WO2021104021A1 - Tropifexor的新晶型及其制备方法 - Google Patents

Tropifexor的新晶型及其制备方法 Download PDF

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WO2021104021A1
WO2021104021A1 PCT/CN2020/128084 CN2020128084W WO2021104021A1 WO 2021104021 A1 WO2021104021 A1 WO 2021104021A1 CN 2020128084 W CN2020128084 W CN 2020128084W WO 2021104021 A1 WO2021104021 A1 WO 2021104021A1
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crystal form
tropifexor
ray powder
solvent
powder diffraction
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PCT/CN2020/128084
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English (en)
French (fr)
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张�杰
廖伟龙
邝润桥
徐巾超
陈勇
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080080617.2A priority Critical patent/CN114728955A/zh
Publication of WO2021104021A1 publication Critical patent/WO2021104021A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a new crystal form of Tropifexor and a preparation method thereof.
  • Tropifexor was originally developed by Novartis and then licensed to Pfizer for collaborative development. It is a non-steroidal FXR (farnesoid receptor) agonist, currently in clinical phase II of indications for NASH (non-alcoholic steatohepatitis), fatty liver and primary biliary cholangitis.
  • FXR farnesoid receptor
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is beneficial to the production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
  • the present invention obtains a new crystal form of the compound through a large number of experimental studies on the Tropifexor compound.
  • the new crystal form has the advantages of high solubility, good stability, low moisture absorption, simple preparation process and easy operation, etc., and has excellent properties in industrial production. Superiority.
  • an object of the present invention is to provide a new crystal form of Tropifexor and a preparation method thereof, which has good solubility and stability.
  • the present invention provides a new crystal form of Tropifexor: crystal form I.
  • the new crystal form of the present invention was studied, and it was found that the crystal form I has good performance in terms of stability, solubility, etc., and can be used in the production of pharmaceutical preparations.
  • the crystal form I by using an X-ray powder diffractometer using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 5.8, 6.7, 8.3, 10.5, 11.5, 13.0, 14.9, 15.6, 16.5, 20.5, 21.1,24.8, 26.2 and 26.7.
  • the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) : 12.5, 13.4, 17.3, 17.9, 18.4, 18.6, 20.1,21.9, 22.5, 23.3, 23.6, 23.9, 27.4, 28.8, 29.6 and 31.6.
  • the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) :5.8,6.7,8.3,10.5,11.5,12.5,13.0,13.4,14.9,15.6,16.5,17.3,17.9,18.4,18.6,20.1,20.5,21.1,21.9,22.5,23.3,23.6,23.9,24.8,26.2 , 26.7, 27.4, 28.8, 29.6 and 31.6.
  • the relative intensity of the peak at 15.6 degrees 2 ⁇ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
  • the crystal form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
  • XRPD pattern X-ray powder diffraction pattern
  • the differential scanning calorimetry (DSC) of the crystalline form I has an endothermic peak at 150°C to 200°C, and the peak temperature of the endothermic peak is at 180°C to 190°C.
  • the crystalline form I has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
  • the crystalline form I has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 200°C, and the weight loss is about 0.4%.
  • TGA thermogravimetric analysis curve
  • the crystal form I has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
  • TGA pattern thermogravimetric analysis curve
  • the purity of the crystalline form I is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, relative to Tropifexor, the purity of the crystalline form I is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the Tropifexor crystal form I of the present invention can be used to treat diseases such as NASH, fatty liver and primary biliary cholangitis.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Tropifexor crystal form I and pharmaceutically acceptable auxiliary materials or excipients.
  • a therapeutically effective amount of Tropifexor crystal form I is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is prepared in a well-known manner in the pharmaceutical field.
  • the pharmaceutical composition or preparation can be used to treat diseases such as NASH, fatty liver, and primary biliary cholangitis.
  • the present invention provides a pharmaceutical composition, which may contain at least 0.1%-10% of the crystal form I of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which may contain at least 0.1%-5% of the crystal form I of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which may contain at least 0.1%-1% of the crystal form I of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-0.5% of the crystal form I of the total weight of the composition.
  • the pharmaceutical composition provided by the present invention contains Tropifexor, and at least 80% of the Tropifexor is the Tropifexor crystal form I according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and at least 90% of Tropifexor is the Tropifexor crystal form I according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and at least 95% of the Tropifexor is the Tropifexor crystal form I according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and at least 99% of Tropifexor is the Tropifexor crystal form I according to the mass ratio.
  • the purity of crystal form I in the pharmaceutical composition is at least 80%. In some embodiments, relative to Tropifexor, the purity of the crystalline form I in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the pharmaceutical composition containing Tropifexor crystal form I of the present invention can be used to prepare pharmaceutical preparations for NASH, fatty liver, primary biliary cholangitis and the like.
  • the pharmaceutical composition containing Tropifexor crystal form I of the present invention can be used in methods for treating diseases such as NASH, fatty liver, and primary biliary cholangitis.
  • the crystal form I provided by the invention has good stability and solubility, is not easy to deliquesce under high humidity conditions, is convenient for long-term storage and placement of drugs, and can well avoid drug storage and crystal transformation during the development process, thereby avoiding bioavailability As well as the change of drug efficacy, it has strong economic value.
  • the present invention proposes a method for preparing the aforementioned Tropifexor crystal form I.
  • a method for preparing Tropifexor crystal form I includes: mixing Tropifexor with a good solvent, heating to complete dissolution, mixing with an anti-solvent, stirring to precipitate crystals, collecting crystals, and removing the solvent to obtain crystal form I.
  • a method for preparing Tropifexor crystal form I includes: mixing Tropifexor with a good solvent, heating to a certain temperature to completely dissolve, adding an anti-solvent to the solution dropwise, stirring to precipitate crystals, and collecting Crystals, removing the solvent, and obtaining crystal form I.
  • a method for preparing Tropifexor crystal form I includes: mixing Tropifexor with a good solvent, heating to 40°C-80°C to completely dissolve it; then adding an anti-solvent at room temperature, stirring to precipitate crystals, The crystals are collected and the solvent is removed to obtain crystal form I.
  • the good solvent is ethanol, acetone or a combination thereof.
  • the mass-volume ratio of the Tropifexor to the good solvent is 1:2 to 1:50; more preferably It is 1:10 ⁇ 1:30.
  • the certain temperature is 40°C-80°C.
  • the anti-solvent is one of water and n-heptane.
  • the “crystal form” of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention
  • the “crystal form” of should be understood as falling within the protection scope of the present invention.
  • the present invention tests various parameters on a sample containing a certain "crystal form” that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different.
  • the experimental error or the value of the difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C.
  • the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the mass unit is grams and the volume unit is milliliters.
  • RH means relative humidity
  • the room temperature is in the range of 20°C-40°C.
  • Figure 1 X-ray powder diffraction (XRPD) pattern of the crystalline form I of the compound of formula (1).
  • FIG. 1 Differential scanning calorimetry (DSC) curve diagram of the crystalline form I of the compound of formula (1).
  • Figure 4 The isothermal adsorption equilibrium (DVS) curve diagram of the crystalline form I of the compound of formula (1).
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 10mm. Using ⁇ - ⁇ Continuous scanning mode, get the effective 2 ⁇ range of 3° ⁇ 40°.
  • the DSC measurement was performed in TA Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.
  • the TGA measurement was performed in TA Instruments TM model Q500.
  • the operation step is to peel the empty crucible, take a solid sample of about 10 mg, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purge, and record the spectrum.
  • DVS test isotherm adsorption equilibrium curve test method, instrument: DVS-INTRINSIC, with relative humidity (0%-95.0%-0%) at 25.0°C, starting from 0% relative humidity, with 10% relative humidity step The change reaches 95% relative humidity, and then a 10% relative humidity step change reaches 0% relative humidity.
  • the absolute value of the sample weight change dm/dt per unit time is less than 0.1% under a certain relative humidity condition, it is considered to be in equilibrium, and then the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions.
  • Deliquescence absorb enough water to form a liquid
  • weight gain by moisture-absorbing is not less than 15%
  • moisture absorption weight gain is less than 15% but not less than 2%
  • weight gain by moisture absorption is less than 2% but not less than 0.2%;
  • the weight gain is less than 0.2%.

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Abstract

本发明提供了Tropifexor的新晶型及其制备方法，属于药物化学领域。所述晶型为晶型I。所述晶型I的XRPD图含有如下2θ(误差±0.2度)值的特征峰：5.8,6.7,8.3,10.5,11.5,13.0,14.9,15.6,16.5,20.5,21.1,24.8,26.2和26.7度。所述晶型I具有较好的溶解性和稳定性，有利于储存、转移、生产工艺中操作，适于制备成制剂。

Description

Tropifexor的新晶型及其制备方法 技术领域
本发明属于药物化学领域，涉及Tropifexor的新晶型及其制备方法。
背景技术
Tropifexor最初由诺华研发，后授权给辉瑞进行合作开发。它是一种非甾体FXR(法尼醇受体)激动剂，目前均处于NASH(非酒精性脂肪性肝炎)、脂肪肝和原发性胆汁性胆管炎适应症的临床II期。
Tropifexor结构如下式(1)所示：
Figure PCTCN2020128084-appb-000001
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于生产或利于药物制剂的晶型，需要对药物的结晶行为进行全面的考察，以得到满足生产要求的晶型。
目前没有文献公开Tropifexor的晶型，也没有相关的文献报道。
本发明通过对Tropifexor化合物进行大量实验研究，得到了该化合物的新晶型，该新晶型具有溶解度高，稳定性好，引湿性低，制备工艺简单易操作等优越性质，在工业生产中具有优越性。
发明内容
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提供Tropifexor新晶型及其制备方法，该晶型具有良好的溶解度和稳定性。
根据本发明的一个方面，本发明提供了Tropifexor的新晶型：晶型I。
对本发明所述新晶型进行研究，发现晶型I在稳定性、溶解度等方面具有良好的性能，可用于制备药物制剂生产中。
所述晶型I，通过使用Cu-Kα辐射的X射线粉末衍射仪，其X-射线粉末衍射图中在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.8,6.7,8.3,10.5,11.5,13.0,14.9,15.6,16.5,20.5,21.1,24.8,26.2和26.7。
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型I的X-射线粉末衍射图中在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：12.5,13.4,17.3,17.9,18.4,18.6,20.1,21.9,22.5,23.3,23.6,23.9,27.4,28.8,29.6和31.6。
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型I的X-射线粉末衍射图中在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.8,6.7,8.3,10.5,11.5,12.5,13.0,13.4,14.9,15.6,16.5,17.3,17.9,18.4,18.6,20.1,20.5,21.1,21.9,22.5,23.3,23.6,23.9,24.8,26.2,26.7,27.4,28.8,29.6和31.6。
在一些实施例中，Tropifexor晶型I的X-射线粉末衍射图中，在2θ为15.6度的峰的相对强度大于70％，或大于80％，或大于90％，或大于99％。
在一些实施例中，所述晶型I具有基本上如图1所示的X-射线粉末衍射图谱(XRPD图谱)。
在一些实施例中，所述晶型I的差示扫描量热曲线(DSC)在150℃-200℃具有吸热峰，吸热峰的峰值温度在180℃-190℃。
在一些实施例中，所述晶型I具有如图2所示的差示扫描量热曲线(DSC图谱)。
在一些实施例中，所述晶型I具有热重分析曲线(TGA)显示在30℃-200℃间有失重，失重量约为0.4％。
在一些实施例中，所述晶型I具有基本上如图3所示的热重分析曲线(TGA图谱)。
相对于Tropifexor，在一些实施例中，所述晶型I的纯度至少为70％，或至少80％，或至少90％，或至少95％，或至少99％。在一些实施例中，相对于Tropifexor，所述晶型I的纯度至少为85％，或至少90％，或至少95％，或至少99％。
本发明所述的Tropifexor晶型I，可用于治疗NASH、脂肪肝和原发性胆汁性胆管炎等疾病。
本发明的另一个目的在于提供包含治疗有效量的Tropifexor晶型I和药学上可接受的辅料或赋形剂的药物组合物。一般是将治疗有效量的Tropifexor晶型I与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组合物或制剂是以制药领域中熟知的方式进行制备的。所述药物组合物或制剂可以用于治疗NASH、脂肪肝和原发性胆汁性胆管炎等疾病。
本发明提供的一种药物组合物，其可以含有至少为组合物的总重量的0.1％-10％的所述晶型I。本发明提供一种药物组合物，其可以含有至少为组合物的总重量的0.1％-5％的所述晶型I。本发明提供一种药物组合物，其可以含有至少为组合物的总重量的0.1％-1％的所述晶型I。在一些实施方式中，本发明提供一种药物组合物，其含有至少为组合物的总重量的0.1％-0.5％的所述晶型I。
本发明提供的一种药物组合物，含有Tropifexor，按照质量比计，其中至少80％的Tropifexor为所述Tropifexor晶型I。在一些实施方式中，一种药物组合物，含有Tropifexor，按照质量比计，其中至少90％的Tropifexor为所述Tropifexor晶型I。在一些实施方式中，一种药物组合物，含有Tropifexor，按照质量比计，其中至少95％的Tropifexor为所述Tropifexor晶型I。在一些实施方式中，一种药物组合物，含有Tropifexor，按照质量比计，其中至少99％的Tropifexor为所述Tropifexor晶型I。
相对于Tropifexor，在一些实施方式中，所述药物组合物中，晶型I的纯度至少80％。在一些实施方式中，相对于Tropifexor，所述药物组合物中，晶型I的纯度至少85％，或至少90％，或至少95％，或至少99％。
本发明所述的含有Tropifexor晶型I的药物组合物，可用于制备NASH、脂肪肝和原发性胆汁性胆管炎等的药物制剂。本发明所述的含有Tropifexor晶型I的药物组合物，可用于治疗NASH、脂肪肝和原发性胆汁性胆管炎等疾病的方法中。
本发明提供的晶型I，具有好的稳定性和溶解度，不易在高湿条件下潮解，方便药物长期贮存放置，能很好的避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变，具有很强的经济价值。
根据本发明的第二方面，本发明提出了一种制备前面所述的Tropifexor晶型I的方法。
一种制备Tropifexor晶型I的方法包括：将Tropifexor与良溶剂混合，加热至完全溶解后，与反溶剂混合，搅拌析出晶体，收集晶体，除去溶剂，得到晶型I。
在一些实施方式中，一种制备Tropifexor晶型I的方法包括：将Tropifexor与良溶剂混合，加热到一定温度下使其完全溶解后，将反溶剂滴加到该溶液中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型I。在一些实施方式中，一种制备Tropifexor晶型I的方法包括：将Tropifexor与良溶剂混合，加热到40℃-80℃，使其完全溶解；然后在室温条件下加入反溶剂，搅拌析出晶体，收集晶体，除去溶剂，得到晶型I。
所述良溶剂为乙醇、丙酮或其组合。
在一些实施方式中，所述良溶剂质量以克(g)计算，溶剂体积以毫升(mL)计算时，所述Tropifexor与良溶剂的质量体积比为1:2～1:50；更优选地为1:10～1:30。
所述的一定温度为40℃-80℃。
所述的反溶剂为水、正庚烷中的一种。
本发明所述“晶型”可以以0.0001％-100％存在于样品中，因此，只要样品中含有即使痕量例如大于0.0001％，大于0.001％，大于0.001％或者大于0.01％的本发明所述的“晶型”都应当理解为落入本发明的保护范围内。为把本发明所述的“晶型”的各种参数描述得更清楚，本发明通过对含基本上纯净的某种“晶型”时的样品进行测试各种参数并对所述晶型进行表征和鉴别。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。基于公开的数字，每一个数字的数值有可能会出现1％，2％，或5％等差异。
所述晶型的差示扫描量热测定(DSC)有实验误差，并受样品的干燥程度有轻微影响，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
在本发明中，计算质量体积比时，质量单位为克，体积单位为毫升。
在本发明中“RH”为相对湿度。
在本发明中，室温在20℃-40℃范围。
附图说明
图1：式(1)化合物的晶型I的X-射线粉末衍射(XRPD)图。
图2：式(1)化合物的晶型I的差示扫描量热(DSC)曲线图。
图3：式(1)化合物的晶型I的热重分析(TGA)曲线图。
图4：式(1)化合物的晶型I的等温吸附平衡(DVS)曲线图。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
为了使本领域的技术人员更好的理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
实施例1 Tropifexor晶型I的制备方法
将50.0mg的Tropifexor加入乙醇(1.0ml)中，加热至60℃搅拌得到澄清溶液后，再将水(3ml)滴加至该Tropifexor的溶液中。搅拌析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末38.5mg。所得晶体经XPRD检测，确认为Tropifexor晶型I；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。
实施例2 Tropifexor晶型I的制备方法
将50.0mg的Tropifexor加入乙醇(1.0ml)中，加热至60℃搅拌得到澄清溶液后，再将正庚烷(3ml)滴加至该Tropifexor的溶液中。搅拌析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末39.7mg。所得晶体经XPRD检测，确认为Tropifexor晶型I；其X射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。
实施例3 Tropifexor晶型I的制备方法
将50.0mg的Tropifexor加入丙酮(1.0ml)中，加热至60℃搅拌得到澄清溶液后，再将正庚烷(3ml)滴加至该Tropifexor的溶液中。搅拌析出固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到固体粉末37.3mg。所得晶体经XPRD检测，确认为Tropifexor晶型I；其X射线粉末衍射图谱与图1基本一致， 其DSC图谱与图2基本一致，TGA图谱与图3基本一致。
实施例4 Tropifexor晶型I的稳定性实验
1)高温试验
取本发明的Tropifexor晶型I样品敞口分别放置于60℃(温度偏差±5℃)/75％相对湿度(湿度偏差±5％)恒温恒湿箱中放置，然后分别于5、10和15天取上述样品约10mg，测试其晶型情况实验结果如下表1。
表1晶型I稳定性研究
Figure PCTCN2020128084-appb-000002
上述结果显示：样品在高温60℃(温度偏差±5℃)/75％相对湿度(湿度偏差±5％)条件分别放置5天，10天，15天后，晶型不变，稳定性良好。
2)高湿试验
取本发明的Tropifexor晶型I样品平铺置于称量瓶中，在25℃/92.5％相对湿度(湿度偏差±5％)恒温恒湿箱中放置，然后分别于5、10和15天取上述样品约10mg，测试其晶型情况实验结果如下表2。
表2晶型I稳定性研究
Figure PCTCN2020128084-appb-000003
上述结果显示：样品在25℃/92.5％相对湿度(湿度偏差±5％)条件分别放置5天，10天，15天后，晶型不变，稳定性良好。
3)光照试验
取本发明的Tropifexor晶型I样品平铺置于称量瓶中，在可见光4500Lux±500Lux、紫外光1.7W*h/m2的恒温恒湿箱(25℃、RH60±5％)条件下放置，然后分别于5、10和15天取上述样品约10mg，测试其晶型情况实验结果如下表3。
表3晶型I稳定性研究
Figure PCTCN2020128084-appb-000004
Figure PCTCN2020128084-appb-000005
上述结果显示：样品在可见光4500Lux±500Lux、紫外光1.7W*h/m 2的恒温恒湿箱(25℃、RH60±5％)条件下分别放置5天，10天，15天后，晶型不变，稳定性良好。
实施例5 Tropifexor晶型I的溶解度实验
预先称重烧瓶和搅拌子，精确称取Tropifexor新晶型I样品，分别加入瓶中，滴加水搅拌，至固体溶解停止加水。无目视可见的颗粒时，视为完全溶解。溶解后称重试管、搅拌子、和水溶液的总重量，计算出所加水的重量，然后计算出溶解度；水的密度按照1.00g/mL计算，测试晶型I样品在25℃或37℃的水中的溶解度，溶解度测试实验结果见表4。
表4 Tropifexor晶型I的溶解度测试实验结果
温度 Tropifexor晶型 溶解度
25℃ 晶型I 0.120mg/ml
37℃ 晶型I 0.129mg/ml
由上表的测试溶解度数据可知：晶型I在水中具有很好的润湿性，溶解性好。
实施例6 Tropifexor晶型I的引湿性分析
取50mg的Tropifexor晶型I固体，利用DVS仪器在25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以10％的相对湿度阶梯变化到达95％相对湿度，然后再以10％的相对湿度阶梯变化到达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.1％时认为达到平衡，则进入下一个相对湿度。检测产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。结果见图4。
由图4可知：晶型I在DVS曲线湿度大于75％后引湿性急剧上升，湿度为95％时引湿增重达到最大，约为7.12％，说明晶型I具有较高的引湿性。
测试仪器及方法
(1)粉末X-射线衍射(XRPD)研究
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2020128084-appb-000006
1.540598；Kα2
Figure PCTCN2020128084-appb-000007
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm.采用θ-θ连续扫描模式，得到3°～40°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0168°的扫描步长在3～40°2θ范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。
采用上述条件，分别对实施例制备的晶型进行XRPD检测。
(2)差示扫描量热法(DSC)分析
DSC测量在TA Instruments TM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在室温到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。
(3)热重分析(TGA)分析
TGA测量在TA Instruments TM型号Q500中进行。操作步骤为空坩埚去皮，取固体样品约10mg、于去皮空坩埚内，铺匀即可。待仪器运行稳定后，在氮气吹扫下，室温到300℃之间以10℃/min的加热速率收集数据，记录图谱。
(4)动态蒸汽吸附分析仪DVS
DVS测试等温吸附平衡曲线测试方法，仪器：DVS-INTRINSIC，25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以10％的相对湿度阶梯变化到达95％相对湿度，然后再以10％的相对湿度阶梯变化到达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.1％时认为达到平衡，则进入下一个相对湿度。检测产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录药物引湿性试验指导原则，实验条件：25±0.2℃，80％相对湿度)：
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％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (11)

  1. Tropifexor的晶型I，其特征在于，使用Cu-Kα辐射，以2θ(误差±0.2度)表示的X射线粉末衍射光谱，晶型I的X-射线粉末衍射图中在2θ为5.8,6.7,8.3,10.5,11.5,13.0,14.9,15.6,16.5,20.5,21.1,24.8,26.2和26.7度的位置有衍射峰。
  2. 权利要求1所述的晶型I，晶型I的X-射线粉末衍射图中在2θ为12.5,13.4,17.3,17.9,18.4,18.6,20.1,21.9,22.5,23.3,23.6,23.9,27.4,28.8,29.6和31.6度的位置有衍射峰；或晶型I的X-射线粉末衍射图中在2θ为5.8,6.7,8.3,10.5,11.5,12.5,13.0,13.4,14.9,15.6,16.5,17.3,17.9,18.4,18.6,20.1,20.5,21.1,21.9,22.5,23.3,23.6,23.9,24.8,26.2,26.7,27.4,28.8,29.6和31.6度的位置有衍射峰；或晶型I的X-射线粉末衍射图如图1所示。
  3. 权利要求1所述的Tropifexor的晶型I，晶型I的热重分析曲线显示在30℃-200℃间有失重。
  4. 权利要求1所述的Tropifexor的晶型I，晶型I的热重分析曲线显示在30℃-200℃间有失重，失重量约为0.4％。
  5. 权利要求1所述的Tropifexor的晶型I，晶型I的纯度至少70％。
  6. 一种制备权利要求1-5任一所述的Tropifexor的晶型I的方法，包括：Tropifexor和良溶剂混合，加热至完全溶解后，与反溶剂混合，搅拌析出晶体，收集晶体，除去溶剂，得到晶型I；其中，所述的良溶剂为乙醇、丙酮中的至少一种；所述的反溶剂为水、正庚烷中的至少一种。
  7. 根据权利要求6所述的方法，其特征在于所述Tropifexor与良溶剂的质量体积比为1:2～1:50。
  8. 一种药物组合物，包含治疗有效量的权利要求1-5任一所述的晶型I及药学上可接受的辅料。
  9. 根据权利要求8所述的药物组合物，其中，按照质量比计，至少80％的Tropifexor为晶型I。
  10. 根据权利要求8或9所述的药物组合物，其特征在于，所述晶型I至少为组合物的总重量的0.1％-10％。
  11. 权利要求1-5任一所述的晶型或权利要求8-10任一所述的组合物在制备治疗NASH、脂肪肝和原发性胆汁性胆管炎的药物中的用途。
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