Crystalline form of Lanifibranor

Abstract

The present invention relates to a crystalline form of Lanifibranor having an X-ray diffraction pattern according to FIG.

Description

[Technical field]

[0001] The present invention relates to crystalline forms of Lanifibranor, pharmaceutical compositions comprising said crystalline forms, and uses of said crystalline forms in therapy. [Background technology]

[0002] Lanifibranor, or 1-(6-benzothiazolylsulfonyl)-5-chloro-1H-indole-2-butanoic acid, is a pan-PPAR agonist currently in clinical development for the treatment of subjects with nonalcoholic steatohepatitis (NASH), for which there is currently no approved treatment.

[0003] Lanifibranor is described as the free base in Example 117 of WO2007 / 026097, where it is obtained as a pale yellow powder with a melting point of 74-80° C. Crystalline forms of lanifibranor are disclosed in WO2022 / 122014, WO2022 / 143479, WO2022 / 258060, WO2022 / 261410, and WO2023 / 016319. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention provides crystalline forms of Lanifibranor that have desirable properties, such as high crystallinity, high purity, low hygroscopicity, favorable mechanical properties, and / or favorable stability. [Means for solving the problem]

[0005] In one embodiment, the present invention provides a crystalline form of Lanifibranor (beta form). The beta form of Lanifibranor is characterized by one or more of the following methods: (1) Powder X-ray Diffraction (PXRD); (2) Differential Scanning Calorimetry (DSC); (3) Thermogravimetry (TGA); (4) Dynamic Vapor Sorption (DVS); (5) Infrared Spectroscopy (IR).

[0006] In another aspect, the present invention provides a method for preparing β-form crystals of Lanifibranor, comprising heating a solution of Lanifibranor in acetic acid and slowly cooling the resulting solution to room temperature.

[0007] In another aspect, the present invention provides a pharmaceutical composition comprising β-crystalline form of lanifibranor and a pharma- ceutically acceptable carrier or excipient.

[0008] In another aspect, the present invention provides a method for treating non-alcoholic fatty liver disease, comprising administering to a subject in need thereof an effective amount of β-crystalline form of lanifibranor.

[0009] In another aspect, the present invention provides a method for treating a subject with cirrhosis at risk of progressing from compensated to decompensated stage, comprising administering to the subject an effective amount of β-crystalline form of lanifibranor.

[0010] In another aspect, the present invention provides β-form crystals of lanifibranor for use in a method for treating non-alcoholic fatty liver disease.

[0011] In another aspect, the present invention provides β-crystalline form of lanifibranor for use in a method of treating a subject with cirrhosis at risk of progressing from compensated to decompensated stage. [Brief description of the drawings]

[0012] [Figure 1] PXRD pattern of the β-form of Lanifibranor. [Diagram 2] 1 shows the DSC curve of the β-form of Lanifibranor. [Diagram 3] 1 shows the TGA curve of the β form of Lanifibranor. [Figure 4] 1 shows a DVS isotherm plot of the beta form of Lanifibranor. [Figure 5A] 1 shows the IR spectrum of the β form of Lanifibranor and indexing of absorption bands for IR analysis. [Figure 5B]1 shows the IR spectrum of the β form of Lanifibranor and indexing of absorption bands for IR analysis. [Figure 6] 1 shows a comparison of the PXRD patterns of the amorphous form (lower curve), the beta form (middle curve), and the alpha form (upper curve) of Lanifibranor. [Figure 7] 1 shows the DSC curve of the α-form of Lanifibranor. [Figure 8] 1 shows a comparison of the DSC curves of the amorphous form (lower curve), the beta form (middle curve), and the alpha form (upper curve) of Lanifibranor. [Figure 9] PXRD patterns of suspensions of mixtures of α- and β-Lanifibranor in various solvents are shown: acetone (FIG. 9), ethanol (FIG. 10), ethyl acetate (FIG. 11), acetic acid (FIG. 12), methyl ethyl ketone (FIG. 13), and methyl isobutyl ketone (FIG. 14). In each figure, the top curve is the PXRD pattern of α-Lanifibranor, the top / middle curves are the PXRD patterns of the suspension at T0, the middle / bottom curves are the PXRD patterns of the suspension at T0+24h, and the bottom curve is the PXRD pattern of β-Lanifibranor. [Figure 10] PXRD patterns of suspensions of mixtures of α- and β-Lanifibranor in various solvents are shown: acetone (FIG. 9), ethanol (FIG. 10), ethyl acetate (FIG. 11), acetic acid (FIG. 12), methyl ethyl ketone (FIG. 13), and methyl isobutyl ketone (FIG. 14). In each figure, the top curve is the PXRD pattern of α-Lanifibranor, the top / middle curves are the PXRD patterns of the suspension at T0, the middle / bottom curves are the PXRD patterns of the suspension at T0+24h, and the bottom curve is the PXRD pattern of β-Lanifibranor. [Figure 11]PXRD patterns of suspensions of mixtures of α- and β-Lanifibranor in various solvents are shown: acetone (FIG. 9), ethanol (FIG. 10), ethyl acetate (FIG. 11), acetic acid (FIG. 12), methyl ethyl ketone (FIG. 13), and methyl isobutyl ketone (FIG. 14). In each figure, the top curve is the PXRD pattern of α-Lanifibranor, the top / middle curves are the PXRD patterns of the suspension at T0, the middle / bottom curves are the PXRD patterns of the suspension at T0+24h, and the bottom curve is the PXRD pattern of β-Lanifibranor. [Figure 12] PXRD patterns of suspensions of mixtures of α- and β-Lanifibranor in various solvents are shown: acetone (FIG. 9), ethanol (FIG. 10), ethyl acetate (FIG. 11), acetic acid (FIG. 12), methyl ethyl ketone (FIG. 13), and methyl isobutyl ketone (FIG. 14). In each figure, the top curve is the PXRD pattern of α-Lanifibranor, the top / middle curves are the PXRD patterns of the suspension at T0, the middle / bottom curves are the PXRD patterns of the suspension at T0+24h, and the bottom curve is the PXRD pattern of β-Lanifibranor. [Figure 13] PXRD patterns of suspensions of mixtures of α- and β-Lanifibranor in various solvents are shown: acetone (FIG. 9), ethanol (FIG. 10), ethyl acetate (FIG. 11), acetic acid (FIG. 12), methyl ethyl ketone (FIG. 13), and methyl isobutyl ketone (FIG. 14). In each figure, the top curve is the PXRD pattern of α-Lanifibranor, the top / middle curves are the PXRD patterns of the suspension at T0, the middle / bottom curves are the PXRD patterns of the suspension at T0+24h, and the bottom curve is the PXRD pattern of β-Lanifibranor. [Figure 14]PXRD patterns of suspensions of mixtures of α- and β-Lanifibranor in various solvents are shown: acetone (FIG. 9), ethanol (FIG. 10), ethyl acetate (FIG. 11), acetic acid (FIG. 12), methyl ethyl ketone (FIG. 13), and methyl isobutyl ketone (FIG. 14). In each figure, the top curve is the PXRD pattern of α-Lanifibranor, the top / middle curves are the PXRD patterns of the suspension at T0, the middle / bottom curves are the PXRD patterns of the suspension at T0+24h, and the bottom curve is the PXRD pattern of β-Lanifibranor. [Figure 15] PXRD patterns of alpha-lanifibranor before (top curve) and after (bottom curve) compression are shown. [Figure 16] 1 shows a PXRD pattern of the solid form CSI described in WO2022 / 122014 (lower curve) overlaid with the PXRD pattern of β-lanifibranor shown in FIG. 1 (upper curve). [Figure 17] 1 shows a PXRD pattern of the solid form CSI described in WO2022 / 122014 (lower curve) overlaid with the PXRD pattern of β-lanifibranor shown in FIG. 1 (upper curve). [Figure 18] 1 shows a superposition of the PXRD pattern of solid form CSII described in WO2022 / 122014 (lower curve) and the PXRD pattern of β-lanifibranor shown in FIG. 1 (upper curve). [Figure 19] 1 shows a superposition of the PXRD pattern of solid form CSII described in WO2022 / 122014 (lower curve) and the PXRD pattern of β-lanifibranor shown in FIG. 1 (upper curve). [Figure 20] 1 shows a superposition of the PXRD pattern of the solid form CSIV described in WO2022 / 122014 (lower curve) and the PXRD pattern of β-lanifibranor shown in FIG. 1 (upper curve). [Figure 21]PXRD patterns of the solid forms described in WO2022 / 143479 are overlaid with the PXRD pattern of β-lanifibranol shown in Figure 1. The following forms are shown from top to bottom: β-lanifibranol; lanifibranol cinnamamide co-crystal; lanifibranol p-toluenesulfonic acid co-crystal; lanifibranol tromethamine salt; and lanifibranol Form A. [Figure 22] 1 shows a superposition of the PXRD pattern of Form A described in WO2022 / 143479 (lower curve) and the PXRD pattern of Form α Lanifibranor shown in FIG. 1 (upper curve). [Figure 23] PXRD patterns of the solid forms CM-A, CM-B, and CM-F described in WO2022 / 258060 are overlaid with the PXRD pattern of β-form Lanifibranol shown in Figure 1. The following forms are shown from top to bottom: β-form; CM-A; CM-B; CM-F-form Lanifibranol. [Figure 24] PXRD patterns of the solid forms CM-C, CM-D, CM-E, CM-G, and CM-I described in WO2022 / 258060 are overlaid with the PXRD pattern of β-form Lanifibranol shown in Figure 1. The following forms are shown from top to bottom: β-form; CM-C; CM-D; CM-E; CM-G; CM-I-form Lanifibranol. [Diagram 25] PXRD patterns of the solid forms LN-1, LN-2, LN-3, and LN-4 described in WO2022 / 261410 are overlaid with the PXRD pattern of β-Lanifibranor shown in Figure 1. The following forms are shown from top to bottom: β-Lanifibranor; LN-1; LN-2; LN-3; LN-4. [Figure 26] 1 shows a superposition of the PXRD pattern of the LN-1 form described in WO2022 / 261410 (lower curve) and the PXRD pattern of the α-form lanifibranor shown in FIG. 1 (upper curve). [Figure 27]Figure 1 shows the overlay of the PXRD patterns of the solid forms CSV (embodiments 2 and 3) and CSIII described in WO2023 / 016319 with the PXRD pattern of the β form of Lanifibranor shown in Figure 1. The following forms are shown from top to bottom: β form; CSV form (embodiment 2); CSV form (embodiment 3); Lanifibranor form CSIII.

[0013] In all figures showing PXRD patterns, the horizontal axis represents 2Theta (°) and the vertical axis represents intensity (counts). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein, the term "lanifibranor" is understood to mean lanifibranor free acid, i.e., the compound of the following formula: [ka]

[0015] In one embodiment, the present invention provides a crystalline form of Lanifibranor (β form).

[0016] As described herein, Lanifibranor (β-form) has been characterized by one or more of the following methods: (1) Powder X-ray Diffraction (PXRD); (2) Differential Scanning Calorimetry (DSC); (3) Thermogravimetry (TGA). Such crystalline forms may also be further characterized by additional techniques, such as: (4) Dynamic Vapor Sorption (DVS); and (5) Infrared Spectroscopy (IR).

[0017] In some embodiments of each aspect of the present invention, the β form of Lanifibranor is characterized by its PXRD pattern. A person skilled in the art will understand that with respect to the X-ray diffraction peak positions (2θ), the positions will typically show some variability, such as ±0.2°, for example ±0.1°. Furthermore, a person skilled in the art will understand that the relative peak intensities should only be considered as a qualitative measure, as they will show variability between instruments and due to crystallinity.

[0018] In other embodiments of each aspect of the invention, Lanifibranor (β form) is characterized by its DSC curve. In yet other embodiments of each aspect of the invention, Lanifibranor (β form) is characterized by its TGA curve.

[0019] It will be appreciated that various combinations of two, three, or four techniques can be used to uniquely characterize Lanifibranor (β form) as disclosed herein.

[0020] In one embodiment, Lanifibranor (β form) has a PXRD pattern having one, two, three, four, five, or more than five peaks selected from each peak in Table 1 (expressed in °2θ±0.2°).

[0021] In one embodiment, Lanifibranor (β Form) has a PXRD pattern with one or more peaks at 2θ values ​​selected from 16.0°±0.2°, 18.7°±0.2°, and 24.6°±0.2°2θ when measured using an X-ray wavelength of 1.5406 Å. In some embodiments, the β Form has a PXRD pattern further having at least one peak at a 2θ value selected from 11.4°±0.2°, 18.0±0.2°, 21.2±0.2°, 22.8±0.2°, 23.5±0.2°, 26.1±0.2°, and 26.7°±0.2°2θ when measured using an X-ray wavelength of 1.5406 Å.

[0022] In some of such embodiments, the PXRD pattern further comprises one or more additional peaks at 2θ values ​​selected from each of the peaks in Table 1.

[0023] [Table 1]

[0024] In one embodiment, the PXRD pattern of Lanifibranor (β form) is substantially in accordance with FIG.

[0025] In one embodiment, Lanifibranor (β form) has a DSC curve with an endothermic peak at 182.3°C.

[0026] In one embodiment, the DSC curve of Lanifibranor (β form) is substantially in accordance with FIG.

[0027] In one embodiment, the TGA curve for Lanifibranor (β form) does not reveal any significant weight loss over the temperature range of 25-200° C. Above 250° C., the weight loss observed likely corresponds to decomposition.

[0028] In one embodiment, the TGA curve of Lanifibranor (β form) is substantially in accordance with FIG.

[0029] In one embodiment, DVS analysis performed on Lanifibranor (β form) shows no significant weight variation over the range of relative humidity values ​​investigated (maximum uptake observed in the range of 0% RH to 95% RH was +0.1%).

[0030] In one embodiment, the DVS isotherm plot for Lanifibranor (β form) is substantially in accordance with FIG.

[0031] In one embodiment, the IR spectrum of Lanifibranor (β form) is substantially in accordance with FIG.

[0032] In another aspect, the present invention provides a method for preparing Lanifibranor (β form), comprising: a) heating a solution of Lanifibranor in acetic acid at a temperature in the range of about 100°C to about 110°C; and b) cooling the resulting solution to room temperature.

[0033] In one embodiment, step a) is carried out at a temperature of about 105°C.

[0034] In one embodiment, the above-defined steps a) and b) are repeated at least once. For example, the method for preparing Lanifibranor (β form) comprises the steps of: heating the solution of lanifibranor in acetic acid at a temperature in the range of about 100°C to about 110°C; - Returning the solution to room temperature; heating the product (recovered from the cooled solution) in acetic acid at a temperature in the range of about 100° C. to about 110° C.; Cool the solution to room temperature may also include

[0035] Lanifibranor free acid can be obtained, for example, as described in WO2007 / 026097 or as described in Example 1 below.

[0036] During screening of the solid forms of Lanifibranor, the inventors identified two crystalline forms of the compound. One form was unstable in the sense that it was easily converted to the other form upon handling / processing. The unstable form was classified as "α-form" and the more stable form was classified as "β-form". Additionally, an amorphous form was also obtained. The amorphous form was found to crystallize into either α-form or β-form even at low temperatures. Furthermore, it was found that the process for preparation of the β-form using acetic acid for crystallization allowed for the scale-up of the production of this crystalline form to obtain batches up to about 150 kg.

[0037] β-lanifibranor can be used as an active ingredient in a pharmaceutical composition.

[0038] Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising Lanifibranor (β-form) and a pharma- ceutically acceptable carrier or excipient. The expression "pharma- ceutically acceptable carrier or excipient" means that the excipient or carrier is suitable for incorporation into a pharmaceutical composition and is compatible with the other components of the composition. In particular, the component is not toxic. Its use facilitates the preparation, storage, and administration of the active ingredient. Such excipients and carriers are well known to those skilled in the art and are described in the French Pharmacopoeia and / or the European Pharmacopoeia. Examples of pharmaceutical carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial agent, antifungal agent, and isotonic agent. Examples of excipients that may also be components of the formulation include fillers, binders, disintegrants, and lubricants.

[0039] In another aspect, the present invention provides a method for treating non-alcoholic fatty liver disease (NAFLD), comprising administering to a subject in need thereof an effective amount of lanifibranor (beta form).

[0040] In one embodiment, NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH).

[0041] In another aspect, the present invention provides a method for treating a subject with cirrhosis at risk of progressing from compensated to decompensated stage, comprising administering to the subject an effective amount of lanifibranor (β form).

[0042] In another aspect, the present invention provides beta-lanifibranor for use in a method for the treatment of non-alcoholic fatty liver disease.

[0043] In another aspect, the present invention provides beta lanifibranor for use in a method for treating a subject with cirrhosis at risk of progressing from compensated to decompensated stage.

[0044] In another aspect, the present invention provides the use of beta-lanifibranor as defined above for the preparation of a medicament for the treatment of non-alcoholic fatty liver disease (NAFLD). In some embodiments, NAFLD includes non-alcoholic fatty liver and non-alcoholic steatohepatitis.

[0045] In another aspect, the present invention provides the use of beta-lanifibranor as defined above for the preparation of a medicinal product intended for the treatment of compensated cirrhosis, in particular for preventing decompensation of cirrhosis.

[0046] The invention is illustrated by the following examples. EXAMPLES

[0047] Abbreviation MeTHF = 2-methyltetrahydrofuran MTBE = methyl tert-butyl ether NAC = N-acetyl-L-cysteine PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride THF = tetrahydrofuran

[0048] PXRD Powder X-ray diffraction analysis was performed using a Panalytical Empyrean S3 diffractometer equipped with a Cu source (Cu wavelength = 1.5406 Å). The analysis was performed in transmission mode (samples placed between Kapton® and polypropylene foil) over the angular range 2θ = 2–50°, with a step size of 0.026° and a time per step of 20.4 s.

[0049] DSC DSC analyses were performed on a Mettler Toledo DSC3+ calorimeter. Analyses were performed on a few milligrams of sample in 40 μL sealed aluminum pans, punctured prior to analysis, under a nitrogen flush of 50 mL / min. The temperature range was scanned from 20 °C to 300 °C at a rate of 10 °C / min.

[0050] TGA TGA analysis was performed on a Mettler Toledo TGA / DSC3+ thermogravimetric analyzer. Analyses were performed on a few milligrams of sample in 100 μL sealed aluminum pans, punctured prior to analysis, under a nitrogen flush of 50 mL / min. The temperature range was scanned from 25 °C to 300 °C at a rate of 10 °C / min.

[0051] DVS DVS analysis was performed on an SMS DVS Intrinsic system. Analysis was performed on a few milligrams of sample in open aluminum pans at 25°C. The stability criterion for each step was less than 0.002% weight change over a 5 minute time frame. The time criterion for each step was 100 minutes (minimum duration of any step: 10 minutes). Relative humidity was scanned from 0% RH to 95% RH in 10% RH steps (40-0-95-0-95).

[0052] IR IR analysis was performed using a Nicolet spectrophotometer equipped with an ATR iD7 accessory. TM The analysis was carried out on an iS5 spectrometer using ATR mode at 4000 cm -1 ~525cm -1 (Resolution 4c -1 ) and 32 scans were taken for background and measurement.

[0053] Example 1: Lanifibranor free acid Degassed triethylamine (200 mL) was added to the THF solution of N-(4-chloro-2-iodo-phenyl)-1,3-benzothiazole-6-sulfonamide, followed by PdCl2(PPh3)2 (1.17 g), CuI (0.85 g), and 5-hexynoic acid (CAS[53293-00-8]) (14.3 g). The reaction mixture was stirred at 40° C. for 3 h. The mixture was concentrated under reduced pressure at 40° C. until the remaining solution volume was 5 times the weight of the sulfonamide starting material. Water (3 volumes) was added and the residual THF was distilled off. The mixture was washed three times with MTBE (2 volumes). The aqueous phase was treated with a mixture of MeTHF and HCl (37%). The MeTHF solution was washed with 6% aqueous NAC (2 times). Washing was performed by adding 20% ​​w / w NAC and stirring the organic phase at 60° C. for 1 h. The organic phase was then washed twice and each NAC phase was combined and washed with pure water (three times). As before, washing was performed by adding water and stirring the NAC phase at 60° C. for 1 h. The MeTHF solution was heated at 60° C. Shirasagi A charcoal (0.5%) was added (w / w with respect to the amount of starting sulfonamide) and the suspension was stirred at 60° C. for 30 min. The mixture was then filtered through a bed of dicalite and washed thoroughly with MeTHF. The resulting lanifibranol-containing solution was used as is in the following examples.

[0054] Example 2: Lanifibranor (β type) The solution obtained in Example 1 was concentrated. Acetic acid was added to the residue and the solution was concentrated. The suspension was heated at 105°C and acetic acid was added in small portions to completely dissolve. The solution was then stirred at 105°C for 1 hour and allowed to cool slowly to room temperature under stirring. The obtained solid product was filtered through a sintered glass G4 filter and washed twice with acetic acid to obtain 41.63 g of product (86.3% yield) with HPLC purity of 99.8%. 41.3 g of product was suspended in acetic acid and the suspension was stirred at 105°C for 1 hour. After complete dissolution, the mixture was allowed to gradually cool to room temperature, filtered through a sintered glass G4 filter and washed with acetic acid. The collected product was dried in vacuum at 60°C for 5 hours to obtain 38.6 g (93.5% yield) of the title compound.

[0055] APCI MS m / z 435 [M+H]+; UPLC-MS (210-260nm) Purity: 99.9%. 1 H NMR(500 MHz DMSO-d6): δ 1.86-2.01 (2H, quint, J= 7.5 Hz); 2.36 (2H, t, J=7.5 Hz); 3.09 (2H, t, J=7.5 Hz); 6.62 (1H, s); 7.32 (1H, dd, J= 8.97 (1H, 2.0 Hz et J= 8.5 Hz); 7.57 (1H, d, J=2.5 Hz); 7.85 (1H, dd, J=2.0 et J=8.5 Hz); d, J=2.0 Hz); 9.67 (1H, s); 12.14 (1H, s).

[0056] Lanifibranol β-form was characterized by PXRD (Figure 1), DSC (Figure 2), TGA (Figure 3), DVS (Figure 4), and IR (Figures 5A and 5B). From Figure 2, it can be seen that Lanifibranol (β-form) has a DSC curve with an endothermic peak at 182.3°C.

[0057] Example 3: Lanifibranor (α type) A homogeneous solution was prepared by dissolving the β-form of Lanifibranor obtained in Example 2 (10 g) in acetic acid (7.5 volumes) at 98°C. The mixture was then stirred at 5°C to induce precipitation while the solution was quenched. The temperature of the mixture was monitored, and when it reached 20°C, the solid phase was recovered by filtration through a No. 3 sintered glass filter. The recovered solid was dried in vacuum at 60°C and kept at room temperature.

[0058] Lanifibranor α-form was characterized by PXRD (Table 2 and Figure 6) and DSC (Figure 7). From Figure 7, it can be seen that α-form has a DSC curve with an endothermic peak at 180.8°C.

[0059] [Table 2]

[0060] Example 4: Lanifibranor (amorphous form) A homogeneous solution was prepared by dissolving 1 g of Lanifibranor (β-form) obtained in Example 2 in 35 mL of acetone at 50° C. The solution was then completely evaporated under vacuum at 50° C. The solid phase was then collected, vacuum dried at room temperature overnight, and stored at −26° C.

[0061] The amorphous form of Lanifibranor was characterized by PXRD (see FIG. 6).

[0062] Example 5: Stability Study Competitive slurry tests were conducted with various solvents such as acetone, ethanol, ethyl acetate, acetic acid, methyl ethyl ketone, and methyl isobutyl ketone.

[0063] A saturated solution of β-lanifibranol (obtained in Example 2) was prepared for each solvent. Equal amounts of α-lanifibranol and β-lanifibranol were introduced into a vial (50 mg + 50 mg), followed by the addition of 250 μL of the previously prepared saturated solution (collected by filtration through a 0.2 μm H-PTFE filter). The mixture was stirred at room temperature, and samples of the solid were taken immediately after stirring began and after 24 hours and analyzed by PXRD to identify the solid form present. The results are shown in Table 2.

[0064] [Table 3]

[0065] It can be seen that after 24 hours, complete conversion to β-lanifibranol is observed in all solvents considered, thus the β-form is the most stable form at room temperature.

[0066] Example 7: Compression Test Compression tests were performed on the crystalline forms (α, β) and amorphous forms of Lanifibranor.

[0067] 100 mg of each sample was introduced between the anvils in a 13 mm die and subjected to a pressure of 10 tons for 15 minutes. The resulting pellets were then decompressed and analyzed by PXRD to monitor changes in the crystal structure of the samples.

[0068] For α-form Lanifibranor (see FIG. 15), after compression, a broadening of the diffraction peaks, a decrease in their intensity, and additional signals were observed that could correspond to a peak shift due to conversion to the β-form. Also, signals characteristic of amorphous materials were evident.

[0069] For β-lanifibranor (diffraction pattern not shown), a decrease in crystallinity was observed after compression (broadening of peaks, decrease in intensity), but no significant change in solid morphology was observed.

[0070] In the amorphous form (diffraction pattern not shown), a weak diffraction signal corresponding to the β form was detected after compression, indicating the onset of crystallization in the sample.

[0071] Example 8: Comparison of β-type Lanifibranor with Lanifibranor obtained in Example 117 of WO2007 / 026097 Lanifibranol was prepared according to the procedure described in Example 117 of WO2007 / 026097. A white amorphous powder was obtained in approximately 75% yield with a melting point (measured on a Kofler bench) in the range of 74-76° C. The product obtained was confirmed to be amorphous and showed a PXRD pattern equivalent to that shown in FIG. 6.

[0072] Example 9: Comparison of beta Lanifibranor with the solid forms disclosed in WO2022 / 122014 The PXRD patterns of the solid forms described in WO2022 / 122014, namely Forms CSI (Examples 2 and 3), Forms CSII (Examples 5 and 6), and Form CSIV (Example 7), were digitized and then compared (overlaid) with the PXRD pattern of β-Lanifibranor (shown in FIG. 1). The results are shown in FIGS. 16-17 (CSI), 18-19 (CSII), and FIG. 20 (CSIV). From these figures, it can be concluded that none of the PXRD patterns described in WO2022 / 122014 match the PXRD pattern of β-Lanifibranor.

[0073] Example 10: Comparison of beta Lanifibranor with the solid forms disclosed in WO2022 / 143479 The PXRD patterns of the solid forms described in WO2022 / 143479, namely, lanifibranor cinnamamide cocrystal (Examples 1-6), lanifibranor p-toluenesulfonic acid cocrystal (Examples 7-11), lanifibranor tromethamine salt (Examples 12-16), and Form A (Examples 17-20), were digitized and then compared (overlaid) with the PXRD pattern of β-form lanifibranor (shown in FIG. 1). The results are shown in FIG. 21. From this figure, it can be concluded that none of the PXRD patterns described in WO2022 / 143479 match the PXRD pattern of β-form lanifibranor. In contrast, as shown in FIG. 22, the PXRD pattern of Form A described in WO2022 / 143479 is substantially identical to the PXRD pattern of α-form lanifibranor (shown in FIG. 6).

[0074] Example 11: Comparison of beta Lanifibranor with the solid forms disclosed in WO2022 / 258060 The PXRD patterns of the solid forms described in WO2022 / 258060, namely the lanifibranol solid forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G, and CM-I, were digitized and then compared (overlaid) with the PXRD pattern of β-lanifibranol (shown in FIG. 1). The results are shown in FIG. 23 (forms CM-A, CM-B, and CM-F) and FIG. 24 (forms CM-C, CM-D, CM-E, CM-G, and CM-I). From these figures, it can be concluded that none of the PXRD patterns described in WO2022 / 258060 match the PXRD pattern of β-lanifibranol. Furthermore, the PXRD patterns of the solid forms described in WO2022 / 258060 also do not match the PXRD pattern of α-lanifibranol (data not shown).

[0075] Example 12: Comparison of beta Lanifibranor with the solid forms disclosed in WO2022 / 261410 The PXRD patterns of the solid forms of Lanifibranor described in WO2022 / 261410, namely, LN-1, LN-2, LN-3, and LN-4, were digitized and then compared (overlaid) with the PXRD pattern of β-Lanifibranor (shown in FIG. 1). The results are shown in FIG. 25. From this figure, it can be concluded that none of the PXRD patterns described in WO2022 / 261410 match the PXRD pattern of β-Lanifibranor. In contrast, as shown in FIG. 26, the PXRD pattern of LN-1 described in WO2022 / 261410 is substantially identical to the PXRD pattern of α-Lanifibranor (shown in FIG. 6).

[0076] Example 13: Comparison of beta Lanifibranor with the solid forms disclosed in WO2023 / 016319 The PXRD patterns of the solid forms described in WO2023 / 016319, i.e., CSV forms (embodiments 2 and 3) and CSIII form of Lanifibranor, were digitized and then compared (overlaid) with the PXRD pattern of β form of Lanifibranor (shown in FIG. 1). The results are shown in FIG. 27. From this figure, it can be concluded that none of the PXRD patterns described in WO2023 / 016319 match the PXRD pattern of β form of Lanifibranor. Furthermore, the PXRD patterns of the solid forms described in WO2023 / 016319 do not match the PXRD pattern of α form of Lanifibranor (data not shown).

[0077] Example 14: Stability Study The β-lanifibranor obtained in Example 2 was subjected to stability testing in accordance with EMA guidance (CPMP / ICH / 2736 / 99, last revised in August 2003). Accordingly, the drug substance was stored under the following conditions: 30℃ / 65%RH for 6 months, 6 months at 40℃ / 75%RH, and 12 months at 25℃ / 60%RH

[0078] At the end of each storage period, the drug substance was characterized by PXRD and DSC. In each case, the PXRD pattern was characteristic of beta Lanifibranol as shown in Figure 1, and the DSC curve was characteristic of beta Lanifibranol (endothermic peak at 182.3°C), indicating that beta Lanifibranol is stable during long-term storage.

Claims

1. The crystalline form of ranifibranol exhibits an X-ray powder diffraction pattern with peaks at 16.0°±0.2°, 18.7°±0.2°, and 24.6°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

2. The crystal morphology according to claim 1, wherein the above-mentioned X-ray diffraction pattern, when measured using an X-ray wavelength of 1.5406 Å, further has at least one peak at a 2θ value selected from 11.4°±0.2°, 15.0°±0.2°, 18.0°±0.2°, 20.6°±0.2°, 21.2°±0.2°, 22.8°±0.2°, 23.5°±0.2°, 26.1°±0.2°, and 26.7°±0.2°2θ.

3. The crystal morphology according to claim 1, having an X-ray powder diffraction pattern with peaks at 16.0°±0.2°, 18.7°±0.2°, 22.8°±0.2°, and 24.6°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

4. The crystal morphology according to claim 1, having an X-ray powder diffraction pattern with peaks at 16.0°±0.2°, 18.7°±0.2°, 21.2°±0.2°, 24.6°±0.2° and 26.1°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

5. The crystal morphology according to claim 1, having an X-ray powder diffraction pattern with peaks at 16.0°±0.2°, 18.7°±0.2°, 21.2°±0.2°, 24.6°±0.2° and 26.7°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

6. The crystal morphology according to claim 1, having an X-ray powder diffraction pattern with peaks at 11.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 21.2°±0.2°, 24.6°±0.2° and 26.1°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

7. The crystal morphology according to claim 1, having an X-ray powder diffraction pattern with peaks at 11.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 21.2°±0.2°, 24.6°±0.2° and 26.7°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

8. The crystal morphology according to claim 1, having an X-ray powder diffraction pattern with peaks at 11.4°±0.2°, 16.0°±0.2°, 18.7°±0.2°, 22.8°±0.2° and 24.6°±0.2°²θ when measured using an X-ray wavelength of 1.5406 Å.

9. The crystal morphology according to claim 1, wherein the above-mentioned X-ray diffraction pattern conforms to Figure 1.

10. The crystal morphology according to claim 1, having a differential scanning calorimetry (DSC) curve with an endothermic peak at 182.3°C.

11. The crystal morphology according to claim 10, wherein the above DSC curve follows Figure 2.

12. A method for preparing the crystalline form described in Claim 1, comprising heating an acetic acid solution of ranifibranol and cooling the obtained solution to room temperature.

13. a) Heating a solution of ranifibranol in acetic acid at a temperature in the range of 100°C to 110°C, b) Cool the resulting solution to room temperature. The method according to claim 12, including the method described in claim 12.

14. The method according to claim 13, wherein step a) is carried out at a temperature of 105°C.

15. The method according to claim 13, wherein step b) is carried out in stages.

16. The method according to claim 13, wherein steps a) and b) are repeated at least once.

17. A pharmaceutical composition comprising the crystalline form of ranifibranol according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.

18. A therapeutic agent for non-alcoholic fatty liver disease (NAFLD), comprising the crystalline form of ranifibranol as described in any one of claims 1 to 11.

19. The therapeutic agent according to claim 18, wherein NAFLD includes non-alcoholic fatty liver and non-alcoholic steatohepatitis.

20. A therapeutic agent for liver cirrhosis at risk of progression from the compensated to the decompensated stage, comprising the crystalline form of ranifibranol as described in any one of claims 1 to 11.

21. A therapeutic agent for compensated cirrhosis of the liver, comprising the crystalline form of ranifibranol as described in any one of claims 1 to 11.

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