Crystalline form of lanistanol

Abstract

The present invention relates to a crystalline form of lanilanol, said crystalline form of lanilanol having an X-ray diffraction pattern according to Figure 1.

Description

Technical Field

[0001] The present invention relates to a crystalline form of lanibranor, a pharmaceutical composition containing the crystalline form and use of the crystalline form in treatment. Background Art

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

[0003] Lanilanol is described as a free base in Example 117 of WO 2007 / 026097, where it is obtained as a pale yellow powder with a melting point of 74-80° C. Crystalline forms of Lanilanol are disclosed in WO 2022 / 122014, WO 2022 / 143479, WO 2022 / 258060, WO 2022 / 261410 and WO 2023 / 016319.

[0004] The present invention provides a crystalline form of Lanilanol, wherein the crystalline form of Lanilanol has desirable properties, such as high crystallinity, high purity, low hygroscopicity, excellent mechanical properties and / or excellent stability. Summary of the invention

[0005] In one aspect, the present invention provides a crystalline form of Lanilanol (crystalline form β). The crystalline form β of Lanilanol is characterized by one or more of the following methods: (1) powder X-ray diffraction (PXRD); (2) differential scanning calorimetry (DSC); (3) thermogravimetric analysis (TGA); (4) dynamic vapor sorption (DVS); (5) infrared spectroscopy (IR).

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

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

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

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

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

[0011] In another aspect, the present invention provides crystalline Form β of Lanilanol for use in a method of treating a cirrhotic subject at risk of progressing from the compensated stage to the decompensated stage. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The PXRD pattern of Form β of Lanilanol is shown.

[0013] Figure 2 The DSC curve of the crystalline form β of Lanilanol is shown.

[0014] Figure 3 The TGA curve of the crystalline form β of Lanilanol is shown.

[0015] Figure 4 The DVS isotherm of Form β of Lanilanol is shown.

[0016] Figure 5A and Figure 5B The IR spectrum of Form β of Lanilanol is shown along with the indexing of the absorption bands used for the IR analysis.

[0017] Figure 6 Shown is a comparison of the PXRD patterns of the amorphous form (bottom curve), Form β (middle curve) and Form α (top curve) of Lanilanol.

[0018] Figure 7 The DSC curve of the crystalline form α of Lanilanol is shown.

[0019] Figure 8 A comparison of the DSC curves of the amorphous form (bottom curve), Form β (middle curve) and Form α (top curve) of Lanilanol is shown.

[0020] Figures 9 to 14 The PXRD patterns of the suspension of the mixture of the Lanilanol crystalline form α and crystalline form β in different 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 the Lanilanol Form α; the top / middle curve is the PXRD pattern of the suspension at T0; the middle / bottom curve is the PXRD pattern of the suspension at T0+24h; and the bottom curve is the PXRD pattern of the Lanilanol Form β.

[0021] Fig.15 PXRD patterns of Lanilanol Form α before (top curve) and after compression (bottom curve) are shown.

[0022] Figure 16 to Figure 17 The PXRD patterns of the solid form CSI described in WO 2022 / 122014 (bottom curve) are shown with Figure 1 Overlay of PXRD patterns of Lanilanol Form β (top curve) is shown.

[0023] Figure 18 to Figure 19 The PXRD patterns of the solid form CSII described in WO 2022 / 122014 (bottom curve) are shown with Figure 1 Overlay of PXRD patterns of Lanilanol Form β (top curve) is shown.

[0024] Fig. 20 The PXRD patterns of the solid form CSIV described in WO 2022 / 122014 (bottom curve) and Figure 1 Overlay of PXRD patterns of Lanilanol Form β (top curve) is shown.

[0025] Fig.21 The PXRD pattern of the solid form described in WO 2022 / 143479 is shown with Figure 1 Overlay of PXRD patterns of Lanilanol Form β shown. From top to bottom the following forms are represented: Lanilanol Form β; Lanilanol cinnamamide cocrystal; Lanilanol p-toluenesulfonic acid cocrystal; Lanilanol tris(hydroxymethyl)aminomethane salt; Lanilanol Form A.

[0026] Fig. 22 The PXRD pattern of Form A described in WO 2022 / 143479 (bottom curve) is shown with Figure 1 Overlay of PXRD patterns of Lanilanol Form α (top curve) is shown.

[0027] Fig.23 The PXRD patterns of solid forms CM-A, CM-B and CM-F described in WO 2022 / 258060 are shown. Figure 1 An overlay of PXRD patterns of Lanilanol Form β is shown. From top to bottom the following forms are represented: Lanilanol Form β; Form CM-A; Form CM-B; Form CM-F.

[0028] Fig.24 The PXRD patterns of solid forms CM-C, CM-D, CM-E, CM-G and CM-I described in WO 2022 / 258060 are shown. Figure 1An overlay of PXRD patterns of Lanilanol Form β is shown. From top to bottom the following forms are represented: Lanilanol Form β; Form CM-C; Form CM-D; CM-E; Form CM-G; Form CM-I.

[0029] Fig.25 The PXRD patterns of solid forms LN-1, LN-2, LN-3 and LN-4 described in WO 2022 / 261410 are shown. Figure 1 An overlay of PXRD patterns of Lanilanol Form β is shown. From top to bottom the following forms are represented: Lanilanol Form β; Form LN-1; Form LN-2; Form LN-3; Form LN-4.

[0030] Fig.26 The PXRD pattern of form LN-1 described in WO 2022 / 261410 (bottom curve) is shown with Figure 1 Overlay of PXRD patterns of Lanilanol Form α (top curve) is shown.

[0031] Fig. 27 The PXRD patterns of the solid forms CSV (Example 2 and Example 3) and CSIII described in WO 2023 / 016319 are shown. Figure 1 An overlay of PXRD patterns of Lanilanol Form β is shown. From top to bottom the following forms are represented: Lanilanol Form β; Form CSV (Example 2); Form CSV (Example 3); Form CSIII.

[0032] In all the figures showing PXRD patterns, the abscissa represents 2Theta (°) and the ordinate represents intensity (counts). DETAILED DESCRIPTION

[0033] As used herein, the term "Ranilanol" is understood to mean the free acid of Ranillanol, a compound of the formula:

[0034]

[0035] In one aspect, the present invention provides a crystalline form of Lanilanol (crystalline form β).

[0036] As described herein, Lanilanol (Form β) is characterized by one or more of the following methods: (1) powder X-ray diffraction (PXRD); (2) differential scanning calorimetry (DSC); (3) thermogravimetric analysis (TGA). Such forms may be further characterized by other techniques, such as: (4) dynamic vapor sorption (DVS); and (5) infrared spectroscopy (IR).

[0037] In some embodiments of the various aspects of the invention, Form β of Lanilanol is characterized by its PXRD pattern. It will be appreciated by those skilled in the art that with respect to X-ray diffraction peak positions (2θ), the positions will show some variation, typically up to ±0.2°, such as ±0.1°. In addition, it will be appreciated by those skilled in the art that relative peak intensities will show variation between devices, as well as variation due to crystallinity, and should be considered only as a qualitative measure.

[0038] In other embodiments of various aspects of the present invention, Lanilanol (crystalline form β) is characterized by its DSC curve. In other embodiments of various aspects of the present invention, Lanilanol (crystalline form β) is characterized by its TGA curve.

[0039] It should be understood that various combinations of two, three, or four techniques may be used to uniquely characterize the Lanilanol (Form β) disclosed herein.

[0040] In one embodiment, the PXRD pattern of Lanilanol (Form β) comprises one, two, three, four, five or more than five peaks selected from the peaks in Table 1 (expressed as 2θ±0.2°).

[0041] In one embodiment, using The Lanilanol (Form β) has a PXRD pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 16.0°±0.2°, 18.7°±0.2°, and 24.6°±0.2°, as measured by an X-ray wavelength of . The crystalline form β has a PXRD pattern further comprising at least one peak at a 2θ value selected from the group consisting of: 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°, as measured by an X-ray wavelength of .

[0042] In some such embodiments, the PXRD pattern further comprises one or more additional peaks at 2θ values ​​selected from the peaks in Table 1.

[0043] Table 1

[0044]

[0045] In one embodiment, the PXRD pattern of Lanilanol (crystalline form β) is Figure 1 Basically the same.

[0046] In one embodiment, the DSC curve of Lanilanol (Form β) comprises an endothermic peak at 182.3°C.

[0047] In one embodiment, the DSC curve of Lanilanol (crystalline form β) is Figure 2 Basically the same.

[0048] In one embodiment, the TGA curve of Lanilanol (Form β) does not highlight any significant weight loss in the temperature range of 25° C. to 200° C. Above 250° C., the observed weight loss may correspond to degradation.

[0049] In one embodiment, the TGA curve of Lanilanol (crystalline form β) is Figure 3 Basically the same.

[0050] In one embodiment, DVS analysis of Lanilanol (Form β) showed no significant weight change over the range of relative humidity values ​​investigated: the maximum adsorption observed was +0.1% in the range of 0% RH to 95% RH.

[0051] In one embodiment, the DVS isotherm of Lanilanol (Form β) is Figure 4 Basically the same.

[0052] In one embodiment, the IR spectrum of Lanilanol (crystalline form β) is substantially consistent with FIG. 5 .

[0053] In another aspect, the present invention provides a method for preparing Lanilanol (Form β), comprising a) heating a solution of Lanilanol 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.

[0054] In one embodiment, step a) is performed at a temperature of about 105°C.

[0055] In one embodiment, step a) and step b) as defined above are repeated at least once. For example, the method for preparing Lanilanol (crystalline form β) may comprise the following steps:

[0056] - heating a solution of Lanilanol in acetic acid at a temperature in the range of about 100° C. to about 110° C.,

[0057] - Allow the solution to return to room temperature,

[0058] - heating a solution of the product (recovered from the cooled solution) in acetic acid at a temperature in the range of about 100° C. to about 110° C.,

[0059] - Allow the solution to cool to room temperature.

[0060] Ranilanol free acid can be obtained as described, for example, in WO 2007 / 026097 or as described in Example 1 below.

[0061] While screening solid forms of Lanilanol, the inventors identified two crystalline forms of the compound, one form being unstable because it easily converts to the other form when handled / processed. This unstable form was labeled "Form α", while the more stable form was labeled "Form β". An amorphous form was also obtained. It was found that the amorphous form would crystallize into Form α or Form β even at low temperatures. It was further found that the method for preparing Form β, in which acetic acid is used for crystallization, can scale up the production of this form to obtain batches of up to about 150 kg.

[0062] The Lanilanol crystalline form β can be used as an active ingredient of a pharmaceutical composition.

[0063] Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, the pharmaceutical composition comprises Lanilanol (crystalline form β) and a pharmaceutically acceptable carrier or excipient. The expression "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient suitable for incorporation into a pharmaceutical composition and compatible with other ingredients of the composition. In particular, it is non-toxic. Its use enables the preparation, preservation and administration of active ingredients to be promoted. 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 and antifungal agents and isotonic agents, and examples of excipients that can also be used as ingredients of preparations include fillers, binders, disintegrants and lubricants.

[0064] In another aspect, the present invention provides a method for treating non-alcoholic fatty liver disease (NAFLD), comprising administering an effective amount of Lanilanol (crystalline form β) to a subject in need thereof.

[0065] In one embodiment, NAFLD includes non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis (NASH).

[0066] In another aspect, the present invention provides a method of treating a subject with liver cirrhosis at risk of progressing from a compensated stage to a decompensated stage, the method comprising administering to the subject an effective amount of Lanilanol (crystalline form β).

[0067] In another aspect, the present invention provides Lanilanol Form β for use in a method for treating non-alcoholic fatty liver disease.

[0068] In another aspect, the present invention provides crystalline Lanilanol Form β for use in a method of treating a cirrhotic subject at risk of progressing from the compensated stage to the decompensated stage.

[0069] In another aspect, the present invention provides the use of the Lanilanol crystalline form β as defined above in the preparation of a medicament for treating non-alcoholic fatty liver disease (NAFLD). In some embodiments, NAFLD includes non-alcoholic fatty liver and non-alcoholic steatohepatitis.

[0070] In another aspect, the present invention provides the use of the Lanilanol crystalline form β as defined above in the preparation of a medicament for treating compensated liver cirrhosis, in particular for preventing decompensated liver cirrhosis.

[0071] The invention is illustrated by the following examples.

[0072] Example

[0073] abbreviation

[0074] MeTHF = 2-methyltetrahydrofuran

[0075] MTBE = methyl tert-butyl ether

[0076] NAC = N-acetyl-L-cysteine

[0077] PdCl2(PPh3)2=Bis(triphenylphosphine)palladium(II) dichloride

[0078] THF = Tetrahydrofuran

[0079] PXRD

[0080] Using a Cu radiation source Powder X-ray diffraction analysis was performed on a Panalytical Empyrean S3 diffractometer. The analysis was performed in transmission mode (the sample was placed and the polypropylene foil), the angle range was 2θ=2°-50°, the step length was 0.026°, and the time per step was 20.4 seconds.

[0081] DSC

[0082] DSC analysis was performed on a Mettler Toledo DSC3+ calorimeter. Several milligrams of sample were analyzed in 40 μL sealed aluminum pans (punched before analysis) under a nitrogen flush of 50 mL / min. The temperature scan range was 20°C to 300°C at a rate of 10°C / min.

[0083] TGA

[0084] TGA analysis was performed on a Mettler Toledo TGA / DSC3+ thermogravimetric analyzer. Several milligrams of sample were analyzed in a 100 μL sealed aluminum pan (punched before analysis) under a nitrogen flush of 50 mL / min. The scanning temperature range was 25°C to 300°C at a rate of 10°C / min.

[0085] DVS

[0086] DVS analysis was performed on an SMS DVS Intrinsic system. Several milligrams of sample were analyzed in open aluminum pans at 25 °C. The stability criterion for each step was a weight change of less than 0.002% within 5 min. The time criterion for each step was 100 min (minimum step duration was 10 min). Relative humidity was scanned from 0% RH to 95% RH with a step size of 10% RH (40–0–95–0–95).

[0087] IR

[0088] On Nicolet equipped with ATR iD7 accessories TM IR analysis was performed on an iS5 spectrometer. Analysis was performed at 4000cm -1 Up to 525cm -1 ATR mode is used within the range (resolution is 4cm -1 ), 32 scans were performed for background and measurement.

[0089] Example 1: Lanilanol free acid

[0090] Degassed triethylamine (200 mL) was added to a solution of N-(4-chloro-2-iodo-phenyl)-1,3-benzothiazole-6-sulfonamide in THF, followed by the addition of 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 hours. The mixture was concentrated under reduced pressure at 40°C until 5 volumes of solution remained relative to the weight of the sulfonamide starting material. Water (3 volumes) was added and the residual THF was removed by distillation. The mixture was washed 3 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 (twice). Washing was performed by stirring the organic phase with 20% w / w NAC at 60°C for 1 hour. The organic phase was then washed twice, the NAC phases were combined and washed with pure water (three times). As previously described, washing was performed by stirring the NAC phase with water at 60° C. for 1 hour. The MeTHF solution was heated at 60° C. Shirasagi A Charcoal (0.5%) (w / w, relative to the amount of starting sulfonamide) was added and the suspension was stirred at 60° C. for 30 minutes. The mixture was then filtered through a diatomaceous earth bed and washed thoroughly with MeTHF. The obtained solution containing Ranilanol was used as is in the next example.

[0091] Example 2: Lanilanol (crystalline form β)

[0092] The solution obtained in Example 1 is concentrated. Acetic acid is added to the residue and the solution is concentrated. The suspension is heated at 105°C and acetic acid is added in small amounts until completely dissolved. The solution is then stirred at 105°C for 1 hour and slowly cooled to room temperature under stirring. The solid product obtained is filtered through a sintered glass G4 filter and washed twice with acetic acid to obtain 41.63g of product (yield 86.3%) with an HPLC purity of 99.8%. 41.3g of the product is suspended in acetic acid and the suspension is stirred at 105°C for 1 hour. After complete dissolution, the mixture is cooled to room temperature in stages, filtered through a sintered glass G4 filter, and washed with acetic acid. The collected product is vacuum dried at 60°C for 5 hours to obtain 38.6g of the title compound (yield 93.5%).

[0093] APCI MS m / z 435 [M+H]+; UPLC-MS (210-260 nm) purity: 99.9%.

[0094] 1H NMR (500MHz DMSO-d6): δ1.86-2.01(2H,quint,J=7.5Hz); 2.36(2H,t,J=7.5Hz); 3.09(2H,t,J=7.5Hz); 6.62(1H,s); 7.32(1H,dd,J=2.0Hz et J=8.5Hz); 7.57(1H,d,J=2.5Hz); 7.85(1H,dd,J=2.0 et J=8.5Hz); 8.09(1H,d,J=8.5Hz); 8.20(1H,d,J=8.5Hz); 8.97(1H,d,J=2.0Hz); 9.67(1H,s); 12.14(1H,s).

[0095] The β-form of Lanilanol was characterized by PXRD ( Figure 1 )、DSC( Figure 2 )、TGA( Figure 3 )、DVS( Figure 4 ) and IR( Figure 5A and Figure 5B ) to characterize. Figure 2 It can be seen that the DSC curve of Lanilanol (crystalline form β) contains an endothermic peak at 182.3°C.

[0096] Example 3: Lanilanol (crystalline form α)

[0097] A homogeneous solution was prepared by dissolving the crystalline form β (10 g) of Lanilanol obtained in Example 2 in acetic acid (7.5 volumes) at 98°C. The solution was then rapidly cooled at 5°C by stirring the mixture until precipitation occurred. The temperature of the mixture was monitored and when the temperature reached 20°C, the solid phase was recovered by filtering through a n°3 sintered glass filter. The recovered solid was vacuum dried at 60°C and kept at room temperature.

[0098] The crystalline form α of Lanilanol was determined by PXRD (Table 2 and Figure 6 ) and DSC( Figure 7 ) to characterize. Figure 7 It can be seen that the DSC curve of Form α contains an endothermic peak at 180.8°C.

[0099] Table 2

[0100]

[0101] Example 4: Lanilanol (amorphous form)

[0102] A homogeneous solution was prepared by dissolving 1 g of Lanilanol (crystalline form β) 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 subsequently recovered, dried under vacuum at room temperature overnight, and stored at −26° C.

[0103] The amorphous form of Lanilanol was characterized by PXRD (see Figure 6 ).

[0104] Example 5: Stability Test

[0105] Competitive slurry tests were conducted in various solvents such as acetone, ethanol, ethyl acetate, acetic acid, methyl ethyl ketone, and methyl isobutyl ketone.

[0106] For each solvent, a saturated solution of the Lanilanol Form β (as obtained in Example 2) was prepared. Equal amounts of the Lanilanol Form α and the Lanilanol Form β were placed in a vial (50 mg + 50 mg), and then 250 μL of the pre-prepared saturated solution (recovered by filtering through a 0.2 μm H-PTFE filter) was added. The mixture was stirred at room temperature, and a solid sample was taken immediately after the start of stirring, and a solid sample was taken after 24 hours, and analyzed by PXRD to determine the solid crystal form present. The results are shown in Table 2.

[0107] Table 2

[0108]

[0109] It can be seen that after 24 hours, complete conversion to the Lanilanol Form β was observed in all solvents considered. Therefore, Form β is the most stable form at room temperature.

[0110] Example 7: Compression Test

[0111] Compression tests were performed on the crystalline (α, β) and amorphous forms of Lanilanol.

[0112] 100 mg of each sample was placed between the anvils of a 13 mm die and the sample was subjected to a 10 ton pressure for 15 minutes. The obtained pellets were then decompressed and analyzed by PXRD to monitor the changes in the crystal structure of the sample.

[0113] For the Lanilanol Form α (see Fig.15 ), after compression a broadening of the diffraction peaks, a weakening of their intensity, and additional signals that may correspond to peak shifts caused by the conversion to form β were observed. The characteristic signals of amorphous material were also highlighted.

[0114] For Lanilanol Form β (diffraction pattern not shown), a decrease in crystallinity (broadening of peaks, weakening of intensity) was observed after compression, but no significant change in the solid form was observed.

[0115] For the amorphous form (diffraction pattern not shown), a weak diffraction signal corresponding to Form β was detected after compression, indicating that the sample began to crystallize.

[0116] Example 8: Comparison of Lanilanol Form β with the Lanilanol obtained in Example 117 of WO 2007 / 026097

[0117] Lanilanol was prepared according to the method described in Example 117 of WO 2007 / 026097. A white amorphous powder was obtained in about 75% yield with a melting point (measured on a Kofler table) in the range of 74°C-76°C. The product obtained was found to be amorphous and its PXRD pattern was consistent with Figure 6 The spectra shown are comparable.

[0118] Example 9: Comparison of Lanilanol Form β with the solid form disclosed in WO 2022 / 122014

[0119] The PXRD patterns of the solid forms described in WO 2022 / 122014 (i.e., Form CSI (Examples 2 and 3), Form CSII (Examples 5 and 6), and Form CSIV (Example 7)) were digitized and then compared (by superposition) with the PXRD pattern of Lanilanol Form β (e.g., Figure 1 The results are shown in Figure 16 to Figure 17 (CSI), Figure 18 to Figure 19 (CSII) and Fig. 20 From these figures, it can be concluded that the PXRD patterns described in WO 2022 / 122014 do not match the PXRD pattern of Lanilanol Form β.

[0120] Example 10: Comparison of Lanilanol Form β with the solid form disclosed in WO 2022 / 143479

[0121] The PXRD patterns of the solid forms described in WO 2022 / 143479 (i.e., Lanilanol cinnamamide cocrystals (Examples 1 to 6), Lanilanol p-toluenesulfonic acid cocrystals (Examples 7 to 11), Lanilanol trishydroxymethylaminomethane salt (Examples 12 to 16), and Form A (Examples 17 to 20)) were digitized and then compared (by overlay) with the PXRD pattern of Lanilanol Form β (e.g., Figure 1 The results are shown in Fig.21From this figure, it can be concluded that the PXRD patterns described in WO 2022 / 143479 do not match the PXRD patterns of the Lanilanol form β. Fig. 22 As shown, the PXRD pattern of Form A described in WO 2022 / 143479 is similar to the PXRD pattern of Lanilanol Form α (as shown in Figure 6 As shown) basically matches.

[0122] Example 11: Comparison of Lanilanol Form β with the solid form disclosed in WO 2022 / 258060

[0123] The PXRD patterns of the solid forms described in WO 2022 / 258060 (i.e., Lanilanol solid forms CM-A, CM-B, CM-C, CM-D, CM-E, CM-F, CM-G, and CM-I) were digitized and then compared (by overlay) with the PXRD pattern of Lanilanol Form β (e.g., Figure 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 the PXRD patterns described in WO 2022 / 258060 do not match the PXRD patterns of Lanilanol Form β. In addition, the PXRD patterns of the solid forms described in WO 2022 / 258060 also do not match the PXRD patterns of Lanilanol Form α (data not shown).

[0124] Example 12: Comparison of Lanilanol Form β with the solid form disclosed in WO 2022 / 261410

[0125] The PXRD patterns of the solid forms described in WO 2022 / 261410 (i.e., Lanilanol forms LN-1, LN-2, LN-3 and LN-4) were digitized and then compared (by superposition) with the PXRD pattern of Lanilanol form β (e.g., Figure 1 The results are shown in Fig.25 From this figure, it can be concluded that the PXRD patterns described in WO 2022 / 261410 do not match the PXRD patterns of the Lanilanol form β. Fig.26 As shown, the PXRD pattern of form LN-1 described in WO 2022 / 261410 is similar to the PXRD pattern of Lanilanol Form α (as shown in Figure 6 As shown) basically matches.

[0126] Example 13: Comparison of Lanilanol Form β with the solid form disclosed in WO 2023 / 016319

[0127] The PXRD patterns of the solid forms described in WO 2023 / 016319 (i.e., Lanilanol Forms CSV (Examples 2 and 3) and CSIII) were digitized and then compared (by superposition) with the PXRD pattern of Lanilanol Form β (e.g., Figure 1 The results are shown in Fig. 27 From this figure, it can be concluded that the PXRD patterns described in WO 2023 / 016319 do not match the PXRD pattern of Lanilanol Form β. In addition, the PXRD pattern of the solid form described in WO 2023 / 016319 also does not match the PXRD pattern of Lanilanol Form α (data not shown).

[0128] Example 14: Stability Test

[0129] The stability test of the crystalline form β of Lanilanol obtained in Example 2 was carried out according to EMA guidelines (CPMP / ICH / 2736 / 99, last revised in August 2003); therefore, the drug substance was stored under the following conditions:

[0130] 6 months at 30°C / 65°RH,

[0131] 6 months at 40℃ / 75%RH, and

[0132] 12 months at 25°C / 60%RH.

[0133] At the end of each storage period, the drug substance was characterized by PXRD and DSC. In each case, the PXRD pattern had Figure 1 The characteristics of Lanilanol Form β are shown, and the DSC curve has the characteristics of Lanilanol Form β (endothermic peak at 182.3° C.), indicating that Lanilanol Form β is stable during long-term storage.

Claims

1. A crystalline form of Lanilanol (crystalline form β), such as using The crystalline form has an X-ray powder diffraction pattern comprising peaks at 16.0°±0.2°, 18.7°±0.2° and 24.6°±0.2° 2θ, measured by an X-ray wavelength of 2. The crystal form according to claim 1, wherein If used The X-ray diffraction pattern further comprises at least one peak at a 2θ value selected from the following: 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°.

3. The crystalline form according to any one of claims 1 or 2, wherein The X-ray diffraction pattern is basically consistent with that in Figure 1.

4. The crystalline form according to any one of claims 1 to 3, wherein the differential scanning calorimetry (DSC) curve of the crystalline form comprises an endothermic peak at 182.3°C.

5. The crystal form according to claim 4, wherein The DSC curve is basically consistent with Figure 2.

6. A method for preparing a crystalline form according to any one of claims 1 to 5, the method comprising: a) heating a solution of Lanilanol in acetic acid at a temperature in the range of about 100° C. to about 110° C., and b) The resulting solution was cooled to room temperature.

7. The method according to claim 6, wherein: Step a) is carried out at a temperature of about 105°C.

8. The method according to claim 6 or 7, wherein: Step b) is carried out in stages.

9. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.

10. The crystalline Ranilanol form β as defined in any one of claims 1 to 5 for use in a method for treating non-alcoholic fatty liver disease (NAFLD).

11. The Lanilanol crystalline form β for the purpose according to claim 10, wherein NAFLD includes nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

12. Lanilanol form beta as defined in any one of claims 1 to 5 for use in a method of treating a cirrhotic subject at risk of progression from the compensated to the decompensated stage.

13. A method for treating non-alcoholic fatty liver disease (NAFLD), the method comprising administering to a subject in need thereof an effective amount of the crystalline form β of Lanilanol as defined in any one of claims 1 to 5.

14. The method according to claim 13, wherein: NAFLD includes nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

15. A method of treating a subject with liver cirrhosis at risk of progressing from the compensated stage to the decompensated stage, the method comprising administering to the subject an effective amount of the crystalline form β of Lanilanol as defined in any one of claims 1 to 5.

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