WO2022258060A1 - Crystal form of lanifibranor and preparation method therefor - Google Patents

Abstract

Provided in the present invention are a crystal form of Lanifibranor and a preparation method therefor. Specifically, provided in the present invention is a crystal form of a compound as represented by formula 1. The crystal form is the crystal form CM-A, the crystal form CM-B, the crystal form CM-C, the crystal form CM-D, the crystal form CM-E, the crystal form CM-F, the crystal form CM-G or the crystal form CM-I. Compared with the Lanifibranor solid, the crystal form of Lanifibranor of the present invention has a higher stability, a lower hygroscopicity and a better fluidity, and provides a better choice for the development of a drug containing Lanifibranor.

Description

A kind of crystal form of Lanifibranor and preparation method thereof technical field

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

Background technique

Nonalcoholic steatohepatitis (NASH) 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 PPARα and PPARδ, and can partially activate PPARγ. 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):

For drug development, 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. Especially for poorly soluble drugs, 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.

Contents of the invention

In order to overcome the shortcomings of the prior art, 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.

Especially the crystalline forms 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.

In one embodiment of the present invention, the crystalline form is crystalline form CM-A.

In a preferred example, the XRPD pattern of the crystalline form CM-A includes 2 or more 2θ 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 2θ values selected from the following group: 11.70°±0.2°, 17.26°±0.2°, 20.10°±0.2°, 20.57° ±0.2°.

In another preferred example, the diffraction angle 2θ 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°.

In another preferred example, the crystal form CM-A has no obvious weight loss peak at 25°C-200°C.

In another preferred example, the crystal form CM-A has an endothermic peak at 114.80°C and 179.34°C respectively.

In another preferred example, the crystalline form CM-A has XRPD data substantially as shown in Table A.

In another preferred example, the crystalline form CM-A has an XRPD spectrum substantially as shown in FIG. 1 .

In another preferred example, the crystalline form CM-A has a TGA spectrum substantially as shown in FIG. 2 .

In another preferred example, the crystalline form CM-A has a DSC spectrum substantially as shown in FIG. 3 .

In another preferred example, the crystalline form CM-A has a 1H NMR spectrum substantially as shown in FIG. 4 .

In another preferred example, the crystal form CM-A is block or cuboid crystal.

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

In a preferred example, the XRPD pattern of the crystalline form CM-B includes 2 or more 2θ 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 2θ 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°.

In another preferred example, the diffraction angle 2θ 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°.

In another preferred example, the crystal form CM-B has no obvious weight loss step at 25°C-150°C.

In another preferred example, the crystal form CM-B has a melting endothermic peak at 178.97°C.

In another preferred example, the crystal form CM-B has XRPD data substantially as shown in Table B.

In another preferred example, the crystal form CM-B has an XRPD spectrum substantially as shown in FIG. 5 .

In another preferred example, the crystal form CM-B has a TGA spectrum substantially as shown in FIG. 6 .

In another preferred example, the crystalline form CM-B has a DSC spectrum substantially as shown in FIG. 7 .

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

In another preferred example, the crystal form CM-B is a fine needle crystal.

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

In a preferred example, the XRPD pattern of the crystalline form CM-F includes 2 or more 2θ 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 2θ 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°.

In another preferred example, the diffraction angle 2θ 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°.

In another preferred example, the crystalline form CM-F has an endothermic peak at 178.50°C.

In another preferred example, the crystal form CM-F has no obvious weight loss step in the range of 25°C-200°C.

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

In another preferred example, the crystalline form CM-F has an XRPD spectrum substantially as shown in FIG. 20 .

In another preferred example, the crystalline form CM-F has a TGA spectrum substantially as shown in FIG. 21 .

In another preferred example, the crystalline form CM-F has a DSC spectrum substantially as shown in FIG. 22 .

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

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

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

In a preferred example, the XRPD pattern of the crystalline form CM-I includes 2 or more 2θ values selected from the following group: 7.83°±0.2°, 9.70°±0.2°, 18.43°±0.2°; more Preferably, the XRPD pattern of the crystalline form CM-I also includes one or more 2θ values selected from the following group: 13.13°±0.2°, 20.59°±0.2°, 22.38°±0.2°, 23.11°± 0.2°.

In another preferred example, the diffraction angle 2θ 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°.

In another preferred example, the crystalline form CM-I has an endothermic peak at 138.07°C and 176.11°C respectively.

In another preferred example, the crystal form CM-I has obvious weight loss steps in the range of 100°C-175°C.

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

In another preferred example, the crystalline form CM-I has an XRPD spectrum substantially as shown in FIG. 27 .

In another preferred example, the crystalline form CM-I has a TGA spectrum substantially as shown in FIG. 28 .

In another preferred example, the crystalline form CM-I has a DSC spectrum substantially as shown in FIG. 29 .

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

In another preferred example, the crystal form CM-I is a short rod crystal.

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

In a preferred example, the XRPD pattern of the crystalline form CM-C includes 2 or more 2θ 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 2θ 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°.

In another preferred example, the diffraction angle 2θ 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.

In another preferred example, the crystalline form CM-C has an obvious weight loss step at 100°C-200°C.

In another preferred example, the crystalline form CM-C has a melting endothermic peak at 177.40°C.

In another preferred example, the crystal form CM-C has XRPD data substantially as shown in Table C.

In another preferred example, the crystalline form CM-C has an XRPD spectrum substantially as shown in FIG. 9 .

In another preferred example, the crystalline form CM-C has a TGA spectrum substantially as shown in FIG. 10 .

In another preferred example, the crystalline form CM-C has a DSC spectrum substantially as shown in FIG. 11 .

In another preferred example, 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 crystalline form CM-D.

In a preferred example, the XRPD pattern of the crystalline form CM-D includes 2 or more 2θ 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 2θ 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°.

In another preferred example, the diffraction angle 2θ 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.

In another preferred example, the crystalline form CM-D has an endothermic peak at 53.27°C, 101.22°C, 122.63°C and 171.01°C.

In another preferred example, 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.

In another preferred example, the crystal form CM-D has XRPD data substantially as shown in Table D.

In another preferred example, the crystalline form CM-D has an XRPD spectrum substantially as shown in FIG. 13 .

In another preferred example, the crystalline form CM-D has a TGA spectrum substantially as shown in FIG. 14 .

In another preferred example, the crystalline form CM-D has a DSC spectrum substantially as shown in FIG. 15 .

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

In a preferred example, the XRPD pattern of the crystalline form CM-E includes 2 or more 2θ 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 2θ 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°.

In another preferred example, the diffraction angle 2θ 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°.

In another preferred example, 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.

In another preferred example, 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.

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

In another preferred example, the crystalline form CM-E has an XRPD spectrum substantially as shown in FIG. 16 .

In another preferred example, the crystalline form CM-E has a TGA spectrum substantially as shown in FIG. 17 .

In another preferred example, the crystalline form CM-E has a DSC spectrum substantially as shown in FIG. 18 .

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

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

In a preferred example, the XRPD pattern of the crystalline form CM-G includes 2 or more 2θ 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 2θ 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°.

In another preferred example, the diffraction angle 2θ 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°.

In another preferred example, 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.

In another preferred example, 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.

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

In another preferred example, the crystalline form CM-G has an XRPD spectrum substantially as shown in FIG. 24 .

In another preferred example, the crystalline form CM-G has a TGA spectrum substantially as shown in FIG. 25 .

In another preferred example, 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.

In one embodiment of the present invention, the crystal form is crystal form CM-A, and its preparation method includes the following steps:

(1) Provide Lanifibranor raw materials in a first solvent, mix and stir until the solution is clear (dissolved);

(2) The solution is volatilized to precipitate a solid, and the solid is collected to obtain the crystal form CM-A.

In a preferred example, 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; and 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: methylene chloride: methanol = (2-4): 1 (v/v), or acetone: ethyl acetate = (0.5-2): (0.5-2) ( v/v).

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

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

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

In another preferred example, step (1) is carried out at room temperature.

In another preferred example, in step (1), 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.

In yet another embodiment of the present invention, the crystal form is crystal form CM-B, and its preparation method includes the following steps:

(1) Lanifibranor raw material is provided in a second solvent to form a mixture or solution containing Lanifibranor raw material;

(2) Cool the solution or continue beating the suspension;

(3) Precipitating solids from the solution and collecting the solids to obtain the crystal form CM-B.

In a preferred example, 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 example, step (1) is carried out at room temperature.

In another preferred example, the mass (g)/volume (mL) of the Lanifibranor raw material and the second solvent is 1:10-50, preferably 1:20-40.

In yet another embodiment of the present invention, the crystal form is crystal form CM-F, and its preparation method includes the following steps:

(1) Provide Lanifibranor raw materials in a third solvent, mix and stir until dissolved;

(2) Place the solution in the water-containing container through the water-proof opening of the medium, and seal the water-containing container;

(3) Precipitating solids from the solution and collecting the solids to obtain the crystalline form CM-F.

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

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

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

In another preferred example, step (1) is carried out at room temperature.

In another preferred example, 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.

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

In yet another embodiment of the present invention, the crystal form is crystal form CM-I, and its preparation method includes the following steps:

(1) providing the Lanifibranor raw material in a fourth solvent to form a mixture containing the Lanifibranor raw material;

(2) Add polymer or seed crystal to the mixture to form a Lanifibranor solution containing polymer or seed crystal;

(3) The solution is volatilized to precipitate a solid, and the solid is collected to obtain the crystal form CM-I.

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

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

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

In another preferred example, 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.

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

In another preferred example, the seed crystal is crystal form CM-A and/or CM-I.

In another preferred example, 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.

In another preferred example, step (1) is carried out at room temperature.

In another preferred example, the volatilization temperature of the solution is 20-80°C.

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

In another preferred embodiment, after the solid is collected, an optional drying step is also included.

In another preferred example, 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.

In another preferred example, 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.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

Description of drawings

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.

Detailed ways

After long-term and in-depth research, the present inventors provided a crystal form CM-A, CM-B, CM-F, and CM-I of the compound Lanifibranor of formula (I). 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.

the term

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.

Herein, unless otherwise specified, each abbreviation has a conventional meaning understood by those skilled in the art.

As used herein, unless otherwise specified, the term "Lanifibranor 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).

Preferably, 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.

As used herein, "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.

As used herein, the method of "slowly adding" includes but is not limited to: adding drop by drop, adding slowly along the wall of the container.

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

Lanifibranor crystal form

As used herein, "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.

In a preferred embodiment, the XRPD pattern of crystalline form CM-A includes 4 or more 2θ 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°.

In a preferred embodiment, the XRPD pattern of crystalline form CM-B includes 4 or more 2θ 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°.

In a preferred embodiment, the XRPD pattern of the crystalline form CM-F includes 4 or more 2θ 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°.

In a preferred embodiment, the XRPD pattern of the crystalline form CM-I includes 4 or more 2θ 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°.

In a preferred embodiment, the XRPD pattern of the crystalline form CM-D includes 3 or more 2θ 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°.

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

In a preferred embodiment, the XRPD pattern of the crystalline form CM-G includes 2 or more 2θ 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°.

Pharmaceutical composition containing crystalline form of Lanifibranor

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.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the field of pharmacy. 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.

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 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.

Compared with the prior art, the main advantages of the present invention include:

(1) The Lanifibranor crystal forms 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;

(2) The Lanifibranor crystal forms 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.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

general method

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

XRPD pattern determination method:

method one:

X-ray powder diffractometer: Bruker D2Phaser X-ray powder diffractometer; radiation source Cu

Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; Initial 2θ: 2.0°, scanning range: 2.0～35.0°. The scanning speed is 0.1s/step, and the step size is 0.02°/step.

Method Two:

X-ray powder diffractometer: Bruker D2Phaser X-ray powder diffractometer; radiation source Cu

Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; Initial 2θ: 2.0°, scanning range: 2.0～50.0°. The scanning speed is 1s/step, and the step size is 0.02°/step.

TGA spectrum determination method:

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 spectrum determination method:

Differential scanning calorimetry (DSC) instrument: TA Q2000 type of TA Company in the United States, within the range of 25-300 °C, the heating rate is 10 °C/min, and the nitrogen flow rate is 50 mL/min.

Determination method of 1H-NMR spectrum:

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

Example 1: Preparation of Lanifibranor Form CM-A

Example 1-1

At room temperature, add 500 mg of Lanifibranor compound to 20 mL of dichloromethane:methanol (3:1, v:v) mixed solvent, stir until the solution is clear (dissolved), and then filter through a membrane. The filtrate was placed at room temperature to evaporate the solvent, and a solid was precipitated. Filter and dry the solid to obtain the crystalline form CM-A of the Lanifibranor compound.

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.

Table A

2θ/°	Relative Strength
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%

Example 1-2

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.

Example 1-3

At room temperature, add 100 mg of Lanifibranor compound to 1.5 mL of 2-methyltetrahydrofuran, stir rapidly until dissolved, and then filter through a membrane. The filtrate was dropped into 15 mL of ethyl acetate at room temperature. After the dropwise addition, move to -20°C environment, continue magnetic stirring for 24h, and precipitate a solid. After filtering, drying the solid, the obtained solid is Lanifibranor compound crystal form CM-A.

Example 2: Preparation of Lanifibranor Crystal Form CM-B

Example 2-1

At room temperature, 100 mg of Lanifibranor crystal form CM-A obtained in Example 1-1 was added to 2 mL of MTBE, and stirred to make a slurry. After beating for 1 day, filter and dry the solid, the obtained solid is Lanifibranor compound crystal form CM-B.

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.

Form B

2θ/°	Relative Strength
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

Add 10 mg of Lanifibranor compound in 0.4 mL of anisole solvent at room temperature. After stirring for 24h, a solid precipitated out. After filtering and drying the solid, the obtained solid is Lanifibranor compound crystal form CM-B.

Example 2-3

Add 10 mg of Lanifibranor compound in 0.2 mL of ethyl acetate at room temperature. Stir quickly until dissolved, then filter through a membrane filter. The filtrate was placed in an environment of -20°C and stood for 24 hours, and a solid was precipitated. After filtering and drying the solid, the obtained solid is Lanifibranor compound crystal form CM-B.

Example 3: Preparation of Lanifibranor Crystal Form CM-C

Example 3-1

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.

Carry out XRPD test on the obtained Lanifibranor compound crystal form CM-C, the result is shown in Figure 9, and the spectrum data are shown in Table 3; TGA test is carried out on the obtained solid, the result is shown in Figure 10, the results show that Lanifibranor crystal form CM There are two obvious weight loss steps in the TGA spectrum of -C, and the crystal form is a solvate; DSC test was carried out on the obtained solid, and the results are shown in Figure 11. The results showed that it had a melting endothermic peak at 177.40°C; Gained solid carries out 1H NMR test, and its result is as shown in Figure 12.

Form C

2θ/°	Relative Strength
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 Lanifibranor Crystal Form CM-D

Example 4-1

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.

Combining TGA and DSC data, Form CM-D is a solvate.

Form D

2θ/°	Relative Strength
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 Lanifibranor Form CM-E

Example 5-1

At room temperature, add 100 mg of Lanifibranor compound to 10 ml of 1,4-dioxane, stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed in a 20ml glass vial, and the 20ml glass vial was placed in an environment of 20-25°C for slow volatilization for 24h. The resulting solid is the Lanifibranor compound in crystalline form CM-E.

Carry out XRPD test on the obtained Lanifibranor compound crystal form CM-E, the result is shown in Figure 16, and the spectrum data is shown in Table 5; TGA test is carried out on the obtained solid, and the result is shown in Figure 17, the result shows that Lanifibranor crystal form CM In the TGA spectrum of -E, the weight loss is about 11.13% in the range of room temperature-78°C, about 3.30% in the range of 78°C-125°C, and about 1.05% in the range of 125°C-210°C. The crystal form is a solvate; DSC test was carried out on the obtained solid, and the results are shown in Figure 18. The results showed that it had an endothermic peak at 51.07°C, 95.75°C and 166.19°C, and an exothermic crystallization peak at 125.39°C; the obtained solid was subjected to 1H NMR test, the results are shown in Figure 19.

Combining TGA and NMR data, Lanifibranor crystal form CM-E is a solvate of 1,4-dioxane.

Form E

2θ/°	Relative Strength
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%

Embodiment 6; Preparation of Lanifibranor crystal form CM-F

Example 6-1

At room temperature, add 10 mg of Lanifibranor compound to 1 ml of N-N dimethylacetamide, stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed in a 2ml glass vial, and the 2ml glass vial was fixed in the mouth of the 20ml glass vial with a raw material tape. Add an appropriate amount of pure water into a 20ml glass vial and let it stand for a week. The obtained solid is Lanifibranor compound crystal form CM-F.

Carry out XRPD test on the obtained Lanifibranor compound crystal form CM-F, the result is shown in Figure 20, and the spectrum data is shown in Table 6; TGA test is carried out on the obtained solid, and the result is shown in Figure 21, the result shows that Lanifibranor crystal form CM In the TGA spectrum of -F, the weight loss is about 1.49% in the range of 25°C-200°C. Endothermic peak; Gained solid is carried out 1H NMR test, and its result is as shown in Figure 23; Solid microscope observation is lump.

Form F

2θ/°	Relative Strength
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

At room temperature, in 1ml dimethyl sulfoxide, add 10mg Lanifibranor compound, stir rapidly until dissolved, then membrane filter. The filtrate was placed in a 2ml glass vial, and the 2ml glass vial was fixed in the mouth of the 20ml glass vial with a raw material tape. Add an appropriate amount of pure water into a 20ml glass vial and let it stand for a week. The obtained solid is Lanifibranor compound crystal form CM-F.

Example 7: Preparation of Lanifibranor Form CM-G

Example 7-1

At room temperature, add 100 mg of Lanifibranor compound to 20 ml of chloroform, stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed in a 50ml one-port bottle, and the one-port bottle was sealed at -20°C to precipitate a solid. The resulting solid is the Lanifibranor compound in crystalline form CM-G.

Carry out XRPD test on the obtained Lanifibranor compound crystal form CM-G, the result is shown in Figure 24, and the spectrum data are shown in Table 7; TGA test is carried out on the obtained solid, the result is shown in Figure 25, the results show that Lanifibranor crystal form CM In the TGA spectrum of -G, the weight loss is about 20.56% in the range of 17°C-88°C, and the weight loss is about 2.75% in the range of 88°C-158°C. 26, the results show that it has a desolvation peak at 54.94°C, a melting and crystallization peak at 92.04°C, and an endothermic melting peak at 176.39°C.

Combining TGA and DSC data, Form CM-G is a chloroform solvate.

Form G

2θ/°	Relative Strength
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 Lanifibranor Form CM-I

Example 8-1

At room temperature, add 100mg of Lanifibranor compound to 10ml of DCM:methanol (3:1, v:v), stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed in a 20ml glass bottle, and 0.01g of polyvinyl alcohol was added. At room temperature, the solvent was left standing to volatilize, and a solid was precipitated, and the obtained solid was Lanifibranor compound crystal form CM-I.

Carry out XRPD test on the obtained Lanifibranor compound crystal form CM-I, the result is shown in Figure 27, and the spectrum data is shown in Table 6; TGA test is carried out on the obtained solid, and the result is shown in Figure 28, the result shows that Lanifibranor crystal form CM The TGA spectrum of -I has a weight loss of 2.8% at 100-175°C. The obtained solid is tested by DSC. The results are shown in Figure 29. The results show that it has a first endothermic peak at 138.07°C and a second endothermic peak at 176.11°C. endothermic peak; gained solid is carried out 1H NMR test, and its result is as shown in Figure 30; Solid microscope observation is short stick shape.

Form H

2θ/°	Relative Strength
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, add 100mg of Lanifibranor compound to 10ml of DCM:methanol (3:1, v:v), stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed in a 20ml centrifuge tube, and 0.01 g of polyvinyl chloride was added to the centrifuge tube. The solvent was evaporated by stirring at room temperature, and a solid was precipitated, which was the Lanifibranor compound crystal form CM-I.

Example 8-3

At room temperature, add 100mg of Lanifibranor compound to 10ml of DCM:methanol (3:1, v:v), stir rapidly until dissolved, and then filter through a membrane. The filtrate was placed in a 20ml centrifuge tube, and 0.001 g was added to the centrifuge tube to obtain seed crystals using the method in Example 8-1. The solvent was evaporated at room temperature, and a solid was precipitated, which was Lanifibranor compound crystal form CM-I.

Effect Example

1. Comparison of melting points

Form CM-A (Example 1-1), Form CM-B (Example 2-1), Form CM-F (Example 6-1) and CM-I (Example 8-1) The sample was compared to the solid melting point of Example 117 in WO2007026097. The results are shown in Table 1.

Table 1 Comparison of melting points of different crystal forms

It can be found from the above examples that 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.

2. Stability inspection

Form CM-A (Example 1-1), Form CM-B (Example 2-1), Form CM-F (Example 6-1) and CM-I (Example 8-1) The samples were placed in the open under the conditions of 25°C/60%RH, 40°C/75%RH and 60°C/92.5%RH, and ground; samples were taken after placing or grinding, and tested by XRPD and HPLC. The crystal form stability is shown in Table 2 and Table 3.

Table 2 Stability at 25°C/60%RH and 40°C/75%RH

Table 3 Stability of different crystal 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 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.

3. Crystal stability in solution

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 .

Table 4 Crystalline stability of different crystal forms in 4 dissolution media

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

4. Suspension competition

The crystal form CM-A (Example 1-1), crystal form CM-B (Example 2-1) and CM-I (Example 8-1) samples were subjected to suspension competition experiments, and different crystal forms were divided into 1: After mixing at a mass ratio of 1, they were beaten in different solvents for 3 days at room temperature. The test results are shown in Table 5.

Table 5 Suspension competition experiments among different crystal forms

It can be found from the above examples that 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.

5. Angle of repose test

According to the Chinese Pharmacopoeia method, 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) The angle of repose of the powder was measured, and the results are shown in Table 6.

Table 6 Angle of repose data of different crystal forms

crystal form	angle of repose
Form CM-A	28.4°
Form CM-B	44.6°
Form CM-F	34.1°
Form CM-I	35.0°

The results show that the crystalline form CM-A, crystalline form CM-F and crystalline form CM-I of the present invention have smaller angles of repose than the crystalline form CM-B, have better fluidity, and are more conducive to formulation development.

6. Hygroscopicity detection

According to the Chinese Pharmacopoeia method, 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.

Table 7 Hygroscopic data of different crystal forms

crystal form	Humidity
Form CM-A	0.19%
Form CM-B	2.5%
Form CM-F	0.40%
Form CM-I	0.80%

The results show that the crystalline form CM-A of the present invention has almost no hygroscopicity, the crystalline form CM-F and CM-I have slight hygroscopicity, and the crystalline form CM-B has hygroscopicity. Compared with the crystalline form CM-B, 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.

7. Feasibility comparison of direct capsule filling

According to the prescription in Table 8, 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 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.

Table 8 Prescription Composition

Element	Single dose (mg/capsule)
APIs	100mg
microcrystalline cellulose	150mg
lactose	45mg
talcum powder	5mg
total	300mg

Table 9 Angles of repose of mixtures of different crystal forms

crystal form	angle of repose
Form CM-A	31°
Form CM-B	48°
Form CM-F	36°
Form CM-I	37°

It can be seen from the data in Table 9 that after mixing different crystal forms and excipients, 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. However, the crystal form CM-B mixture has an angle of repose of 48°, poor fluidity and cannot meet the requirements of direct capsule filling.

It can be seen that 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.

8. Tablet embodiment

For each crystal form of the present invention, tablets can be prepared according to the formulation prescription in Table 10 below.

Tablet prescription (100mg)

Table 10 Prescription Composition

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.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (11)

1. A crystal form of the compound shown in 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.
2. The crystal form according to claim 1, characterized in that,

   The crystal form is crystal form CM-A, and the XRPD pattern of the crystal form CM-A includes 2 or more 2θ values selected from the following group: 9.9°±0.2°, 15.65°±0.2°, 23.95 °±0.2°;

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

   The crystal form is crystal form CM-F, and the XRPD pattern of the crystal form CM-F includes 2 or more 2θ values selected from the following group: 16.75°±0.2°, 17.87°±0.2°, 25.25 °±0.2°;

   The crystal form is crystal form CM-I, and the XRPD pattern of the crystal form CM-I includes 2 or more 2θ values selected from the following group: 7.83°±0.2°, 9.70°±0.2°, 18.43 °±0.2°.
3. The crystal form according to claim 2, wherein the crystal form is crystal form CM-A, and the crystal form CM-A also has one or more of the following characteristics:

   (1) The XRPD pattern of the crystalline form CM-A includes one or more 2θ values selected from the following group: 11.70°±0.2°, 17.26°±0.2°, 20.10°±0.2°, 20.57°±0.2 °;

   (2) The XRPD pattern diffraction angle 2θ value 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°±0.2°, There are characteristic peaks at 30.43°±0.2° and 31.78°±0.2°;

   (3) The crystal form CM-A has an endothermic peak at 114.80°C and 179.34°C;

   (4) The crystal form CM-A has XRPD data substantially as shown in Table A;

   (5) The crystal form CM-A has an XRPD spectrum as shown in Figure 1;

   (6) The crystal form CM-A has a TGA spectrum basically as shown in Figure 2;

   (7) The crystal form CM-A has a DSC spectrum as shown in Figure 3;

   (8) The crystalline form CM-A has a 1 H NMR spectrum as shown in Figure 4;

   (9) The crystal form CM-A is block or cuboid crystal.
4. The crystal form according to claim 2, wherein the crystal form is crystal form CM-B, and the crystal form CM-B also has one or more of the following characteristics:

   (1) The XRPD pattern of the crystalline form CM-B includes one or more 2θ 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°;

   (2) The XRPD pattern diffraction angle 2θ value 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°±0.2°, There are characteristic peaks at 27.45°±0.2°, 27.63°±0.2°, 29.69°±0.2°, 32.27°±0.2° and 33.03°±0.2°;

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

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

   (5) The crystal form CM-B has an XRPD spectrum as shown in Figure 5;

   (6) The crystal form CM-B has a TGA spectrum basically as shown in Figure 6;

   (7) The crystal form CM-B has a DSC spectrum as shown in Figure 7;

   (8) The crystal form CM-B has a 1 H NMR spectrum as shown in Figure 8;

   (9) The crystal form CM-B is a fine needle crystal.
5. The crystal form according to claim 2, wherein the crystal form is crystal form CM-F, and the crystal form CM-F also has one or more of the following characteristics:

   (1) The XRPD pattern of the crystalline form CM-F includes one or more 2θ 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°;

   (2) The XRPD pattern diffraction angle 2θ value 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°±0.2°, There are characteristic peaks at 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°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 spectrum substantially as shown in Figure 20;

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

   (7) The crystalline form CM-F has a DSC spectrum as shown in Figure 22;

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

   (9) The crystal form CM-F is block crystal.
6. The crystal form according to claim 2, wherein the crystal form is crystal form CM-I, and the crystal form CM-I also has one or more of the following characteristics:

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

   (2) The XRPD pattern diffraction angle 2θ value 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 31.24°±0.2 There is a characteristic peak at °;

   (3) The crystalline form CM-I has an endothermic peak at 138.07°C and 176.11°C;

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

   (5) The crystalline form CM-I has an XRPD spectrum substantially as shown in FIG. 27;

   (6) The crystal form CM-I has a TGA spectrum substantially as shown in Figure 28;

   (7) The crystalline form CM-I has a DSC spectrum as shown in Figure 29;

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

   (9) The crystal form CM-I is a short rod crystal.
7. The crystal form according to claim 1, characterized in that,

   The crystal form is crystal form CM-C, and the XRPD pattern of the crystal form CM-C includes 2 or more 2θ values selected from the following group: 9.38°±0.2°, 10.20°±0.2°, 24.42 °±0.2°;

   The crystal form is crystal form CM-D, and the XRPD pattern of the crystal form CM-D includes 2 or more 2θ values selected from the following group: 5.74°±0.2°, 9.15°±0.2°, 16.39 °±0.2°;

   The crystal form is crystal form CM-E and the XRPD pattern of the crystal form CM-E includes 2 or more 2θ values selected from the following group: 11.50°±0.2°, 17.33°±0.2°, 18.63° ±0.2°;

   The crystal form is crystal form CM-G, and the XRPD pattern of the crystal form CM-G includes 2 or more 2θ values selected from the following group: 17.95°±0.2°, 18.42°±0.2°, 20.96 °±0.2°.
8. A method for preparing the crystal form according to any one of claims 1 to 6, wherein the preparation method is any one of the following methods (i) to (iv);

   (i) the crystal form is crystal form CM-A, comprising the following steps:

   (1) Provide Lanifibranor raw materials in a first solvent, mix and stir until the solution is clear;

   (2) volatilize the solution to separate out solids, collect the solids to obtain the crystal form CM-A,

   (ii) the crystal form is crystal form CM-B, comprising the following steps:

   (1) Lanifibranor raw material is provided in a second solvent to form a mixture or solution containing Lanifibranor raw material;

   (2) Cool the solution or continue beating the suspension;

   (3) Precipitating solids from the solution and collecting the solids to obtain the crystal form CM-B,

   (iii) the crystal form is crystal form CM-F, comprising the following steps:

   (1) Provide Lanifibranor raw materials in a third solvent, mix and stir until dissolved;

   (2) Place the solution in the water-containing container through the water-proof opening of the medium, and seal the water-containing container;

   (3) Precipitating solids from the solution and collecting the solids to obtain the crystal form CM-F,

   (iv) the crystal form is crystal form CM-I, comprising the following steps:

   (1) providing the Lanifibranor raw material in a fourth solvent to form a mixture containing the Lanifibranor raw material;

   (2) Add polymer or seed crystal to the mixture to form a Lanifibranor solution containing polymer or seed crystal;

   (3) The solution is volatilized to precipitate a solid, and the solid is collected to obtain the crystal form CM-I.
9. The method for preparing a crystal form according to claim 8, wherein in method (i), the first solvent is selected from the group consisting of ketone solvents, alcohol solvents, ester solvents, and 2-methyltetrahydrofuran , or a combination thereof; or, the first solvent is a combination of a halogenated hydrocarbon solvent and an alcohol solvent;

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

   In 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 Lanifibranor 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 Lanifibranor raw material and the third solvent is 1:10～100;

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

   In the method (iv), the mass (g)/volume (mL) of the Lanifibranor raw material and the fourth solvent is 1:10～100;

   In method (iv), the high polymer is polyvinyl alcohol and/or polyvinyl chloride; and/or,

   In the method (iv), the added seed crystal or high polymer is 0.3-10wt% of the mass of the Lanifibranor raw material.
10. A pharmaceutical composition, characterized in that it contains (a) active ingredient, said active ingredient being the crystal form of Lanifibranor as claimed in claim 1; and (b) a pharmaceutically acceptable carrier.
11. A use of the crystal form according to claims 1-9, characterized in that the use comprises: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a compound for the treatment of non-alcoholic steatohepatitis drug.

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