Crystalline forms of resmetirom

Abstract

The present invention relates to novel crystalline forms of Resmetirom and processes for preparation thereof. Specifically, the present application relates to crystalline forms of REE-1, REE-2 and REE-7 of Resmetirom and processes for preparation thereof.

Description

[0001] CRYSTALLINE FORMS OF RESMETIROM

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel crystalline forms of Resmetirom and processes for preparation thereof. Specifically, the present invention relates to crystalline forms of REE-1, REE-2, REE-7, REE-8, REE-9, REE-10 and REE-11 of Resmetirom and processes for preparation thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Resmetirom is a thyroid hormone receptor (THR) P-selective agonist, and it is developed for the treatment of for non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and associated dyslipidemias. The chemical name of Resmetirom is 2-[3,5-Dichloro-4-((6-oxo-5-(propan-2-yl)-l,6- dihydropyridazin-3yl)oxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6- carbonitrile, has the following chemical structure of Formula (I).

[0006] Formula I

[0007] Resmetirom and its preparation are disclosed in US 7452882. WO 2014043706 describes morphic forms of Resmetirom including Form I, hydrate and solvates of methylisobutylketone and dimethylacetamide. WO 2020010068 describes crystalline forms, solvates, amorphous solid dispersion of Resmetirom, and salts of Resmetirom.

[0008] WO 2021063367, WO 2021129465, WO 2022052822, CN 114907327 and CN 115124515 describe crystalline forms of Resmetirom. WO 2022086894 describes Co-crystals and salts of Resmetirom. A novel polymorphic form of a pharmaceutical active substance can lead to improved bioavailability, stability and yield, selectivity of chemical reactions and flowability of the material. The new polymorphic form of a pharmaceutical substance can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Therefore, there is a need to develop new polymorphic forms of Resmetirom with improved physicochemical properties.

[0009] OBJECTIVE OF THE INVENTION

[0010] The objective of the present invention is to provide novel crystalline forms of Resmetirom and their pharmaceutical compositions, and their use in medicament for treatment and / or prevention of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias.

[0011] SUMMARY OF THE INVENTION

[0012] In an aspect of the present invention provides a crystalline form of Resmetirom, selected from:

[0013] REE-2 which is characterized by XRPD pattern comprising two or more peaks at about 6.5, 11.7, 12.9, 16.4 and 19.4 ± 0.2° 20,

[0014] REE-7 which is characterized by XRPD pattern comprising two or more peaks at about 5.7, 9.5, 11.4, 18.8 and 23.0 ± 0.2° 20,

[0015] REE-9 which is characterized by XRPD pattern comprising two or more peaks at about 6.4, 7.7, 19.6, 20.9, 22.6, 23.3, 24.1, 25.3 and 26.5 ± 0.2° 20.

[0016] REE- 10 which is characterized by XRPD pattern comprising two or more peaks at about 5.2, 6.2, 8.2, 8.7, 11.0, 12.1, 14.4, 20.0, 21.0, 23.2 and 24.5 ± 0.2° 20., and

[0017] REE-11 which is characterized by XRPD pattern comprising two or more peaks at about 5.8, 6.5, 7.7, 9.6, 11.6, 14.6, 20.0, 22.4, 23.4 and 24.7 ± 0.2° 20. In another aspect of the present invention provides benzyl alcohol solvate of Resmetirom characterized by two or more peaks at about 6.5, 11.7, 12.9, 16.4 and 19.4 ± 0.2° 20.

[0018] Yet another aspect of the present invention provides a process for the preparation of REE- 1, REE-2, REE-7, REE-9, REE- 10 and REE-11.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1: PXRD pattern of crystalline Form REE-1 of Resmetirom. Figure 2: PXRD pattern of crystalline Form REE-2 of Resmetirom. Figure 3: PXRD pattern of crystalline Form REE-7 of Resmetirom. Figure 4: PXRD pattern of crystalline Form REE-8 of Resmetirom. Figure 5: PXRD pattern of crystalline Form REE-9 of Resmetirom. Figure 6: PXRD pattern of crystalline Form REE-10 of Resmetirom. Figure 7: PXRD pattern of crystalline Form REE-11 of Resmetirom. Figure 8: DSC curve of crystalline Form REE-2 of Resmetirom.

[0021] Figure 9: TGA curve of crystalline Form REE-2 of Resmetirom.

[0022] Figure 10: Single crystal Form REE-2 of Resmetirom.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] The suitable solvents of the present invention comprises halogenated solvent is selected from carbon tetrachloride, chloroform, 2-chloropropane; the nitrile solvent is selected from acetonitrile and benzonitrile; the hydrocarbon solvent is selected from hexane, heptane, cyclohexane; the alcohol solvent is selected from methanol, ethanol, isopropanol, 1,2-propanediol and benzyl alcohol; the ether solvent is selected from methyl t-butyl ether, diethylether, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, ethyl tert-butyl ether, 2- methyltetrahydrofuran, polyethylene glycol and tetrahydropyran; ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, mesityl oxide, isophorone, methyl isopropyl ketone, acetophenone, cyclopentanone, methyl secbutyl ketone and pentanone; polar aprotic solvents is selected from dimethylacetamide, formamide, acetamide, N-methylpyrrolidine (NMP), dimethyl formamide, n-methylformamide, 1,3 -dimethyl -2-imidazolidinone, n- formylmorpholine, 2-pyrrolidone, tetramethylurea, n-vinylpyrrolidone and n- vinylacetamide and dimethyl sulfoxide.

[0025] Resmetirom used as starting material in the present invention can be obtained by the procedure disclosed in US patent No 7,452,882 and 9,266,861.

[0026] The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0027] The X-ray powder diffraction patterns of the present invention can be determined in accordance with procedures that are known in the art, or it may be measured using Bruker D8 advance-Eco with lynex detector equipped with Cu source Z= 1.58 A) measured using CuKaradiation.

[0028] The Differential Scanning Calorimetry (DSC) thermogram is obtained on TA DSC Q2000 or equivalent with ramp 10.00°C / min to 350.00°C.

[0029] The Thermogravimetric analyzer (TGA) thermogram is obtained on a TA TGA Q500 or equivalent with ramp 10.00°C / min to 350.00°C.

[0030] In an aspect of the present invention is to provide novel crystalline forms of Resmetirom having purity greater than 99%, a process for the preparation thereof. In another aspect of the present invention provides a crystalline Resmetirom Form REE-2, which is characterized by XRPD pattern comprising 20 peaks at 6.5, 11.7, 12.9, 16.4 and 19.4 ± 0.2°, and comprising 20 peaks at 12.1, 17.9, 18.8, 21.5 and 23.0 ± 0.2°; The REE-2 may be characterized by XPRD pattern substantially as illustrated in Figure 2. Further, the REE-2 may be characterized by DSC thermogram substantially as illustrated in Figure 8 and TGA substantially as illustrated in Figure 9.

[0031] The crystalline Form REE-2 of Resmetirom obtained from the present invention is benzyl alcohol solvate and having purity of greater than about 99 % by HPLC. The X-ray single crystal of the present invention is measured on Bruker D8 VENTUREPHOTON III C14 Detector and the software is SHELXTL-PLUS.

[0032] Further, the Form REE-2 characterized by X-ray single crystal, which is measured on Bruker D8 VENTUREPHOTON III C14 Detector and the software is SHELXTL-PLUS, having:

[0033] Space Group: Pl a = 7.515(2) A; b = 11.571(3) A; c = 14.316(4) A a= 104.913(7) °; p= 94.573(8) °; = 101.201(8) °; Volume 1168.9(6) A3

[0034] The solvate association with Resmetirom is characterized by asymmetric unit that is one Resmetirom molecule and half benzyl alcohol solvent (all atoms of the benzyl alcohol solvent molecule have 0.5 site occupancy).

[0035] In another aspect of the present invention provides a process for the preparation of crystalline Form REE -2 of Resmetirom comprising: a) providing a solution of Resmetirom in benzyl alcohol; b) combining the solution obtained in step (a) with a second solvent; and c) isolating crystalline form REE-2 of Resmetirom. The step (a) of the process involves providing a solution of Resmetirom by dissolving Resmetirom in benzyl alcohol and / or an additional solvent or the solution obtained from the previous processing step of Resmetirom. The additional solvent used for providing solution comprises alcohol solvents; ester solvents; ketone solvents; halogenated hydrocarbon solvents; nitrile solvents; polar aprotic solvents; water; and any mixtures of two or more thereof. In an embodiment, the second solvent comprises hydrocarbon solvents or more thereof.

[0036] The solution can be prepared by heating the contents at a temperature of about 35 to about 150°C or reflux temperature of the solvents used. Resmetirom used for preparing solution can be in crystalline form or amorphous form or semisolid or oily liquid. The obtained solution optionally fdtered to remove undissolved particles.

[0037] The step (b) involves combining solution obtained in step (a) with a second solvent or mixtures thereof at a temperature of about 20 to about 150°C or 40°C to about 100°C. The suitable second solvent comprises aliphatic hydrocarbons; aromatic hydrocarbons; ether solvents; and any mixtures of two or more thereof. The resultant reaction mixture is cooled to about 0°C to about 10°C or less and is stirred for about 30 minutes to 30 hours. The stirring can be carried out at a temperature of less than about 30°C or less than about 0°C to obtain as a solid.

[0038] The step (c) involves isolation of REE -2 from the suspension by fdtration or by decantation or by any suitable method. The solid obtained in step (c) is dried. Drying may be suitably carried out using known equipment for a period of about 1 hour to about 15 hours, or longer.

[0039] Further, the process for the preparation of crystalline Form REE-2 of Resmetirom comprises drying of REE-1 at a temperature of about 50°C under vacuum for a period of about 10 hours to about 30 hours. In another aspect of the present invention provides a crystalline Resmetirom Form REE-7, which is characterized by XRPD pattern comprising 20 peaks at 5.7, 9.5, 11.4, 18.8 and 23.0 ± 0.2°, and comprising 20 peaks at 15.2, 20.1, 21.4, 23.9 and 27.2 ± 0.2° 20. The REE-7 may be characterized by XRPD pattern substantially as illustrated in Figure 3.

[0040] In another aspect of the present invention, provides a process for the preparation of Resmetirom REE-7, comprising dissolving Resmetirom in acetic acid to obtain clear solution, combining the solution with hydrocarbon solvent, isolating the solid and drying to obtain crystalline form REE-7 of Resmetirom.

[0041] The solution may be combined with hydrocarbon solvent at a temperature of about 20 to about 150°C or 40°C to about 100°C. The hydrocarbon comprises n-heptane, hexane and cyclohexane. The isolation of REE 7 from the suspension involves fdtration or decantation or any suitable method to obtain solid, which is dried for a period of about 1 hour to about 18 hours, or longer. The ratio of the solvent system in the range of 1 : 1 to 1: 10.

[0042] In another aspect of the present invention provides a crystalline Resmetirom Form REE-9, which is characterized by XRPD pattern comprising 20 peaks at 6.4, 7.7, 19.6, 24.1 and 25.3 ± 0.2°, and comprising 20 peaks at 20.9, 22.6, 23.3 and 26.5 ± 0.2°. The REE-9 may be characterized by XRPD pattern substantially as illustrated in Figure 5.

[0043] In another aspect of the present invention provides a process for the preparation of Resmetirom REE-9 comprising dissolving Resmetirom in a solvent selected from 2-chloropropane, THF, or methyl THF to obtain clear solution, precipitating the solid by addition of a second solvent, suspending the obtained solid in methyl tert-butyl ether solvent, isolating the solid and drying to obtain crystalline form REE-9 of Resmetirom. The solution can be prepared at room temperature or by heating the contents at a temperature of about 35 to about 150°C or reflux temperature of the solvents used. The solution is obtained mixed with a second solvent to precipitate the solid. The second solvent comprises ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; aliphatic hydrocarbons like n-hexane, n-heptane, cyclohexane, isooctane and like; aromatic hydrocarbons like toluene, xylene and like; and any mixtures of two or more thereof.

[0044] The obtained solid is suspended in methyl tert-butyl ether or its combination with other solvent comprising ether and / or hydrocarbon at a temperature of about 20 to about 150°C or 40°C to about 100°C. The resultant solid is recovered by fdtration or by decantation or by any suitable method to obtain solid. The solid obtained is dried at temperatures less than about 100°C, to obtain Form REE-8, which is further dried at a temperature of about 100°C to 150 °C for a desired time period to achieve a desired crystalline Form REE-9 with desired purity, for example, from about 1 hour to about 5 hours, or longer.

[0045] In another aspect of the present invention provides a crystalline Form REE- 10 of Resmetirom characterized by XRPD pattern comprising two or more peaks at 5.2, 6.2, 8.2, 8.7, 11.0, 12.1, 14.4, 20.0, 21.0, 23.2 and 24.5 ± 0.2° 29.

[0046] In another aspect of the present invention provides a crystalline Resmetirom Form REE-11, which is characterized by XRPD spectrum substantially as illustrated in Figure 7, wherein the most intense diffraction two or more peaks present at 7.7, 9.6, 11.6, 22.4 and 23.4 ± 0.2° 20, and also having additional peaks at 5.8, 6.5, 14.6, 20.0 and 24.7 ± 0.2° 20.

[0047] In another aspect the present invention provides a process for the preparation of Resmetirom Form REE- 11 comprising dissolving Resmetirom in a solvent, combining with methyl tert-butyl ether to obtain solid, slurring the obtained solid in mixture of n-heptane and methyl tert-butyl ether solvent, isolating the solid of REE- 10, and then drying to obtain crystalline form REE- 11 of Resmetirom.

[0048] The solvent used for the dissolution comprises 2-chloropropane, THF and methyl THF or combination thereof. The solution and precipitation of solid can be performed at a temperature of about 20 to about 150°C. The obtained solid is isolated from the suspension by fdtration to obtain REE- 10.

[0049] The resultant REE- 10 is dried at a temperature of about 60°C to about 100°C or about 80 °C for a period of 1 hour to about 24 hours or more to obtain REE-11.

[0050] The crystalline form of the present invention can be used for the preparation of amorphous form, solid dispersions along with pharmaceutically acceptable excipient and their pharmaceutical compositions.

[0051] The resultant new crystalline forms of the present invention can be used for the preparation of a medicament for treatment and / or prevention of nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias.

[0052] Suitable pharmaceutically acceptable excipients which may be used for solid dispersion and composition include, but are not limited to: diluents; binders; disintegrants; lubricants; glidants; solubility' or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents; release rate controlling agents. Other pharmaceutically acceptable excipients that are of use include but are not limited to fdm formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, and antioxidants known in the art. The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

[0053] EXAMPLES

[0054] Example 1: Preparation of crystalline Form REE-1 of Resmetirom:

[0055] Resmetirom (500.0 mg) was dissolved in benzyl alcohol (8ml) at 123-135°C to obtain a clear solution. The clear solution added to pre-heated n-heptane at 45 °C and stirred reaction mixture for 10 - 15 minutes. The reaction mixture was cooled to 0 - 5°C and stirred for 17-18 hours. The solid obtained was filtered and suck dried 10-15 minutes to obtain crystalline form REE-1 of Resmetirom (Purity by HPLC: 99.90%), PXRD pattern is shown in Figure 1.

[0056] Example 2: Preparation of crystalline Form REE-2 of Resmetirom:

[0057] Resmetirom (500.0 mg) was dissolved in a mixture of 1,2-propanediol and benzyl alcohol (1: 1) (8ml) at 123-135°C to obtain a clear solution. The clear solution was added to pre-heated n-heptane at 45 °C and stirred reaction mixture for 10-15 minutes followed by cooling to 0 - 5 °C and maintained for 17-18 hours. The solid obtained was filtered and suck dried for 10-15 minutes, followed by drying at 50°C under vacuum for 26 hours to obtain crystalline Form REE-2 of Resmetirom (Purity by HPLC: 99.88%).

[0058] DSC endothermic peak at about 158.0°C and 334.59°C;

[0059] TGA loss about 11.6%;

[0060] PXRD pattern is shown in Figure 2.

[0061] Example 3: Preparation of crystalline Form REE-2 of Resmetirom:

[0062] Resmetirom (45.0 gm) was dissolved in a mixture of benzyl alcohol and 1- propanol / acetonitrile / ethanol (9.7:0.3) (22V) at 90°C to obtain clear solution. The clear solution was cooled to 20-25°C and stirred reaction mixture for 18-24 hours. The solid obtained was filtered and washed with Di-isopropyl ether (0.5V), followed by suck dried for 10-15mins, followed by drying at 50°C under vacuum for 18-24 hours to crystalline Form REE-2 of Resmetirom.

[0063] Example 4: Preparation of crystalline Form REE-7 of Resmetirom:

[0064] Resmetirom Form-1 (200.0 mg) was dissolved in acetic acid (8ml) at 98-100°C to obtain a clear solution. The clear solution was added to pre-cooled heptane at 0- 5°C and stirred reaction mixture for 2-48 hours. The solid obtained was filtered and suck dried for 10-15 minutes, followed by drying at 40°C under vacuum for 18 hours to obtain crystalline Form REE-7 of Resmetirom.

[0065] DSC endothermic peak at about 135.75°C and 335.10°C;

[0066] TGA loss about 8.956% weight loss upto 230°C.

[0067] Water content is 4.2%.

[0068] PXRD pattern is shown in Figure 3.

[0069] Example 5: Preparation of crystalline Form REE-9 of Resmetirom:

[0070] Resmetirom Form-1 (200.0 mg) was dissolved in 2-chloropropane (8ml) at 30- 35°C. The clear solution was added to pre-cooled diisopropyl ether at 60-65°C and stirred the reaction mixture for 2-4 hours and filter the solid. The solid obtained was slurried in MTBE for 2-18 hours at 20°C. The solid obtained was filtered, suck dried for 10-15 minutes and dried at 100 °C for 2 hours to obtain crystalline Form REE-8. PXRD pattern is shown in Figure 4.

[0071] The resultant REE-8 was further dried at 145 °C for 2 hours to obtain crystalline Form REE-9 of Resmetirom.

[0072] PXRD pattern is shown in Figure 5. The endothermic peak of REE 9 shown at about 334.78°C in DSC; The weight loss about 1.1% upto 220°C in TGA.

[0073] The same experiment of the above was performed in THF instead of 2- chloropropane and obtained REE 9. Example 6: Preparation of crystalline Form REE-11 of Resmetirom:

[0074] Resmetirom (200.0 mg) was dissolved in tetrahydrofuran (THF) (5ml) at reflux to obtain clear solution. The clear solution was added to methyl tert-butyl ether (MTBE) (5 ml) at room temperature and stirred the reaction mixture for 2-4 hours and fdtered the solid. The solid obtained was slurried in heptane: methyl tert-butyl ether (MTBE) (2ml) (1:3) for 2 hours at 20°C. The solid obtained was filtered and dried for 10-15 minutes to obtain Form REE- 10 (PXRD pattern is shown in Figure-6).

[0075] The resultant Form REE- 10 was further dried at 80 °C for 24 hours to obtain Form REE-11.

[0076] PXRD pattern is shown in Figure-7.

[0077] DSC of Form REE-11: A broad exothermic peak at about 211.59°C and endothermic peaks at about 336.21°C;

[0078] TGA of Form REE-11: The weight loss at about 2.3% upto 240°C.

Claims

WE CLAIM:

1. A crystalline form of Resmetirom, selected from:REE-2 which is characterized by XRPD pattern comprising two or more peaks at about 6.5, 11.7, 12.9, 16.4 and 19.4 ± 0.2° 29,REE-7 which is characterized by XRPD pattern comprising two or more peaks at about 5.7, 9.5, 11.4, 18.8 and 23.0 ± 0.2° 20,REE-9 which is characterized by XRPD pattern comprising two or more peaks at about 6.4, 7.7, 19.6, 20.9, 22.6, 23.3, 24.1, 25.3 and 26.5 ± 0.2° 20.REE- 10 which is characterized by XRPD pattern comprising two or more peaks at about 5.2, 6.2, 8.2, 8.7, 11.0, 12.1, 14.4, 20.0, 21.0, 23.2 and 24.5 ± 0.2° 20., andREE-11 which is characterized by XRPD pattern comprising two or more peaks at about 5.8, 6.5, 7.7, 9.6, 11.6, 14.6, 20.0, 22.4, 23.4 and 24.7 ± 0.2° 20.

2. The crystalline form as claimed in claim 1, wherein the REE-2 is hemi benzyl alcohol solvate.

3. The crystalline form as claimed in claim 1, wherein the REE-2 is characterized by single crystal XRPD, parameters:Space Group: Pl a = 7.515(2) A; b = 11.571(3) A; c = 14.316(4) A a= 104.913(7) °;P= 94.573(8) °; = 101.201(8) °;Volume 1168.9(6) A3.

4. The crystalline form as claimed in claim 1, wherein the REE-2 has chemical purity of about > 99%.

5. A process for the preparation of crystalline Form REE-2 of Resmetirom comprising: a) providing a solution of Resmetirom in benzyl alcohol; b) combining the solution obtained in step (a) with a second solvent; and c) isolating crystalline Form REE-2 of Resmetirom.

6. The process as claimed in claim 5, wherein the solution of step (a) further comprises additional solvent selected from methanol, ethanol, isopropanol, 1,2-propanediol, acetonitrile and benzonitrile.

7. The process as claimed in claim 5, wherein the solvent of step (b) is selected from hexane, heptane, cyclohexane, methyl t-butyl ether, diethylether, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, ethyl tert-butyl ether, 2- methyltetrahydrofuran, polyethylene glycol and tetrahydropyran.

8. A process for the preparation of crystalline Form REE-7 of Resmetirom comprising dissolving Resmetirom in acetic acid to obtain clear solution, combining the solution with hydrocarbon solvent, isolating the solid and drying.

9. The process as claimed in claim 8, wherein the hydrocarbon solvent is selected from hexane, heptane and cyclohexane.

10. The crystalline form as claimed in claim 1, wherein the REE-9 of Resmetirom is obtained by dissolving Resmetirom in a solvent selected from 2- chloropropane, THF, or methyl THF to obtain clear solution, precipitating the solid by addition of a second solvent, suspending the obtained solid in methyltert-butyl ether, isolating the solid and drying to obtain crystalline Form REE- 9 of Resmetirom11. The process as claimed in claim 10, wherein the second solvent is selected from methyl t-butyl ether, diethylether, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, ethyl tert-butyl ether, 2-methyltetrahydrofuran, polyethylene glycol and tetrahydropyran.

12. The crystalline form as claimed in claim 1, wherein the REE- 11 of Resmetirom is obtained by dissolving Resmetirom in a solvent, combining with methyl tert-butyl ether to obtain solid, slurring the obtained solid in mixture of n-heptane and methyl tert-butyl ether solvent, isolating the solid and drying to obtain crystalline form REE- 11 of Resmetirom13. The process as claimed in claim 12, wherein the solvent is selected from methyl t-butyl ether, diethyl ether, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, ethyl tert-butyl ether, 2-methyltetrahydrofuran, polyethylene glycol and tetrahydropyran.

14. Use of the crystalline Resmetirom of claims 1, for the preparation of pharmaceutical composition in combination with a pharmaceutically acceptable excipient.

15. Use of the crystalline Resmetirom of claims 1, for the treatment of nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias.

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