WO2022122014A1 - Lanifibranor的晶型及其制备方法和用途 - Google Patents

Lanifibranor的晶型及其制备方法和用途 Download PDF

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WO2022122014A1
WO2022122014A1 PCT/CN2021/137078 CN2021137078W WO2022122014A1 WO 2022122014 A1 WO2022122014 A1 WO 2022122014A1 CN 2021137078 W CN2021137078 W CN 2021137078W WO 2022122014 A1 WO2022122014 A1 WO 2022122014A1
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crystal form
compound
ray powder
powder diffraction
diffraction pattern
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PCT/CN2021/137078
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English (en)
French (fr)
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陈敏华
朱宏艳
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苏州科睿思制药有限公司
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Publication of WO2022122014A1 publication Critical patent/WO2022122014A1/zh
Priority to US17/887,681 priority Critical patent/US11827630B2/en
Priority to US18/518,719 priority patent/US20240092771A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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 present invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of Lanifibranor and its preparation method and use.
  • Nonalcoholic steatohepatitis is a severe liver disease with steatosis accompanied by inflammation and liver cell damage.
  • Peroxisome proliferator-activated receptor is a ligand-activated transcription factor belonging to the nuclear hormone receptor family that regulates gene expression. PPARs play crucial roles in regulating cell differentiation, development and tumorigenesis.
  • Lanifibranor is an oral small-molecule drug that induces anti-fibrotic, anti-inflammatory effects in vivo by activating three PPAR isoforms (named PPAR ⁇ , PPAR ⁇ , and PPAR ⁇ ) and addresses fat by enhancing fatty acid metabolism and ultimately reducing lipogenesis Transgender issues.
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • Amorphous is an amorphous material without long-range order, and its X-ray powder diffraction pattern usually shows a broad "steamed bread peak".
  • Example 117 discloses the preparation method of compound I as follows: white precipitate is extracted with ethyl acetate, the organic phase is separated, dried with magnesium sulfate, and concentrated under reduced pressure to obtain compound I as pale yellow powder (yield 83%).
  • Prior art WO2019024776A1 Example 3 discloses the preparation method of compound I as follows: extracting the white precipitate with ethyl acetate, separating the organic phase, drying with magnesium sulfate, and concentrating under reduced pressure to obtain 83 mg of compound I as a pale yellow solid. The inventors of the present application repeated the preparation method of compound I disclosed in the prior art to obtain the amorphous form of compound I.
  • the inventors of the present application have conducted a systematic and comprehensive study on the amorphous obtained according to the prior art and found that the amorphous has the problems of a large amount of moisture introduction, a high residual amount of organic solvent, poor solid state of the sample, difficulty in quantification and large transfer loss. Suitable for medicinal use.
  • the 1,4-dioxane solvate crystal form, the trichloromethane solvate crystal form and the tetrahydrofuran solvate crystal form contain 10.1 wt% of 1,4-dioxane, 3.3 wt% of trioxane, respectively Methyl chloride and 6.0 wt% tetrahydrofuran, not suitable for medicinal use.
  • the anhydrous crystal form and hydrate crystal form of Compound I provided in the present application are excellent in solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc.
  • the present invention provides a new crystal form of compound I, a preparation method thereof, and a pharmaceutical composition comprising the new crystal form.
  • the present invention provides a new crystalline form of compound I which is a hydrate.
  • the present invention provides a new crystalline form of compound I which is anhydrous.
  • the present invention provides a new crystalline form of compound I containing no more than 5% by mass of water.
  • the present invention provides a new crystalline form of compound I containing no more than 3% by mass of water.
  • crystal form CSI crystal form CSI
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 1 of 20.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 24.5° ⁇ 0.2°, or 2
  • a diffraction angle 2 ⁇ value of 1 of 20.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 24.5° ⁇ 0.2°, or 2
  • the X-ray powder diffraction pattern of the crystalline form CSI is at 3 places in the diffraction angle 2 ⁇ value of 20.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 24.5° ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 7.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, or 2
  • a diffraction angle 2 ⁇ value 7.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, or 2
  • characteristic peaks at or at 3 places preferably, the X-ray powder diffraction pattern of the crystalline form CSI has 3 places in the diffraction angle 2 ⁇ of 7.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, and 21.2° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 10.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, or 2
  • a diffraction angle 2 ⁇ value 10.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, or 2
  • characteristic peaks at or at 3 places preferably, the X-ray powder diffraction pattern of the crystalline form CSI has 3 places in the diffraction angle 2 ⁇ of 10.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, and 19.1° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 20.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 24.5° ⁇ 0.2°, 7.7° ⁇ 0.2° , 17.8° ⁇ 0.2°, 21.2° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 19.1° ⁇ 0.2°, 25.3° ⁇ 0.2°, 14.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.0 ° ⁇ 0.2° any 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or There are characteristic peaks at 12 or 13 positions.
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 1 .
  • the crystalline form CSI has a mass loss of about 0.02% when heated to 170° C.
  • the thermogravimetric analysis diagram is shown in FIG. 2 .
  • the crystalline form CSI is anhydrous.
  • the present invention also provides the preparation method of described crystal form CSI, and described preparation method comprises:
  • Method 1 The solid compound I is placed in an alcohol solvent or an ether solvent, stirred, and separated to obtain crystal form CSI; or
  • Method 2 Dissolve the solid compound I in an ether solvent or a hydrocarbon solvent, and volatilize the clear solution to obtain the crystal form CSI.
  • the alcohols are preferably C1-C8 alcohols, more preferably methanol; the ethers are preferably C4-C7 ethers, more preferably methyl tert-butyl ether; the stirring time is preferably at least 10 minutes .
  • the ethers are preferably C4-C7 ethers, more preferably 2-methyltetrahydrofuran;
  • the hydrocarbons are preferably C5-C8 hydrocarbons, more preferably aromatic hydrocarbons, more preferably toluene.
  • crystal form CSII of compound I provided by the present invention
  • the X-ray powder diffraction pattern of the crystalline form CSII has a diffraction angle 2 ⁇ value of 18.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 25.3° ⁇ 0.2°, or 2 There are characteristic peaks at or 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSII is at 3 places in the diffraction angle 2 ⁇ value of 18.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 25.3° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSII has a diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 13.2° ⁇ 0.2°, 20.6° ⁇ 0.2°, or 2
  • a diffraction angle 2 ⁇ value 7.9° ⁇ 0.2°, 13.2° ⁇ 0.2°, 20.6° ⁇ 0.2°, or 2
  • characteristic peaks at or at 3 places preferably, the X-ray powder diffraction pattern of the crystalline form CSII has 3 places in the diffraction angle 2 ⁇ of 7.9° ⁇ 0.2°, 13.2° ⁇ 0.2°, and 20.6° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSII has a diffraction angle 2 ⁇ value of 9.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.2° ⁇ 0.2° at 1 or 2
  • a diffraction angle 2 ⁇ value of 9.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.2° ⁇ 0.2° at 1 or 2
  • characteristic peaks at or at 3 places preferably, the X-ray powder diffraction pattern of the crystalline form CSII has 3 places in the diffraction angle 2 ⁇ of 9.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, and 24.2° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSII has diffraction angle 2 ⁇ values of 18.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 25.3° ⁇ 0.2°, 7.9° ⁇ 0.2° , 13.2° ⁇ 0.2°, 20.6° ⁇ 0.2°, 9.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.2° ⁇ 0.2°, 26.3° ⁇ 0.2°, 14.4° ⁇ 0.2°, 16.8° ⁇ 0.2° Any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or 10, or 11, or 12 characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSII has diffraction angle 2 ⁇ values of 18.5° ⁇ 0.2°, 22.4° ⁇ 0.2°, 25.5° ⁇ 0.2°, 7.9° ⁇ 0.2° , 13.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, 9.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, 26.4° ⁇ 0.2°, 14.4° ⁇ 0.2°, 16.9° ⁇ 0.2° Any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or 10, or 11, or 12 characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSII is substantially as shown in FIG. 5 .
  • thermogravimetric analysis diagram of the crystalline form CSII is shown in Figure 6, which has a mass loss of about 2.2% when heated to 180°C.
  • the crystalline form CSII has an endothermic peak near 143 °C, an exothermic peak near 151 °C, and an endothermic peak begins to appear near 177 °C, and its differential scanning calorimetry analysis diagram is basically shown in Figure 7. .
  • the crystalline form CSII is a hydrate.
  • the present invention also provides a preparation method of the crystal form CSII, the preparation method comprising:
  • the solid compound I was placed in a mixed solvent of alcohols, ketones or ethers and nitriles, and the clear solution was volatilized to obtain crystal form CSII.
  • the alcohols are preferably C1-C8 alcohols
  • the ketones are preferably C3-C6 ketones
  • the ethers are preferably C4-C7 ethers
  • the nitriles are preferably C2-C4 nitriles.
  • the alcohols are preferably methanol and/or n-propanol
  • the ketones are preferably methyl ethyl ketone
  • the ethers are preferably tetrahydrofuran
  • the nitriles are preferably acetonitrile.
  • volume ratio of ethers and nitriles in the mixed solvent is preferably 10:1-1:10.
  • the present invention provides a crystalline form CSIV of Compound I (hereinafter referred to as "crystalline form CSIV").
  • the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angle 2 ⁇ values of 11.4° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSIV has a diffraction angle 2 ⁇ value of 15.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 27.6° ⁇ 0.2°, or 2
  • the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2 ⁇ of 15.3° ⁇ 0.2°, 20.1° ⁇ 0.2°, 27.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSIV has a diffraction angle 2 ⁇ value of 8.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 20.9° ⁇ 0.2°, or 2
  • the X-ray powder diffraction pattern of the crystalline form CSIV has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 20.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSIV has diffraction angle 2 ⁇ values of 11.4° ⁇ 0.2°, 24.7° ⁇ 0.2°, 25.8° ⁇ 0.2°, 15.3° ⁇ 0.2° , 20.1° ⁇ 0.2°, 27.6° ⁇ 0.2°, 8.9° ⁇ 0.2°, 15.9° ⁇ 0.2°, 20.9° ⁇ 0.2°, 7.3° ⁇ 0.2°, 9.4° ⁇ 0.2°, 11.7° ⁇ 0.2°, 17.8 ° ⁇ 0.2°, 18.8° ⁇ 0.2°, 24.3° ⁇ 0.2° any 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15 with characteristic peaks.
  • the X-ray powder diffraction pattern of crystalline form CSIV is substantially as shown in FIG. 9 .
  • thermogravimetric analysis diagram of the crystalline form CSIV is substantially as shown in Figure 10, which has a mass loss of about 0.06% when heated to 120°C.
  • the crystalline form CSIV is anhydrous.
  • the present invention also provides a preparation method of the crystalline form CSIV, the preparation method comprising:
  • the certain temperature is preferably 120°C-160°C.
  • the present invention provides the use of crystal form CSI, crystal form CSII, crystal form CSIV or any mixture of the above crystal forms for preparing other crystal forms or salts of compound I.
  • the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of the crystal form of Compound I and pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSI, crystal form CSII, crystal form CSIV or any mixture of the above crystal forms and pharmaceutically acceptable auxiliary materials.
  • the present invention provides the use of the crystalline form of Compound I in the preparation of a pan-PPAR agonist drug.
  • the present invention provides the use of crystal form CSI, crystal form CSII, crystal form CSIV, or any mixture thereof in the preparation of a pan-PPAR agonist drug.
  • the present invention provides the use of the crystal form of compound I in the preparation of a medicament for the treatment of nonalcoholic steatohepatitis.
  • the present invention provides the use of crystalline form CSI, crystalline form CSII, crystalline form CSIV, or any mixture thereof in the preparation of a medicament for treating nonalcoholic steatohepatitis.
  • the inventor of the present application After studying the amorphous obtained by the preparation method disclosed in the prior art, the inventor of the present application found that the amorphous has a large amount of moisture intensification and poor chemical stability, which is not conducive to production; high. In order to solve the problems existing in the prior art, the inventors of the present application have carried out more than 600 experiments, and tried methods such as beating, volatilization, gas-liquid diffusion, gas-solid diffusion, humidity induction, anti-solvent addition and heating in different solvent systems, Finally, the crystal form of compound I provided by the present invention was obtained unexpectedly.
  • the crystalline form CSI provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the prior art amorphous under the conditions of 0-60% RH and 0-70% RH is about 6 times and 7 times that of the crystalline form CSI of the present application, respectively.
  • Crystal form CSI under 0-60%RH conditions and 0-70%RH conditions moisture-inducing weight gain is 0.17%
  • the prior art amorphous under 0-60%RH conditions and 0-70%RH conditions moisture-inducing weight gain The weights were 0.94% and 1.18%, respectively.
  • high hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSI provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSI provided by the present invention has a good powder appearance.
  • the crystal form CSI powder provided by the invention has good dispersibility, which is beneficial to transfer in industrial production and reduce material loss.
  • the crystal form CSI API provided by the present invention has good stability. Crystalline CSI APIs are placed in open and sealed packages at 25°C/60%RH, the crystal form has not changed for at least 6 months, and the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of CSI API has not changed in sealed packaging and open packaging for at least 6 months at 40°C/75%RH, and the purity remains basically unchanged during storage; at 60°C/75%RH
  • the crystal form did not change under the conditions of sealed and open storage for at least 3 months, and the purity remained basically unchanged during storage.
  • the crystalline form CSI API has better stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • the crystal form CSI provided by the present invention has a uniform particle size distribution. Uniform particle size helps ensure content uniformity and reduces variability in in vitro dissolution.
  • the crystal form CSI provided by the present invention has good fluidity. Better fluidity can avoid clogging of production equipment and improve production efficiency; ensure the content uniformity of preparations, reduce weight differences, and improve product quality.
  • the crystal form CSI provided by the present invention has better adhesion. Better adhesion performance can effectively reduce the agglomeration of raw materials, can effectively improve or avoid the phenomenon of sticking wheel, sticking and punching caused by dry granulation and tablet pressing, etc. Mixing uniformity during mixing, ultimately improving product quality.
  • the crystalline form CSII provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the prior art amorphous under the conditions of 0-60% RH and 0-70% RH is about 4 times and 5 times that of the crystal form CSII of the present application, respectively.
  • the hygroscopic weight gain of crystal form CSII is 0.21% and 0.27% under the condition of 0-60%RH and 0-70%RH, respectively, and the amorphous form of the prior art is under the condition of 0-60%RH and 0-70%RH.
  • the wet weight gain was 0.94% and 1.18%, respectively.
  • high hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, high hygroscopicity can easily cause changes in the content of active ingredients in medicines, affecting the quality of medicines.
  • the crystal form CSII provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSII provided by the present invention has better powder appearance.
  • the crystal form CSII powder provided by the invention has good dispersibility, is beneficial to the transfer in industrial production and reduces material loss.
  • the crystal form CSII bulk drug provided by the present invention has good stability.
  • the bulk drug of crystal form CSII is placed in sealed packaging and open packaging at 25°C/60% RH, the crystal form has not changed for at least 3 months, and the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form CSII API has not changed in sealed packaging and open packaging for at least 3 months at 40°C/75% RH, and the purity remains basically unchanged during storage. Under the condition of 60°C/75%RH, the crystal form remained unchanged for at least one month, and the purity remained basically unchanged during storage. It shows that the crystalline form CSII API has better stability under accelerated conditions and more severe conditions. High temperature and humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form CSII API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Crystal form CSII has good mechanical stability.
  • Crystal form CSII API has good physical stability after tableting and grinding. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process. Under different pressures, the crystalline form CSII API has good physical stability, which is conducive to maintaining the crystal form stability in the preparation and tableting process.
  • the crystal form CSII provided by the present invention has better adhesion. Better adhesion performance can effectively reduce the agglomeration of raw materials, can effectively improve or avoid the phenomenon of sticking wheel, sticking and punching caused by dry granulation and tablet pressing, etc. Mixing uniformity during mixing, ultimately improving product quality.
  • the crystalline form CSIV provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the prior art amorphous under the conditions of 0-60% RH and 0-70% RH is about 4 times that of the crystalline form CSIV of the present application.
  • the hygroscopic weight gain of crystal form CSIV is 0.23% and 0.27% under the condition of 0-60%RH and 0-70%RH, respectively, and the amorphous form of the prior art is under the condition of 0-60%RH and 0-70%RH.
  • the wet weight gain was 0.94% and 1.18%, respectively.
  • high hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, high hygroscopicity can easily cause changes in the content of active ingredients in medicines, affecting the quality of medicines.
  • the crystal form CSIV provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSIV provided by the present invention has no organic solvent residue.
  • the crystalline form CSIV has no organic solvent residues, while the prior art amorphous contains 2.70% ethyl acetate solvent, which is far beyond the limit of residual solvent specified in the Pharmacopoeia (0.5%).
  • Ethyl acetate has toxic side effects on the central nervous system, and long-term exposure can cause conjunctival irritation and corneal opacity, and even cause liver and kidney congestion.
  • the preparation of the crystal form CSIV does not require any solvent and has no solvent residue, which can not only reduce the drug toxicity effect of the raw material drug due to the solvent residue, but also reduce the production cost.
  • the crystal form CSIV provided by the present invention has good powder appearance.
  • the crystal form CSIV powder provided by the invention has good dispersibility, which is beneficial to transfer in industrial production and reduce material loss.
  • the crystal form CSIV bulk drug provided by the present invention has good stability.
  • the crystalline form CSIV API is placed in sealed packaging and open packaging at 25°C/60% RH, the crystalline form has not changed for at least 3 months, and the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of the CSIV API was kept in sealed packaging and open packaging for at least 3 months at 40°C/75% RH, and the crystalline form did not change, and the purity remained basically unchanged during storage. Under the condition of 60°C/75%RH, the crystal form did not change in sealed packaging and open packaging for at least one month, and the purity remained basically unchanged during storage. It shows that the crystalline form CSIV API has better stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug. The crystalline form CSIV API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • the crystalline form CSIV has good mechanical stability.
  • the crystalline form CSIV API has good physical stability after tableting and grinding. In the process of preparation processing, it is often necessary to grind and pulverize the API. Good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process. Under different pressures, the crystalline form CSIV API has good physical stability, which is beneficial to maintain the crystal form stability in the preparation and tableting process.
  • the crystal form CSIV provided by the present invention has better adhesion. Better adhesion performance can effectively reduce the agglomeration of raw materials, can effectively improve or avoid the phenomenon of sticking wheel, sticking and punching caused by dry granulation and tablet pressing, etc. Mixing uniformity during mixing, ultimately improving product quality.
  • Fig. 1 is the XRPD pattern of the crystal form CSI obtained in Example 2
  • Fig. 2 is the TGA diagram of the crystal form CSI obtained in Example 2
  • Fig. 3 is the XRPD pattern of the crystal form CSI obtained in Example 3
  • Example 4 is a structural diagram of an asymmetric unit in the crystal form CSI single crystal structure obtained in Example 4
  • Fig. 5 is the XRPD pattern of the crystal form CSII obtained in Example 5
  • Fig. 6 is the TGA diagram of crystal form CSII obtained in Example 5
  • Fig. 7 is the DSC chart of the crystal form CSII obtained in Example 5
  • Fig. 8 is the XRPD pattern of the crystal form CSII obtained in Example 6
  • Fig. 9 is the XRPD pattern of the crystal form CSIV obtained in Example 7
  • Figure 10 is the TGA diagram of the crystal form CSIV obtained in Example 7
  • Figure 11 is the XRPD pattern of the amorphous obtained in Example 8.
  • Figure 12 is a TGA diagram of the amorphous obtained in Example 8.
  • Figure 13 is the XRPD comparison chart of the crystal form CSI before and after being placed under different placement conditions (from top to bottom: before placement, 25°C/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging 6 months in 40°C/75%RH open packaging, 6 months in 40°C/75%RH sealed packaging, 3 months in 60°C/75%RH open packaging, 60°C/75 %RH sealed package for 3 months)
  • Figure 14 is the XRPD overlay of crystalline form CSI before and after DVS (top: before test, bottom: after test)
  • Figure 15 shows the powder appearance of crystal form CSI
  • Figure 16 is the XRPD comparison chart of the crystal form CSII before and after storage under different conditions (from top to bottom: before storage, 25°C/60%RH open packaging for 3 months, 25°C/60%RH sealed packaging for storage 3 months, 40°C/75%RH open packaging for 3 months, 40°C/75%RH sealed packaging for 3 months, 60°C/75%RH open packaging for 1 month.)
  • Figure 17 shows the XRPD stacks of crystal form CSII before and after tableting (from top to bottom: before tableting, 5kN, 10kN, 20kN)
  • Figure 18 is the XRPD overlay before and after grinding of crystal form CSII (top: before grinding, bottom: after grinding)
  • Figure 19 is the XRPD overlay of the crystal form CSII before and after the DVS test (top: before the test, bottom; after the test)
  • Figure 20 shows the powder appearance of crystal form CSII
  • Figure 21 is the XRPD comparison chart of crystalline form CSIV before and after storage under different conditions (from top to bottom: before storage, 25°C/60%RH open package for 3 months, 25°C/60%RH sealed package for storage 3 months, 40°C/75%RH open packaging for 3 months, 40°C/75%RH sealed packaging for 3 months, 60°C/75%RH open packaging for 1 month, 60°C/75% RH sealed package for 1 month.)
  • Figure 22 shows the XRPD stacks before and after tableting of crystalline form CSIV (from top to bottom: before tableting, 5kN, 10kN, 20kN)
  • Figure 23 is the XRPD overlay before and after grinding of the crystalline form CSIV (top: before grinding, bottom: after grinding)
  • Figure 24 is the XRPD overlay of crystalline form CSIV before and after DVS test (top: before test, bottom: after test)
  • Figure 25 shows the powder appearance of crystalline form CSIV
  • PSD particle size distribution
  • the X-ray powder diffraction patterns of the present invention were collected on a Bruker X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction are as follows:
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M Hz nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • the single crystal X-ray diffraction (SC-XRD) described in the present invention is equipped with a CMOS area detector and Cu/K ⁇ radiation
  • the single-crystal X-ray data were collected by the Agilent Gemini A diffractometer of the Microfocal Enclosed X-ray Generator.
  • the single crystal was at 293(2)K at the time of data collection.
  • Table 2 shows the related substance detection method of the present invention.
  • the particle size distribution results described in the present invention were collected on a Mastersizer 3000 laser particle size analyzer from Malvern Company. This test adopts the wet method, the hydro MV dispersion device is used for the wet method, and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are shown in Table 3.
  • Particle Size Distribution Volume Distribution Acquisition time: 10 seconds
  • Dispersion medium Isopar G
  • Particle shape non-spherical Collection times: 3 times Refractive index of dispersion medium: 1.42
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is preferably 300-900 rev/min, and the mechanical stirring It is preferably 100-300 revolutions per minute.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: put the sample to be separated into a centrifuge tube, and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • volatilization is accomplished by conventional methods in the art. For example, slow volatilization means sealing the container with a sealing film, puncturing holes, and standing to volatilize; rapid volatilization means leaving the container open to volatilize.
  • concentration under reduced pressure is accomplished by conventional methods in the art.
  • the operation of concentration under reduced pressure is: the flask containing the solution is rotated at a constant speed under the condition of a certain temperature and a certain negative pressure to evaporate the solvent.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the "characteristic peak” refers to a representative diffraction peak used for identifying crystals, and usually has an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • Form CSI, Form CSII, Form CSIV of the present invention are pure and substantially not mixed with any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the compound I as a starting material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as starting material is in solid form.
  • Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2007026097A1 document.
  • the inventors of the present application characterized the 1,4-dioxane solvate crystal form, chloroform solvate crystal form and tetrahydrofuran solvate crystal form obtained in the present application by TGA, DSC and 1 H NMR, and the results are shown in the table 4 shown.
  • Embodiment 2 The preparation method of crystal form CSI
  • Embodiment 3 The preparation method of crystal form CSI
  • the unit cell parameters of the crystal form CSI are obtained, as shown in Table 9, and the asymmetric unit of the crystal form CSI is shown in Figure 4.
  • the results show that the asymmetric unit of the crystal form CSI is composed of one compound I molecule, and the crystal form CSI is anhydrous.
  • Embodiment 5 The preparation method of crystal form CSII
  • samples 1-4 are all the crystal form CSII of the present invention.
  • sample 4 When sample 4 is heated to 180°C, it has a mass loss of about 2.2%, and its thermogravimetric analysis chart is shown in Figure 6 .
  • Sample 4 has an endothermic peak around 143°C, an exothermic peak around 151°C, and an endothermic peak around 177°C, and its DSC chart is shown in Fig. 7 .
  • Embodiment 6 The preparation method of crystal form CSII
  • the obtained crystalline solid is crystal form CSII, its XRPD pattern is shown in Figure 8, and its XRPD data is shown in Table 12.
  • Embodiment 7 The preparation method of crystal form CSIV
  • the obtained crystalline solid is the crystalline form CSIV described in the present invention.
  • the XRPD pattern of the crystal form CSIV of the present invention is shown in FIG. 9 , and the XRPD data is shown in Table 13.
  • the TGA of the crystalline form CSIV of the present invention is shown in Figure 10, and when it is heated to 120°C, it has a mass loss of about 0.06%.
  • Samples 1-2 were all amorphous by XRPD.
  • Open packaging put the sample in a glass vial, cover the bottle with a layer of aluminum foil and make 5-10 small holes in the aluminum foil.
  • Airtight packaging place the sample in a glass vial, seal the bottle with a cap, and seal it in an aluminum foil bag.
  • the crystalline form CSI can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSI can maintain good stability under both long-term and accelerated conditions. It can be stable for at least 3 months under the condition of 60°C/75%RH, and it can be seen that the stability is also very good under more severe conditions.
  • Example 10 Amorphous hygroscopicity
  • Example 8 Take an appropriate amount of the amorphous solid obtained in Example 8, use a dynamic moisture adsorption (DVS) instrument to test its hygroscopicity, cycle once under 0-95%-0 relative humidity, and record the mass change under each humidity.
  • the experimental results show that the hygroscopic weight gain of the amorphous is 0.94% and 1.18% under the conditions of 0-60%RH and 0-70%RH, respectively. .
  • the experimental results show that the hygroscopic weight gain of crystal form CSI is 0.17% under the conditions of 0-60% RH and 0-70% RH, and the amorphous of the prior art under the conditions of 0-60% RH and 0-70% RH
  • the wet weight gain was about 6 times and 7 times that of the crystalline form CSI, respectively.
  • the XRPD patterns of the crystal form CSI before and after the DVS test are shown in Figure 14. The results showed that the crystalline form of CSI remained unchanged after the DVS test.
  • Example 13 Particle size distribution of crystal form CSI
  • the fluidity evaluation results of the crystal form CSI are shown in Table 18, and the results show that the crystal form CSI has better fluidity.
  • Open packaging put the sample in a glass vial, cover the bottle with a layer of aluminum foil and make 5-10 small holes in the aluminum foil.
  • Airtight packaging place the sample in a glass vial, seal the bottle with a cap, and seal it in an aluminum foil bag.
  • the crystalline form CSII can be stable for at least 3 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSII can maintain good stability under both long-term and accelerated conditions. It can be stable for at least 1 month under 60°C/75%RH conditions, and it can be seen that the stability is also very good under more severe conditions.
  • the crystalline form CSII was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The XRPD images before and after grinding are shown in Figure 18. The results showed that the crystal form of CSII did not change after grinding.
  • the experimental results show that under the conditions of 0-60% RH and 0-70% RH, the weight gain of crystal form CSII is 0.21% and 0.27% respectively. About 4 times and 5 times the weight gain.
  • the XRPD patterns of the crystalline form CSII before and after the DVS test are shown in Figure 19. The results showed that the crystal form of CSII remained unchanged after the DVS test.
  • Open packaging put the sample in a glass vial, cover the bottle with a layer of aluminum foil and make 5-10 small holes in the aluminum foil.
  • Airtight packaging place the sample in a glass vial, seal the bottle with a cap, and seal it in an aluminum foil bag.
  • the crystalline form CSIV can be stable for at least 3 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSIV can maintain good stability under both long-term and accelerated conditions. It can be kept stable for at least 1 month under the condition of 60°C/75%RH, and it can be seen that the stability of crystalline form CSIV is also very good under more severe conditions.
  • the crystalline form CSIV was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The XRPD patterns before and after grinding are shown in Figure 23. The results show that the crystal form of CSIV does not change before and after grinding, and has good stability.

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Abstract

提供Lanifibranor(称为"化合物I")的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备泛PPAR激动剂药物和治疗非酒精性脂肪性肝炎药物中的用途。提供的化合物I的新晶型比现有技术具有一种或多种改进的性质，解决了现有技术存在的问题，对含化合物I药物的优化和开发具有重要价值。

Description

Lanifibranor的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及Lanifibranor的晶型及其制备方法和用途。
背景技术
非酒精性脂肪性肝炎(NASH)是一种严重的肝脏疾病，伴随有炎症及肝细胞损伤的脂肪变性现象。
过氧化物酶体增殖物激活受体(PPAR)是一种配体激活的转录因子，属于核激素受体家族，可调节基因的表达。PPAR在调节细胞分化，发育和肿瘤发生方面起着至关重要的作用。
Lanifibranor是一种口服小分子药物，可通过激活三种PPAR亚型(分别称为PPARα，PPARδ和PPARγ)诱导体内产生抗肝纤维化、抗炎作用并通过增强脂肪酸代谢最终减少脂肪生成来解决脂肪变性问题。
Lanifibranor的化学名称为5-氯-1-[(6-苯并噻唑基)磺酰基]-1H-吲哚-2-丁酸(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2021137078-appb-000001
晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的理化性质对生产过程至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。
无定形是不具有长程有序的非晶型材料，其X射线粉末衍射图通常表现为较宽的“馒头峰”。
现有技术WO2007026097A1实施例117公开化合物I的制备方法为：乙酸乙酯萃取白色沉淀，分离有机相，用硫酸镁干燥，减压浓缩，得到化合物I的淡黄色粉末(产率83％)。现有技术WO2019024776A1实施例3公开化合物I的制备方法为：用乙酸乙酯萃取白色沉淀，分离有机相，用硫酸镁干燥，减压浓缩，得到83mg化合物I的淡黄色固体。本申请发明人重复现有技术中公开的化合物I的制备方法，得到化合物I的无定形。本申请发明人对根据现有技术得到的无定形进行系统全面的研究后发现，无定形存在引湿增重大、有机溶剂残留量高、样品固体状态差、难以定量及转移损耗大的问题，不适合药用。
为克服现有技术的缺点，仍然需要一种符合药用标准的新晶型，以用于含化合物I药物的开发。本申请发明人意外得到了化合物I的1,4-二氧六环溶剂合物晶型、三氯甲烷溶剂合物晶 型、四氢呋喃溶剂合物晶型、无水晶型和水合物晶型。其中1,4-二氧六环溶剂合物晶型、三氯甲烷溶剂合物晶型和四氢呋喃溶剂合物晶型分别含有10.1wt％的1,4-二氧六环、3.3wt％的三氯甲烷和6.0wt％的四氢呋喃，不适合药用。本申请提供的化合物I的无水晶型和水合物晶型，其在溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是稳定性好、引湿性增重小、无溶剂残留、粒度分布均匀、流动性好、黏附性低、晶型的粉体分散性好，解决了现有技术存在的问题，对含化合物I的药物开发具有非常重要的意义。
发明内容
本发明提供化合物I的新晶型及其制备方法以及包含该新晶型的药物组合物。
进一步地，本发明提供化合物I的新晶型为水合物。
进一步地，本发明提供化合物I的新晶型为无水物。
进一步地，本发明提供化合物I的新晶型含有不高于5％质量分数的水。
进一步地，本发明提供化合物I的新晶型含有不高于3％质量分数的水。
进一步地，本发明提供化合物I的晶型为晶型CSI(以下称作“晶型CSI”)。
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为20.2°±0.2°、22.2°±0.2°、24.5°±0.2°中的1处，或2处，或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为20.2°±0.2°、22.2°±0.2°、24.5°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为7.7°±0.2°、17.8°±0.2°、21.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为7.7°±0.2°、17.8°±0.2°、21.2°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为10.9°±0.2°、16.4°±0.2°、19.1°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ为10.9°±0.2°、16.4°±0.2°、19.1°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为20.2°±0.2°、22.2°±0.2°、24.5°±0.2°、7.7°±0.2°、17.8°±0.2°、21.2°±0.2°、10.9°±0.2°、16.4°±0.2°、19.1°±0.2°、25.3°±0.2°、14.0°±0.2°、15.6°±0.2°、17.0°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处、或10、或11处、或12处、或13处有特征峰。
非限制性地，晶型CSI的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSI加热至170℃具有约0.02％的质量损失，热重分析图如图2所示。
非限制性地，晶型CSI为无水物。
非限制性地，晶型CSI的单晶数据如表1所示。
表1
Figure PCTCN2021137078-appb-000002
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括:
方法1：将化合物I固体置于醇类溶剂或醚类溶剂中搅拌，分离，得到晶型CSI；或
方法2：将化合物I固体溶解于醚类溶剂或烃类溶剂，取澄清溶液挥发得到晶型CSI。
进一步地，方法1中：所述醇类优选C1-C8的醇，更优选甲醇；所述醚类优选C4-C7的醚，更优选甲基叔丁基醚；所述搅拌时间优选至少10分钟。
进一步地，方法2中：所述醚类优选C4-C7的醚，更优选2-甲基四氢呋喃；所述烃类优选C5-C8的烃，更优选芳香烃，更优选甲苯。
根据本发明的目的，本发明提供的化合物I的晶型CSII(以下称作“晶型CSII”)
一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.4°±0.2°、22.4°±0.2°、25.3°±0.2°中的1处，或2处，或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.4°±0.2°、22.4°±0.2°、25.3°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.9°±0.2°、13.2°±0.2°、20.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为7.9°±0.2°、13.2°±0.2°、20.6°±0.2°中的3处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为9.7°±0.2°、23.1°±0.2°、24.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ为9.7°±0.2°、23.1°±0.2°、24.2°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.4°±0.2°、22.4°±0.2°、25.3°±0.2°、7.9°±0.2°、13.2°±0.2°、20.6°±0.2°、9.7°±0.2°、23.1°±0.2°、 24.2°±0.2°、26.3°±0.2°、14.4°±0.2°、16.8°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处、或10、或11处、或12处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.5°±0.2°、22.4°±0.2°、25.5°±0.2°、7.9°±0.2°、13.2°±0.2°、20.7°±0.2°、9.8°±0.2°、23.2°±0.2°、24.2°±0.2°、26.4°±0.2°、14.4°±0.2°、16.9°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处、或10、或11处、或12处有特征峰。
非限制性地，晶型CSII的X射线粉末衍射图基本如图5所示。
非限制性地，晶型CSII的热重分析图如图6所示，其加热至180℃时，具有约2.2％的质量损失。
非限制性地，晶型CSII在143℃附近存在吸热峰，在151℃附近存在放热峰，在177℃附近开始出现吸热峰，其差式扫描量热分析图基本如图7所示。
非限制性地，晶型CSII为水合物。
根据本发明的目的，本发明还提供所述晶型CSII的制备方法，所述制备方法包括：
将化合物I固体置于醇类、酮类或醚类和腈类的混合溶剂中，取澄清溶液挥发得到晶型CSII。
进一步地，所述醇类优选C1-C8的醇，所述酮类优选C3-C6的酮，所述醚类优选C4-C7的醚，所述腈类优选C2-C4的腈。
进一步地，所述醇类优选甲醇和/或正丙醇，所述酮类优选甲基乙基酮，所述醚类优选四氢呋喃，所述腈类优选乙腈。
进一步地，所述混合溶剂中醚类和腈类的体积比优选10:1-1:10。
根据本发明的目的，本发明提供化合物I的晶型CSIV(以下称作“晶型CSIV”)。
一方面，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为11.4°±0.2°、24.7°±0.2°、25.8°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为15.3°±0.2°、20.1°±0.2°、27.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIV的X射线粉末衍射图在衍射角2θ为15.3°±0.2°、20.1°±0.2°、27.6°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为8.9°±0.2°、15.9°±0.2°、20.9°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIV的X射线粉末衍射图在衍射角2θ为8.9°±0.2°、15.9°±0.2°、20.9°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为11.4°±0.2°、24.7°±0.2°、25.8°±0.2°、15.3°±0.2°、20.1°±0.2°、27.6°±0.2°、8.9°±0.2°、15.9°±0.2°、20.9°±0.2°、7.3°±0.2°、9.4°±0.2°、11.7°±0.2°、17.8°±0.2°、18.8°±0.2°、24.3°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处、或10、或11处、或12、或13、或14、或15处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSIV的X射线粉末衍射图基本如图9所示。
非限制性地，晶型CSIV的热重分析图基本如图10所示，其加热至120℃具有约0.06％的质量损失。
非限制性地，晶型CSIV为无水物。
根据本发明的目的，本发明还提供所述晶型CSIV的制备方法，所述制备方法包括：
将化合物I游离态固体加热至180℃-200℃后，降温至室温，将所得固体继续加热至一定温度后，降温至室温得到晶型CSIV。
进一步地，所述一定温度优选120℃-160℃。
根据本发明的目的，本发明提供晶型CSI、晶型CSII、晶型CSIV或以上晶型的任意混合用于制备化合物I其他晶型或盐的用途。
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的化合物I的晶型及药学上可接受的辅料。
进一步地，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI、晶型CSII、晶型CSIV或以上晶型的任意混合及药学上可接受的辅料。
根据本发明的目的，本发明提供化合物I的晶型在制备泛PPAR激动剂药物中的用途。
进一步地，本发明提供晶型CSI、晶型CSII、晶型CSIV，或它们的任意混合在制备泛PPAR激动剂药物中的用途。
根据本发明的目的，本发明提供化合物I的晶型在制备治疗非酒精性脂肪性肝炎药物中的用途。
进一步地，本发明提供晶型CSI、晶型CSII、晶型CSIV，或它们的任意混合在制备治疗非酒精性脂肪性肝炎药物中的用途。
本发明解决的技术问题
本申请发明人通过研究现有技术公开的制备方法得到的无定形后发现，无定形的引湿增重大，化学稳定性差，不利于生产；有机溶剂残留量远超出药典规定的溶剂残留限度，毒性高。为了解决现有技术存在的问题，本申请发明人进行了超过600次实验，尝试在不同溶剂体系中通过打浆、挥发、气液扩散、气固扩散、湿度诱导、反溶剂添加和加热等方法，最终意外获得了本发明提供的化合物I的晶型。
有益效果
本发明提供的晶型CSI具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSI具有更低的引湿性。测试结果表明，现有技术无定形在0-60％RH和0-70％RH条件下的引湿增重分别是本申请晶型CSI引湿增重的约6倍和7倍。晶型CSI在0-60％RH条件和0-70％RH条件下引湿性增重均为0.17％，现有技术无定形在0-60％RH条件和0-70％RH条件下引湿增重分别为0.94％和1.18％。
一方面，高引湿性易引起原料药发生化学降解和晶型转变，从而直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，从而影响原料药的加工工艺。
另一方面，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSI引湿性低，对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(2)本发明提供的晶型CSI具有较好的粉体外观。本发明提供的晶型CSI粉体分散性好，有利于工业生产中的转移以及降低物料损失。
(3)本发明提供的晶型CSI原料药具有良好的稳定性。晶型CSI原料药在25℃/60％RH条件下敞口包装和密封包装放置，至少6个月晶型未发生变化，储存过程中纯度基本保持不变。说明晶型CSI原料药在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CSI原料药在40℃/75％RH条件下密封包装放置和敞口包装放置至少6个月晶型未发生变化，储存过程中纯度基本保持不变；在60℃/75％RH条件下密封放置和敞口放置至少3月晶型未发生变化，储存过程中纯度基本保持不变。说明晶型CSI原料药在加速条件及更严苛的条件下，具有较好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSI原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
(4)本发明提供的晶型CSI具有均匀的粒度分布。均匀的粒度有助于保证含量均匀度，降低体外溶出度的变异性。
(5)本发明提供的晶型CSI具有良好的流动性。更好的流动性可以避免堵塞生产设备，提升生产效率；保证制剂的含量均匀度、降低重量差异，提升产品质量。
(6)本发明提供的晶型CSI具有较优的黏附性。较优的黏附性能有效减少原料药的团聚，能有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于原料的分散及与辅料的混合，提高物料混合时的混合均匀度，最终提高产品质量。
本发明提供的晶型CSII具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSII具有更低的引湿性。测试结果表明，现有技术无定形在0-60％RH和0-70％RH条件下的引湿增重分别是本申请晶型CSII引湿增重的约4倍和5倍。晶型CSII在0-60％RH条件和0-70％RH条件下引湿性增重分别为0.21％和0.27％，现有技术无定形在0-60％RH条件和0-70％RH条件下引湿增重分别为0.94％和1.18％。
一方面，高引湿性易引起原料药发生化学降解和晶型转变，从而直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，从而影响原料药的加工工艺。
另一方面，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSII引湿性低，对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(2)本发明提供的晶型CSII具有较好的粉体外观。本发明提供的晶型CSII粉体分散性好，有利于工业生产中的转移以及降低物料损失。
(3)本发明提供的晶型CSII原料药具有良好的稳定性。晶型CSII原料药在25℃/60％RH条件下密封包装和敞口包装放置，至少3个月晶型未发生变化，储存过程中纯度基本保持不变。说明晶型CSI原料药在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CSII原料药在40℃/75％RH条件下密封包装和敞口包装放置至少3个月晶型未发生变化，储存过程中纯度基本保持不变。在60℃/75％RH条件下敞口放置至少1月晶型未发生变化，储存过程中纯度基本保持不变。说明晶型CSII原料药在加速条件及更严苛的条件下，具有较好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影 响原料药的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSII原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
同时，晶型CSII具有良好的机械稳定性。晶型CSII原料药压片及研磨后具有良好的物理稳定性。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。在不同压力下，晶型CSII原料药均具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
(4)本发明提供的晶型CSII具有较优的黏附性。更优的黏附性能有效减少原料药的团聚，能有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于原料的分散及与辅料的混合，提高物料混合时的混合均匀度，最终提高产品质量。
本发明提供的晶型CSIV具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型CSIV具有更低的引湿性。测试结果表明，现有技术无定形在0-60％RH和0-70％RH条件下的引湿增重分别是本申请晶型CSIV引湿增重的约4倍。晶型CSIV在0-60％RH条件和0-70％RH条件下引湿性增重分别为0.23％和0.27％，现有技术无定形在0-60％RH条件和0-70％RH条件下引湿增重分别为0.94％和1.18％。
一方面，高引湿性易引起原料药发生化学降解和晶型转变，从而直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，从而影响原料药的加工工艺。
另一方面，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
本发明提供的晶型CSIV引湿性低，对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。
(2)与现有技术相比，本发明提供的晶型CSIV无有机溶剂残留。晶型CSIV无有机溶剂残留，而现有技术无定形含有2.70％的乙酸乙酯溶剂，其远远超出药典中规定的残留溶剂限度(0.5％)。乙酸乙酯对中枢神经系统有毒副作用，长期接触会导致结膜刺激和角膜混浊，甚至引起肝脏和肾脏充血。与现有技术无定形相比，晶型CSIV的制备无需使用任何溶剂，无溶剂残留，不仅可降低原料药因溶剂残留带来的药物毒性作用，还能降低生产成本。
(3)本发明提供的晶型CSIV具有较好的粉体外观。本发明提供的晶型CSIV粉体分散性好，有利于工业生产中的转移以及降低物料损失。
(4)本发明提供的晶型CSIV原料药具有良好的稳定性。晶型CSIV原料药在25℃/60％RH条件下密封包装和敞口包装放置，至少3个月晶型未发生变化，储存过程中纯度基本保持不变。说明晶型CSI原料药在长期条件下具有较好的稳定性，有利于药物的储存。
同时，晶型CSIV原料药在40℃/75％RH条件下密封包装和敞口包装放置至少3个月晶型未发生变化，储存过程中纯度基本保持不变。在60℃/75％RH条件下密封包装和敞口包装放置至少1月晶型未发生变化，储存过程中纯度基本保持不变。说明晶型CSIV原料药在加速条件及更严苛的条件下，具有较好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSIV原料药在苛刻的条件下具有更好的稳定性，有利 于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
同时，晶型CSIV具有良好的机械稳定性。晶型CSIV原料药压片及研磨后具有良好的物理稳定性。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。在不同压力下，晶型CSIV原料药均具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
(5)本发明提供的晶型CSIV具有较优的黏附性。更优的黏附性能有效减少原料药的团聚，能有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于原料的分散及与辅料的混合，提高物料混合时的混合均匀度，最终提高产品质量。
附图说明
图1为实施例2所得晶型CSI的XRPD图
图2为实施例2所得晶型CSI的TGA图
图3为实施例3所得晶型CSI的XRPD图
图4为实施例4所得晶型CSI单晶结构中一个不对称单元结构图
图5为实施例5所得晶型CSII的XRPD图
图6为实施例5所得晶型CSII的TGA图
图7为实施例5所得晶型CSII的DSC图
图8为实施例6所得晶型CSII的XRPD图
图9为实施例7所得晶型CSIV的XRPD图
图10为实施例7所得晶型CSIV的TGA图
图11为实施例8所得无定形的XRPD图
图12为实施例8所得无定形的TGA图
图13为晶型CSI在不同放置条件下放置前后的XRPD对比图(从上至下依次为：放置前，25℃/60％RH敞口包装放置6个月，25℃/60％RH密封包装放置6个月，40℃/75％RH敞口包装放置6个月，40℃/75％RH密封包装放置6个月，60℃/75％RH敞口包装放置3个月，60℃/75％RH密封包装放置3个月)
图14为晶型CSI在DVS前后的XRPD叠图(上：测试前，下：测试后)
图15为晶型CSI的粉体外观
图16为晶型CSII在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，25℃/60％RH敞口包装放置3个月，25℃/60％RH密封包装放置3个月，40℃/75％RH敞口包装放置3个月，40℃/75％RH密封包装放置3个月，60℃/75％RH敞口包装放置1个月。)
图17为晶型CSII压片前后的XRPD叠图(从上到下依次为：压片前，5kN，10kN，20kN)
图18为晶型CSII研磨前后的XRPD叠图(上：研磨前，下：研磨后)
图19为晶型CSII在DVS测试前后的XRPD叠图(上：测试前，下；测试后)
图20为晶型CSII的粉体外观
图21为晶型CSIV在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，25℃/60％RH敞口包装放置3个月，25℃/60％RH密封包装放置3个月，40℃/75％RH敞口包装放置3个月，40℃/75％RH密封包装放置3个月，60℃/75％RH敞口包装放置1个 月，60℃/75％RH密封包装放置1个月。)
图22为晶型CSIV压片前后的XRPD叠图(从上到下依次为：压片前，5kN，10kN，20kN)
图23为晶型CSIV研磨前后的XRPD叠图(上：研磨前，下：研磨后)
图24为晶型CSIV在DVS测试前后的XRPD叠图(上：测试前，下：测试后)
图25为晶型CSIV的粉体外观
具体实施方式
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
TGA：热重分析
DSC：差示扫描量热分析
1H NMR：液态核磁氢谱
DVS：动态水分吸附
PSD：粒度分布
HPLC：高效液相色谱
RH：相对湿度
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Bruker X射线粉末衍射仪上采集。所述X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Figure PCTCN2021137078-appb-000003
1.54060；
Figure PCTCN2021137078-appb-000004
1.54439
Kα2/Kα1强度比例：0.50
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DSC的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M Hz核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2，200毫升/分钟
相对湿度范围：0％RH-95％RH
本发明所述的单晶X射线衍射(SC-XRD)使用配有CMOS区域探测器和Cu/Kα放射
Figure PCTCN2021137078-appb-000005
的微焦斑封闭X射线发生器的Agilent Gemini A衍射器收集单晶X射线数据。在数据收集时，所述单晶处在293(2)K。
本发明有关物质检测方法如表2所示。
表2
Figure PCTCN2021137078-appb-000006
本发明中所述的粒度分布结果是在Malvern公司的Mastersizer 3000型激光粒度分析仪上采集。本测试采用湿法，湿法测试使用Hydro MV分散装置，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如表3所示。
表3
粒度分布：体积分布 采集时间：10秒
分散介质：Isopar G 颗粒形状：非球形
采集次数：3次 分散介质折射率：1.42
吸收率：0.1 超声功率/时间：30瓦/30秒
颗粒折射率：1.52 转速：2000rpm
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“减压浓缩”，采用本领域的常规方法完成，例如减压浓缩的操作是：将装有溶液的烧瓶在一定温度，一定负压的条件下恒速旋转以蒸发溶剂。
所述“室温”不是特定的温度值，是指10-30℃温度范围。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，通常可以有±0.2°的误差。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSI、晶型CSII、晶型CSIV是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物I包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I为固体形式。
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2007026097A1文献所记载的方法制备获得。
实施例1 化合物I溶剂合物晶型的表征
本申请发明人通过TGA、DSC、 1H NMR表征本申请得到的1,4-二氧六环溶剂合物晶型、三氯甲烷溶剂合物晶型和四氢呋喃溶剂合物晶型，结果如表4所示。
表4
Figure PCTCN2021137078-appb-000007
快速挥发：敞口挥发。
慢速挥发：用铝箔封容器口，扎孔，静置挥发。
实施例2 晶型CSI的制备方法
根据表5，称取一定质量的化合物I固体于玻璃瓶中，加入0.3mL溶剂，室温搅拌，分离，将得到的固体分别标记为样品1-2。经检测，样品1-2均为本发明所述晶型CSI。
样品1的XRPD图如图1所示，XRPD数据如表6所示。
样品1加热至170℃时，具有约0.02％的质量损失，TGA图如图2所示。
样品1的 1H NMR数据为： 1H NMR(400MHz,DMSO)δ12.13(s,1H),9.66(s,1H),8.97(d,J＝1.8Hz,1H),8.20(d,J＝8.7Hz,1H),8.09(d,J＝8.9Hz,1H),7.85(dd,J＝8.7,1.9Hz,1H),7.58(d,J＝2.0Hz,1H),7.32(dd,J＝8.9,2.1Hz,1H),6.62(s,1H),3.09(t,J＝7.4Hz,2H),2.36(t,J＝7.3Hz,2H),1.99–1.90(m,2H)。
表5
样品 化合物I质量(mg) 溶剂(v/v) 搅拌时间 晶型
1 11.4 乙醇 24小时 晶型CSI
2 10.1 甲基叔丁基醚 2小时 晶型CSI
表6
Figure PCTCN2021137078-appb-000008
Figure PCTCN2021137078-appb-000009
实施例3 晶型CSI的制备方法
根据表7，称取一定质量的化合物I固体于玻璃瓶中，加入一定体积的溶剂，溶解，挥 发，将得到的固体分别标记为样品1-2。经检测，样品1-2均为本发明所述晶型CSI。
样品1的XRPD图如图3所示，XRPD数据如表8所示。
表7
Figure PCTCN2021137078-appb-000010
表8
Figure PCTCN2021137078-appb-000011
Figure PCTCN2021137078-appb-000012
实施例4 晶型CSI的单晶制备
将375.9mg的化合物I固体溶于22mL的丙酮中，过滤，取10mL的滤液，向其中加入10mL乙腈，过滤，取3.2mL的滤液于室温挥发9天，得到晶型CSI的单晶。
经X射线单晶衍射测试和解析，得到晶型CSI的晶胞参数，如表9所示，晶型CSI的不对称单元如图4所示。结果表明：晶型CSI的不对称单元由1个化合物I分子构成，晶型CSI为无水物。
表9
Figure PCTCN2021137078-appb-000013
实施例5 晶型CSII的制备方法
根据表10，称取一定质量的化合物I固体于玻璃瓶中，加入一定体积的溶剂，取一定体积的澄清溶液在50℃挥发，得到固体，分别标记为样品1-4。经检测，样品1-4均为本发明所述晶型CSII。
样品4的XRPD图如图5所示，XRPD数据如表11所示。
样品4加热至180℃时，具有约2.2％的质量损失，其热重分析图如图6所示。
样品4在143℃附近存在吸热峰，在151℃附近存在放热峰，在177℃附近存在吸 热峰，其DSC图如图7所示。
表10
序号 化合物I质量(mg) 溶剂 溶剂体积(mL) 澄清溶液体积(mL) 晶型
1 5.0 甲醇 3.6 3.6 晶型CSII
2 4.6 正丙醇 3.6 3.6 晶型CSII
3 24.6 甲基乙基酮 2 1.0 晶型CSII
4 28.7 甲醇 21 3.5 晶型CSII
表11
Figure PCTCN2021137078-appb-000014
Figure PCTCN2021137078-appb-000015
实施例6 晶型CSII的制备方法
称取112.4mg的化合物I固体置于玻璃小瓶中，向其中加入5mL的四氢呋喃和5mL的乙腈，过滤，取1.5mL的滤液于室温挥发2天，得到固体。将所得固体在50℃真空干燥2周，得到结晶固体。
经XRPD检测，所得结晶固体为晶型CSII，其XRPD图如图8所示，其XRPD数据如表12所示。
表12
Figure PCTCN2021137078-appb-000016
Figure PCTCN2021137078-appb-000017
实施例7 晶型CSIV的制备方法
称量609.9mg化合物I固体，置于真空烘箱中加热至185℃后，降温至室温，得到固体。称取19.58mg该固体置于坩埚中，将其加热至140℃后，降温至室温，得到结晶固体。
经XRPD检测，所得结晶固体为本发明所述晶型CSIV。
本发明所述晶型CSIV的XRPD图如图9所示，XRPD数据如表13所示。
本发明所述晶型CSIV的TGA如图10所示，将其加热至120℃时，具有约0.06％的质量损失。
晶型CSIV的核磁数据为： 1H NMR(400MHz,DMSO-d 6)δ12.12(s,1H),9.65(s,1H),8.97(d,J＝1.9Hz,1H),8.20(d,J＝8.7Hz,1H),8.09(d,J＝8.9Hz,1H),7.84(dd,J＝8.7,2.1Hz,1H),7.57(d,J＝2.1Hz,1H),7.31(dd,J＝8.9,2.2Hz,1H),6.62(s,1H),3.08(t,J＝7.4Hz,2H),2.36(t,J＝7.3Hz,2H),2.00–1.88(m,2H)。由核磁数据可知，晶型CSIV无溶剂残留。
表13
Figure PCTCN2021137078-appb-000018
Figure PCTCN2021137078-appb-000019
实施例8 重复现有技术披露的化合物I制备方法
根据表14，取一定体积的乙酸乙酯溶解一定量的化合物I固体，溶清，过滤。取一定体积的滤液，在一定温度下减压浓缩得到固体，分别标记为样品1-2。
表14
Figure PCTCN2021137078-appb-000020
经XRPD检测，样品1-2均为无定形。
样品1的XRPD图如图11所示。
样品1的TGA图如图12所示，结果表明，加热至200℃时，样品1具有约5.3％的质量损失。
样品1的 1H NMR数据为： 1H NMR(400MHz,DMSO-d6)δ(ppm)12.11(s,1H)，9.65(s,1H)，8.97(d,J＝2.0Hz,1H)，8.20(d,J＝8.8Hz,1H)，8.09(d,J＝8.9Hz,1H)，7.84(dd,J＝8.7,2.1Hz,1H)，7.57(d,J＝2.1Hz,1H)，7.31(dd,J＝8.9,2.3Hz,1H)，6.61(s,1H)，3.08(t,J＝14.8Hz,1H)，2.36(t,J＝7.3Hz,2H)，1.97–1.90(m,2H)，其中乙酸乙酯的核磁共振信号为(δ(ppm)4.03(q,J＝7.1Hz),1.17(t,J＝7.1Hz,0.58H))。核磁结果表明，现有技术无定形含2.70wt％的乙酸乙酯。
实施例9 晶型CSI的物理化学稳定性
取一定量本发明制备得到的晶型CSI，分别置于25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表15所示，XRPD对 比图如图13所示。
表15
Figure PCTCN2021137078-appb-000021
敞口包装：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开5-10个小孔。
密封包装：将样品置于玻璃小瓶中，瓶口使用瓶盖密封，最后密封于铝箔袋中。
结果表明，晶型CSI在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，可见，晶型CSI在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定3个月，可见在更严苛的条件下稳定性也很好。
实施例10 无定形的引湿性
取适量上述实施例8得到的无定形固体，采用动态水分吸附(DVS)仪测试其引湿性，在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化。实验结果表明，无定形在0-60％RH和0-70％RH条件下引湿性增重分别为0.94％和1.18％。。
实施例11 晶型CSI的引湿性
取适量晶型CSI采用动态水分吸附(DVS)仪测试其引湿性，在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化。
实验结果表明，晶型CSI在0-60％RH和0-70％RH条件下引湿性增重为0.17％，现有技术无定形在0-60％RH和0-70％RH条件下的引湿增重分别是晶型CSI引湿增重的约6倍和7倍。晶型CSI在DVS测试前后XRPD图如图14所示。结果表明，晶型CSI在DVS测试后晶型保持不变。
实施例12 晶型CSI的粉体外观
取适量晶型CSI，置于称量纸上，观察其粉体状态。晶型CSI的外观如图15所示。由结果可知，晶型CSI呈粉末状，分散均匀，无黏附现象。
实施例13 晶型CSI的粒度分布
取适量制备得到的晶型CSI，加入一定量Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入Hydro MV分散装置中，使遮光度达到合适范围，开始实验，超声30秒后进行粒度分布的测试。测试结果如表16所示。
表16
晶型 MV(μm) D10(μm) D50(μm) D90(μm)
晶型CSI 4.54 0.725 1.89 7.15
结果表明，晶型CSI的粒径较小且分布均匀。
实施例14 晶型CSI的流动性
制剂工艺过程中，通常可采用可压性系数(Compressibility index)来评价粉体或颗粒的流动性，测定方法为将一定量的粉体轻轻装入量筒后测量振实前体积；采用轻敲法使粉体处于最紧状态，测量振实后体积；计算松密度ρ 0与振实密度ρ f；根据公式c＝(ρ f－ρ 0)/ρ f计算可压性系数。
可压性系数对粉体流动性的界定标准参考ICH Q4B附录13，详见表17。
表17
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型CSI的流动性评价结果见表18，结果表明晶型CSI具有较好的流动性。
表18
晶型 堆密度(g/mL) 振实密度(g/mL) 流动性
CSI 0.405 0.526 可接受
实施例15 晶型CSI的黏附性
将约30mg晶型CSI加入到8mm圆形平冲中，采用ENERPAC手动压片机，10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录压制过程中冲头的平均黏附量。实验结果表明，晶型CSI的平均黏附量为0.45mg。
实施例16 晶型CSII的物理化学稳定性
取一定量本发明制备得到的晶型CSII，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用HPLC和XRPD法测定纯度与晶型。结果如表19所示，XRPD对比图如图16所示。
表19
Figure PCTCN2021137078-appb-000022
敞口包装：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开5-10个小孔。
密封包装：将样品置于玻璃小瓶中，瓶口使用瓶盖密封，最后密封于铝箔袋中。
结果表明，晶型CSII在25℃/60％RH和40℃/75％RH条件下至少可稳定3个月，可见，晶型CSII在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定1个月，可见在更严苛的条件下稳定性也很好。
实施例17 晶型CSII的机械稳定性
取适量晶型CSII选择合适的压片模具，在不同压力下压制成形，压片前后进行XRPD测试，测试结果如表20所示，压片前后XRPD图如图17所示。结果表明，在不同的压力下，晶型CSII均具有较好的稳定性。
表20
Figure PCTCN2021137078-appb-000023
将晶型CSII置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，研磨前后XRPD图如图18所示。结果表明，研磨后，晶型CSII未发生变化。
实施例18 晶型CSII的引湿性
取适量晶型CSII，采用动态水分吸附(DVS)仪测试其引湿性，DVS湿度区间：50％RH-95％RH-0％-95％RH。
实验结果表明，晶型CSII在0-60％RH和0-70％RH条件下引湿增重分别为0.21％和0.27％，现有技术无定形的引湿增重约是晶型CSII引湿增重的约4倍和5倍。晶型CSII在DVS测试前后的XRPD图如图19所示。结果表明，晶型CSII在DVS测试后晶型保持不变。
实施例19 晶型CSII的粉体外观
取适量晶型CSII，置于称量纸上，观察其粉体状态。晶型CSII的外观如图20所示。由结果可知，晶型CSII呈粉末状，分散均匀，无黏附现象。
实施例20 晶型CSII的黏附性
将约30mg晶型CSII加入到8mm圆形平冲中，采用ENERPAC手动压片机，10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录压制过程中冲头的平均黏附量。结果表明，晶型CSII的平均黏附量为0.20mg。
实施例21 晶型CSIV的物理化学稳定性
取一定量本发明制备得到的晶型CSIV，分别置于25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用HPLC和XRPD法测定纯度与晶型。结果如表21所示，XRPD对比图如图21所示。
表21
Figure PCTCN2021137078-appb-000024
Figure PCTCN2021137078-appb-000025
敞口包装：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开5-10个小孔。
密封包装：将样品置于玻璃小瓶中，瓶口使用瓶盖密封，最后密封于铝箔袋中。
结果表明，晶型CSIV在25℃/60％RH和40℃/75％RH条件下至少可稳定3个月，可见，晶型CSIV在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定1个月，可见晶型CSIV在更严苛的条件下稳定性也很好。
实施例22 晶型CSIV的机械稳定性
取适量晶型CSIV选择合适的压片模具，在不同压力下压制成形，压片前后进行XRPD测试，测试结果如表22所示，压片前后XRPD图如图22所示。结果表明，在不同的压力下，晶型CSIV均具有较好的稳定性。
表22
Figure PCTCN2021137078-appb-000026
将晶型CSIV置于研钵中，手动研磨5分钟，研磨前后进行XRPD测试，研磨前后XRPD图如图23所示。结果表明，晶型CSIV研磨前后晶型未发生变化，具有较好的稳定性。
实施例23 晶型CSIV的引湿性
分别取适量晶型CSIV及现有技术无定形，采用动态水分吸附(DVS)仪测试其引湿性，在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化。
实验结果表明，晶型CSIV在0-60％RH和0-70％RH条件下引湿性增重分别为0.23％和0.27％，现有技术无定形的引湿增重约是晶型CSIV引湿增重的4倍。晶型CSIV在DVS测试前后的XRPD图如图24所示。结果表明，晶型CSIV在DVS测试前后晶型保持不变。
实施例24 晶型CSIV的粉体外观
取适量晶型CSIV，置于称量纸上，观察其粉体状态。晶型CSIV的外观如图25所示。由结果可知，晶型CSIV呈粉末状，分散均匀，无黏附现象。
实施例25 晶型CSIV的黏附性
将约30mg晶型CSIV加入到8mm圆形平冲中，采用ENERPAC手动压片机，10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录压制过程中冲头的平均黏附量。实验结果表明，晶型CSIV的平均黏附量为0.05mg。
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 (30)

  1. 一种化合物I的晶型
    Figure PCTCN2021137078-appb-100001
  2. 根据权利要求1所述的化合物I的晶型，其特征在于，含有不高于5％质量分数的水。
  3. 根据权利要求1所述的化合物I的晶型，其特征在于，含有不高于3％质量分数的水。
  4. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为20.2°±0.2°、22.2°±0.2°、24.5°±0.2°中的至少一处具有特征峰。
  5. 根据权利要求4所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.7°±0.2°、17.8°±0.2°、21.2°±0.2°中的至少一处具有特征峰。
  6. 根据权利要求4所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为10.9°±0.2°、16.4°±0.2°、19.1°±0.2°中的至少一处具有特征峰。
  7. 根据权利要求5所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为10.9°±0.2°、16.4°±0.2°、19.1°±0.2°中的至少一处具有特征峰。
  8. 根据权利要求4所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。
  9. 权利要求4所述的化合物I的晶型，其特征在于，其制备方法为：
    (1)将化合物I固体置于醇类溶剂或醚类溶剂中搅拌，分离得到晶型；或
    (2)将化合物I固体溶解于醚类溶剂或烃类溶剂，取澄清溶液挥发得到晶型。
  10. 根据权利要求9所述的制备方法，其特征在于，方法(1)中，所述醇类为C1-C8的醇，所述醚类为C4-C7的醚，所述搅拌时间为至少10分钟；方法(2)中，所述醚类为C4-C7的醚，所述烃类为C5-C8的烃。
  11. 根据权利要求9所述的制备方法，其特征在于，方法(1)中，所述醇类为甲醇，所述醚类为甲基叔丁基醚；方法(2)中，所述醚类为2-甲基四氢呋喃，所述烃类为甲苯。
  12. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.4°±0.2°、22.4°±0.2°、25.3°±0.2°中的至少一处具有特征峰。
  13. 根据权利要求12所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.9°±0.2°、13.2°±0.2°、20.6°±0.2°中的至少一处具有特征峰。
  14. 根据权利要求12所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为9.7°±0.2°、23.1°±0.2°、24.2°±0.2°中的至少一处具有特征峰。
  15. 根据权利要求13所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为9.7°±0.2°、23.1°±0.2°、24.2°±0.2°中的至少一处具有特征峰。
  16. 根据权利要求12所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图5所示。
  17. 权利要求12所述的化合物I的晶型，其特征在于，其制备方法为：
    将化合物I固体置于醇类、酮类或醚类和腈类的混合溶剂中，取澄清溶液挥发得到晶型。
  18. 根据权利要求17所述的制备方法，其特征在于，所述醇类为C1-C8的醇，所述酮类为C3-C6的酮，所述醚类为C4-C7的醚，所述腈类为C2-C4的腈。
  19. 根据权利要求17所述的制备方法，其特征在于，所述醇类为甲醇、正丙醇；所述酮类为甲基乙基酮，所述醚类为四氢呋喃，所述腈类为乙腈。
  20. 根据权利要求17所述的制备方法，其特征在于，所述混合溶剂中醚类和腈类的体积比为10:1-1:10。
  21. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为11.4°±0.2°、24.7°±0.2°、25.8°±0.2°处具有特征峰。
  22. 根据权利要求21所述的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为15.3°±0.2°、20.1°±0.2°、27.6°±0.2°的至少一处具有特征峰。
  23. 根据权利要求21所述的晶型。其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.9°±0.2°、15.9°±0.2°、20.9°±0.2°的至少一处具有特征峰。
  24. 根据权利要求22所述的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.9°±0.2°、15.9°±0.2°、20.9°±0.2°的至少一处具有特征峰。
  25. 根据权利要求21所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图9所示。
  26. 根据权利要求21所述的化合物I的晶型，其特征在于，其制备方法为：
    将化合物I固体加热至180℃-200℃，自然降温至室温，降温后的固体再次加热至一定温度后，自然降温至室温得到晶型。
  27. 根据权利要求26所述的制备方法，其特征在于，所述一定温度为120℃-160℃。
  28. 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所述的化合物I的晶型及药学上可接受的辅料。
  29. 权利要求1所述的化合物I的晶型在制备泛PPAR激动剂药物中的用途。
  30. 权利要求1所述的化合物I的晶型在制备治疗非酒精性脂肪性肝炎药物中的用途。
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