度为5-50℃；方法(2)中，所述挥发温度为20-50℃。
  9. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型CSI及药学上可接受的载体或辅料。
  10. 权利要求1中所述的晶型CSI在制备THR-β选择性激动剂药物中的用途。
  11. 权利要求1中所述的晶型CSI在制备治疗NASH和HeFH药物中的用途。
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