WO2018133705A1 - Gft-505的晶型及其制备方法和用途 - Google Patents

Gft-505的晶型及其制备方法和用途 Download PDF

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WO2018133705A1
WO2018133705A1 PCT/CN2018/071917 CN2018071917W WO2018133705A1 WO 2018133705 A1 WO2018133705 A1 WO 2018133705A1 CN 2018071917 W CN2018071917 W CN 2018071917W WO 2018133705 A1 WO2018133705 A1 WO 2018133705A1
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Prior art keywords
solvent
crystal form
alcohol
ketone
ray powder
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PCT/CN2018/071917
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
王金秋
刘凯
张晓宇
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苏州科睿思制药有限公司
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Application filed by 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Priority to AU2018208913A priority Critical patent/AU2018208913A1/en
Priority to CN201880005221.4A priority patent/CN110312705B/zh
Priority to US16/479,659 priority patent/US20210363101A1/en
Priority to JP2019538619A priority patent/JP2020505355A/ja
Priority to EP18741904.9A priority patent/EP3572399A4/en
Priority to CA3051146A priority patent/CA3051146A1/en
Publication of WO2018133705A1 publication Critical patent/WO2018133705A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • 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
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, the crystal form involving GFT-505, its preparation method and use, belong to the field of medicine.
  • Non-alcoholic steatohepatitis is a serious liver disease that precedes hepatocellular carcinoma and is currently incurable.
  • Elafibranor also known as GFT-505, was developed by Genfit and is clinically used to treat NASH for good safety and efficacy.
  • GFT-505 is an agonist of peroxisome proliferator-activated receptor-alpha (PPARA) and receptor-delta (PPARD). Studies have shown that GFT-505 can improve insulin sensitivity, blood glucose balance, lipid metabolism, and reduce inflammation, and is expected to become a new treatment for NASH.
  • PPARA peroxisome proliferator-activated receptor-alpha
  • PPARD receptor-delta
  • GFT-505 1-[4-Methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethoxyphenyl]prop-2-en-one , having the chemical structure shown by formula (I):
  • Solid chemical drugs have different crystal forms that can cause differences in solubility, stability, fluidity, and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compound (see K. Knapman, Modern Drug Discovery, 3, 53-54, 57, 2000.), resulting in differences in clinical efficacy.
  • New crystalline forms of pharmaceutically active ingredients (including anhydrates, hydrates, solvates, etc.) have been found to produce more processing advantages or to provide materials with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processed, easy to purify or as an intermediate crystal form that facilitates conversion to other crystal forms.
  • the new crystalline form of the pharmaceutically acceptable compound can help improve the performance of the drug and expand the formulation of the raw materials that can be used in the formulation.
  • GFT-505 The chemical structure of GFT-505 and the preparation method thereof are disclosed in the patent CN100548960C.
  • the inventors repeat the method to obtain a light yellow viscous oil, which is difficult to sample and quantify, has low purity and poor stability, and is difficult to be made.
  • Pharmaceutical preparations are not suitable for medicinal use.
  • the inventors have accidentally discovered the crystal forms CS1, CS2, CS5 and CS6 of the present invention by a large number of experiments.
  • the crystal forms CS1, CS2, CS5 and CS6 of GFT-505 provided by the invention have high purity, good stability, low moisture permeability, good solubility and high mechanical stability, and provide preparation for preparation of pharmaceutical preparations containing GFT-505. New and better choices are very important for drug development.
  • the main object of the present invention is to provide a crystal form of GFT-505 and a preparation method and use thereof.
  • the present invention provides a crystal form CS1 of a compound of the formula (I) (hereinafter referred to as "crystal form CS1").
  • the crystal form CS1 is an anhydride.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 14.8° ⁇ 0.2°, and 16.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 18.7° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 18.7° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at one or two or three points in the diffraction angle 2 ⁇ value of 11.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 25.1° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 11.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 14.8° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.4°. Characteristic peaks are present at ⁇ 0.2°, 26.6° ⁇ 0.2°, 11.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 8.0° ⁇ 0.2° and 12.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 8.0° ⁇ 0.2° and 12.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 14.8° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.4°. Characteristic peaks are present at ⁇ 0.2°, 26.6° ⁇ 0.2°, 11.4° ⁇ 0.2°, 23.5° ⁇ 0.2°, 25.1° ⁇ 0.2°, 8.0° ⁇ 0.2°, and 12.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS1 is as shown in FIG.
  • the crystal form CS1 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 146 ° C to start the first endothermic peak.
  • This endothermic peak is the melting endothermic peak of the crystal form CS1, and its DSC curve is shown in Fig. 3.
  • the crystal form CS1 provided by the present invention when subjected to thermogravimetric analysis (TGA), has almost no mass loss when heated to around 150 ° C, and its TGA curve is attached.
  • TGA thermogravimetric analysis
  • the present invention also provides a process for producing a crystalline form CS1 of the compound of the formula (I), characterized in that the method comprises (1) or (2) of the following methods:
  • GFT-505 is added to a ketone solvent to be dissolved, and then an anti-solvent is added and stirred, and crystals are precipitated and then separated and dried.
  • the ketone solvent is a C3-C5 ketone or a mixture thereof;
  • the ketone comprises one of acetone, methyl ethyl ketone or a mixture thereof, preferably acetone.
  • the anti-solvent is a C5-C9 alkane or a mixture thereof;
  • the alkane-based solvent contains one of n-hexane, n-heptane, n-octane or a mixture thereof, preferably n-heptane.
  • the volume ratio of the ketone to the alkane is from 1:20 to 20:1, preferably 1:20.
  • the GFT-505 is dissolved in a mixed system of aromatic hydrocarbons and ketones at a high temperature, and the crystals are cooled and precipitated at a low temperature, and then separated and dried.
  • the aromatic hydrocarbon is a C 7 -C 9 aromatic hydrocarbon or a mixture thereof;
  • the aromatic hydrocarbon comprises one of toluene, ethylbenzene or a mixture thereof, preferably toluene.
  • the ketone solvent is a C3-C7 ketone or a mixture thereof;
  • the ketone comprises one of acetone, methyl ethyl ketone, methyl isobutyl ketone or a mixture thereof, preferably methyl isobutyl ketone.
  • the volume ratio of the aromatic hydrocarbon to the ketone is from 1:20 to 20:1, preferably 13:1.
  • the high temperature has a temperature in the range of 40 to 70 ° C
  • the low temperature has a temperature in the range of 0 to 10 ° C, preferably a high temperature of 50 ° C and a low temperature of 4 ° C.
  • the present invention also provides a crystal form CS2 of the compound of the formula (I) (hereinafter referred to as "crystal form CS2").
  • crystal form CS2 is a hydrate.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 25.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 11.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, and 19.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 11.7° ⁇ 0.2°, 12.2° ⁇ 0.2°, and 19.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 20.0° ⁇ 0.2°, 26.8° ⁇ 0.2°, and 27.5° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 20.0° ⁇ 0.2°, 26.8° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ value of 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 25.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.2°. Characteristic peaks are present at ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.0° ⁇ 0.2°, 26.8° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ value of 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 25.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.2°. There are characteristic peaks at ⁇ 0.2°, 19.4° ⁇ 0.2°, 20.0° ⁇ 0.2°, 26.8° ⁇ 0.2°, 27.5° ⁇ 0.2°, and 14.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is as shown in FIG.
  • the crystal form CS2 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 91 ° C to start the first endothermic peak.
  • a second endothermic peak began to appear near 145 ° C and its DSC curve is shown in Figure 7.
  • the crystalline form CS2 provided by the present invention when subjected to thermogravimetric analysis (TGA), has a mass loss gradient of about 2.5% when heated to around 87 °C. When heated to around 130 ° C, there is a further gradient of mass loss of about 1.9%. Its TGA curve is shown in Figure 8.
  • the present invention also provides a process for producing a crystalline form CS2 of the compound of the formula (I), characterized in that the method comprises (1) or (2) or (3) of the following methods:
  • GFT-505 is added to a pure water or a mixed system of an alcohol and water, and after stirring, the solid is separated and dried to obtain.
  • the alcohol solvent is a C1-C5 alcohol or a mixture thereof
  • the alcohol comprises one of methanol, ethanol, isopropanol or a mixture thereof, preferably ethanol.
  • the volume ratio of the alcohol to water in the mixed system of the alcohol and water is from 1:5 to 5:1, preferably 4:5.
  • the alcohol solvent is a C1-C5 alcohol or a mixture thereof
  • the alcohol comprises one of methanol, ethanol, isopropanol or a mixture thereof, preferably methanol.
  • the volume ratio of the alcohol to water is from 1:10 to 10:1, preferably 1:7.
  • GFT-505 is dissolved in a mixed system of an alcohol and an alkane solvent, and a high polymer is added and volatilized at a temperature of 10 to 50 °C.
  • the alcohol solvent is a C1-C5 alcohol or a mixture thereof
  • the alcohol comprises one of methanol, ethanol, isopropanol or a mixture thereof, preferably ethanol.
  • the alkane solvent is a C6 to C9 alkane or a mixture thereof;
  • the alkane-based solvent contains one of hexane, n-heptane, n-octane or a mixture thereof, preferably n-heptane.
  • volume ratio of the alcohol to the alkane is from 1:15 to 15:1, preferably 15:4.
  • the high polymer consists of equal masses of polycaprolactone, polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose and sodium alginate.
  • the volatilization temperature is room temperature.
  • the present invention also provides a crystal form CS5 of the compound of the formula (I) (hereinafter referred to as "crystal form CS5").
  • crystal form CS5 is an anhydrate.
  • the X-ray powder diffraction of the crystal form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 7.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS5 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 25.3° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 25.3° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 19.5° ⁇ 0.2°, 27.5° ⁇ 0.2°, and 28.9° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 19.5° ⁇ 0.2°, 27.5° ⁇ 0.2°, and 28.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has a diffraction angle 2 ⁇ values of 7.4° ⁇ 0.2°, 14.6° ⁇ 0.2°, 18.7° ⁇ 0.2°, 25.3° ⁇ 0.2°, 15.4°. Characteristic peaks are present at ⁇ 0.2°, 25.9° ⁇ 0.2°, 19.5° ⁇ 0.2°, 27.5° ⁇ 0.2°, and 28.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS5 is as shown in FIG.
  • the crystalline form CS5 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 110 ° C to start the first endothermic peak.
  • a second endothermic peak began to appear near 145 ° C, and its DSC curve is shown in FIG.
  • the crystalline form CS2 provided by the present invention when subjected to thermogravimetric analysis (TGA), has a mass loss gradient of about 0.46% when heated to around 146 °C. Its TGA curve is shown in Figure 12.
  • the present invention also provides a process for the preparation of the crystalline form CS5 of the compound of the formula (I), characterized in that the method comprises:
  • GFT-505 is dissolved in a mixed solvent of a ketone and an aromatic hydrocarbon or a mixed solvent of an ester and an aromatic hydrocarbon, and is obtained by volatilization at a temperature of 10 to 50 °C.
  • the ketone is a C 3 -C 5 ketone or a mixture thereof;
  • the ketone comprises one of acetone, methyl ethyl ketone or a mixture thereof, preferably acetone.
  • the aromatic hydrocarbon is a C 7 -C 9 aromatic hydrocarbon or a mixture thereof;
  • the aromatic hydrocarbon comprises one of toluene, ethylbenzene or a mixture thereof, preferably toluene.
  • the esters are C 3 -C 6 esters or mixtures thereof.
  • ester comprises one of ethyl acetate, isopropyl acetate or a mixture thereof, preferably ethyl acetate;
  • the volume ratio of the ketone to the aromatic hydrocarbon or ester and the aromatic hydrocarbon in the mixed solvent is from 1:3 to 3:1, preferably 1:1.
  • the volatilization temperature is room temperature.
  • the present invention also provides a crystalline form CS6 (hereinafter referred to as "crystalline form CS6") of the compound of the formula (I).
  • crystalline form CS6 is an acetic acid solvate.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristic peaks at diffraction angle 2 ⁇ values of 12.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 15.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristic peaks at diffraction angle 2 ⁇ values of 15.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 6.6° ⁇ 0.2°, 10.3 ⁇ °°, and 18.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristic peaks at diffraction angle 2 ⁇ values of 6.6° ⁇ 0.2°, 10.3° ⁇ 0.2°, and 18.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has a diffraction angle 2 ⁇ of 12.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 23.6° ⁇ 0.2°, 15.2° ⁇ 0.2°, 20.7°. There are characteristic peaks at ⁇ 0.2°, 26.4° ⁇ 0.2°, 6.6° ⁇ 0.2°, 10.3° ⁇ 0.2°, and 18.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has a diffraction angle 2 ⁇ of 11.1° ⁇ 0.2°, 13.2° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 25.1° ⁇ 0.2°. There are characteristic peaks in one or more of them.
  • the X-ray powder diffraction of the crystalline form CS6 is at a diffraction angle 2 ⁇ of 11.1° ⁇ 0.2°, 13.2° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 25.1° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystalline form CS6 has a diffraction angle 2 ⁇ of 12.5° ⁇ 0.2°, 19.4° ⁇ 0.2°, 23.6° ⁇ 0.2°, 15.2° ⁇ 0.2°, 20.7°. ⁇ 0.2°, 26.4° ⁇ 0.2°, 6.6° ⁇ 0.2°, 10.3° ⁇ 0.2°, 18.2° ⁇ 0.2°, 11.1° ⁇ 0.2°, 13.2° ⁇ 0.2°, 16.2° ⁇ 0.2°, 17.0° ⁇ 0.2 There are characteristic peaks at °, 25.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form CS6 is as shown in FIG.
  • the crystalline form CS6 provided by the present invention when subjected to differential scanning calorimetry (DSC), is heated to a temperature near 83 ° C to start the first endothermic peak. A second endothermic peak began to appear near 132 °C. Its DSC curve is shown in Figure 15.
  • the crystalline form CS6 provided by the present invention when subjected to thermogravimetric analysis (TGA), has a mass loss gradient of about 13.0% when heated to near 88 °C. Calculated from TGA, about 1.0 mole of acetic acid per mole of CS6. Its TGA curve is shown in Figure 16.
  • the present invention also provides a process for the preparation of the crystalline form CS6 of the compound of the formula (I), characterized in that the method comprises:
  • the GFT-505 was placed in a closed apparatus containing an acetic acid solvent atmosphere and obtained by gas-solid permeation.
  • the GFT-505 refers to a solid, semi-solid, wax or oil form of the compound of formula (I).
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • the novel crystalline forms CS1, CS2, CS5, and CS6 of the present invention are pure, single, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • anti-solvent means a poor solvent for the compound of the formula (I), and the gas-solid permeation method means that the starting material is placed in a closed environment having a specific solvent atmosphere, and the starting material is not directly Contact with a solvent, but a method of preparing a new solid form by indirect contact of a solvent volatilization diffusion with a starting material.
  • the crystal forms CS1, CS2, CS5 and CS6 provided by the present invention have the following advantages:
  • the crystal form provided by the present invention has a markedly improved purity as compared with the prior art oil.
  • the purity of the prior art oil is only 83.87%, while the crystal form of the present invention is relatively pure.
  • the present invention provides a crystalline form purity of greater than 98%.
  • the present invention provides a crystalline form having a purity greater than 99%.
  • the crystal form of the invention has strong impurity elimination ability, and can obtain a higher purity raw material medicine through a crystallization process, and is not prone to the problem of solvent residue, so that the residual solvent of the sample is easy to meet the standard and meets the quality requirement, and is suitable for medicinal use. ;
  • the crystal form provided by the invention has low wettability and can overcome the disadvantages caused by high wettability, such as the weight change of the raw material crystal component due to weight change of water absorption; and is beneficial to long-term storage of the medicine and reduction of material storage. And quality control costs.
  • the crystal forms CS1, CS2 and CS5 provided by the present invention have weight gains of 0.042%, 0.101% and 0.325% under the conditions of 80% relative humidity, respectively, and the wettability is low.
  • the low wettability of the crystal forms CS1, CS2 and CS5 of the present invention can well resist the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unworkability of the preparation caused by external factors such as environmental moisture, and is advantageous. Accurate quantification and subsequent transport and storage in preparation of the preparation;
  • the crystal form provided by the invention has good stability, thereby ensuring that the quality standard of the sample is consistent and controllable, and meets the stringent requirements for the crystal form in the pharmaceutical application and the preparation process.
  • the crystalline forms CS1, CS2 and CS5 of the present invention are stable for at least one month at 25 ° C / 60% relative humidity and / or 40 ° C / 75% relative humidity and / or 60 ° C / 75% relative humidity, preferably It can be placed at least for 6 months, preferably at least for one year. Therefore, the crystal forms CS1, CS2 and CS5 of the present invention have good stability, which is favorable for preservation of the sample and stabilization of the preparation;
  • the crystal form provided by the invention has good solubility, can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug, and can achieve the desired therapeutic blood concentration without a high dose after oral administration. Conducive to the absorption of drugs in the human body, so as to achieve the desired bioavailability and efficacy of the drug, in line with medicinal requirements;
  • the crystal form provided by the invention has good mechanical stability and reduces the risk of crystal transformation during grinding or tableting during preparation of the preparation.
  • the crystal forms CS1, CS2, CS5 and CS6 of the invention have high grinding stability, and the grinding and pulverization of the raw material medicine are often required in the processing of the preparation, and the high grinding stability can reduce the crystallinity change of the raw material medicine during the processing of the preparation. And the risk of crystal transformation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the crystalline form CS1, CS2, CS5 or CS6 of the invention, and at least one pharmaceutically acceptable form Agent.
  • the present invention provides the crystalline form CS1, CS2, CS5 or CS6 of GFT-505 in the preparation of a pharmaceutical preparation for treating nonalcoholic steatohepatitis and/or type II diabetes and/or dyslipidemia and/or atherosclerotic disease. the use of.
  • Figure 1 is an XRPD pattern of a crystal form CS1 obtained according to Example 1 of the present invention.
  • Example 2 is a 1 H NMR chart of the crystal form CS1 obtained according to Example 1 of the present invention.
  • Figure 3 is a DSC chart of a crystalline form CS1 obtained according to Example 1 of the present invention.
  • Example 4 is a TGA diagram of a crystal form CS1 obtained according to Example 1 of the present invention.
  • Figure 5 is an XRPD pattern of a crystalline form CS2 obtained according to Example 4 of the present invention.
  • Figure 6 is a 1 H NMR chart of the crystalline form CS2 obtained according to Example 4 of the present invention.
  • Figure 7 is a DSC chart of a crystalline form CS2 obtained according to Example 4 of the present invention.
  • Figure 8 is a TGA diagram of a crystalline form CS2 obtained in accordance with Example 4 of the present invention.
  • Figure 9 is an XRPD pattern of a crystalline form CS5 obtained according to Example 7 of the present invention.
  • Figure 10 is a 1 H NMR chart of the crystalline form CS5 obtained according to Example 7 of the present invention.
  • Figure 11 is a DSC chart of a crystalline form CS5 obtained according to Example 7 of the present invention.
  • Figure 12 is a TGA diagram of a crystalline form CS5 obtained according to Example 7 of the present invention.
  • Figure 13 is an XRPD pattern of a crystalline form CS6 obtained according to Example 9 of the present invention.
  • Figure 14 is a 1 H NMR chart of the crystalline form CS6 obtained according to Example 9 of the present invention.
  • Figure 15 is a DSC chart of a crystalline form CS6 obtained according to Example 9 of the present invention.
  • Figure 16 is a TGA diagram of a crystalline form CS6 obtained according to Example 9 of the present invention.
  • Figure 17 is a DVS diagram of the crystal form CS1 of the present invention.
  • Figure 18 is an XRPD overlay of the DVS before and after the DCS of the crystal form CS1 of the present invention (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS).
  • Figure 19 is a DVS diagram of the crystalline form CS2 of the present invention.
  • Figure 20 is an XRPD overlay of the DVS before and after the DCS of the crystalline form CS2 of the present invention (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS).
  • Figure 21 is a DVS diagram of a crystalline form CS5 of the present invention.
  • Figure 22 is an XRPD overlay of the DVS before and after DVS of the crystalline form CS5 of the present invention (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS).
  • Figure 23 is an XRPD overlay of the crystalline form CS1 of the present invention placed at 25 ° C / 60% relative humidity for 6 months (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement).
  • Figure 24 is an XRPD overlay of the crystalline form CS1 of the present invention placed at 40 ° C / 75% relative humidity for 6 months (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement).
  • Figure 25 is an XRPD overlay of the crystalline form CS1 of the present invention placed at 60 ° C / 75% relative humidity for 1 month (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement).
  • Figure 26 is an XRPD overlay of the crystalline form CS2 of the present invention placed at 25 ° C / 60% relative humidity for 6 months (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after placement).
  • Figure 27 is an XRPD overlay of the crystalline form CS2 of the present invention placed at 40 ° C / 75% relative humidity for 6 months (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement).
  • Figure 28 is an XRPD overlay of the crystalline form CS2 of the present invention placed at 60 ° C / 75% relative humidity for 1 month (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after placement).
  • Figure 29 is an XRPD overlay of the crystalline form CS5 of the present invention placed at 25 ° C / 60% relative humidity for 6 months (the upper image shows the XRPD pattern before placement, and the lower figure shows the XRPD pattern after placement).
  • Figure 30 is an XRPD overlay of the crystalline form CS5 of the present invention placed at 40 ° C / 75% relative humidity for 6 months (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement).
  • Figure 31 is an XRPD overlay of the crystalline form CS5 of the present invention placed at 60 ° C / 75% relative humidity for 1 month (the upper image shows the XRPD pattern before placement, and the lower image shows the XRPD pattern after placement).
  • Figure 32 is an XRPD diagram of the crystal form CS1 of the present invention before and after polishing (the upper figure is before polishing, and the lower figure is after grinding).
  • Figure 33 is an XRPD diagram of the crystal form CS2 before and after polishing according to the present invention (the figure above is before polishing, and the figure below is after grinding).
  • Fig. 34 is an XRPD diagram of the crystal form CS5 of the present invention before and after polishing (the upper drawing is before polishing, and the lower drawing is after polishing).
  • Fig. 35 is an XRPD diagram of the crystal form CS6 of the present invention before and after polishing (the figure above is before polishing, and the figure below is after grinding).
  • Fig. 36 is a view showing the morphology of the crystal form CS1 and the oil form of the invention (the left side is a view of the form of the crystal form CS1 of the present invention, and the right side is a view of the form of the oil form prepared by the prior art).
  • PSD particle size distribution
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • Nuclear magnetic resonance spectroscopy ( 1 H NMR) data was taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • the particle size distribution results described in the specific embodiments of the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method in which the dispersion medium is Isopar G (containing 0.2% lecithin).
  • the GFT-505 used in the following examples was prepared according to the prior art, for example according to the preparation method disclosed in CN100548960C.
  • the nuclear magnetic resonance spectrum is shown in Figure 2.
  • the DSC curve of the crystalline form CS1 obtained in Example 1 is shown in Fig. 3, and the TGA curve is shown in Fig. 4.
  • the nuclear magnetic resonance spectrum is shown in Fig. 6.
  • the DSC curve is shown in Figure 7, and the TGA curve is shown in Figure 8.
  • the DSC spectrum is shown in Figure 11, and the TGA map is shown in Figure 12.
  • a 10.9 mg GFT-505 sample was placed in a 3 mL glass vial, placed in a 20 mL glass vial containing 3 mL of acetic acid solvent, and then a 20 mL glass vial was sealed for one week, and the resulting solid was collected.
  • the nuclear magnetic spectrum is shown in Figure 14.
  • the DSC spectrum is shown in Figure 15, and the TGA map is shown in Figure 16.
  • Example 10 Comparison of purity of existing oils and crystalline forms CS1 and CS2 of the present invention
  • the purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the high content of impurities in the existing oils may cause the drug content to be significantly lower or the activity to be lowered; the high impurity content may also significantly increase the toxic side effects, and thus cannot be used as a drug substance for the preparation of the preparation.
  • the crystal form of the present invention has high purity and is advantageous for industrial production.
  • the crystal form of the invention has strong impurity elimination ability, and can obtain a higher purity raw material medicine through a crystallization process, and is not prone to the problem of solvent residue, so that the residual solvent of the sample is easy to meet the standard and meets the quality requirement, and is suitable for medicinal use. .
  • Example 11 Study on the wettability of crystalline forms CS1, CS2 and CS5
  • the crystal form CS1 has a weight gain of 0.042% after being equilibrated at 80% relative humidity, and has almost no hygroscopicity. Its DVS diagram is shown in Figure 17. In addition, the XRPD pattern of the crystalline form CS1 was detected before and after the DVS experiment. The results are shown in Fig. 18 (the above figure is the XRPD pattern before DVS, and the figure below is the XRPD chart after DVS), indicating that the crystal form CS1 did not change before and after DVS. .
  • the weight gain is 0.101% compared with the initial relative humidity of 30%, and there is almost no hygroscopicity, which is convenient for long-term storage and placement, and the DVS chart is shown in FIG.
  • the XRPD pattern of the crystal form CS2 was separately detected before and after the DVS, and the results are shown in Fig. 20 (the above figure is an XRPD chart before DVS, and the figure below is an XRPD chart after DVS), indicating that the crystal form CS2 before and after DVS did not change.
  • the weight gain is 0.325%, which is slightly wetted, and its DVS pattern is shown in Fig. 21.
  • the XRPD pattern of the crystalline form CS5 was detected before and after DVS. The results are shown in Fig. 22 (the above figure is the XRPD pattern before DVS, and the figure below is the XRPD chart after DVS), indicating that the crystal form CS5 before and after the dynamic moisture adsorption experiment. no change.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • Example 12 Stability Study of Forms CS1, CS2 and CS5
  • the crystal form CS1 of the present invention remains unchanged after being left for 6 months at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity; after being placed at 60 ° C / 75% relative humidity for 1 month The crystal form remains unchanged.
  • the above test results show that the crystalline form CS1 of the present invention has good stability.
  • the crystal form CS2 of the present invention remains unchanged after being left for 6 months at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity; after being placed at 60 ° C / 75% relative humidity for 1 month The crystal form remains unchanged.
  • the above test results show that the crystalline form CS2 of the present invention has good stability.
  • the crystalline form CS5 of the present invention remains unchanged after being left for 6 months at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity; after being placed at 60 ° C / 75% relative humidity for 1 month The crystal form remains unchanged.
  • the above test results show that the crystalline form CS5 of the present invention has good stability.
  • the stability of the drug is very important, especially during the commercial period. Maintaining good stability can reduce the risk of drug dissolution rate and bio-profit change due to crystal form changes, and ensure the efficacy and safety of the drug.
  • the occurrence of adverse drug reactions is of great significance.
  • the more stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystal, and it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent quality control of the sample and ensuring the preparation.
  • the dissolution profile of the product does not change as the storage time changes.
  • Example 13 Dynamic Solubility Study of Forms CS1, CS2, CS5 and CS6
  • the crystal forms CS1, CS2 and CS5 samples of the present invention were respectively used with pH 1.8 SGF (simulated gastric juice), pH 5.0 FeSSIF (simulated intestinal juice in simulated feeding state), pH 6.5 FaSSIF (simulated artificial intestinal juice in fasting state) and H 2 O
  • a saturated solution was prepared, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 1 hour, 4 hours, and 24 hours.
  • the crystal form CS6 sample of the present invention is prepared into a saturated solution by using pH 1.8 SGF (simulated gastric juice), pH 5.0 FeSSIF (simulated intestinal juice in simulated feeding state) and pH 6.5 FaSSIF (simulated intestinal juice in simulated fasting state), respectively.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography after hours, 4 hours, and 24 hours.
  • the results of the solubility test of the crystalline form CS1 are shown in Table 13, and the results of the solubility test of the crystalline form CS2 are shown in Table 14.
  • the results of the solubility test of the crystalline form CS5 are shown in Table 15, and the results of the solubility test of the crystalline form CS6 are shown in Table 16. Show.
  • Solubility is one of the key properties of drugs, directly affecting the absorption of drugs in the human body.
  • the solubility of different crystal forms may be significantly different, and the absorption dynamics in the body may also change, resulting in differences in bioavailability, which ultimately affects the clinical safety and efficacy of the drug.
  • the solubility of the crystalline forms CS1, CS2 and CS5 of the present invention in SGF, FaSSIF, FeSSIF and water, and the solubility of the crystalline form CS6 of the present invention in SGF, FaSSIF and FeSSIF meet the medicinal requirements, especially in FaSSIF (The solubility in artificial intestinal fluid in simulated fasting state and FeSSIF (in artificial intestinal juice in simulated feeding state) is higher.
  • the ideal solubility of the crystalline forms CS1, CS2, CS5 and CS6 of the present invention can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug, and the desired therapeutic blood concentration can be achieved without a high dose after oral administration. It is beneficial to the absorption of drugs in the human body, achieving the desired bioavailability and efficacy of the drug, and meeting the medicinal requirements.
  • Example 14 Study on the grinding stability of crystalline forms CS1, CS2, CS5 and CS6
  • the crystalline drug with better mechanical stability has low requirements on the crystallization equipment, requires no special post-treatment conditions, is more stable in the preparation process, can significantly reduce the development cost of the drug, enhance the quality of the drug, and has strong economic value.
  • the crystal forms CS1, CS2, CS5 and CS6 of the present invention have better mechanical stability in the subsequent process, and provide more options for subsequent formulation processes.
  • the crystal forms CS1, CS2, CS5 and CS6 can be ground by subsequent dry grinding means to obtain particles having a smaller particle size.
  • Example 15 Morphology comparison of the crystalline forms CS1, CS2, CS5 and CS6 of the present invention with existing oils
  • the morphological comparison chart of the crystalline form CS1 and the oily substance of the present invention is shown in Fig. 36, and the crystal forms CS1, CS2, CS5 and CS6 of the present invention are all in the form of a pale yellow powder, which is convenient for sampling and quantification, and is light yellow according to the prior art method.
  • Oily, viscous honey Figure 36 right. Sampling and quantification of oils is often difficult, and the oil is low in purity and poor in stability, which is detrimental to drug storage.
  • the solid preparation of the oil as a raw material medicine often requires a special complicated treatment process, which increases the preparation cost and is disadvantageous for the preparation of the preparation.

Abstract

涉及GFT-505的晶型及其制备方法和用途。所提供的GFT-505的晶型CS1、CS2、CS5和CS6的纯度高，稳定性好，引湿性低，溶解性良好以及机械稳定性高，为含GFT-505的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

GFT-505的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及GFT-505的晶型及其制备方法和用途，属于医药领域。
背景技术
非酒精性脂肪性肝炎(Non-alcoholic steatohepatitis,NASH)是一种严重的肝脏疾病，先于肝细胞癌出现，当前无法医治。Elafibranor，又称GFT-505，由Genfit研发，临床用于治疗NASH表现出良好的安全性和有效性。GFT-505是一种过氧化物酶体增殖物激活受体-α(PPARA)和受体-δ(PPARD)的激动剂。研究表明GFT-505可以改善胰岛素的敏感性、血糖平衡、脂质代谢，还能减少炎症反应，有望成为NASH的新疗法。GFT-505的化学名称为：1-[4-甲硫基苯基]-3-[3，5-二甲基-4-羧基二甲基甲氧基苯基]丙-2-烯-酮，具有式(I)所示的化学结构：
Figure PCTCN2018071917-appb-000001
固体化学药物晶型不同，可造成其溶解度、稳定性、流动性和可压性等不同，从而影响含有该化合物的药物产品的安全性和有效性(参见K.Knapman,Modern Drug Discovery,3,53-54,57,2000.)，从而导致临床药效的差异。发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势或提供具有更好理化特性的物质，比如更好的生物利用度、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。药学上化合物的新晶型可以帮助改善药物的性能，扩大制剂学上可选用的原料型态。
专利CN100548960C中公开了GFT-505的化学结构及其制备方法，本发明人重复该方法得到浅黄色粘稠的油状物，该油状物的取样和定量困难，且纯度低，稳定性差，难以做成药物制剂，不适合药用。目前还没有GFT-505相关晶型信息的报道，因此，需要开发GFT-505的晶型，寻找稳定的、低引湿性的、具有较高纯度等各方面性能优越的晶型，以适于工业化生产及药物制剂中的应用。
本发明人通过大量的实验偶然发现本发明的晶型CS1、CS2、CS5和CS6。本发明提供的GFT-505的晶型CS1、CS2、CS5和CS6的纯度高，稳定性好，引湿性低，溶解性良好以及机械稳定性高，为含GFT-505的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
发明内容
本发明的主要目的是提供GFT-505的晶型及其制备方法和用途。
根据本发明的目的，本发明提供式(I)所示化合物的晶型CS1(以下称作“晶型CS1”)。
所述晶型CS1为无水物。
使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.5°±0.2°、14.8°±0.2°、16.9°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为18.7°±0.2°、20.4°±0.2°、26.6°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为18.7°±0.2°、20.4°±0.2°、26.6°±0.2°处均有特征峰。
更进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为11.4°±0.2°、23.5°±0.2°、25.1°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为11.4°±0.2°、23.5°±0.2°、25.1°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.5°±0.2°、14.8°±0.2°、16.9°±0.2°、18.7°±0.2°、20.4°±0.2°、26.6°±0.2°、11.4°±0.2°、23.5°±0.2°、25.1°±0.2°处有特征峰。
更进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为8.0°±0.2°、12.3°±0.2°中的一处或两处有特征峰。优选的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为8.0°±0.2°、12.3°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.5°±0.2°、14.8°±0.2°、16.9°±0.2°、18.7°±0.2°、20.4°±0.2°、26.6°±0.2°、11.4°±0.2°、23.5°±0.2°、25.1°±0.2°、8.0°±0.2°、12.3°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射谱图如附图1所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS1，当进行差示扫描量热分析(DSC)时，加热至146℃附近开始出现第一个吸热峰，该吸热峰为晶型CS1的熔化吸热峰，其DSC曲线如附图3所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS1，当进行热重分析(TGA)时，加热至150℃附近时，几乎无质量损失，其TGA曲线如附图4所示。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS1的制备方法，其特征在于，所述方法包含下述方法中的(1)或(2)：
(1)将GFT-505加至酮类溶剂中溶解，后添加反溶剂并搅拌，析出晶体后分离干燥得到。
其中：
所述酮类溶剂为C3～C5的酮类或者它们的混合物；
进一步的，所述酮类包含丙酮、甲基乙基酮中的一种或它们的混合物，优选为丙酮。
所述反溶剂为C5～C9烷烃或者它们的混合物；
进一步的，所述烷烃类溶剂包含正己烷、正庚烷、正辛烷中的一种或它们的混合物，优选为正庚烷。
所述酮类与烷烃类的体积比为1:20～20:1，优选为1:20。
(2)在高温下将GFT-505溶于芳香烃和酮类的混合体系中，在低温下冷却析出晶体，后分离干燥得到。
其中：
所述芳香烃为C 7～C 9芳香烃或者它们的混合物；
进一步的，所述芳香烃包含甲苯、乙苯中的一种或它们的混合物，优选为甲苯。
所述酮类溶剂为C3～C7的酮类或者它们的混合物；
进一步的，所述酮类包含丙酮、甲基乙基酮、甲基异丁基酮中的一种或它们的混合物，优选为甲基异丁基酮。
所述芳香烃和酮类的体积比为1:20～20:1，优选为13:1。
所述高温的温度范围为40～70℃，所述低温的温度范围为0～10℃，优选高温为50℃，低温为4℃。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS2(以下称作“晶型CS2”)。所述晶型CS2为水合物。
使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为15.2°±0.2°、15.9°±0.2°、25.8°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为11.7°±0.2°、12.2°±0.2°、19.4°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为11.7°±0.2°、12.2°±0.2°、19.4°±0.2°处均有特征峰。
更进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为20.0°±0.2°、26.8°±0.2°、 27.5°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为20.0°±0.2°、26.8°±0.2°、27.5°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS2的X射线粉末衍射在衍射角2θ值为15.2°±0.2°、15.9°±0.2°、25.8°±0.2°、11.7°±0.2°、12.2°±0.2°、19.4°±0.2°、20.0°±0.2°、26.8°±0.2°、27.5°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型CS2的X射线粉末衍射在衍射角2θ值为15.2°±0.2°、15.9°±0.2°、25.8°±0.2°、11.7°±0.2°、12.2°±0.2°、19.4°±0.2°、20.0°±0.2°、26.8°±0.2°、27.5°±0.2°、14.7°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS2的X射线粉末衍射谱图如附图5所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS2，当进行差示扫描量热分析(DSC)时，加热至91℃附近开始出现第一个吸热峰，在145℃附近开始出现第二个吸热峰，其DSC曲线如附图7所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS2，当进行热重分析(TGA)时，加热至87℃附近时，具有约2.5％的质量损失梯度。加热至130℃附近时，进一步约有1.9％的质量损失梯度。其TGA曲线如附图8所示。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS2的制备方法，其特征在于，所述方法包含下述方法中的(1)或(2)或(3)：
(1)将GFT-505加入纯水或醇类与水的混合体系中，搅拌后分离固体，干燥而得到。
其中：
所述醇类溶剂为C1～C5的醇类或者它们的混合物；
进一步的，所述醇类包含甲醇、乙醇、异丙醇中的一种或它们的混合物，优选为乙醇。
所述醇类与水的混合体系中醇类与水的体积比为1:5～5:1，优选为4:5。
(2)将GFT-505溶解于醇类体系中，添加反溶剂水并搅拌至析出晶体，经分离，干燥而得到；
其中：
所述醇类溶剂为C1～C5的醇类或者它们的混合物；
进一步的，所述醇类包含甲醇、乙醇、异丙醇中的一种或它们的混合物，优选为甲醇。
所述醇类与水的体积比为1:10～10:1，优选为1:7。
(3)将GFT-505溶于醇类和烷烃类溶剂的混合体系中，并加入高聚物，于10～50℃温度下挥发得到。
其中：
所述醇类溶剂为C1～C5的醇类或者它们的混合物；
进一步的，所述醇类包含甲醇、乙醇、异丙醇中的一种或它们的混合物，优选为乙醇。
所述烷烃类溶剂为C6～C9的烷烃或者它们的混合物；
进一步的，所述烷烃类溶剂包含己烷、正庚烷、正辛烷中的一种或它们的混合物，优选为正庚烷。
进一步的，所述醇类与烷烃的体积比为1:15～15:1，优选为15:4。
进一步的，所述高聚物由等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成。
进一步的，所述挥发温度为室温。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS5(以下称作“晶型CS5”)。所述晶型CS5为无水物。
使用Cu-Kα辐射，所述晶型CS5的X射线粉末衍射在衍射角2θ值为7.4°±0.2°、14.6°±0.2°、18.7°±0.2°处有特征峰。
进一步的，所述晶型CS5的X射线粉末衍射在衍射角2θ值为25.3°±0.2°、15.4°±0.2°、25.9°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS5的X射线粉末衍射在衍射角2θ值为25.3°±0.2°、15.4°±0.2°、25.9°±0.2°处均有特征峰。
更进一步的，所述晶型CS5的X射线粉末衍射在衍射角2θ值为19.5°±0.2°、27.5°±0.2°、28.9°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS5的X射线粉末衍射在衍射角2θ值为19.5°±0.2°、27.5°±0.2°、28.9°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS5的X射线粉末衍射在衍射角2θ值为7.4°±0.2°、14.6°±0.2°、18.7°±0.2°、25.3°±0.2°、15.4°±0.2°、25.9°±0.2°、19.5°±0.2°、27.5°±0.2°、28.9°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS5的X射线粉末衍射谱图如附图9所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS5，当进行差示扫描量热分析(DSC)时，加热至110℃附近开始出现第一个吸热峰，在145℃附近开始出现第二个吸热峰，其DSC曲线如附图11所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS2，当进行热重分析(TGA)时，加热至146℃附近时，具有约0.46％的质量损失梯度。其TGA曲线如附图12所示。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS5的制备方法，其特征在于，所述方法包括：
将GFT-505溶解于酮类和芳香烃类的混合溶剂或酯类和芳香烃类的混合溶剂中，在10～50℃温度下挥发而得到。
其中：
所述酮类为C 3～C 5的酮类或者它们的混合物；
进一步的，所述酮类包含丙酮、甲基乙基酮中的一种或它们的混合物，优选为丙酮。
所述芳香烃为C 7～C 9芳香烃或者它们的混合物；
进一步的，所述芳香烃包含甲苯、乙苯中的一种或它们的混合物，优选为甲苯。
所述酯类为C 3～C 6酯类或者它们的混合物。
进一步的，所述酯类包含乙酸乙酯、乙酸异丙酯中的一种或它们的混合物，优选为乙酸乙酯；
进一步的，所述混合溶剂中酮类和芳香烃或酯类和芳香烃的体积比为1:3～3:1，优选为1:1。
进一步的，所述挥发温度为室温。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS6(以下称作“晶型CS6”)。所述晶型CS6为乙酸溶剂合物。
使用Cu-Kα辐射，所述晶型CS6的X射线粉末衍射在衍射角2θ值为12.5°±0.2°、19.4°±0.2°、23.6°±0.2°处有特征峰。
进一步的，所述晶型CS6的X射线粉末衍射在衍射角2θ值为15.2°±0.2°、20.7°±0.2°、26.4°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS6的X射线粉末衍射在衍射角2θ值为15.2°±0.2°、20.7°±0.2°、26.4°±0.2°处均有特征峰。
进一步的，所述晶型CS6的X射线粉末衍射在衍射角2θ值为6.6°±0.2°、10.3°±0.2°、18.2°±0.2°中的一处或两处或三处有特征峰。优选的，所述晶型CS6的X射线粉末衍射在衍射角2θ值为6.6°±0.2°、10.3°±0.2°、18.2°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS6的X射线粉末衍射在衍射角2θ值为12.5°±0.2°、19.4°±0.2°、23.6°±0.2°、15.2°±0.2°、20.7°±0.2°、26.4°±0.2°,6.6°±0.2°、10.3°±0.2°、18.2°±0.2°处有特征峰。
更近一步的，所述晶型CS6的X射线粉末衍射在衍射角2θ值为11.1°±0.2°、13.2°±0.2°、16.2°±0.2°、17.0°±0.2°、25.1°±0.2°中的一处或多处有特征峰。优选的，所述晶型CS6的X射线粉末衍射在衍射角2θ值为11.1°±0.2°、13.2°±0.2°、16.2°±0.2°、17.0°±0.2°、25.1°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS6的X射线粉末衍射在衍射角2θ值为12.5°±0.2°、19.4°±0.2°、23.6°±0.2°、15.2°±0.2°、20.7°±0.2°、26.4°±0.2°、6.6°±0.2°、10.3°±0.2°、18.2°±0.2°、11.1°±0.2°、13.2°±0.2°、16.2°±0.2°、17.0°±0.2°、25.1°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS6的X射线粉末衍射谱图如附图13所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS6，当进行差示扫描量热分析(DSC)时，加热至83℃附近开始出现第一个吸热峰，在132℃附近开始出现第二个吸热峰。其DSC曲线如附图15所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS6，当进行热重分析(TGA)时，加热至88℃附近时，具有约13.0％的质量损失梯度。从TGA计算得，每摩尔CS6含有约1.0摩尔的乙酸。其TGA曲线如附图16所示。
根据本发明的目的，本发明还提供式(I)所示化合物的晶型CS6的制备方法，其特征在于，所述方法包括：
将GFT-505放置于含有乙酸溶剂氛围的密闭装置中，通过气固渗透得到。
在本发明的晶型CS1、CS2、CS5和CS6的制备方法中：
所述GFT-505是指式(I)化合物的固体、半固体、蜡或油形式。
所述“室温”不是精确的温度值，是指10-30℃温度范围。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。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射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的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图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
在一些实施方案中，本发明的新晶型CS1、CS2、CS5和CS6是纯的、单一的，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。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明中所述“反溶剂”是指对式(I)化合物的不良溶剂，所述气固渗透法是指：将起始原料置于具有特定溶剂氛围的密闭环境中，起始原料不直接与溶剂接触，而是通过溶剂挥发扩散与起始原料间接接触制备得到新固体形态的方法。
本发明提供的晶型CS1、CS2、CS5和CS6具有下列优势：
(1)本发明提供的晶型与现有技术油状物相比，纯度显著提高。现有技术油状物的纯度仅为83.87％，而本发明的晶型纯度较高。在具体的实施例中，本发明提供的晶型纯度大于98％，在另一个具体的实施例中，本发明提供的晶型的纯度大于99％。本发明的晶型具有较强的杂质排除能力，且还可通过结晶工艺得到纯度更高的原料药，并且不容易出现溶剂残留的问题，使得样品残留溶剂容易达标并符合质量要求，适合药用；
(2)本发明提供的晶型引湿性低，能够克服高引湿性带来的弊端，如因吸水发生重量变化导致原料晶型组份含量不确定；且有利于药品的长期贮存，降低物料储存以及质量控制成本。本发明提供的晶型CS1、CS2和CS5在80％相对湿度条件下增重量分别为0.042％、0.101％和0.325％，引湿性低。本发明晶型CS1、CS2和CS5的低引湿性能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存；
(3)本发明提供的晶型稳定性好，从而保证样品的质量标准一致可控，符合药物应用及制剂工艺中对晶型的苛刻要求。本发明的晶型CS1、CS2和CS5在25℃/60％相对湿度和/或40℃/75％相对湿度和/或60℃/75％相对湿度条件下至少可稳定放置1个月，优选的至少可稳定放置6个月，优选的至少可稳定放置一年。因此，本发明的晶型CS1、CS2和CS5具有良好的稳定性，有利于样品的保存和制剂的稳定；
(4)本发明提供的晶型溶解性良好，可降低给药剂量从而降低药品的副作用并提高药品的安全性，且在口服后不需要高剂量即可达到所需的治疗血药浓度，有利于药物在人体内的吸收，从而达到理想的药物生物利用度和药效，符合药用要求；
(5)本发明提供的晶型机械稳定性好，降低制剂制备时研磨或压片过程发生转晶的风险。本发明的晶型CS1、CS2、CS5和CS6具有高的研磨稳定性，制剂加工过程中常需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
此外，本发明提供一种药用组合物，所述药用组合物包含治疗和/或预防有效量的本发明晶型CS1、CS2、CS5或CS6，以及至少一种药学上可接受的赋形剂。
进一步的，本发明提供GFT-505的晶型CS1、CS2、CS5或CS6在制备治疗非酒精性脂肪肝炎和/或II型糖尿病和/或血脂异常和/或动脉粥样硬化疾病的药物制剂中的用途。
附图说明
图1为根据本发明实施例1所得晶型CS1的XRPD图。
图2为根据本发明实施例1所得晶型CS1的 1HNMR图。
图3为根据本发明实施例1所得晶型CS1的DSC图。
图4为根据本发明实施例1所得晶型CS1的TGA图。
图5为根据本发明实施例4所得晶型CS2的XRPD图。
图6为根据本发明实施例4所得晶型CS2的 1HNMR图。
图7为根据本发明实施例4所得晶型CS2的DSC图。
图8为根据本发明实施例4所得晶型CS2的TGA图。
图9为根据本发明实施例7所得晶型CS5的XRPD图。
图10为根据本发明实施例7所得晶型CS5的 1HNMR图。
图11为根据本发明实施例7所得晶型CS5的DSC图。
图12为根据本发明实施例7所得晶型CS5的TGA图。
图13为根据本发明实施例9所得晶型CS6的XRPD图。
图14为根据本发明实施例9所得晶型CS6的 1HNMR图。
图15为根据本发明实施例9所得晶型CS6的DSC图。
图16为根据本发明实施例9所得晶型CS6的TGA图。
图17为本发明晶型CS1的DVS图。
图18为本发明晶型CS1的DVS前后的XRPD叠图(上图为DVS前的XRPD图，下图为DVS后的XRPD图)。
图19为本发明晶型CS2的DVS图。
图20为本发明晶型CS2的DVS前后的XRPD叠图(上图为DVS前的XRPD图，下图为DVS后的XRPD图)。
图21为本发明晶型CS5的DVS图。
图22为本发明晶型CS5的DVS前后的XRPD叠图(上图为DVS前的XRPD图，下图为DVS后的XRPD图)。
图23为本发明晶型CS1在25℃/60％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图24为本发明晶型CS1在40℃/75％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图25为本发明晶型CS1在60℃/75％相对湿度条件下放置1个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图26为本发明晶型CS2在25℃/60％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图27为本发明晶型CS2在40℃/75％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图28为本发明晶型CS2在60℃/75％相对湿度条件下放置1个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图29为本发明晶型CS5在25℃/60％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图30为本发明晶型CS5在40℃/75％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图31为本发明晶型CS5在60℃/75％相对湿度条件下放置1个月前后的XRPD叠图(上图为放置前的XRPD图，下图为放置后的XRPD图)。
图32为本发明晶型CS1研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图33为本发明晶型CS2研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图34为本发明晶型CS5研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图35为本发明晶型CS6研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图36为发明晶型CS1与油状物的形态对比图(左图为本发明晶型CS1的形态图，右图为现有技术制备得到的油状物的形态图)。
具体实施方式
本发明进一步参考以下实施例限定，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
HPLC：高效液相色谱
1HNMR：核磁共振氢谱
PSD：粒径分布
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Panalytical Empyrean 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射线反射参数：Cu,Kα
Figure PCTCN2018071917-appb-000002
1.540598；
Figure PCTCN2018071917-appb-000003
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：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。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：如无特别说明为10℃/min
保护气体：N 2
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为紫外可变波长检
测器(VWD)。本发明所述的测试纯度的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18,150×4.6mm,5μm
2、流动相：A：0.1％的磷酸水溶液
B：乙腈
洗脱梯度如下：
Time(min) ％B
0.0 25
25.0 80
30.0 80
30.1 25
35.0 25
3、流速：1.0mL/min
4、进样量：5μL
5、检测波长：350nm
6、柱温：40℃
7、稀释剂：乙腈
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。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
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱( 1HNMR)数据采自于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。
本发明中具体实施方式所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含有0.2％卵磷脂)。
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用到的GFT-505是根据现有技术制备得到，例如根据CN100548960C中公开的制备方法得到。
实施例1
将7.2mg GFT-505溶解于0.1mL 丙酮溶剂中，过滤后逐滴加入2.0mL的反溶剂正庚烷，室温下搅拌后收集析出的固体，离心并在室温下真空干燥。经检测，所得固体为本发明的 晶型CS1，其X射线粉末衍射图谱如图1，X射线粉末衍射数据如表1所示。
实施例1所得晶型CS1的核磁数据为： 1HNMR(400MHz,DMSO)δ8.10(d,J＝8.5Hz,2H),7.82(d,J＝15.5Hz,1H),7.66-7.54(m,3H),7.40(d,J＝8.5Hz,2H),2.57(s,3H),2.22(s,6H),1.39(s,6H)。核磁共振谱图如附图2所示
实施例1所得晶型CS1的DSC曲线如图3所示，TGA曲线如图4所示。
表1
衍射角2θ d值 相对强度(％)
8.02 11.03 17.70
10.45 8.47 35.74
11.35 7.80 23.35
12.34 7.17 17.06
14.82 5.98 100.00
16.31 5.44 10.64
16.89 5.25 64.41
17.02 5.21 42.36
18.73 4.74 23.77
20.40 4.35 24.78
23.46 3.79 35.86
25.12 3.54 20.07
25.92 3.44 11.30
26.63 3.35 39.14
27.35 3.26 5.27
28.76 3.10 14.05
实施例2
在50℃下将20.5mg GFT-505溶解于0.7mL体积比为13:1的甲苯和甲基异丁基酮的混合溶剂中，过滤后于4℃下冷却析出晶体，离心并在室温下真空干燥得到结晶固体。经检测，所得结晶固体为本发明的晶型CS1，其X射线粉末衍射数据表2所示。
表2
衍射角2θ d值 相对强度(％)
3.38 26.14 0.40
8.04 11.00 26.15
10.45 8.46 50.11
11.35 7.79 37.94
12.36 7.16 18.40
14.84 5.97 100.00
16.30 5.44 15.31
16.90 5.25 99.98
18.75 4.73 42.21
20.42 4.35 29.56
23.45 3.79 43.38
25.11 3.55 16.15
25.92 3.44 16.19
26.68 3.34 48.48
28.76 3.10 14.39
实施例3
将1.0g GFT-505加至4.5mL体积比为4:5的乙醇和水的混合溶剂中，于室温下搅拌，分离所得固体后真空干燥得到本发明的晶型CS2，其X射线粉末衍射图如图5所示，X射线粉末衍射数据如表3所示。
本实施例所得晶型CS2的核磁数据为： 1HNMR(400MHz,DMSO)δ8.09(d,J＝8.5Hz,2H),7.82(d,J＝15.5Hz,1H),7.67-7.52(m,3H),7.40(d,J＝8.5Hz,2H),2.57(s,3H),2.22(s,6H),1.39(s,6H)。核磁共振谱图如图6所示。
其DSC曲线如图7所示，TGA曲线如图8所示。
表3
衍射角2θ d值 相对强度(％)
9.68 9.13 3.76
11.17 7.92 9.76
11.66 7.59 41.04
12.17 7.28 44.01
14.74 6.01 19.59
15.21 5.82 93.64
15.89 5.58 99.14
16.53 5.36 9.11
19.06 4.66 51.10
19.24 4.61 63.21
19.35 4.59 66.96
20.02 4.43 29.96
21.38 4.16 16.10
22.20 4.00 5.34
22.91 3.88 6.45
23.40 3.80 7.62
24.63 3.61 5.48
25.39 3.51 9.84
25.75 3.46 100.00
26.29 3.39 5.19
26.77 3.33 18.14
27.50 3.24 23.27
29.19 3.06 7.80
29.53 3.03 5.87
30.75 2.91 10.29
36.09 2.49 7.44
实施例4
称取103.5mg的GFT-505溶于1.0mL的甲醇溶剂中，于室温条件下添加约7.0mL的反溶剂水，搅拌24小时后离心干燥得到固体。经检测，所得固体为本发明的晶型CS2，其X射线粉末衍射数据表4所示。
表4
衍射角2θ d值 相对强度(％)
9.65 9.16 7.78
11.17 7.92 10.05
11.63 7.61 48.14
12.16 7.28 28.74
14.72 6.02 16.51
15.21 5.83 67.12
15.90 5.57 98.50
16.51 5.37 10.32
19.03 4.66 42.92
19.33 4.59 100.00
20.00 4.44 38.97
21.37 4.16 10.01
22.19 4.01 4.30
23.40 3.80 8.33
25.75 3.46 77.65
26.75 3.33 16.29
27.50 3.24 18.33
29.16 3.06 6.87
30.72 2.91 7.29
32.17 2.78 2.39
35.96 2.50 1.75
实施例5
称取7.5mg GFT-505样品，将其溶于0.6mL体积比为15:4的乙醇和正庚烷的混合溶剂中，过滤后加入等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成的高聚物并封上扎孔的封口膜，于室温下挥发约5天析出固体。经检测，所得固体为晶型CS2，其X射线粉末衍射数据如表5所示。
表5
衍射角2θ d值 相对强度(％)
11.18 7.92 5.66
11.65 7.60 22.81
12.15 7.29 26.34
14.72 6.02 15.20
15.21 5.82 65.10
15.89 5.58 56.45
16.51 5.37 7.81
19.03 4.66 43.77
19.31 4.60 74.42
20.02 4.43 19.48
21.39 4.15 16.80
22.20 4.00 5.29
22.91 3.88 7.88
24.63 3.61 6.62
25.80 3.45 100.00
26.77 3.33 14.92
27.55 3.24 24.47
29.61 3.02 6.88
30.87 2.90 10.45
35.06 2.56 4.92
36.10 2.49 6.77
39.07 2.31 6.25
实施例6
将6.4mg的GFT-505样品溶解在0.6mL体积比为1:1的丙酮和甲苯的混合溶剂中，过滤后封上扎孔的封口膜，于室温下挥发约3天析出固体。经检测，所得固体为本发明的晶型CS5。其X射线粉末衍射谱图如图9所示，X射线粉末衍射数据如表6所示。
本实施例所得晶型CS5的核磁数据为： 1HNMR(400MHz,DMSO)δ8.09(d,J＝8.5Hz,2H),7.81(d,J＝15.6Hz,1H),7.66-7.53(m,3H),7.40(d,J＝8.5Hz,2H),2.56(s,3H),2.22(s,6H),1.39(s,6H)。其核磁谱图如图10所示。
其DSC图谱如图11所示，TGA图谱如图12所示。
表6
衍射角2θ d值 相对强度(％)
7.37 11.99 57.43
14.32 6.19 21.43
14.58 6.08 100.00
15.44 5.74 45.41
16.71 5.31 6.78
17.66 5.02 9.37
18.68 4.75 79.74
19.47 4.56 10.85
21.48 4.14 2.85
25.32 3.52 43.73
25.85 3.45 64.55
27.51 3.24 30.47
28.88 3.09 12.67
实施例7
将18.5mg的GFT-505样品溶解在1.5mL体积比为1:2的丙酮和甲苯的混合溶剂中，过滤后封上扎孔的封口膜，于室温下挥发约10天后析出固体。经检测，所得固体为晶型CS5，其X射线粉末衍射数据如表7所示。
表7
衍射角2θ d值 相对强度％
7.26 12.17 46.05
14.56 6.08 71.42
15.18 5.84 31.66
15.43 5.74 22.46
16.78 5.28 5.44
17.56 5.05 21.90
18.71 4.74 100.00
19.47 4.56 19.66
20.31 4.37 1.56
21.58 4.12 3.12
22.03 4.04 4.32
22.98 3.87 3.76
24.24 3.67 5.48
25.44 3.50 8.89
26.00 3.43 14.08
26.81 3.33 2.82
27.60 3.23 9.54
28.86 3.09 14.67
实施例8
将8.0mg的GFT-505样品溶解在0.5mL体积比为1:1的乙酸乙酯和甲苯的混合溶剂中，过滤后封上扎孔的封口膜，于室温下挥发约3天后析出固体。经检测，所得固体为晶型CS5。
实施例9
将10.9mg GFT-505样品用3mL玻璃瓶装好后，放入装有3mL乙酸溶剂的20mL的玻璃瓶中，然后将20mL的玻璃瓶封口静置一周，收集所得固体。
经检测，所得固体为晶型CS6。其X射线粉末衍射图谱如图13所示，X射线粉末衍射数据如表8所示。
本实施例所得晶型CS6的核磁数据为： 1HNMR(400MHz,DMSO)δ8.09(d,J＝8.6Hz,2H),7.81(d,J＝15.5Hz,1H),7.57(s,3H),7.40(d,J＝8.6Hz,2H),2.57(s,3H),2.22(s,6H),1.91(s,3H),1.39(s,6H)。核磁谱图如图14所示。
其DSC图谱如图15所示，TGA图谱如图16所示。
表8
衍射角2θ d值 相对强度(％)
6.60 13.40 31.51
10.33 8.57 61.94
11.14 7.94 20.54
12.50 7.08 63.30
13.25 6.68 20.50
14.97 5.92 51.20
15.19 5.83 100.00
16.24 5.46 31.07
16.96 5.23 35.83
18.21 4.87 37.41
19.39 4.58 43.47
19.76 4.49 14.69
20.74 4.28 42.06
22.59 3.94 13.99
23.13 3.85 21.58
23.55 3.78 68.43
25.11 3.55 16.03
26.38 3.38 81.16
26.99 3.30 19.01
29.68 3.01 7.79
32.64 2.74 3.95
实施例10：现有油状物和本发明晶型CS1、晶型CS2的纯度对比
采用HPLC测定根据现有技术制备得到的油状物、本发明的晶型CS1和本发明晶型CS2的纯度，结果如下表9所示。
表9
形态 油状物 晶型CS1 晶型CS2
纯度 83.87％ 99.25％ 99.56％
药物的纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义。现有油状物的杂质含量极高，会使药物含量明显偏低或活性降低；杂质含量高也会使毒副作用显著增加，因此不能作为原料药用于制剂的制备。
本发明晶型的纯度较高，利于工业化生产。本发明的晶型具有较强的杂质排除能力，且还可通过结晶工艺得到纯度更高的原料药，并且不容易出现溶剂残留的问题，使得样品残留溶剂容易达标并符合质量要求，适合药用。
实施例11：晶型CS1、CS2和CS5的引湿性研究
在25℃条件下，取本发明的CS1、CS2和CS5晶型各约10mg进行动态水分吸附(DVS)测试其引湿性。结果表明：
晶型CS1在80％相对湿度下平衡后增重0.042％，几乎无引湿性。其DVS图如图17所示。此外，DVS实验前后分别检测晶型CS1的XRPD图，结果如图18(上图为DVS前的XRPD图，下图为DVS后的XRPD图)所示，表明在DVS前后晶型CS1没有发生变化。
晶型CS2在80％相对湿度下平衡后，相较于30％的起始相对湿度，增重0.101％，几乎无引湿性，方便长期贮存放置，其DVS图如图19所示。此外，在DVS前后分别检测晶型CS2的XRPD图，结果如图20(上图为DVS前的XRPD图，下图为DVS后的XRPD图)所示，表明DVS前后晶型CS2没有发生变化。
晶型CS5在80％相对湿度下平衡后，增重0.325％，属于略有引湿性，其DVS图如图21所示。此外，在DVS前后分别检测晶型CS5的XRPD图，结果如图22(上图为DVS前的XRPD图，下图为DVS后的XRPD图)所示，表明在动态水分吸附实验前后晶型CS5没有变化。
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)：
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％
实施例12：晶型CS1、CS2和CS5的稳定性研究
取本发明晶型CS1的样品分别置于25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，放置前后取样测其XRPD图分别如图23、图24和图25所示，结果如表10所示：
表10
Figure PCTCN2018071917-appb-000004
Figure PCTCN2018071917-appb-000005
本发明晶型CS1在25℃/60％相对湿度和40℃/75％相对湿度条件下，放置6个月后晶型保持不变；在60℃/75％相对湿度条件下放置1个月后晶型保持不变。上述试验结果表明，本发明晶型CS1具有良好的稳定性。
取本发明晶型CS2的样品分别置于25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，放置前后取样测其XRPD图分别如图26、图27和图28所示，结果如表11所示：
表11
Figure PCTCN2018071917-appb-000006
本发明晶型CS2在25℃/60％相对湿度和40℃/75％相对湿度条件下，放置6个月后晶型保持不变；在60℃/75％相对湿度条件下放置1个月后晶型保持不变。上述试验结果表明，本发明晶型CS2具有良好的稳定性。
取本发明晶型CS5的样品分别置于25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度下敞口放置，放置前后取样测其XRPD图分别如图29、图30和图31所示，结果如表12所示：
表12
Figure PCTCN2018071917-appb-000007
Figure PCTCN2018071917-appb-000008
本发明晶型CS5在25℃/60％相对湿度和40℃/75％相对湿度条件下，放置6个月后晶型保持不变；在60℃/75％相对湿度条件下放置1个月后晶型保持不变。上述试验结果表明，本发明晶型CS5具有良好的稳定性。
药物的稳定性至关重要，尤其在市售有效期内，保持较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的风险，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。更稳定的晶型在结晶工艺过程中更加可控，不容易出现混晶，且在制剂工艺及储存过程中，不容易转变成其它晶型，从而保证样品的质量标准一致可控，并确保制剂产品的溶出曲线不会随着储存的时间变化而发生改变。
结果表明，本发明晶型CS1、CS2和CS5具有良好的稳定性，符合药物应用中及制剂工艺中对晶型可能的苛刻要求。
实施例13：晶型CS1、CS2、CS5和CS6的动态溶解度研究
为测试本发明晶型CS1、CS2、CS5和CS6的溶解性，发明人做了如下实验：
将本发明中的晶型CS1、CS2和CS5样品分别用pH1.8SGF(模拟胃液),pH5.0FeSSIF(模拟进食状态下人工肠液)，pH6.5FaSSIF(模拟空腹状态下人工肠液)和H 2O配制成饱和溶液，在1个小时、4个小时后和24个小时后采用高效液相色谱测定饱和溶液中样品的含量。将本发明中的晶型CS6样品分别用pH1.8SGF(模拟胃液),pH5.0FeSSIF(模拟进食状态下人工肠液)和pH6.5FaSSIF(模拟空腹状态下人工肠液)配制成饱和溶液，在1个小时、4个小时后和24个小时后采用高效液相色谱测定饱和溶液中样品的含量。晶型CS1的溶解度实验结果如表13所示，晶型CS2的溶解度实验结果如表14所示，晶型CS5的溶解度实验结果如表15所示，晶型CS6的溶解度实验结果如表16所示。
表13晶型CS1在SGF、FeSSIF、FaSSIF和水中的溶解度
Figure PCTCN2018071917-appb-000009
表14晶型CS2在SGF、FeSSIF、FaSSIF和水中的溶解度
Figure PCTCN2018071917-appb-000010
表15晶型CS5在SGF、FeSSIF、FaSSIF和水中的溶解度
Figure PCTCN2018071917-appb-000011
表16晶型CS6在SGF、FeSSIF和FaSSIF中的溶解度
Figure PCTCN2018071917-appb-000012
溶解度是药物的关键性质之一，直接影响药物在人体内的吸收。不同晶型药物的溶解度可能会存在明显差异，体内吸收动态也会发生变化，造成生物利用度的差异，最终影响到药物的临床安全性和疗效。
从以上数据可知，本发明的晶型CS1、CS2和CS5在SGF、FaSSIF、FeSSIF和水中的溶解度，以及本发明晶型CS6在SGF、FaSSIF和FeSSIF的溶解度符合药用要求，尤其是在FaSSIF(模拟空腹状态下人工肠液)和FeSSIF(模拟进食状态下人工肠液)中的溶解度较高。本发明晶型CS1、CS2、CS5和CS6理想的溶解度，可降低给药剂量从而降低药品的副作用并提高药品的安全性，且在口服后不需要高剂量即可达到所需的治疗血药浓度，有利于药物在人体内的吸收，达到理想的药物生物利用度和药效，符合药用要求。
实施例14：晶型CS1、CS2、CS5和CS6的研磨稳定性研究
取本发明晶型CS1、CS2、CS5和CS6各约20毫克，分别用研钵手动研磨5分钟，研磨前后对样品进行XRPD测试。晶型CS1的测试结果见图32(上图为研磨前，下图为研磨后)，晶型CS2的测试结果见图33(上图为研磨前，下图为研磨后)，晶型CS5的测试结果见图34(上图为研磨前，下图为研磨后)，晶型CS6的测试结果见图35(上图为研磨前，下图为研磨后)。从图中可以看出，本发明晶型CS1、CS2、CS5和CS6经过研磨后晶型不变且结晶度保持良好。
更好的机械稳定性表现在一定机械应力的作用下，仍可保持稳定的物理化学性质。具有较好的机械稳定性的晶型药物对结晶设备要求低，无需特别的后处理条件，在制剂过程中更加稳定，可显著降低药物的开发成本，提升药物质量，具有很强的经济价值。
上述结果表明，本发明的晶型CS1、CS2、CS5和CS6在后续的工艺过程中具备更好的机械稳定性，为后续制剂工艺提供更多选择。例如，可以通过后续干法研磨手段对晶型CS1、CS2、CS5和CS6进行研磨从而得到粒径更小的颗粒。
实施例15：本发明晶型CS1、CS2、CS5和CS6与现有油状物的形态对比
本发明晶型CS1与油状物的形态对比图如图36所示，本发明晶型CS1、CS2、CS5和CS6均呈浅黄色粉末状，取样及定量方便，而根据现有技术方法得到浅黄色油状物，呈粘稠的蜂蜜状(如图36右图)。油状物的取样和定量通常比较困难，且油状物纯度低，稳定性较差，不利于药物存储。此外，油状物作为原料药做成固体制剂往往需要特殊复杂的处理工序，增加制备成本，不利于制剂的制备。
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 (24)

  1. 一种式(I)所示化合物的晶型CS1，其特征在于，其X射线粉末衍射图在2θ值为10.5°±0.2°、14.8°±0.2°、16.9°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2θ值为18.7°±0.2°、20.4°±0.2°、26.6°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2θ值为11.4°±0.2°、23.5°±0.2°、25.1°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种权利要求1-3中任一项所述晶型CS1的制备方法，其特征在于，所述方法包括：
    (1)将GFT-505加至酮类溶剂中溶解，后添加反溶剂并搅拌，析出晶体后分离干燥得到；或
    (2)在40～70℃温度下将GFT-505溶解于芳香烃和酮类的混合溶剂体系中，在0～10℃温度下冷却析出晶体，后分离干燥得到。
  5. 根据权利要求4所述的制备方法，其特征在于：
    方法(1)中所述酮类溶剂包含丙酮、甲基乙基酮中的一种或它们的混合物，所述反溶剂为烷烃类溶剂且包含正己烷、正庚烷、正辛烷中的一种或它们的混合物，所述酮类与烷烃类溶剂的体积比为1:20～20:1；
    方法(2)中所述芳香烃包含甲苯、乙苯中的一种或它们的混合物，所述酮类包含丙酮、甲基乙基酮、甲基异丁基酮中的一种或它们的混合物，所述芳香烃和酮类的体积比为1:20～20:1，所述溶解温度为50℃，所述冷却温度为4℃。
  6. 根据权利要求5所示的制备方法，其特征还在于：
    方法(1)中所述酮类溶剂为丙酮，所述烷烃类反溶剂为正庚烷，所述酮类与烷烃类溶剂的体积比为1:20；
    方法(2)中所述芳香烃类溶剂为甲苯，所述酮类溶剂为甲基异丁基酮，所述芳香烃和酮类溶剂的体积比为13:1。
  7. 一种式(I)所示化合物的晶型CS2，其特征在于，其X射线粉末衍射图在2θ值为15.2°±0.2°、15.9°±0.2°、25.8°±0.2°处具有特征峰。
  8. 根据权利要求7所述的晶型CS2，其特征还在于，其X射线粉末衍射图在2θ值为11.7°±0.2°、12.2°±0.2°、19.4°±0.2°中的一处或两处或三处具有特征峰。
  9. 根据权利要求7所述的晶型CS2，其特征还在于，其X射线粉末衍射图在2θ值为20.0°±0.2°、26.8°±0.2°、27.5°±0.2°中的一处或两处或三处具有特征峰。
  10. 一种权利要求7-9中任一项所述晶型CS2的制备方法，其特征在于，所述方法包括：
    (1)将GFT-505加入纯水或醇类与水的混合体系中，搅拌后分离固体，干燥而得到；或
    (2)将GFT-505溶解于醇类体系中，添加反溶剂水并搅拌至析出晶体，经分离，干燥而得到；或
    (3)将GFT-505溶于醇类和烷烃类溶剂的混合体系中，并加入高聚物，于10～50℃温度下挥发得到。
  11. 根据权利要求10所述的制备方法，其特征在于：
    方法(1)中所述醇类包含甲醇、乙醇、异丙醇中的一种或它们的混合物，所述醇类与水的混合体系中醇类与水的体积比为1:5～5:1；
    方法(2)中所述醇类包含甲醇、乙醇、异丙醇中的一种或它们的混合物，所述醇类与水的体积比为1:10～10:1；
    方法(3)中所述醇类包含甲醇、乙醇、异丙醇中的一种或它们的混合物，所述烷烃类包含己烷、正庚烷、正辛烷中的一种或它们的混合物，所述醇类与烷烃溶剂的体积比为1:15～15:1，所述挥发温度为室温。
  12. 根据权利要求11所示的制备方法，其特征还在于：
    方法(1)中所述醇类溶剂为乙醇，所述醇类与水的混合体系中醇类与水的体积比为4:5；
    方法(2)中所述醇类溶剂为甲醇，所述醇类与水的体积比为1:7；
    方法(3)中所述醇类溶剂为乙醇，所述烷烃类溶剂为正庚烷，所述醇类与烷烃类溶剂的体积比为15:4。
  13. 一种式(I)所示化合物的晶型CS5，其特征在于，其X射线粉末衍射图在2θ值为7.4°±0.2°、14.6°±0.2°、18.7°±0.2°处具有特征峰。
  14. 根据权利要求13所述的晶型CS5，其特征还在于，其X射线粉末衍射图在2θ值为25.3°±0.2°、15.4°±0.2°、25.9°±0.2°中的一处或两处或三处具有特征峰。
  15. 根据权利要求13所述的晶型CS5，其特征还在于，其X射线粉末衍射图在2θ值为19.5°±0.2°、27.5°±0.2°、28.9°±0.2°中的一处或两处或三处具有特征峰。
  16. 一种权利要求13-15中任一项所述晶型CS5的制备方法，其特征在于，所述方法包括：将GFT-505溶解于酮类和芳香烃类的混合溶剂或酯类和芳香烃类的混合溶剂中，在10～50℃温度下挥发而得到。
  17. 根据权利要求16所述的制备方法，其特征在于：
    所述酮类包含丙酮、甲基乙基酮中的一种或它们的混合物，所述芳香烃包含甲苯、乙苯中的 一种或它们的混合物，所述酯类包含乙酸乙酯、乙酸异丙酯中的一种或它们的混合物，所述混合溶剂中酮类和芳香烃或酯类和芳香烃的体积比为1:3～3:1，所述挥发温度为室温。
  18. 根据权利要求17所示的制备方法，其特征还在于：
    所述酮类溶剂为丙酮，所述芳香烃类溶剂为甲苯，所述酯类溶剂为乙酸乙酯，所述混合溶剂中酮类和芳香烃或酯类和芳香烃的体积比为1:1。
  19. 一种式(I)所示化合物的晶型CS6，所述晶型CS6为乙酸溶剂合物，其特征在于，其X射线粉末衍射图在2θ值为12.5°±0.2°、19.4°±0.2°、23.6°±0.2°处具有特征峰。
  20. 根据权利要求19所述的晶型CS6，其特征还在于，其X射线粉末衍射图在2θ值为15.2°±0.2°、20.7°±0.2°、26.4°±0.2°中的一处或两处或三处具有特征峰。
  21. 根据权利要求19所述的晶型CS6，其特征还在于，其X射线粉末衍射图在2θ值为6.6°±0.2°、10.3°±0.2°、18.2°±0.2°中的一处或两处或三处具有特征峰。
  22. 一种权利要求19-21中任一项所述晶型CS6的制备方法，其特征在于，所述方法包括：将GFT-505放置于含有乙酸溶剂氛围的密闭装置中，通过气固渗透得到。
  23. 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1-3中任意一项所述的晶型CS1或权利要求7-9中任意一项所述的晶型CS2或权利要求13-15中任意一项所述的晶型CS5或权利要求19-21中任意一项所述的晶型CS6及药学上可接受的载体、稀释剂或赋形剂。
  24. 权利要求1-3中任意一项所述的晶型CS1或权利要求7-9中任意一项所述的晶型CS2或权利要求13-15中任意一项所述的晶型CS5或权利要求19-21中任意一项所述的晶型CS6，在制备治疗非酒精性脂肪肝炎和/或II型糖尿病和/或血脂异常和/或动脉粥样硬化疾病的药物制剂中的用途。
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