CN117545755A

CN117545755A - Lanifibror crystal form and preparation method thereof

Info

Publication number: CN117545755A
Application number: CN202280036190.5A
Authority: CN
Inventors: 刘天杰; 高沛琳; 申淑匣; 张良
Original assignee: Shanghai Qisheng Heyan Pharmaceutical Technology Co ltd
Current assignee: Shanghai Qisheng Heyan Pharmaceutical Technology Co ltd
Priority date: 2021-06-11
Filing date: 2022-06-10
Publication date: 2024-02-09
Also published as: WO2022258060A1; CN115466252A

Abstract

The invention provides a Lanifibronor crystal form and a preparation method thereof. specifically,theinventionprovidesacrystalformofthecompoundshownintheformula1,whereinthecrystalformisacrystalformCM-A,acrystalformCM-B,acrystalformCM-C,acrystalformCM-D,acrystalformCM-E,acrystalformCM-F,acrystalformCM-GoracrystalformCM-I. Compared with Lanibrator solid, the Lanibrator crystal form has higher stability, lower hygroscopicity and better fluidity, and provides better choice for the development of the medicine containing Lanibrator.

Description

Lanifibror crystal form and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a crystal form of Lanifibronor and a preparation method thereof.

Background

Non-alcoholic steatohepatitis (NASH), an extremely developed form of non-alcoholic fatty liver, is defined as a steatosis phenomenon accompanied by inflammation and hepatocyte damage. NASH can lead to advanced liver fibrosis, cirrhosis, liver failure, and liver tumor production.

Lanibrator is a universal PPAR agonist, can generate balanced activation on PPARalpha and PPARdelta, can partially activate PPARgamma, and has good effectiveness and safety in clinical research of non-alcoholic steatohepatitis under the action of multiple mechanisms. The chemical name of the medicine is: 5-chloro-1- [ (6-benzothiazolyl) sulfonyl ]-1H-indole-2-butyric acid of formula: c (C) ₁₉ H ₁₅ ClN ₂ O ₄ S ₂ The molecular weight is: 434.92, cas number: 927961-18-0, the chemical structural formula is shown as formula (I):

polymorphic forms of a drug are a critical research context for drug discovery. Different crystal forms have different solubilities, dissolution rates and stability, and can obviously influence the bioavailability of the medicine, thereby leading to different clinical effects. Especially for poorly soluble drugs, the effect of the crystalline form is greater.

WO2007026097A1 discloses Lanibrator compounds and methods of preparing the same. This patent example 117 discloses that a pale yellow powder is obtained, but with a low melting point, only 74-80 ℃, and may have poor stability from the melting point.

Disclosure of Invention

To overcome the shortcomings of the prior art, the inventors of the present application have unexpectedly discovered that the present invention provides compound I crystalline forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G and CM-I. The preparation has advantages in at least one aspect of melting point, stability, solubility, hygroscopicity, in-vivo and in-vitro dissolution, bioavailability, compressibility, fluidity, preparation quality, processing performance and the like, particularly in the aspects of melting point, stability, hygroscopicity, fluidity, preparation tablet uniformity, preparation process operability and the like, provides a new better choice for the development of the medicine containing Lanifibroor, and has very important significance.

Especially, the crystal forms CM-A, CM-B, CM-F and CM-I have better solubility and fluidity compared with the prior art, and have important significance for subsequent preparation dissolution; the electrostatic effect is small, and the preparation is suitable for the production of preparations; the preparation method has the advantages of simple process, strong operability, high yield, stable quality, short production period and easy realization of large-scale production.

The invention aims to provide a novel Lanibrinor crystal form with high melting point and good stability so as to meet the requirements of drug development and application.

It is another object of the present invention to provide a method for preparing new crystalline forms of lanibranor suitable for formulation production.

In a first aspect of the present invention, there is provided a crystalline form of a compound of formula I, characterized in that,

the crystalline form is selected from the group consisting of: formCM-A,formCM-B,formCM-C,formCM-D,formCM-E,formCM-F,formCM-GorformCM-I.

inoneembodimentoftheinvention,thecrystallineformisformCM-A.

inapreferredembodiment,thexrpdpatternofcrystallineformCM-acomprises2ormore2θvaluesselectedfromthegroupconsistingof: 9.9 ° ± 0.2 °, 15.65 ° ± 0.2 °, 23.95 ° ± 0.2 °. morepreferably,thexrpdpatternofcrystallineformCM-afurthercomprises1ormore2θvaluesselectedfromthegroupconsistingof: 11.70 ° ± 0.2 °, 17.26 ° ± 0.2 °, 20.10 ° ± 0.2 °, 20.57 ° ± 0.2 °.

inanotherpreferredembodiment,thecrystallineformCM-ahasxrpdpatterndiffractionangle2θvaluescharacterizedbypeaksat9.90°±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°±0.2°,30.43°±0.2°and31.78°.

inanotherpreferredembodiment,thecrystallineformCM-ahasnosignificantloss-in-weightpeakat25℃to200℃.

inanotherpreferredembodiment,thecrystallineformofCM-Ahasanendothermicpeakat114.80℃and179.34℃.

inanotherpreferredembodiment,thecrystallineformCM-ahasxrpddatasubstantiallyasshownintablea.

inanotherpreferredembodiment,thecrystallineformCM-ahasanxrpdpatternsubstantiallyasshowninfigure1.

inanotherpreferredembodiment,thecrystallineformCM-ahasatgaprofilesubstantiallyasshowninfigure2.

inanotherpreferredembodiment,thecrystallineformCM-ahasadscprofilesubstantiallyasshowninfigure3.

inanotherpreferredembodiment,thecrystallineformCM-ahasa1hnmrspectrumsubstantiallyasshowninfig.4.

inanotherpreferredembodiment,thecrystallineformCM-aisabulkorrectangularparallelepipedcrystal.

In yet another embodiment of the present invention, the crystalline form is crystalline form CM-B.

In a preferred embodiment, the XRPD pattern of crystalline form CM-B comprises 2 or more 2θ values selected from the group consisting of: 7.75 ° ± 0.2 °, 10.89 ° ± 0.2 °, 20.18 ° ± 0.2 °, 22.18 ° ± 0.2 °. More preferably, the XRPD pattern of crystalline form CM-B further comprises 1 or more 2θ values selected from the group consisting of: 8.36 ° ± 0.2 °, 16.41 ° ± 0.2 °, 16.98 ° ± 0.2 °, 17.83 ° ± 0.2 °, 19.14 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-B has XRPD pattern diffraction angle 2θ values at 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 °, 27.45 ° ± 0.2 °, 27.27 ° ± 0.27 ° ± 0.63 ° ± 0.32 ° -2.32 ° -2 and a peak characteristic of 2.35 ° -2.32.2.2 °.

In another preferred embodiment, the crystalline form CM-B has no significant step in weight loss at 25 ℃ to 150 ℃.

In another preferred embodiment, the crystalline form CM-B has a melting endotherm at 178.97 ℃.

In another preferred embodiment, the crystalline form CM-B has XRPD data substantially as shown in table B.

In another preferred embodiment, the crystalline form CM-B has an XRPD pattern substantially as shown in figure 5.

In another preferred embodiment, the crystalline form CM-B has a TGA profile substantially as shown in figure 6.

In another preferred embodiment, the crystalline form CM-B has a DSC profile substantially as shown in figure 7.

In another preferred embodiment, the crystalline form CM-B has a 1H NMR spectrum substantially as shown in fig. 8.

In another preferred embodiment, the crystalline form CM-B is a fine needle-like crystal.

In yet another embodiment of the present invention, the crystalline form is crystalline form CM-F.

In a preferred embodiment, the XRPD pattern of crystalline form CM-F comprises 2 or more 2θ values selected from the group consisting of: 16.75 ° ± 0.2 °, 17.87 ° ± 0.2 °, 25.25 ° ± 0.2 °; more preferably, the XRPD pattern of crystalline form CM-F further comprises 1 or more 2θ values selected from the group consisting of: 19.16 ° ± 0.2 °, 20.14 ° ± 0.2 °, 21.11 ° ± 0.2 °, 22.20 ° ± 0.2 °, 24.09 ° ± 0.2 °, 24.40 ° ± 0.2 °.

In another preferred example, the crystalline form CM-F has XRPD pattern diffraction angle 2θ values at 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 ° ± 0.2 °, 29.60 ° ± 0.32 ° ± 0.25 ° ± 0.2 ° and 33.92 ° -2.

In another preferred embodiment, the crystalline form of CM-F has an endothermic peak at 178.50 ℃.

In another preferred embodiment, the crystalline form CM-F has no significant step in weight loss in the range of 25 ℃ to 200 ℃.

In another preferred embodiment, the crystalline form CM-F has XRPD data substantially as shown in table F.

In another preferred embodiment, the crystalline form CM-F has an XRPD pattern substantially as shown in figure 20.

In another preferred embodiment, the crystalline form CM-F has a TGA profile substantially as shown in figure 21.

In another preferred embodiment, the crystalline form CM-F has a DSC profile substantially as shown in figure 22.

In another preferred embodiment, the crystalline form CM-F has a 1H NMR spectrum substantially as shown in fig. 23.

In another preferred embodiment, the crystalline form CM-F is a bulk crystal.

In yet another embodiment of the present invention, the crystalline form is form CM-I.

In a preferred embodiment, the XRPD pattern of crystalline form CM-I comprises 2 or more 2θ values selected from the group consisting of: 7.83 ° ± 0.2 °, 9.70 ° ± 0.2 °, 18.43 ° ± 0.2 °; more preferably, the XRPD pattern of crystalline form CM-I further comprises 1 or more 2θ values selected from the group consisting of: 13.13 ° ± 0.2 °, 20.59 ° ± 0.2 °, 22.38 ° ± 0.2 °, 23.11 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-I has XRPD pattern diffraction angle 2θ values with characteristic peaks at 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 31.24 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-I has an endothermic peak at 138.07 ℃ and 176.11 ℃ each.

In another preferred embodiment, the crystalline form CM-I has a significant step in weight loss in the range of 100 ℃ to 175 ℃.

In another preferred embodiment, the crystalline form CM-I has XRPD data substantially as shown in table H.

In another preferred embodiment, the crystalline form CM-I has an XRPD pattern substantially as shown in figure 27.

In another preferred embodiment, the crystalline form CM-I has a TGA profile substantially as shown in figure 28.

In another preferred embodiment, the crystalline form CM-I has a DSC profile substantially as shown in figure 29.

In another preferred embodiment, the crystalline form CM-I has a 1H NMR spectrum substantially as shown in fig. 30.

In another preferred embodiment, the crystalline form CM-I is a short rod-like crystal.

In yet another embodiment of the present invention, the crystalline form is form CM-C.

In a preferred embodiment, the XRPD pattern of crystalline form CM-C comprises 2 or more 2θ values selected from the group consisting of: 9.38 ° ± 0.2 °, 10.20 ° ± 0.2 °, 24.42 ° ± 0.2 °; more preferably, the XRPD pattern of crystalline form CM-C further comprises 1 or more 2θ values selected from the group consisting of: 16.36 ° ± 0.2 °, 17.78 ° ± 0.2 °, 19.06 ° ± 0.2 °, 22.16 ° ± 0.2 °, 23.44 ° ± 0.2 °, 27.54 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-C has XRPD pattern diffraction angle 2θ values with characteristic peaks at 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 °.

In another preferred embodiment, the crystalline form CM-C has a significant step in weight loss at 100 ℃ to 200 ℃.

In another preferred embodiment, the crystalline form CM-C has a melting endotherm at 177.40 ℃.

In another preferred embodiment, the crystalline form CM-C has XRPD data substantially as shown in table C.

In another preferred embodiment, the crystalline form CM-C has an XRPD pattern substantially as shown in figure 9.

In another preferred embodiment, the crystalline form CM-C has a TGA profile substantially as shown in figure 10.

In another preferred embodiment, the crystalline form CM-C has a DSC profile substantially as shown in figure 11.

In another preferred embodiment, the crystalline form CM-C has a 1H NMR spectrum substantially as shown in fig. 12.

In yet another embodiment of the present invention, the crystalline form is form CM-D.

In a preferred embodiment, the XRPD pattern of crystalline form CM-D comprises 2 or more 2θ values selected from the group consisting of: 5.74 ° ± 0.2 °, 9.15 ° ± 0.2 °, 16.39 ° ± 0.2 °; more preferably, the XRPD pattern of crystalline form CM-D further comprises 1 or more 2θ values selected from the group consisting of: 11.54 ° ± 0.2 °, 14.70 ° ± 0.2 °, 18.27 ° ± 0.2 °, 20.55 ° ± 0.2 °, 23.67 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-D has XRPD pattern diffraction angle 2θ values with characteristic peaks at 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 °.

In another preferred embodiment, the crystalline form of CM-D has an endothermic peak at 53.27 ℃, 101.22 ℃, 122.63 ℃ and 171.01 ℃.

In another preferred embodiment, the crystalline form CM-D loses weight about 10.08% in the range of room temperature-75 ℃, about 2.20% in the range of 75-115 ℃, about 5.08% in the range of 115-165 ℃, and about 1.24% in the range of 165-210 ℃.

In another preferred embodiment, the crystalline form CM-D has XRPD data substantially as shown in table D.

In another preferred embodiment, the crystalline form CM-D has an XRPD pattern substantially as shown in figure 13.

In another preferred embodiment, the crystalline form CM-D has a TGA profile substantially as shown in figure 14.

In another preferred embodiment, the crystalline form CM-D has a DSC profile substantially as shown in figure 15.

In yet another embodiment of the present invention, the crystalline form is crystalline form CM-E.

In a preferred embodiment, the XRPD pattern of crystalline form CM-E comprises 2 or more 2θ values selected from the group consisting of: 11.50 ° ± 0.2 °, 17.33 ° ± 0.2 °, 18.63 ° ± 0.2 °; more preferably, the XRPD pattern of crystalline form CM-E further comprises 1 or more 2θ values selected from the group consisting of: 6.97 ° ± 0.2 °, 9.14 ° ± 0.2 °, 13.02 ° ± 0.2 °, 13.83 ° ± 0.2 °, 19.52 ° ± 0.2 °, 21.54 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-E has XRPD pattern diffraction angle 2θ values with characteristic peaks at 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 °, 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 °.

In another preferred embodiment, the crystalline form CM-E has one endothermic peak at 51.07 ℃, 95.75 ℃ and 166.19 ℃ each, and an exothermic seeding peak at 125.4 ℃.

In another preferred embodiment, the crystalline form CM-E loses weight about 11.13% in the range of room temperature-78 ℃, about 3.30% in the range of 78 ℃ -125 ℃, and about 1.05% in the range of 125 ℃ -210 ℃.

In another preferred embodiment, the crystalline form CM-E has XRPD data substantially as shown in table E.

In another preferred embodiment, the crystalline form CM-E has an XRPD pattern substantially as shown in figure 16.

In another preferred embodiment, the crystalline form CM-E has a TGA profile substantially as shown in figure 17.

In another preferred embodiment, the crystalline form CM-E has a DSC profile substantially as shown in figure 18.

In another preferred embodiment, the crystalline form CM-E has a 1H NMR spectrum substantially as shown in fig. 19.

In yet another embodiment of the present invention, the crystalline form is form CM-G.

In a preferred embodiment, the XRPD pattern of crystalline form CM-G comprises 2 or more 2θ values selected from the group consisting of: 17.95 ° ± 0.2 °, 18.42 ° ± 0.2 °, 20.96 ° ± 0.2 °; more preferably, the XRPD pattern of crystalline form CM-G comprises 2 theta values of 1 or more selected from the group consisting of: 6.09 ° ± 0.2 °, 8.16 ° ± 0.2 °, 9.27 ° ± 0.2 °, 9.82 ° ± 0.2 °, 15.72 ° ± 0.2 °, 19.72 ° ± 0.2 °.

In another preferred embodiment, the crystalline form CM-G has XRPD pattern diffraction angle 2θ values with characteristic peaks at 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 °, 29.40 ° ± 0.2 °, 30.13 ° ± 0.2 °, 31.85 ° ± 0.2 ° and 32.72 ° ± 0.2 °.

In another preferred embodiment, the crystalline form of CM-G has a desolvation peak at 54.94 ℃, a melt seeding peak at 92.04 ℃ and an endothermic melting peak at 176.39 ℃.

In another preferred embodiment, the crystalline form of CM-G loses weight about 20.56% in the range of 17 ℃ to 88 ℃, and loses weight about 2.75% in the range of 88 ℃ to 158 ℃.

In another preferred embodiment, the crystalline form CM-G has XRPD data substantially as shown in table G.

In another preferred embodiment, the crystalline form CM-G has an XRPD pattern substantially as shown in figure 24.

In another preferred embodiment, the crystalline form CM-G has a TGA profile substantially as shown in figure 25.

In another preferred embodiment, the crystalline form CM-G has a DSC profile substantially as shown in figure 26.

In a second aspect of the invention, there is provided a process for the preparation of a crystalline form according to the first aspect of the invention.

inoneembodimentofthepresentinvention,thecrystallineformisthecrystallineformCM-A,andthepreparationmethodthereofcomprisesthefollowingsteps:

(1) Providing Lanibror raw materials in a first solvent, mixing and stirring until the solution is clear (solution clear);

(2) andvolatilizingthesolutiontoseparateoutsolid,andcollectingthesolidtoobtainthecrystalformCM-A.

In a preferred embodiment, in step (1), 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; the ester solvent is ethyl acetate.

In another preferred example, the first solvent is a combination of a halogenated hydrocarbon solvent and an alcohol solvent, or a combination of a ketone solvent and an ester solvent. More preferably, the first solvent is: dichloromethane: methanol= (2-4): 1 (v/v), or, acetone: ethyl acetate= (0.5-2): (0.5-2) (v/v).

In another preferred embodiment, the first solvent is methylene chloride: methanol=3:1 (v/v).

In another preferred embodiment, the first solvent is acetone: ethyl acetate=1:1 (v/v).

In another preferred embodiment, the first solvent is 2-methyltetrahydrofuran.

In another preferred embodiment, step (1) is performed at room temperature.

In another preferred embodiment, in the step (1), the mass (g)/volume (mL) of the Lanibrator raw material and the first solvent is 1:10-100, preferably 1:10-50, more preferably 1:10-20.

In yet another embodiment of the present invention, the crystalline form is crystalline form CM-B, and the preparation method thereof comprises the steps of:

(1) Providing a lanibrior feedstock in a second solvent to form a mixture or solution comprising the lanibrior feedstock;

(2) Cooling the solution or continuously pulping the suspension;

(3) Allowing the solution to precipitate out a solid, and collecting the solid, thereby obtaining the crystal form CM-B.

In a preferred embodiment, 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.

In another preferred embodiment, step (1) is performed at room temperature.

In another preferred embodiment, the Lanibror feedstock and the second solvent have a mass (g)/volume (mL) of 1:10 to 50, preferably 1:20 to 40.

In yet another embodiment of the present invention, the crystalline form is crystalline form CM-F, and the preparation method thereof comprises the steps of:

(1) Providing Lanibror raw materials in a third solvent, mixing and stirring until the Lanibror raw materials are dissolved;

(2) Placing the solution in a water-containing container through a medium water-proof opening, and sealing the water-containing container;

(3) Allowing the solution to precipitate out a solid, and collecting the solid, thereby obtaining the crystalline form CM-F.

In a preferred embodiment, the third solvent is selected from the group consisting of: dimethyl sulfoxide (DMSO), N-N dimethylacetamide, N-methylpyrrolidone (NMP), or a combination thereof.

In another preferred embodiment, the third solvent is N-N dimethylacetamide.

In another preferred embodiment, the third solvent is dimethyl sulfoxide.

In another preferred embodiment, step (1) is performed at room temperature.

In another preferred embodiment, the Lanibror feedstock and the third solvent have a mass (g)/volume (mL) of 1:10 to 100, preferably 1:10 to 50, more preferably 1:10 to 20.

In another preferred embodiment, the medium is a glass vial.

In yet another embodiment of the present invention, the crystalline form is crystalline form CM-I, and the preparation method thereof comprises the steps of:

(1) Providing a lanibrior feedstock in a fourth solvent to form a mixture comprising the lanibrior feedstock;

(2) Adding a polymer or seed to the mixture to form a lanifibror solution containing the polymer or seed;

(3) Volatilizing the solution to separate out solid, and collecting the solid to obtain the crystal form CM-I.

In a preferred embodiment, the fourth solvent is an alcohol solvent and/or dichloromethane. More preferably, the alcoholic solvent is methanol and/or ethanol.

In another preferred embodiment, the fourth solvent is selected from the group consisting of dichloromethane: methanol= (2-4): 1 (v/v).

In another preferred embodiment, the fourth solvent is dichloromethane: methanol=3:1 (v/v).

In another preferred embodiment, the weight to volume ratio of the lanibror feedstock to the fourth solvent is 1:10 to 100, preferably 1:10 to 50, more preferably 1:10 to 20.

In another preferred example, the high polymer is polyvinyl alcohol and/or polyvinyl chloride.

inanotherpreferredembodiment,theseedcrystalsarecrystallineformsCM-Aand/orCM-I.

In another preferred embodiment, the seed or polymer is added in an amount of 0.3 to 10wt%, preferably 0.5 to 5wt% based on the mass of the Lanibror feedstock.

In another preferred embodiment, step (1) is performed at room temperature.

In another preferred embodiment, the solution is volatilized at a temperature of 20-80 ℃.

In another preferred embodiment, the volatilization time is 1 to 48 hours; preferably 2-36h; more preferably 3 to 24 hours.

In another preferred embodiment, an optional drying step is also included after the collection of solids.

In another preferred embodiment, the means for collecting the solids is filtration.

In a third aspect of the invention, there is provided a pharmaceutical composition comprising (a) an active ingredient which is a lanibranor crystal form according to the first aspect of the invention; and (b) a pharmaceutically acceptable carrier.

In another preferred embodiment, the dosage form of the pharmaceutical composition or formulation is selected from the group consisting of: powder for injection, capsule, granule, tablet, pill or injection.

In a fourth aspect of the invention there is provided the use of a crystalline form according to the first aspect of the invention, the use comprising: 1) Preparing a compound of formula (I) or a salt thereof; 2) Preparing the medicine for treating the nonalcoholic steatohepatitis.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG.1isanXRPDpatternforcrystallineformCM-AofLanibroraccordingtotheinvention.

FIG.2isaTGAspectrumofthecrystallineformCM-AofLanibroraccordingtothepresentinvention.

FIG.3isaDSCofcrystallineformCM-AofLanibroraccordingtothepresentinvention.

FIG.4isa1HNMRspectrumofthecrystallineformCM-AofLanibroraccordingtothepresentinvention.

FIG. 5 is an XRPD pattern for crystalline form CM-B of Lanibror according to the invention.

FIG. 6 is a TGA spectrum of the crystalline form CM-B of Lanibror according to the present invention.

FIG. 7 is a DSC of crystalline form CM-B of Lanibror according to the present invention.

FIG. 8 is a 1H NMR spectrum of the crystalline form CM-B of Lanibror according to the present invention.

FIG. 9 is an XRPD pattern for crystalline form CM-C of Lanibror according to the invention.

FIG. 10 is a TGA spectrum of the crystalline form CM-C of Lanibror according to the present invention.

FIG. 11 is a DSC of crystalline form CM-C of Lanibror according to the present invention.

FIG. 12 is a 1H NMR spectrum of the crystalline form CM-C of Lanibror according to the present invention.

FIG. 13 is an XRPD pattern for crystalline form CM-D of Lanibror according to the invention.

FIG. 14 is a TGA spectrum of the crystalline form CM-D of Lanibror according to the present invention.

FIG. 15 is a DSC of crystalline form CM-D of Lanibror according to the present invention.

FIG. 16 is an XRPD pattern for crystalline form CM-E of Lanibror according to the invention.

FIG. 17 is a TGA spectrum of the crystalline form CM-E of Lanibror according to the present invention.

FIG. 18 is a DSC of crystalline form CM-E of Lanibror according to the present invention.

FIG. 19 is a 1H NMR spectrum of the crystalline form CM-E of Lanibror according to the present invention.

FIG. 20 is an XRPD pattern for crystalline form CM-F of Lanibror according to the invention.

FIG. 21 is a TGA spectrum of the crystalline form CM-F of Lanibrator according to the present invention.

FIG. 22 is a DSC of crystalline form CM-F of Lanibror according to the present invention.

FIG. 23 is a 1H NMR spectrum of the crystalline form CM-F of Lanibrator according to the present invention.

FIG. 24 is an XRPD pattern for crystalline form CM-G of Lanibror according to the invention.

FIG. 25 is a TGA spectrum of the crystalline form CM-G of Lanibror according to the present invention.

FIG. 26 is a DSC of crystalline form CM-G of Lanibror according to the present invention.

FIG. 27 is an XRPD pattern for crystalline form CM-I of Lanibror according to the invention.

FIG. 28 is a TGA spectrum of the crystalline form CM-I of Lanibrator according to the present invention.

FIG. 29 is a DSC of crystalline form CM-I of Lanibror according to the present invention.

FIG. 30 is a 1H NMR spectrum of the crystalline form CM-I of Lanibrator according to the invention.

Detailed Description

The present inventors have conducted extensive studies and have provided a crystalline form CM-A, CM-B, CM-F, CM-I of the compound Lanifibror of formula (I). The 4 crystal forms have at least one advantage in the aspects of solubility, hygroscopicity, mechanical stability, tabletting stability, fluidity, process development, preparation development, purification effect, powder processing performance and the like. Based on the above findings, the inventors have completed the present invention.

Terminology

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In this document, each abbreviation is in a conventional sense as understood by those skilled in the art unless otherwise indicated.

As used herein, unless otherwise indicated, the term "lanifibronor feedstock" refers to the various solid forms of the compounds of formula lanifibronor (including the various crystalline or amorphous forms mentioned herein, and the crystalline or amorphous forms mentioned in various documents or patents, whether disclosed or not).

Preferably, the Lanibrator raw material used in the present invention is Lanibrator prepared according to the preparation method provided in the examples of the present invention.

As used herein, "crystalline forms of the invention" refer to the lanifibronor crystalline forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G and CM-I as described herein.

As used herein, means for "slow-joining" include, but are not limited to: dropwise adding slowly along the container wall.

As used herein, the term "room temperature" generally refers to 4-30 ℃, preferably 20±5 ℃.

Lanifibror crystal form

As used herein, "the 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-I as described herein.

inapreferredembodiment,thexrpdpatternofcrystallineformCM-acomprises4ormore2θvaluesselectedfromthegroupconsistingof: 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 °.

In a preferred embodiment, the XRPD pattern of crystalline form CM-B comprises 4 or more 2θ values selected from the group consisting of: 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 ° and 22.18 ° ± 0.2 °.

In a preferred embodiment, the XRPD pattern of crystalline form CM-F comprises 4 or more 2θ values selected from the group consisting of: 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 °.

In a preferred embodiment, the XRPD pattern of crystalline form CM-I comprises 4 or more 2θ values selected from the group consisting of: 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 °.

In a preferred embodiment, the XRPD pattern of crystalline form CM-D comprises 3 or more 2θ values selected from the group consisting of: 5.74 ° ± 0.2 °, 9.15 ° ± 0.2 °, 16.39 ° ± 0.2 °, 20.55 ° ± 0.2 °, 23.67 ° ± 0.2 °.

In a preferred embodiment, the XRPD pattern of crystalline form CM-E comprises 2 or more 2θ values selected from the group consisting of: 6.97 ° ± 0.2 °, 11.50 ° ± 0.2 °, 17.33 ° ± 0.2 °, 18.63 ° ± 0.2 °.

In a preferred embodiment, the XRPD pattern of crystalline form CM-G comprises 2 or more 2θ values selected from the group consisting of: 6.09 ° ± 0.2 °, 9.82 ° ± 0.2 °, 17.95 ° ± 0.2 °, 18.42 ° ± 0.2 °, 20.96 ° ± 0.2 °, 21.21 ° ± 0.2 °.

Pharmaceutical composition containing Lanibrchor crystal form

In another aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a lanibranor crystalline form according to the present invention, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. The auxiliary materials are, for example, odorants, flavoring agents, sweeteners and the like.

The pharmaceutical composition provided by the invention preferably contains 1-99% by weight of active ingredients, wherein the preferable proportion is that the compound shown in the general formula I is 65-99% by weight of the total weight of the active ingredients, and the rest is pharmaceutically acceptable carrier, diluent or solution or salt solution.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilization apparatus for injection or infusion.

The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the formulation formula comprises 1mg to 700mg of the compound of the general formula I, preferably 25mg to 300mg of the compound of the general formula I.

The compounds and pharmaceutical compositions of the present invention may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably orally. Most preferably, the daily dosage is 50-1400mg/kg body weight, taken at one time, or 25-700mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.

In the present invention, unless otherwise specified, the method used for drying is a conventional drying method in the art, for example, drying in the examples of the present invention means vacuum drying or normal pressure drying in a conventional drying oven. Typically, the drying is carried out for 0.1 to 50 hours or 1 to 30 hours.

Compared with the prior art, the invention has the main advantages that:

(1) The Lanibrator crystal form CM-A, CM-B, CM-F, CM-I has better thermal stability, pressure stability and chemical stability, and has important significance for preparation, namely storage of subsequent preparations;

(2) The Lanibrator crystal form CM-A, CM-B, CM-F, CM-I has better fluidity, smaller repose angle and low hygroscopicity, can meet the requirement of direct capsule filling, and is suitable for preparation production.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

General method

All the test methods of the invention are universal methods, and the test parameters are as follows:

XRPD pattern determination method:

the method comprises the following steps:

x-ray powder diffractometer: bruker D2 PhaseX-ray powder diffractometer; radiation source CuGenerator (producer) kv:30kv; generator (Generator) mA:10mA; starting 2θ:2.0 °, scan range: 2.0-35.0 deg.. The scanning speed is 0.1s/step, the step size is 0.02 DEG/step.

The second method is as follows:

x-ray powder diffractometer: bruker D2 PhaseX-ray powder diffractometer; radiation source CuGenerator (producer) kv:30kv; generator (Generator) mA:10mA; starting 2θ:2.0 °, scan range: 2.0-50.0 deg.. The scanning speed is 1s/step, the step size is 0.02 DEG/step.

TGA profile determination method:

thermogravimetric analysis (TGA) instrument: TGA55 type of TA company in America, 20-300 ℃ range, heating rate 10 ℃/min, nitrogen flow rate 40mL/min.

DSC determination method:

differential Scanning Calorimetry (DSC) instrument: TA Q2000 from TA company of America, heating rate of 10 ℃/min and nitrogen flow rate of 50mL/min at 25-300 ℃.

Determination of 1H-NMR Spectroscopy:

hydrogen nuclear magnetic resonance (1H-NMR) instrument Bruker Avance II DMX M HZ nuclear magnetic resonance spectrometer; frequency: 400MHz; solvent: deuterated DMSO.

Example 1: preparationofLanibratorCrystalformCM-A

Example 1-1

At room temperature, at 20mL dichloromethane: 500mg of Lanibrator compound was added to a methanol (3:1, v:v) mixture, and the solution was stirred until clear (solution clear) and then filtered through a filter membrane. The filtrate was left to evaporate the solvent at room temperature, and a solid was precipitated. filtering,anddryingthesolidtoobtaintheLanibratorcompoundcrystalformCM-A.

xrpdtestingwasperformedontheresultinglanibranorcompoundformCM-a,theresultsofwhichareshowninfig.1,andthepatterndataareshownintable1. theobtainedsolidissubjectedtoTGAtest,theresultisshowninfigure2,andtheresultshowsthattheTGAspectrumoftheLanibratorcrystalformCM-Ahasnoobviousweightlossstep,andthecrystalformisananhydroussubstance; the obtained solid was subjected to DSC measurement, the results of which are shown in FIG. 3, and the results of which show that it has the 1 st endothermic peak at 114.80 ℃and the 2 nd endothermic peak at 179.34 ℃; the obtained solid was subjected to 1H NMR test, and the results thereof are shown in FIG. 4. The solid microscope observation is a block or a cuboid.

Table A

2θ/°	Relative intensity
7.77±0.2	4.1％
9.90±0.2	100.0％
11.70±0.2	9.9％
12.62±0.2	2.0％
14.99±0.2	3.1％

15.65±0.2	56.8％
16.36±0.2	2.4％
17.26±0.2	21.2％
17.96±0.2	12.6％
18.49±0.2	14.3％
19.19±0.2	2.2％
20.10±0.2	28.6％
20.57±0.2	18.8％
21.48±0.2	18.8％
22.20±0.2	15.4％
22.60±0.2	8.9％
23.41±0.2	12.4％
23.95±0.2	65.0％
24.46±0.2	3.5％
25.02±0.2	70.3％
26.05±0.2	8.6％
26.71±0.2	39.5％
27.00±0.2	17.3％
27.32±0.2	6.4％
29.04±0.2	5.7％
30.01±0.2	6.4％
30.43±0.2	14.6％
31.78±0.2	2.3％

Examples 1 to 2

At room temperature, at 8mL acetone: to a mixed solvent of ethyl acetate (1:1, v:v) was added 100mg of the lanifibronor compound, which was rapidly stirred to dissolve, followed by filtration through a filter membrane. The filtrate was left to evaporate the solvent at room temperature, and a solid was precipitated. filtering,anddryingthesolidtoobtainthesolidwhichisthecrystalformCM-AoftheLanifibronorcompound.

Examples 1 to 3

100mg of Lanifibronor compound was added to 1.5mL of 2-methyltetrahydrofuran at room temperature, stirred rapidly until dissolved, and then filtered through a filter. The filtrate was added dropwise to 15mL of ethyl acetate at room temperature. After the dripping is finished, the mixture is moved into an environment of minus 20 ℃ and is continuously magnetically stirred for 24 hours, and solids are separated out. filtering,anddryingthesolidtoobtainthesolidwhichisthecrystalformCM-AoftheLanifibronorcompound.

Example 2: preparation of Lanibrator Crystal form CM-B

Example 2-1

100mgofLanibratorcrystallineformCM-Afromexample1-1wasaddedto2mLofMTBEatroomtemperatureandbeatenwithstirring. After beating for 1 day, the solid was filtered and dried, and the obtained solid was the lanifibror compound crystalline form CM-B.

XRPD testing was performed on the resulting lanibranor compound form CM-B, the results of which are shown in fig. 5, and the pattern data are shown in table 2. The obtained solid is subjected to TGA test, the result is shown in figure 6, and the result shows that the Lanibrator crystal form CM-B has no obvious weightlessness peak within the range of 25-150 ℃ in the TGA spectrum, and the crystal form is anhydrous; the obtained solid was subjected to DSC measurement, and the result is shown in FIG. 7, which shows that it has a melting endotherm at 178.97 ℃; the obtained solid was subjected to 1H NMR test, and the results thereof are shown in FIG. 8. The solid microscope observation was a fine needle.

Table B

2θ/°	Relative intensity
7.75±0.2	17.8％
8.36±0.2	8.0％
10.89±0.2	21.6％
13.99±0.2	7.8％
15.60±0.2	10.1％
16.41±0.2	30.4％
16.77±0.2	25.5％
16.98±0.2	40.8％
17.83±0.2	67.2％
19.14±0.2	30.3％
20.18±0.2	86.3％
21.15±0.2	30.4％
22.18±0.2	100.0％
22.50±0.2	14.0％
23.30±0.2	16.2％
24.02±0.2	28.6％
24.06±0.2	33.6％
24.47±0.2	68.7％
25.25±0.2	38.0％
25.55±0.2	22.8％
26.32±0.2	10.5％
26.68±0.2	4.9％

27.45±0.2	9.3％
27.63±0.2	11.4％
29.69±0.2	6.7％
32.27±0.2	5.7％
33.03±0.2	9.4％

Example 2-2

10mg of the lanifibronor compound was added to 0.4mL of anisole solvent at room temperature. Stirring for 24h, and separating out solid. The solid was filtered and dried, and the obtained solid was the crystalline form CM-B of the Lanibrator compound.

Examples 2 to 3

10mg of Lanibrator compound was added to 0.2mL of ethyl acetate at room temperature. Rapidly stirring to dissolve, and filtering with a filter membrane. Placing the filtrate in an environment of-20deg.C, standing for 24 hr, and separating out solid. The solid was filtered and dried, and the obtained solid was the crystalline form CM-B of the Lanibrator compound.

Example 3: preparation of Lanibrator Crystal form CM-C

Example 3-1

100mg of Lanifibronor compound was added to 2mL of 1, 4-dioxane at room temperature, stirred rapidly until dissolved, and then filtered through a filter membrane. The filtrate is placed in a 20mL glass bottle, 12mL of ethanol is added, and the mixture is placed at 20-25 ℃ for volatilization. Filtering, volatilizing the obtained solid, and placing the solid in a 60 ℃ oven for vacuum drying for 12 hours to obtain the Lanibrator crystal form CM-C.

XRPD testing was performed on the resulting lanibranor compound form CM-C, the results of which are shown in fig. 9, and the profile data are shown in table 3; the obtained solid was subjected to TGA test, the result of which is shown in FIG. 10, and the result shows that the Lanibrator crystal form CM-C has 2 obvious weight loss steps in the TGA spectrum, and the crystal form is a solvate; the obtained solid was subjected to DSC measurement, and the result is shown in FIG. 11, which shows that it has a melting endotherm at 177.40 ℃; the obtained solid was subjected to 1H NMR test, and the results thereof are shown in FIG. 12.

Table C

2θ/°	Relative intensity
9.38±0.2	78.7％
10.20±0.2	92.3％
16.36±0.2	39.3％
17.78±0.2	42.3％
19.06±0.2	33.3％
22.16±0.2	47.0％
23.44±0.2	23.0％

24.42±0.2	100.0％
27.54±0.2	31.8％

Example 4: preparation of Lanibrator Crystal form CM-D

Example 4-1

100mg of Lanifibronor compound was added to 2mL of 1, 4-dioxane at room temperature, stirred rapidly until dissolved, and then filtered through a filter membrane. Placing the filtrate into a 20mL glass bottle, adding 12mL of ethanol, volatilizing at 20-25 ℃ for 5D to obtain solid, filtering, and drying in a 25 ℃ oven for 12h to obtain Lanibrator crystal form CM-D.

XRPD testing was performed on the resulting lanibranor compound form CM-D, the results of which are shown in fig. 13, and the profile data are shown in table 4; the results of TGA testing of the resulting solid are shown in fig. 14, and show that the lanibranor crystal form CM-D has a TGA profile with about 10.08% weight loss at room temperature to 75 ℃, about 2.20% weight loss at 75 ℃ to 115 ℃, about 5.08% weight loss at 115 ℃ to 165 ℃ and about 1.24% weight loss at 165 ℃ to 210 ℃, which is a solvate; the obtained solid was subjected to DSC measurement, the result of which is shown in FIG. 15, and the result showed that it had one endothermic peak at 53.27 ℃, 101.22 ℃, 122.63 ℃ and 171.01 ℃.

In combination with TGA and DSC data, form CM-D is a solvate.

Table D

2θ/°	Relative intensity
5.74±0.2	60.80％
9.15±0.2	100.00％
11.54±0.2	11.90％
14.70±0.2	13.30％
16.39±0.2	48.10％
18.27±0.2	22.10％
20.55±0.2	38.00％
23.67±0.2	49.50％

Example 5: preparation of Lanibrator Crystal form CM-E

Example 5-1

To 10ml of 1, 4-dioxane was added 100mg of lanifibror compound at room temperature, and the mixture was stirred rapidly until dissolved, followed by filtration through a filter membrane. The filtrate was placed in a 20ml glass vial and the 20ml glass vial was placed in an environment of 20-25 ℃ and slowly evaporated for 24h. The resulting solid was the lanifibror compound form CM-E.

XRPD testing was performed on the resulting lanibranor compound crystalline form CM-E, the results of which are shown in fig. 16, and the profile data are shown in table 5; the results of TGA testing the obtained solid are shown in FIG. 17, and the results show that the weight loss in the TGA spectrum of the Lanibrator crystal form CM-E is about 11.13% in the range of room temperature to 78 ℃, about 3.30% in the range of 78 ℃ to 125 ℃ and about 1.05% in the range of 125 ℃ to 210 ℃, and the crystal form is a solvate; the obtained solid was subjected to DSC measurement, the result of which is shown in FIG. 18, and the result shows that each of the solid has an endothermic peak at 51.07 ℃, 95.75 ℃ and 166.19 ℃ and an exothermic crystal transformation peak at 125.39 ℃; the obtained solid was subjected to 1H NMR test, and the results thereof are shown in FIG. 19.

Combining TGA and nuclear magnetic data, lanibrator crystalline form CM-E is a 1, 4-dioxane solvate.

Table E

2θ/°	Relative intensity
6.97±0.2	12.00％
9.14±0.2	11.40％
11.50±0.2	54.90％
13.02±0.2	29.70％
13.83±0.2	7.10％
17.33±0.2	52.60％
18.63±0.2	100.00％
19.52±0.2	14.40％
21.54±0.2	9.00％
22.57±0.2	21.00％
23.15±0.2	31.00％
23.63±0.2	21.70％
24.51±0.2	17.60％
24.57±0.2	13.40％
25.46±0.2	13.90％
27.65±0.2	14.30％
28.92±0.2	8.00％
29.78±0.2	11.40％
32.32±0.2	6.80％

Example 6; preparation of Lanibrator Crystal form CM-F

Example 6-1

To 1ml of N-N dimethylacetamide was added 10mg of Lanibrator compound at room temperature, which was stirred rapidly until dissolved, and then filtered through a filter. The filtrate was placed in a 2ml glass vial and the 2ml glass vial was secured in the 20ml glass vial mouth with a raw material tape. A20 ml glass vial was filled with an appropriate amount of pure water and allowed to stand for one week to give a solid as the crystalline form CM-F of the Lanifibroor compound.

XRPD testing was performed on the resulting lanibranor compound crystalline form CM-F, the results of which are shown in fig. 20, and the profile data are shown in table 6; the resulting solid was subjected to TGA testing, the results of which are shown in fig. 21, and the results show that the laniferron crystal form CM-F loses about 1.49% of weight in the range of 25-200 ℃ in the TGA spectrum, and the crystal form is anhydrous; the obtained solid was subjected to DSC measurement, and the result is shown in FIG. 22, which shows that it has an endothermic peak at 178.50 ℃; the obtained solid was subjected to 1H NMR measurement, and the result thereof is shown in fig. 23; the solid microscopic observation was in the form of a block.

Table F

2θ/°	Relative intensity
7.76°±0.2°	6.5％
8.38±0.2°	10.3％
10.92±0.2°	4.3％
14.05±0.2	7.3％
15.69±0.2	4.4％
16.48±0.2	10.4％
16.75±0.2	42.0％
17.01±0.2	8.0％
17.87±0.2	58.8％
19.16±0.2	20.8％
20.14±0.2	26.3％
21.11±0.2	16.3％
22.20±0.2	71.2％
22.56±0.2	12.6％
23.30±0.2	13.5％
24.09±0.2	39.3％
24.40±0.2	40.6％
25.25±0.2	100.0％
25.58±0.2	12.1％
26.35±0.2	6.9％
27.57±0.2	12.1％
28.16±0.2	10.0％
29.60±0.2	4.9％
32.25±0.2	9.8％
33.92±0.2	10.7％

Example 6-2

10mg of Lanibrator compound was added to 1ml of dimethyl sulfoxide at room temperature, stirred rapidly until clear, and then filtered through a filter membrane. The filtrate was placed in a 2ml glass vial and the 2ml glass vial was secured in the 20ml glass vial mouth with a raw material tape. A20 ml glass vial was filled with an appropriate amount of pure water and allowed to stand for one week to give a solid as the crystalline form CM-F of the Lanifibroor compound.

Example 7: preparation of Lanibrator Crystal form CM-G

Example 7-1

100mg of Lanibrator compound was added to 20ml of chloroform at room temperature, stirred rapidly until dissolved, and then filtered through a filter membrane. The filtrate was placed in a 50ml single-necked flask, and the single-necked flask was sealed in an environment of-20℃to precipitate a solid. The resulting solid was the crystalline form CM-G of the Lanibrator compound.

XRPD testing was performed on the obtained lanibranor compound crystalline form CM-G, the results of which are shown in fig. 24, and the profile data are shown in table 7; the obtained solid was subjected to TGA test, the result of which is shown in FIG. 25, and the result shows that the weight loss in the TGA spectrum of the Lanibrator crystal form CM-G is about 20.56% in the range of 17-88 ℃, and about 2.75% in the range of 88-158 ℃, and the crystal form is a solvate; the obtained solid was subjected to DSC measurement, and the result is shown in FIG. 26, which shows that it has a desolvation peak at 54.94 ℃, a melting and crystal transformation peak at 92.04 ℃ and an endothermic melting peak at 176.39 ℃.

In combination with TGA and DSC data, form CM-G is a chloroform solvate.

Table G

2θ/°	Relative intensity
6.09±0.2	12.10％
8.16±0.2	16.30％
9.27±0.2	8.50％
9.82±0.2	28.20％
15.72±0.2	13.70％
17.95±0.2	100.00％
18.42±0.2	81.30％
19.72±0.2	16.70％
20.96±0.2	30.50％
21.21±0.2	27.20％
21.76±0.2	8.90％
27.91±0.2	18.60％
28.26±0.2	16.80％
29.40±0.2	12.60％
30.13±0.2	9.50％
31.85±0.2	8.50％
32.72±0.2	14.20％

Example 8: preparation of Lanibrator Crystal form CM-I

Example 8-1

At room temperature, at 10ml DCM: to methanol (3:1, v:v) was added 100mg of Lanibrator compound, stirred rapidly to dissolve, and then filtered through a filter. The filtrate was placed in a 20ml glass bottle, and 0.01g of polyvinyl alcohol was added. And standing at room temperature to volatilize the solvent, and separating out solid, wherein the obtained solid is the Lanibrator compound crystal form CM-I.

XRPD testing was performed on the resulting lanibranor compound form CM-I, the results of which are shown in fig. 27, and the profile data are shown in table 6; the obtained solid was subjected to TGA test, the result of which is shown in FIG. 28, and the result shows that the TGA spectrum of the Lanibrator crystal form CM-I loses weight by 2.8% at 100-175 ℃, and the result of which is shown in FIG. 29, and the result shows that the obtained solid has the 1 st endothermic peak at 138.07 ℃ and the 2 nd endothermic peak at 176.11 ℃; the obtained solid was subjected to 1H NMR measurement, and the result thereof is shown in fig. 30; the solid microscope was observed to be a short bar.

Table H

2θ/°	Relative intensity
2.50±0.2	6.00％
7.83±0.2	38.60％
9.70±0.2	40.10％
13.13±0.2	27.20％
15.76±0.2	3.70％
18.43±0.2	100.00％
20.59±0.2	26.30％
22.38±0.2	26.70％
23.11±0.2	41.00％
24.13±0.2	23.00％
25.32±0.2	58.10％
26.30±0.2	5.90％
29.62±0.2	5.90％
31.24±0.2	5.80％

Example 8-2

At room temperature, at 10ml DCM: to methanol (3:1, v:v) was added 100mg of Lanibrator compound, stirred rapidly to dissolve, and then filtered through a filter. The filtrate was placed in a 20ml centrifuge tube, and 0.01g of polyvinyl chloride was added to the centrifuge tube. The solvent was evaporated under stirring at room temperature, and a solid was precipitated, and the obtained solid was the crystalline form CM-I of the Lanibrator compound.

Examples 8 to 3

At room temperature, at 10ml DCM: to methanol (3:1, v:v) was added 100mg of Lanibrator compound, stirred rapidly to dissolve, and then filtered through a filter. The filtrate was placed in a 20ml centrifuge tube, and 0.001g of seed crystals obtained in the same manner as in example 8-1 were added to the centrifuge tube. The solvent was evaporated at room temperature and a solid was precipitated, and the obtained solid was the crystalline form CM-I of the Lanibrator compound.

Effect examples

1. Melting point comparison

thesolidmeltingpointsofthesamplesofcrystallineformCM-A(example1-1),crystallineformCM-B(example2-1),crystallineformCM-F(example6-1)andCM-I(example8-1)werecomparedwiththoseofexample117inWO2007026097. The results are shown in Table 1.

TABLE 1 comparison of melting points of different crystal forms

From the above examples, it was found that the CM-A, CM-B, CM-F and CM-I of the present invention have higher melting points and better thermal stability than the solid of example 117 of patent WO 2007026097.

2. Stability investigation

samplesofcrystallineformCM-A(example1-1),crystallineformCM-B(example2-1),crystallineformCM-F(example6-1)andCM-I(example8-1)wereleftopenat25℃/60%RH,40℃/75%RHand60℃/92.5%RH,respectively,andground; samples after standing or grinding were taken and tested for XRPD and HPLC, respectively, and the crystal form stability conditions are shown in tables 2 and 3.

TABLE 2 stability at 25 ℃/60% RH and 40 ℃/75% RH conditions

TABLE 3 stability of the different crystalline forms at 60 ℃/92.5% RH

From the above examples, it can be found that the crystalline forms CM-A, CM-F and CM-I and the crystalline form CM-B of the invention have better crystal form stability and chemical stability under the conditions of 25 ℃/60% RH, 40 ℃/75% RH and 60 ℃/92.5% RH, and the stability of the crystalline form under pressure is good.

3. Stability of crystalline forms in solution

100mgofeachofthecrystallineformCM-A(example1-1),thecrystallineformCM-B(example2-1),thecrystallineformCM-F(example6-1)andthecrystallineformCM-I(example8-1)wasaddedtoeachofthe4dissolutionmedia(pH1.2,pH4.0,pH6.8andpurifiedwater)buffersolutions,stirredat37℃for2hours,andXRDwasdetectedasasolid,andthedetectionresultsareshowninTable4.

TABLE 4 Crystal form stability of different Crystal forms in 4 dissolution media

From the above examples, it can be found that the crystalline forms CM-A, CM-F and CM-I and CM-B of the present invention have good crystal form stability in 4 buffer media.

4. Suspension competition

samplesofcrystallineformCM-A(example1-1),crystallineformCM-B(example2-1)andCM-I(example8-1)weresubjectedtosuspensioncompetitionexperiments,andthedifferentcrystallineformswereslurriedindifferentsolventsatroomtemperaturefor3daysafterbeingmixedinamassratioof1:1. The test results are shown in Table 5.

TABLE 5 suspension competition experiments between different crystal forms

From the above examples, it can be seen that the crystalline form CM-B of the present invention is thermodynamically stable at room temperature, and that other crystalline forms can be induced to convert to crystalline form CM-B by CM-B in different solvents.

5. Angle of repose test

powderreposeanglesweremeasuredforformCM-A(example1-1),formCM-B(example2-1),formCM-F(example6-1)andformCM-I(example8-1)accordingtotheChinesepharmacopoeiamethod,andtheresultsareshowninTable6.

TABLE 6 Angle of repose data for different crystal forms

Crystal form	Angle of repose
CrystalformCM-A	28.4°
Crystal form CM-B	44.6°
Crystal form CM-F	34.1°
Crystal form CM-I	35.0°

theresultsshowthatthecrystalformsCM-A,CM-FandCM-IhavesmallerreposeanglerelativetothecrystalformCM-B,havebetterfluidityandaremorebeneficialtoformulationdevelopment.

6. Moisture absorption detection

thehygroscopicitytestwasperformedonformCM-A(example1-1),formCM-B(example2-1),formCM-F(example6-1)andformCM-I(example8-1)accordingtotheChinesepharmacopoeiamethod,andtheresultsareshowninTable7.

TABLE 7 hygroscopicity data for different crystal forms

Crystal form	Moisture permeability
CrystalformCM-A	0.19％
Crystal form CM-B	2.5％
Crystal form CM-F	0.40％
Crystal form CM-I	0.80％

theresultsshowthatthecrystalformCM-Ahasalmostnohygroscopicity,thecrystalformsCM-FandCM-Ihaveslightlyhygroscopicity,andthecrystalformCM-Bhashygroscopicity. thecrystalformsCM-A,CM-FandCM-IhavelowerhygroscopicitycomparedwiththecrystalformCM-B,andareconvenienttostoreandtransport.

7. Comparison of the feasibility of direct Capsule filling

accordingtotheprescriptionofTable8,amixturecomprisingthecrystallineformsCM-A(example1-1),CM-B(example2-1),CM-F(example6-1)andCM-I(example8-1)ofthepresentinventionandthefollowingproportionsofauxiliarymaterialswasprepared,theanglesofreposeofthemixturesofthedifferentcrystallineformswereexamined,andthefeasibilityofdirectcapsulefillingwascomparedforthedifferentcrystallineforms.

Table 8 prescription composition

Composition of the components	Single dose (mg/grain)
API	100mg
Microcrystalline cellulose	150mg
Lactose and lactose	45mg
Talc powder	5mg
Totals to	300mg

TABLE 9 Angle of repose for mixtures of different crystal forms

Crystal form	Angle of repose
CrystalformCM-A	31°
Crystal form CM-B	48°
Crystal form CM-F	36°
Crystal form CM-I	37°

ascanbeseenfromthedataintable9,afterthedifferentcrystalformsaremixedwiththeauxiliarymaterials,thereposeangleofthemixtureofthecrystalformCM-ais31degrees,andthefluidityofthemixturecompletelymeetstherequirementofdirectlyfillingcapsules. The angles of repose of the crystalline form CM-F mixture and the CM-I mixture are 36 DEG and 37 DEG, and the fluidity thereof meets the requirement of directly filling capsules. The angle of repose of the crystal form CM-B mixture is 48 degrees, and the fluidity is poor, so that the requirement of directly filling capsules cannot be met.

therefore,thecrystallineformCM-A,thecrystallineformCM-FandthecrystallineformCM-IhaveobviousflowabilityadvantagerelativetothecrystallineformCM-Bafterbeingmixedwithauxiliarymaterials,canbedirectlyfilledintocapsules,donotneedtocarryoutpreparationgranulatingoperation,simplifypreparationprocessflowandimprovepreparationproductionefficiency.

8. Tablet examples

Each of the crystalline forms of the present invention may be prepared as a tablet according to the formulation recipe of table 10 below.

Tablet prescription (100 mg)

Table 10 prescription composition

Composition of the components	Single dose (mg/grain)
API	100mg
Microcrystalline cellulose	135mg
Lactose and lactose	45mg
Hydroxypropyl methylcellulose	15mg
Talc powder	5mg
Totals to	250mg

The preparation method comprises the following steps: mixing Lanibror with microcrystalline cellulose and lactose, sieving with 80 mesh sieve, adding hydroxypropyl methylcellulose water solution to make soft mass, sieving with 20 mesh sieve, granulating, drying, adding pulvis Talci, mixing, and tabletting.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

A crystal form of a compound shown in a formula I is characterized in that,

the crystalline form is selected from the group consisting of: formCM-A,formCM-B,formCM-C,formCM-D,formCM-E,formCM-F,formCM-GorformCM-I.
The crystalline form of claim 1, wherein,

thecrystallineformiscrystallineformCM-a,andthexrpdpatternofthecrystallineformCM-acomprises2ormore2θvaluesselectedfromthegroupconsistingof: 9.9 ° ± 0.2 °, 15.65 ° ± 0.2 °, 23.95 ° ± 0.2 °;

the crystalline form is crystalline form CM-B, and the XRPD pattern of the crystalline form CM-B comprises 2 or more 2θ values selected from the group consisting of: 7.75 ° ± 0.2 °, 10.89 ° ± 0.2 °, 20.18 ° ± 0.2 °, 22.18 ° ± 0.2 °;

the crystalline form is crystalline form CM-F, and the XRPD pattern of the crystalline form CM-F comprises 2 or more 2θ values selected from the group consisting of: 16.75 ° ± 0.2 °, 17.87 ° ± 0.2 °, 25.25 ° ± 0.2 °;

The crystalline form is crystalline form CM-I, and the XRPD pattern of the crystalline form CM-I comprises 2 or more 2θ values selected from the group consisting of: 7.83 ° ± 0.2 °, 9.70 ° ± 0.2 °, 18.43 ° ± 0.2 °.
thecrystallineformofclaim2,whereinthecrystallineformisformCM-a,andthecrystallineformCM-afurtherhasoneormoreofthefollowingfeatures:

(1) thexrpdpatternofcrystallineformCM-acomprises1ormore2θvaluesselectedfromthegroupconsistingof: 11.70 ° ± 0.2 °, 17.26 ° ± 0.2 °, 20.10 ° ± 0.2 °, 20.57 ° ± 0.2 °;

(2) thexrpdpatterndiffractionangle2θvaluesofthecrystallineformCM-aarecharacterizedbypeaksat9.90°±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°±0.2°,30.43°±0.2°and31.78°±0.2°;

(3) thecrystalformCM-Ahasanendothermicpeakat114.80℃and179.34℃;

(4) thecrystallineformCM-ahasxrpddatasubstantiallyasshownintablea;

(5) thecrystallineformCM-ahasanxrpdpatternsubstantiallyasshowninfigure1;

(6) thecrystallineformCM-ahasatgaprofilesubstantiallyasshowninfigure2;

(7) thecrystallineformCM-ahasadscprofilesubstantiallyasshowninfigure3;

(8) thecrystallineformCM-ahasa1hnmrspectrumsubstantiallyasshowninfig.4;

(9) thecrystalformCM-Aisablockorcuboidcrystal.
The crystalline form of claim 2, wherein the crystalline form is form CM-B, and wherein the crystalline form CM-B further has one or more of the following features:

(1) The XRPD pattern of crystalline form CM-B comprises 1 or more 2θ values selected from the group consisting of: 8.36 ° ± 0.2 °, 16.41 ° ± 0.2 °, 16.98 ° ± 0.2 °, 17.83 ° ± 0.2 °, 19.14 ° ± 0.2 °;

(2) The XRPD pattern diffraction angle 2θ values of the crystalline form CM-B are characterized by peaks at 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 °, 27.45 ° ± 0.2 °, 27.63 ° ± 0.2 °, 27.32 ° ± 0.32 ° ± 0.2 °;

(3) The crystal form CM-B has an endothermic peak at 178.97 ℃;

(4) The crystalline form CM-B has XRPD data substantially as shown in table B;

(5) The crystalline form CM-B has an XRPD pattern substantially as shown in figure 5;

(6) The crystalline form CM-B has a TGA profile substantially as shown in figure 6;

(7) The crystalline form CM-B has a DSC profile substantially as shown in figure 7;

(8) The crystalline form CM-B has a 1H NMR spectrum substantially as shown in fig. 8;

(9) The crystal form CM-B is a fine needle-like crystal.
The crystalline form of claim 2, wherein the crystalline form is form CM-F, and the crystalline form CM-F further has one or more of the following features:

(1) The XRPD pattern of crystalline form CM-F comprises 1 or more 2θ values selected from the group consisting of: 19.16 ° ± 0.2 °, 20.14 ° ± 0.2 °, 21.11 ° ± 0.2 °, 22.20 ° ± 0.2 °, 24.09 ° ± 0.2 °, 24.40 ° ± 0.2 °;

(2) The XRPD pattern diffraction angle 2θ values of the crystalline form CM-F are characterized by peaks at 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 ° ± 0.2 °, 29.60 ° ± 0.2 °, 32.25 ° ± 0.2 °, and 33.92 ° ± 0.2 °;

(3) The crystal form CM-F has an endothermic peak at 178.50 DEG C

(4) The crystalline form CM-F has XRPD data substantially as shown in table F;

(5) The crystalline form CM-F has an XRPD pattern substantially as shown in figure 20;

(6) The crystalline form CM-F has a TGA profile substantially as shown in figure 21;

(7) The crystalline form CM-F has a DSC profile substantially as shown in figure 22;

(8) The crystalline form CM-F has a 1H NMR spectrum substantially as shown in figure 23;

(9) The form CM-F is a bulk crystal.
The crystalline form of claim 2, wherein the crystalline form is form CM-I, and wherein the crystalline form CM-I further has one or more of the following features:

(1) The XRPD pattern of crystalline form CM-I comprises 1 or more 2θ values selected from the group consisting of: 13.13 ° ± 0.2 °, 20.59 ° ± 0.2 °, 22.38 ° ± 0.2 °, 23.11 ° ± 0.2 °;

(2) The XRPD pattern diffraction angle 2θ values of the crystalline form CM-I have characteristic peaks at 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 31.24 ° ± 0.2 °;

(3) The crystal form CM-I has an endothermic peak at 138.07 ℃ and 176.11 ℃;

(4) The crystalline form CM-I has XRPD data substantially as shown in table H;

(5) The crystalline form CM-I has an XRPD pattern substantially as shown in figure 27;

(6) The crystalline form CM-I has a TGA profile substantially as shown in figure 28;

(7) The crystalline form CM-I has a DSC profile substantially as shown in figure 29;

(8) The crystalline form CM-I has a 1H NMR spectrum substantially as shown in figure 30;

(9) The form CM-I is a short rod-like crystal.
The crystalline form of claim 1, wherein,

the crystalline form is crystalline form CM-C, and the XRPD pattern of the crystalline form CM-C comprises 2 or more 2θ values selected from the group consisting of: 9.38 ° ± 0.2 °, 10.20 ° ± 0.2 °, 24.42 ° ± 0.2 °;

the crystalline form is crystalline form CM-D, and the XRPD pattern of the crystalline form CM-D comprises 2 or more 2θ values selected from the group consisting of: 5.74 ° ± 0.2 °, 9.15 ° ± 0.2 °, 16.39 ° ± 0.2 °;

the crystalline form is crystalline form CM-E and the XRPD pattern of the crystalline form CM-E comprises 2 or more 2θ values selected from the group consisting of: 11.50 ° ± 0.2 °, 17.33 ° ± 0.2 °, 18.63 ° ± 0.2 °;

the crystalline form is crystalline form CM-G, and the XRPD pattern of the crystalline form CM-G comprises 2 or more 2θ values selected from the group consisting of: 17.95 ° ± 0.2 °, 18.42 ° ± 0.2 °, 20.96 ° ± 0.2 °.
A process for the preparation of a crystalline form according to any one of claims 1 to 6, wherein the process is any one of the following processes (i) to (iv);

(i) thecrystalformisacrystalformCM-A,andcomprisesthefollowingsteps:

(1) Providing Lanibror raw materials in a first solvent, mixing and stirring until the solution is clear;

(2) volatilizingthesolutiontoseparateoutsolid,collectingthesolidtoobtainthecrystalformCM-A,

(ii) The crystal form is a crystal form CM-B, and comprises the following steps:

(1) Providing a lanibrior feedstock in a second solvent to form a mixture or solution comprising the lanibrior feedstock;

(2) Cooling the solution or continuously pulping the suspension;

(3) Allowing the solution to precipitate out solids, collecting the solids, thereby obtaining the crystalline form CM-B,

(iii) The crystal form is CM-F, and comprises the following steps:

(1) Providing Lanibror raw materials in a third solvent, mixing and stirring until the Lanibror raw materials are dissolved;

(2) Placing the solution in a water-containing container through a medium water-proof opening, and sealing the water-containing container;

(3) Allowing the solution to precipitate out solids, collecting the solids, thereby obtaining the crystalline form CM-F,

(iv) The crystal form is a crystal form CM-I, and comprises the following steps:

(1) Providing a lanibrior feedstock in a fourth solvent to form a mixture comprising the lanibrior feedstock;

(2) Adding a polymer or seed to the mixture to form a lanifibror solution containing the polymer or seed;

(3) Volatilizing the solution to separate out solid, and collecting the solid to obtain the crystal form CM-I.
The process for preparing a crystalline form of claim 8, wherein in process (i), the first solvent is selected from the group consisting of: ketone solvents, alcohol solvents, ester solvents, 2-methyltetrahydrofuran, or combinations thereof; or the first solvent is a combination of halogenated hydrocarbon solvents and alcohol solvents;

in the method (i), the mass (g)/volume (mL) of the Lanibror raw material and the first solvent is 1:10-100;

in the method (ii), the second solvent is an ether solvent and/or an ester solvent;

in the method (ii), the mass (g)/volume (mL) of the Lanibror raw material and the second solvent is 1:10-50;

in method (iii), the third solvent is selected from the group consisting of: dimethyl sulfoxide, N-N dimethylacetamide, N-methylpyrrolidone, or a combination thereof;

in the method (iii), the mass (g)/volume (mL) of the Lanibror raw material and the third solvent is 1:10-100;

in the method (iv), the fourth solvent is an alcohol solvent and/or dichloromethane;

in the method (iv), the mass (g)/volume (mL) of the Lanibror raw material and the fourth solvent is 1:10-100;

in method (iv), the polymer is polyvinyl alcohol and/or polyvinyl chloride; and/or the number of the groups of groups,

In the method (iv), the seed crystal or the polymer is added in an amount of 0.3 to 10wt% based on the mass of the Lanibror raw material.
A pharmaceutical composition comprising (a) an active ingredient which is a lanifibronor crystalline form according to claim 1; and (b) a pharmaceutically acceptable carrier.
Use of the crystalline form of claims 1-9, wherein the use comprises: 1) Preparing a compound of formula (I) or a salt thereof; 2) Preparing the medicine for treating the nonalcoholic steatohepatitis.