WO2022258060A1 - Forme cristalline de lanifibranor et son procédé de préparation - Google Patents
Forme cristalline de lanifibranor et son procédé de préparation Download PDFInfo
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- WO2022258060A1 WO2022258060A1 PCT/CN2022/098241 CN2022098241W WO2022258060A1 WO 2022258060 A1 WO2022258060 A1 WO 2022258060A1 CN 2022098241 W CN2022098241 W CN 2022098241W WO 2022258060 A1 WO2022258060 A1 WO 2022258060A1
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- Prior art keywords
- crystal form
- lanifibranor
- crystal
- solvent
- crystalline form
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- 239000013078 crystal Substances 0.000 title claims abstract description 256
- 229940126032 IVA-337 Drugs 0.000 title claims abstract description 130
- OQDQIFQRNZIEEJ-UHFFFAOYSA-N 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloroindol-2-yl]butanoic acid Chemical compound C1=C2N=CSC2=CC(S(=O)(=O)N2C3=CC=C(Cl)C=C3C=C2CCCC(=O)O)=C1 OQDQIFQRNZIEEJ-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000007787 solid Substances 0.000 claims abstract description 75
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 89
- 238000001228 spectrum Methods 0.000 claims description 77
- 239000002904 solvent Substances 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000002994 raw material Substances 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 20
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 3
- 239000004800 polyvinyl chloride Substances 0.000 claims description 3
- 239000005456 alcohol based solvent Substances 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 239000003759 ester based solvent Substances 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 239000005453 ketone based solvent Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000011161 development Methods 0.000 abstract description 3
- 238000002411 thermogravimetry Methods 0.000 description 38
- -1 Lanifibranor compound Chemical class 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000000113 differential scanning calorimetry Methods 0.000 description 26
- 238000012360 testing method Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 230000004580 weight loss Effects 0.000 description 21
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 9
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 7
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
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- 208000019425 cirrhosis of liver Diseases 0.000 description 2
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- 229960003943 hypromellose Drugs 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
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- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 206010019837 Hepatocellular injury Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 229940126033 PPAR agonist Drugs 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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Images
Classifications
-
- 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
-
- 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
-
- 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 medicinal chemistry, in particular to a crystal form of Lanifibranor and a preparation method thereof.
- Nonalcoholic steatohepatitis is an extreme form of nonalcoholic fatty liver disease, defined as steatosis accompanied by inflammation and hepatocellular damage. NASH can lead to advanced liver fibrosis, cirrhosis, liver failure and the development of liver tumors.
- Lanifibranor is a pan-PPAR agonist, which produces a balanced activation of PPAR ⁇ and PPAR ⁇ , and can partially activate PPAR ⁇ . Under the action of multiple mechanisms, Lanifibranor has shown good efficacy in clinical studies of nonalcoholic steatohepatitis and security.
- the chemical name of the drug is: 5-chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indole-2-butyric acid, the molecular formula is: C 19 H 15 ClN 2 O 4 S 2 , the molecular weight It is: 434.92, the CAS number is: 927961-18-0, and the chemical structural formula is as shown in formula (I):
- the polymorphic form of drugs is a crucial research content.
- Different crystal forms have different solubility, dissolution rate, and stability, which will significantly affect the bioavailability of the drug, which in turn will lead to different clinical effects.
- the impact of crystal form is greater.
- WO2007026097A1 discloses Lanifibranor compounds and their preparation methods.
- Example 117 of this patent discloses that a light yellow powder is obtained, but its melting point is low, only 74-80°C, and its stability may be poor in terms of melting point.
- the inventors of the present application unexpectedly discovered that the compound I crystal forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM- G and CM-I. It has advantages in at least one aspect of melting point, stability, solubility, hygroscopicity, dissolution in vivo and in vitro, bioavailability, compressibility, fluidity, preparation quality and processing performance, especially melting point, stability, Wettability, fluidity, preparation tablet uniformity and preparation process operability provide a new and better choice for the development of drugs containing Lanifibranor, which is of great significance.
- CM-A, CM-B, CM-F and CM-I have better solubility and fluidity than the prior art, which is of great significance to the dissolution of subsequent preparations; they have little electrostatic effect , the advantages of being suitable for the production of preparations; the preparation process is simple, the operability is strong, the yield is high, the quality is stable, the production cycle is short, and it is easy to realize large-scale production.
- the purpose of the present invention is to provide a new crystal form of Lanifibranor with high melting point and good stability, so as to meet the needs of drug development and application.
- Another object of the present invention is to provide a method for preparing a new crystal form of Lanifibranor suitable for formulation production.
- the first aspect of the present invention provides a crystal form of the compound represented by formula I, characterized in that,
- the crystal form is selected from the group consisting of crystal form CM-A, crystal form CM-B, crystal form CM-C, crystal form CM-D, crystal form CM-E, crystal form CM-F, and crystal form CM-G or crystalline form CM-I.
- the crystalline form is crystalline form CM-A.
- the XRPD pattern of the crystalline form CM-A includes 2 or more 2 ⁇ values selected from the following group: 9.9° ⁇ 0.2°, 15.65° ⁇ 0.2°, 23.95° ⁇ 0.2°. More preferably, the XRPD pattern of the crystalline form CM-A also includes one or more 2 ⁇ values selected from the following group: 11.70° ⁇ 0.2°, 17.26° ⁇ 0.2°, 20.10° ⁇ 0.2°, 20.57° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-A is 9.90° ⁇ 0.2°, 11.70° ⁇ 0.2°, 12.62° ⁇ 0.2°, 14.99° ⁇ 0.2°, 15.65° ⁇ 0.2 °, 17.26° ⁇ 0.2°, 17.96° ⁇ 0.2°, 18.49° ⁇ 0.2°, 20.10° ⁇ 0.2°, 20.57° ⁇ 0.2°, 21.48° ⁇ 0.2°, 22.20° ⁇ 0.2°, 22.60° ⁇ 0.2°, 23.41° ⁇ 0.2°, 23.95° ⁇ 0.2°, 25.02° ⁇ 0.2°, 26.05° ⁇ 0.2°, 26.71° ⁇ 0.2°, 27.00° ⁇ 0.2°, 27.32° ⁇ 0.2°, 29.04° ⁇ 0.2°, 30.01° There are characteristic peaks at ⁇ 0.2°, 30.43° ⁇ 0.2° and 31.78° ⁇ 0.2°.
- the crystal form CM-A has no obvious weight loss peak at 25°C-200°C.
- the crystal form CM-A has an endothermic peak at 114.80°C and 179.34°C respectively.
- the crystalline form CM-A has XRPD data substantially as shown in Table A.
- the crystalline form CM-A has an XRPD spectrum substantially as shown in FIG. 1 .
- the crystalline form CM-A has a TGA spectrum substantially as shown in FIG. 2 .
- the crystalline form CM-A has a DSC spectrum substantially as shown in FIG. 3 .
- the crystalline form CM-A has a 1H NMR spectrum substantially as shown in FIG. 4 .
- the crystal form CM-A is block or cuboid crystal.
- the crystal form is crystal form CM-B.
- the XRPD pattern of the crystalline form CM-B includes 2 or more 2 ⁇ values selected from the following group: 7.75° ⁇ 0.2°, 10.89° ⁇ 0.2°, 20.18° ⁇ 0.2°, 22.18 ° ⁇ 0.2°. More preferably, the XRPD pattern of the crystalline form CM-B also includes one or more 2 ⁇ values selected from the following group: 8.36° ⁇ 0.2°, 16.41° ⁇ 0.2°, 16.98° ⁇ 0.2°, 17.83° ⁇ 0.2°, 19.14° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-B is 7.75° ⁇ 0.2°, 8.36° ⁇ 0.2°, 10.89° ⁇ 0.2°, 13.99° ⁇ 0.2°, 15.60° ⁇ 0.2 °, 16.41° ⁇ 0.2°, 16.77° ⁇ 0.2°, 16.98° ⁇ 0.2°, 17.83° ⁇ 0.2°, 19.14° ⁇ 0.2°, 20.18° ⁇ 0.2°, 21.15° ⁇ 0.2°, 22.18° ⁇ 0.2°, 22.50° ⁇ 0.2°, 23.30° ⁇ 0.2°, 24.02° ⁇ 0.2°, 24.06° ⁇ 0.2°, 24.47° ⁇ 0.2°, 25.25° ⁇ 0.2°, 25.55° ⁇ 0.2°, 26.32° ⁇ 0.2°, 26.68° There are characteristic peaks at ⁇ 0.2°, 27.45° ⁇ 0.2°, 27.63° ⁇ 0.2°, 29.69° ⁇ 0.2°, 32.27° ⁇ 0.2° and 33.03° ⁇ 0.2°.
- the crystal form CM-B has no obvious weight loss step at 25°C-150°C.
- the crystal form CM-B has a melting endothermic peak at 178.97°C.
- the crystal form CM-B has XRPD data substantially as shown in Table B.
- the crystal form CM-B has an XRPD spectrum substantially as shown in FIG. 5 .
- the crystal form CM-B has a TGA spectrum substantially as shown in FIG. 6 .
- the crystalline form CM-B has a DSC spectrum substantially as shown in FIG. 7 .
- the crystalline form CM-B has a 1H NMR spectrum substantially as shown in FIG. 8 .
- the crystal form CM-B is a fine needle crystal.
- the crystalline form is crystalline form CM-F.
- the XRPD pattern of the crystalline form CM-F includes 2 or more 2 ⁇ values selected from the following group: 16.75° ⁇ 0.2°, 17.87° ⁇ 0.2°, 25.25° ⁇ 0.2°; more Preferably, the XRPD pattern of the crystalline form CM-F also includes one or more 2 ⁇ values selected from the following group: 19.16° ⁇ 0.2°, 20.14° ⁇ 0.2°, 21.11° ⁇ 0.2°, 22.20° ⁇ 0.2°, 24.09° ⁇ 0.2°, 24.40° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-F is 7.76° ⁇ 0.2°, 8.38° ⁇ 0.2°, 10.92° ⁇ 0.2°, 14.05° ⁇ 0.2°, 15.69° ⁇ 0.2 °, 16.48° ⁇ 0.2°, 16.75° ⁇ 0.2°, 17.01° ⁇ 0.2°, 17.87° ⁇ 0.2°, 19.16° ⁇ 0.2°, 20.14° ⁇ 0.2°, 21.11° ⁇ 0.2°, 22.20° ⁇ 0.2°, 22.56° ⁇ 0.2°, 23.30° ⁇ 0.2°, 24.09° ⁇ 0.2°, 24.40° ⁇ 0.2°, 25.25° ⁇ 0.2°, 25.58° ⁇ 0.2°, 26.35° ⁇ 0.2°, 27.57° ⁇ 0.2°, 28.16° There are characteristic peaks at ⁇ 0.2°, 29.60° ⁇ 0.2°, 32.25° ⁇ 0.2° and 33.92° ⁇ 0.2°.
- the crystalline form CM-F has an endothermic peak at 178.50°C.
- the crystal form CM-F has no obvious weight loss step in the range of 25°C-200°C.
- the crystalline form CM-F has XRPD data substantially as shown in Table F.
- the crystalline form CM-F has an XRPD spectrum substantially as shown in FIG. 20 .
- the crystalline form CM-F has a TGA spectrum substantially as shown in FIG. 21 .
- the crystalline form CM-F has a DSC spectrum substantially as shown in FIG. 22 .
- the crystalline form CM-F has a 1H NMR spectrum substantially as shown in Figure 23.
- the crystal form CM-F is a bulk crystal.
- the crystalline form is crystalline form CM-I.
- the XRPD pattern of the crystalline form CM-I includes 2 or more 2 ⁇ values selected from the following group: 7.83° ⁇ 0.2°, 9.70° ⁇ 0.2°, 18.43° ⁇ 0.2°; more
- the XRPD pattern of the crystalline form CM-I also includes one or more 2 ⁇ values selected from the following group: 13.13° ⁇ 0.2°, 20.59° ⁇ 0.2°, 22.38° ⁇ 0.2°, 23.11° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-I is 2.50° ⁇ 0.2°, 7.83° ⁇ 0.2°, 9.70° ⁇ 0.2°, 13.13° ⁇ 0.2°, 15.76° ⁇ 0.2 °, 18.43° ⁇ 0.2°, 20.59° ⁇ 0.2°, 22.38° ⁇ 0.2°, 23.11° ⁇ 0.2°, 24.13° ⁇ 0.2°, 25.32° ⁇ 0.2°, 26.30° ⁇ 0.2°, 29.62° ⁇ 0.2° and There is a characteristic peak at 31.24° ⁇ 0.2°.
- the crystalline form CM-I has an endothermic peak at 138.07°C and 176.11°C respectively.
- the crystal form CM-I has obvious weight loss steps in the range of 100°C-175°C.
- the crystalline form CM-I has XRPD data substantially as shown in Table H.
- the crystalline form CM-I has an XRPD spectrum substantially as shown in FIG. 27 .
- the crystalline form CM-I has a TGA spectrum substantially as shown in FIG. 28 .
- the crystalline form CM-I has a DSC spectrum substantially as shown in FIG. 29 .
- the crystalline form CM-I has a 1H NMR spectrum substantially as shown in Figure 30.
- the crystal form CM-I is a short rod crystal.
- the crystalline form is crystalline form CM-C.
- the XRPD pattern of the crystalline form CM-C includes 2 or more 2 ⁇ values selected from the following group: 9.38° ⁇ 0.2°, 10.20° ⁇ 0.2°, 24.42° ⁇ 0.2°; more Preferably, the XRPD pattern of the crystalline form CM-C also includes one or more 2 ⁇ values selected from the following group: 16.36° ⁇ 0.2°, 17.78° ⁇ 0.2°, 19.06° ⁇ 0.2°, 22.16° ⁇ 0.2°, 23.44° ⁇ 0.2°, 27.54° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-C is 9.38° ⁇ 0.2°, 10.20° ⁇ 0.2°, 16.36° ⁇ 0.2°, 17.78° ⁇ 0.2°, 19.06° ⁇ 0.2 °, 22.16° ⁇ 0.2°, 23.44° ⁇ 0.2°, 24.42° ⁇ 0.2° and 27.54° ⁇ 0.2° have characteristic peaks.
- the crystalline form CM-C has an obvious weight loss step at 100°C-200°C.
- the crystalline form CM-C has a melting endothermic peak at 177.40°C.
- the crystal form CM-C has XRPD data substantially as shown in Table C.
- the crystalline form CM-C has an XRPD spectrum substantially as shown in FIG. 9 .
- the crystalline form CM-C has a TGA spectrum substantially as shown in FIG. 10 .
- the crystalline form CM-C has a DSC spectrum substantially as shown in FIG. 11 .
- the crystalline form CM-C has a 1H NMR spectrum substantially as shown in FIG. 12 .
- the crystalline form is crystalline form CM-D.
- the XRPD pattern of the crystalline form CM-D includes 2 or more 2 ⁇ values selected from the following group: 5.74° ⁇ 0.2°, 9.15° ⁇ 0.2°, 16.39° ⁇ 0.2°; more Preferably, the XRPD pattern of the crystalline form CM-D also includes one or more 2 ⁇ values selected from the following group: 11.54° ⁇ 0.2°, 14.70° ⁇ 0.2°, 18.27° ⁇ 0.2°, 20.55° ⁇ 0.2°, 23.67° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-D is 5.74° ⁇ 0.2°, 9.15° ⁇ 0.2°, 11.54° ⁇ 0.2°, 14.70° ⁇ 0.2°, 16.39° ⁇ 0.2 °, 18.27° ⁇ 0.2°, 20.55° ⁇ 0.2° and 23.67° ⁇ 0.2° have characteristic peaks.
- the crystalline form CM-D has an endothermic peak at 53.27°C, 101.22°C, 122.63°C and 171.01°C.
- the crystalline form CM-D has a weight loss of about 10.08% in the range of room temperature-75°C, a weight loss of about 2.20% in the range of 75°C-115°C, a weight loss of about 5.08% in the range of 115°C-165°C, The weight loss is about 1.24% in the range of 165°C-210°C.
- the crystal form CM-D has XRPD data substantially as shown in Table D.
- the crystalline form CM-D has an XRPD spectrum substantially as shown in FIG. 13 .
- the crystalline form CM-D has a TGA spectrum substantially as shown in FIG. 14 .
- the crystalline form CM-D has a DSC spectrum substantially as shown in FIG. 15 .
- the crystal form is crystal form CM-E.
- the XRPD pattern of the crystalline form CM-E includes 2 or more 2 ⁇ values selected from the following group: 11.50° ⁇ 0.2°, 17.33° ⁇ 0.2°, 18.63° ⁇ 0.2°; more Preferably, the XRPD pattern of the crystalline form CM-E also includes one or more 2 ⁇ values selected from the following group: 6.97° ⁇ 0.2°, 9.14° ⁇ 0.2°, 13.02° ⁇ 0.2°, 13.83° ⁇ 0.2°, 19.52° ⁇ 0.2°, 21.54° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-E is 6.97° ⁇ 0.2°, 9.14° ⁇ 0.2°, 11.50° ⁇ 0.2°, 13.02° ⁇ 0.2°, 13.83° ⁇ 0.2 °, 17.33° ⁇ 0.2°, 18.63° ⁇ 0.2°, 19.52° ⁇ 0.2°, 21.54° ⁇ 0.2°, 22.57° ⁇ 0.2°, 23.15° ⁇ 0.2°, 23.63° ⁇ 0.2°, 24.51° ⁇ 0.2°, There are characteristic peaks at 24.57° ⁇ 0.2°, 25.46° ⁇ 0.2°, 27.65° ⁇ 0.2°, 28.92° ⁇ 0.2°, 29.78° ⁇ 0.2° and 32.32° ⁇ 0.2°.
- the crystal form CM-E has an endothermic peak at 51.07°C, 95.75°C and 166.19°C, and an exothermic crystallization peak at 125.4°C.
- the crystalline form CM-E has a weight loss of about 11.13% in the range of room temperature-78°C, a weight loss of about 3.30% in the range of 78°C-125°C, and a weight loss of about 1.05% in the range of 125°C-210°C.
- the crystalline form CM-E has XRPD data substantially as shown in Table E.
- the crystalline form CM-E has an XRPD spectrum substantially as shown in FIG. 16 .
- the crystalline form CM-E has a TGA spectrum substantially as shown in FIG. 17 .
- the crystalline form CM-E has a DSC spectrum substantially as shown in FIG. 18 .
- the crystalline form CM-E has a 1H NMR spectrum substantially as shown in Figure 19.
- the crystalline form is crystalline form CM-G.
- the XRPD pattern of the crystalline form CM-G includes 2 or more 2 ⁇ values selected from the following group: 17.95° ⁇ 0.2°, 18.42° ⁇ 0.2°, 20.96° ⁇ 0.2°; more Preferably, the XRPD pattern of the crystalline form CM-G includes a 2 ⁇ value of 1 or more selected from the following group: 6.09° ⁇ 0.2°, 8.16° ⁇ 0.2°, 9.27° ⁇ 0.2°, 9.82° ⁇ 0.2°, 15.72° ⁇ 0.2°, 19.72° ⁇ 0.2°.
- the diffraction angle 2 ⁇ value of the XRPD pattern of the crystal form CM-G is 6.09° ⁇ 0.2°, 8.16° ⁇ 0.2°, 9.27° ⁇ 0.2°, 9.82° ⁇ 0.2°, 15.72° ⁇ 0.2 °, 17.95° ⁇ 0.2°, 18.42° ⁇ 0.2°, 19.72° ⁇ 0.2°, 20.96° ⁇ 0.2°, 21.21° ⁇ 0.2°, 21.76° ⁇ 0.2°, 27.91° ⁇ 0.2°, 28.26° ⁇ 0.2°, There are characteristic peaks at 29.40° ⁇ 0.2°, 30.13° ⁇ 0.2°, 31.85° ⁇ 0.2° and 32.72° ⁇ 0.2°.
- the crystalline form CM-G has a desolvation peak at 54.94°C, a melting transformation peak at 92.04°C, and an endothermic melting peak at 176.39°C.
- the crystalline form CM-G loses about 20.56% in weight in the range of 17°C-88°C, and loses about 2.75% in the range of 88°C-158°C.
- the crystalline form CM-G has XRPD data substantially as shown in Table G.
- the crystalline form CM-G has an XRPD spectrum substantially as shown in FIG. 24 .
- the crystalline form CM-G has a TGA spectrum substantially as shown in FIG. 25 .
- the crystalline form CM-G has a DSC spectrum substantially as shown in FIG. 26 .
- the second aspect of the present invention provides a method for preparing the crystal form described in the first aspect of the present invention.
- the crystal form is crystal form CM-A, and its preparation method includes the following steps:
- the first solvent is selected from the group consisting of ketone solvents, alcohol solvents, ester solvents, or combinations thereof. More preferably, the ketone solvent is acetone and/or 2-butanone; the alcohol solvent is methanol and/or ethanol; and the ester solvent is ethyl acetate.
- the first solvent is 2-methyltetrahydrofuran.
- step (1) is carried out at room temperature.
- the mass (g)/volume (mL) of the Lanifibranor raw material and the first solvent is 1:10-100, preferably 1:10-50, more preferably 1 :10 ⁇ 20.
- the crystal form is crystal form CM-B, and its preparation method includes the following steps:
- Lanifibranor raw material is provided in a second solvent to form a mixture or solution containing Lanifibranor raw material;
- the second solvent is an ether solvent and/or an ester solvent. More preferably, the ether solvent is methyl tert-butyl ether and/or anisole; the ester is ethyl acetate.
- step (1) is carried out at room temperature.
- the mass (g)/volume (mL) of the Lanifibranor raw material and the second solvent is 1:10-50, preferably 1:20-40.
- the crystal form is crystal form CM-F, and its preparation method includes the following steps:
- the third solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), N-N dimethylacetamide, N-methylpyrrolidone (NMP), or combinations thereof.
- DMSO dimethyl sulfoxide
- NMP N-methylpyrrolidone
- the third solvent is N-N dimethylacetamide.
- the third solvent is dimethyl sulfoxide.
- step (1) is carried out at room temperature.
- the mass (g)/volume (mL) of the Lanifibranor raw material and the third solvent is 1:10-100, preferably 1:10-50, more preferably 1:10-20.
- the medium is a glass vial.
- the crystal form is crystal form CM-I, and its preparation method includes the following steps:
- the fourth solvent is alcohol solvent and/or dichloromethane. More preferably, the alcoholic solvent is methanol and/or ethanol.
- the weight volume ratio of the Lanifibranor raw material to the fourth solvent is 1:10-100, preferably 1:10-50, more preferably 1:10-20.
- the high polymer is polyvinyl alcohol and/or polyvinyl chloride.
- the seed crystal is crystal form CM-A and/or CM-I.
- the added seed crystal or high polymer is 0.3-10 wt%, preferably 0.5-5 wt%, of the mass of the Lanifibranor raw material.
- step (1) is carried out at room temperature.
- the volatilization temperature of the solution is 20-80°C.
- the volatilization time is 1-48h; preferably 2-36h; more preferably 3-24h.
- an optional drying step is also included.
- the method of collecting solids is filtering.
- the third aspect of the present invention provides a pharmaceutical composition
- the pharmaceutical composition contains (a) active ingredient, the active ingredient is the Lanifibranor crystal form as described in the first aspect of the present invention; and (b) pharmaceutical acceptable carrier.
- the dosage form of the pharmaceutical composition or preparation is selected from the group consisting of powder injection, capsule, granule, tablet, pill or injection.
- the fourth aspect of the present invention provides a use of the crystal form as described in the first aspect of the present invention, the use comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a compound for the treatment of non-alcoholic Drugs for steatohepatitis.
- Figure 1 is the XRPD spectrum of the crystalline form CM-A of Lanifibranor according to the present invention.
- Fig. 2 is the TGA spectrum of the crystalline form CM-A of Lanifibranor according to the present invention.
- Fig. 3 is the DSC spectrum of the crystalline form CM-A of Lanifibranor according to the present invention.
- Fig. 4 is the 1H NMR spectrogram of the crystalline form CM-A of Lanifibranor according to the present invention.
- Fig. 5 is the XRPD spectrum of the crystalline form CM-B of Lanifibranor according to the present invention.
- Fig. 6 is a TGA spectrum of the crystalline form CM-B of Lanifibranor according to the present invention.
- Fig. 7 is the DSC spectrum of the crystalline form CM-B of Lanifibranor according to the present invention.
- Fig. 8 is the 1H NMR spectrum of the crystalline form CM-B of Lanifibranor according to the present invention.
- Fig. 9 is the XRPD spectrum of the crystalline form CM-C of Lanifibranor according to the present invention.
- Fig. 10 is the TGA spectrum of the crystalline form CM-C of Lanifibranor according to the present invention.
- Fig. 11 is the DSC spectrum of the crystalline form CM-C of Lanifibranor according to the present invention.
- Fig. 12 is the 1H NMR spectrum of the crystalline form CM-C of Lanifibranor according to the present invention.
- Fig. 13 is the XRPD spectrum of the crystalline form CM-D of Lanifibranor according to the present invention.
- Fig. 14 is the TGA spectrum of the crystalline form CM-D of Lanifibranor according to the present invention.
- Fig. 15 is a DSC spectrum of the crystalline form CM-D of Lanifibranor according to the present invention.
- Figure 16 is the XRPD spectrum of the crystalline form CM-E of Lanifibranor according to the present invention.
- Fig. 17 is a TGA spectrum of the crystalline form CM-E of Lanifibranor according to the present invention.
- Figure 18 is the DSC spectrum of the crystalline form CM-E of Lanifibranor according to the present invention.
- Figure 19 is the 1H NMR spectrum of the crystalline form CM-E of Lanifibranor according to the present invention.
- Figure 20 is the XRPD spectrum of the crystalline form CM-F of Lanifibranor according to the present invention.
- Fig. 21 is the TGA spectrum of the crystalline form CM-F of Lanifibranor according to the present invention.
- Figure 22 is the DSC spectrum of the crystalline form CM-F of Lanifibranor according to the present invention.
- Figure 23 is the 1H NMR spectrum of the crystalline form CM-F of Lanifibranor according to the present invention.
- Figure 24 is the XRPD spectrum of the crystalline form CM-G of Lanifibranor according to the present invention.
- Fig. 25 is the TGA spectrum of the crystalline form CM-G of Lanifibranor according to the present invention.
- Fig. 26 is a DSC spectrum of the crystalline form CM-G of Lanifibranor according to the present invention.
- Figure 27 is the XRPD spectrum of the crystalline form CM-I of Lanifibranor according to the present invention.
- Fig. 28 is a TGA spectrum of the crystalline form CM-I of Lanifibranor according to the present invention.
- Figure 29 is the DSC spectrum of the crystalline form CM-I of Lanifibranor according to the present invention.
- Figure 30 is the 1H NMR spectrum of the crystalline form CM-I of Lanifibranor according to the present invention.
- These four crystal forms have at least one advantage in terms of solubility, hygroscopicity, mechanical stability, tablet stability, fluidity, process developability, formulation development, purification and powder processing performance. Based on the above findings, the inventors have accomplished the present invention.
- Libranor raw material refers to various solid forms of the compound of formula Lanifibranor (comprising various crystal forms or amorphous forms mentioned herein, and mentioned in various documents or patents published or unpublished. crystalline or amorphous form).
- the Lanifibranor raw material used in the present invention is Lanifibranor prepared according to the preparation method provided in the examples of the present invention.
- a crystalline form of the invention refers to Lanifibranor crystalline forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G and CM-I.
- the method of "slowly adding” includes but is not limited to: adding drop by drop, adding slowly along the wall of the container.
- room temperature generally refers to 4-30°C, preferably 20 ⁇ 5°C.
- a crystalline form of the invention refers to crystalline forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G and CM as described herein -I.
- the XRPD pattern of crystalline form CM-A includes 4 or more 2 ⁇ values selected from the following group: 9.90° ⁇ 0.2°, 11.70° ⁇ 0.2°, 15.65° ⁇ 0.2°, 17.26° ⁇ 0.2°, 17.96° ⁇ 0.2°, 18.49° ⁇ 0.2°, 20.10° ⁇ 0.2°, 20.57° ⁇ 0.2°, 23.95° ⁇ 0.2°.
- the XRPD pattern of crystalline form CM-B includes 4 or more 2 ⁇ values selected from the following group: 7.75° ⁇ 0.2°, 8.36° ⁇ 0.2°, 10.89° ⁇ 0.2°, 15.60° ⁇ 0.2°, 16.41° ⁇ 0.2°, 16.77° ⁇ 0.2°, 16.98° ⁇ 0.2°, 17.83° ⁇ 0.2°, 19.14° ⁇ 0.2°, 20.18° ⁇ 0.2°, 22.18° ⁇ 0.2°.
- the XRPD pattern of the crystalline form CM-F includes 4 or more 2 ⁇ values selected from the following group: 7.76° ⁇ 0.2°, 8.38° ⁇ 0.2°, 10.92° ⁇ 0.2 °, 14.05° ⁇ 0.2°, 15.69° ⁇ 0.2°, 16.48° ⁇ 0.2°, 16.75° ⁇ 0.2°, 17.01° ⁇ 0.2°, 17.87° ⁇ 0.2°, 19.16° ⁇ 0.2°, 20.14° ⁇ 0.2°, 21.11° ⁇ 0.2°, 22.20° ⁇ 0.2°, 24.09° ⁇ 0.2°, 24.40° ⁇ 0.2°, 25.25° ⁇ 0.2°.
- the XRPD pattern of the crystalline form CM-I includes 4 or more 2 ⁇ values selected from the following group: 7.83° ⁇ 0.2°, 9.70° ⁇ 0.2°, 13.13° ⁇ 0.2 °, 18.43° ⁇ 0.2°, 20.59° ⁇ 0.2°, 23.11° ⁇ 0.2°, 25.32° ⁇ 0.2°.
- the XRPD pattern of the crystalline form CM-D includes 3 or more 2 ⁇ values selected from the following group: 5.74° ⁇ 0.2°, 9.15° ⁇ 0.2°, 16.39° ⁇ 0.2 °, 20.55° ⁇ 0.2°, 23.67° ⁇ 0.2°.
- the XRPD pattern of the crystalline form CM-E includes 2 or more 2 ⁇ values selected from the following group: 6.97° ⁇ 0.2°, 11.50° ⁇ 0.2°, 17.33° ⁇ 0.2 °, 18.63° ⁇ 0.2°.
- the XRPD pattern of the crystalline form CM-G includes 2 or more 2 ⁇ values selected from the following group: 6.09° ⁇ 0.2°, 9.82° ⁇ 0.2°, 17.95° ⁇ 0.2° 0.2°, 18.42° ⁇ 0.2°, 20.96° ⁇ 0.2°, 21.21° ⁇ 0.2°.
- Another aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of Lanifibranor crystal form as described in the present invention, and optionally, one or more pharmaceutically acceptable carriers, excipients, Adjuvants, excipients and/or diluents.
- the excipients are, for example, flavoring agents, flavoring agents, sweetening agents, and the like.
- the pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 1-99%, and its preferred ratio is that the compound of general formula I accounts for 65wt%-99wt% of the total weight as the active ingredient, and the rest is pharmaceutically acceptable carrier, diluent or solution or saline solution.
- the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents Neutralize in suitable sterile equipment for injection or infusion.
- the unit dose of the preparation formula contains 1 mg-700 mg of the compound of general formula I, preferably, the unit dose of the preparation formula contains 25 mg-300 mg of the compound of general formula I.
- the compounds and pharmaceutical compositions of the present invention can be clinically used in mammals, including humans and animals, and can be administered through oral, nasal, dermal, pulmonary or gastrointestinal routes. Oral administration is most preferred.
- the most preferred daily dose is 50-1400 mg/kg body weight, taken once, or 25-700 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual should depend on the specific treatment. Usually, start with a small dose and gradually increase the dose until you find the most suitable dose.
- the method used for drying is a conventional drying method in the art, for example, drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, it is dried for 0.1 to 50 hours or 1 to 30 hours.
- the main advantages of the present invention include:
- CM-A, CM-B, CM-F, and CM-I described in the present invention have better thermal stability, pressure stability and chemical stability, and are useful for the preparation and storage of subsequent preparations. important meaning;
- CM-A, CM-B, CM-F, and CM-I described in the present invention have better fluidity, smaller angle of repose, and low hygroscopicity, which can meet the requirements of direct filling of capsules, and are suitable for Formulation production.
- test methods of the present invention are general methods, and test parameters are as follows:
- X-ray powder diffractometer Bruker D2Phaser X-ray powder diffractometer; radiation source Cu Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; Initial 2 ⁇ : 2.0°, scanning range: 2.0 ⁇ 35.0°. The scanning speed is 0.1s/step, and the step size is 0.02°/step.
- X-ray powder diffractometer Bruker D2Phaser X-ray powder diffractometer; radiation source Cu Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; Initial 2 ⁇ : 2.0°, scanning range: 2.0 ⁇ 50.0°. The scanning speed is 1s/step, and the step size is 0.02°/step.
- Thermogravimetric analysis (TGA) instrument TGA55 type of TA Company in the United States, 20-300°C range, heating rate 10°C/min, nitrogen flow rate 40mL/min.
- DSC Differential scanning calorimetry
- the obtained Lanifibranor compound crystal form CM-A was tested by XRPD, and the results are shown in FIG. 1 , and the spectrum data are shown in Table 1.
- the obtained solid was tested by TGA, and the results are shown in Figure 2.
- the results showed that there was no obvious weight loss step in the TGA spectrum of Lanifibranor crystal form CM-A, and the crystal form was anhydrous; the obtained solid was tested by DSC, and the result As shown in Figure 3, the results show that it has a first endothermic peak at 114.80°C and a second endothermic peak at 179.34°C; the resulting solid was tested by 1H NMR, and the results are shown in Figure 4. Solid microscope observation is block or cuboid.
- Lanifibranor compound crystal form CM-A At room temperature, add 100 mg of Lanifibranor compound to 8 mL of acetone:ethyl acetate (1:1, v:v) mixed solvent, stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed at room temperature to evaporate the solvent, and a solid was precipitated. After filtering, drying the solid, the obtained solid is Lanifibranor compound crystal form CM-A.
- the obtained Lanifibranor compound crystal form CM-B was tested by XRPD. The results are shown in FIG. 5 , and the spectral data are shown in Table 2.
- the TGA test was performed on the obtained solid, and the results are shown in Figure 6.
- the results show that there is no obvious weight loss peak in the TGA spectrum of Lanifibranor crystal form CM-B in the range of 25°C-150°C, and the crystal form is anhydrous;
- the obtained solid was tested by DSC, and the results are shown in Figure 7.
- the results showed that it had a melting endothermic peak at 178.97°C; the obtained solid was tested by 1H NMR, and the results were shown in Figure 8. Solid microscope observation is fine needle.
- Lanifibranor compound At room temperature, add 100 mg of Lanifibranor compound to 2 mL of 1,4-dioxane, stir rapidly until dissolved, and then filter through a membrane. Put the filtrate in a 20mL glass bottle, add 12mL of ethanol, and place it at 20-25°C to volatilize. Filtrate, volatilize the resulting solid and place it in an oven at 60°C for 12 hours under vacuum to obtain Lanifibranor crystal form CM-C.
- Lanifibranor compound At room temperature, add 100 mg of Lanifibranor compound to 2 mL of 1,4-dioxane, stir rapidly until dissolved, and then filter through a membrane. Put the filtrate in a 20mL glass bottle, add 12mL of ethanol, and volatilize at 20-25°C. After volatilization for 5 days, a solid is obtained, filtered, and dried in an oven at 25°C for 12h to obtain Lanifibranor crystal form CM-D.
- the obtained Lanifibranor compound crystal form CM-D was tested by XRPD, the results are shown in Figure 13, and the spectrum data are shown in Table 4; the obtained solid was tested by TGA, and the results were shown in Figure 14, the results showed that Lanifibranor crystal form CM In the TGA spectrum of -D, the weight loss is about 10.08% in the range of room temperature-75°C, about 2.20% in the range of 75°C-115°C, about 5.08% in the range of 115°C-165°C, and about 5.08% in the range of 165°C-210°C About 1.24%, the crystal form is a solvate; DSC test was performed on the obtained solid, and the results are shown in Figure 15. The results showed that each of them had an endothermic peak at 53.27°C, 101.22°C, 122.63°C and 171.01°C.
- Form CM-D is a solvate.
- Lanifibranor crystal form CM-E is a solvate of 1,4-dioxane.
- Embodiment 6 Preparation of Lanifibranor crystal form CM-F
- Form CM-G is a chloroform solvate.
- CM-A, CM-B, CM-F and CM-I of the present invention have a higher melting point and better thermal stability than the solid in Example 117 of patent WO2007026097.
- the crystalline forms CM-A, CM-F and CM-I of the present invention and the crystalline form CM-B can be separated at 25°C/60%RH, 40°C/75%RH and 60°C/92.5%RH Under the conditions, the crystal form stability and chemical stability are good, and the crystal form stability is good under pressure.
- Form CM-A (Example 1-1), Form CM-B (Example 2-1), Form CM-F (Example 6-1) and Form CM-I (Example 8- 1)
- Add 100mg each to the buffer solutions of 4 dissolution media (pH1.2, pH4.0, pH6.8 and purified water), stir at 37°C for 2h, detect the solid by XRD, and the test results are shown in Table 4 .
- the crystalline form CM-B of the present invention is a thermodynamically stable crystalline form at room temperature, and other crystalline forms can be transformed into crystalline form CM-B by induction of the CM-B crystal form in different solvents.
- crystal form CM-A (Example 1-1), crystal form CM-B (Example 2-1), crystal form CM-F (Example 6-1) and crystal form CM-I (Example 8-1) carried out the hygroscopicity test, and the results are shown in Table 7.
- the crystalline form CM-A of the present invention has almost no hygroscopicity
- the crystalline form CM-F and CM-I have slight hygroscopicity
- the crystalline form CM-B has hygroscopicity.
- the crystalline form CM-A, crystalline form CM-F and crystalline form CM-I of the present invention have lower hygroscopicity and are convenient for storage and transportation.
- the preparation includes crystal form CM-A (Example 1-1), crystal form CM-B (Example 2-1), crystal form CM-F (Example 6-1) and crystal form of the present invention
- CM-I Example 8-1
- the mixture of CM-I Example 8-1 and the following proportions of excipients was used to detect the angle of repose of the mixture of different crystal forms, and then compare whether the different crystal forms have the feasibility of direct capsule filling.
- Element Single dose (mg/capsule) APIs 100mg microcrystalline cellulose 150mg lactose 45mg talcum powder 5mg total 300mg
- the angle of repose of the crystal form CM-A mixture is 31°, and its fluidity fully meets the requirements for direct capsule filling.
- the angles of repose of the crystal form CM-F mixture and CM-I mixture are 36° and 37°, and their fluidity meets the requirement of direct capsule filling.
- the crystal form CM-B mixture has an angle of repose of 48°, poor fluidity and cannot meet the requirements of direct capsule filling.
- the crystalline form CM-A, crystalline form CM-F and CM-I of the present invention have obvious advantages in fluidity after mixing with the auxiliary materials relative to the crystalline form CM-B, and can be directly filled into capsules without preparation preparation.
- the granule operation simplifies the preparation process and improves the production efficiency of the preparation.
- tablets can be prepared according to the formulation prescription in Table 10 below.
- Element Single dose (mg/capsule) APIs 100mg microcrystalline cellulose 135mg lactose 45mg hypromellose 15mg talcum powder 5mg total 250mg
- Preparation method mix Lanifibranor with microcrystalline cellulose and lactose, pass through an 80-mesh sieve and mix, then add hypromellose aqueous solution to make a soft material, pass through a 20-mesh sieve to granulate, dry, add talcum powder, mix evenly, and press into tablets.
Abstract
La présente invention concerne une forme cristalline de lanifibranor, et son procédé de préparation. Plus particulièrement, la présente invention concerne une forme cristalline d'un composé représenté par la formule 1. La forme cristalline est la forme cristalline CM-A, la forme cristalline CM-B, la forme cristalline CM-C, la forme cristalline CM-D, la forme cristalline CM-E, la forme cristalline CM-F, la forme cristalline CM-G ou la forme cristalline CM-I. Par rapport au lanifibranor solide, la forme cristalline de lanifibranor selon la présente invention a une stabilité supérieure, une hygroscopicité inférieure et une meilleure fluidité, et offre un meilleur choix pour le développement d'un médicament contenant du lanifibranor.
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WO2023194339A1 (fr) | 2022-04-05 | 2023-10-12 | Inventiva | Forme cristalline de lanifibranor |
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WO2022143479A1 (fr) * | 2020-12-29 | 2022-07-07 | 广东东阳光药业有限公司 | Forme solide de composé, son procédé de préparation et son utilisation |
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- 2021-06-11 CN CN202110655795.XA patent/CN115466252A/zh active Pending
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WO2023194339A1 (fr) | 2022-04-05 | 2023-10-12 | Inventiva | Forme cristalline de lanifibranor |
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