Solid state forms of resmetirom

Abstract

The present invention relates to crystalline and amorphous form of Resmetirom, process for their preparation as well as their pharmaceutical composition.

Description

[0001] SOLID STATE FORMS OF RESM ETIROM

[0002] Related applications:

[0003] This application claims the benefit under Indian Provisional Application No’s. 202441011020, filed on February 16, 2024 and 202441030737, filed on April 17, 2024, the contents of which are incorporated by reference herein.

[0004] Field of the invention:

[0005] The present invention relates to crystalline form of Resmetirom, process for its preparation and pharmaceutical composition comprising the same.

[0006] The present invention also relates to amorphous Resmetirom, process for its preparation and pharmaceutical composition comprising the same.

[0007] Background of the invention:

[0008] Resmetirom is an experimental drug for the treatment of non-alcoholic steatohepatitis (NASH). It is a selective agonist of thyroid hormone receptor-0 which increases hepatic fat metabolism and reduces lipotoxicity. Resmetirom recently approved by USFDA and is chemically known as 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-l,6-dihydro-pyridazin-3-yloxy) -phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[l,2,4]triazine-6-carbonitrile and is structurally represented by the following formula I.

[0009] Formula I

[0010] Resmetirom and process for its preparation was first disclosed in US7452882B2. There is no characteristic data for Resmetirom in this patent.

[0011] The US9266861B2 patent discloses crystalline anhydrous Form I of Resmetirom, which is obtained by converting Resmetirom dimethylacetamide solvate to dihydrate form then to MIBK solvate and finally converted into anhydrous Form I. US20210122740A1 discloses different solvates of Resmetirom including methanol solvate, ethanol solvate and acetone solvate and an amorphous solid dispersion of Resmetirom. Further, WO2021063367A1, WO2021129465A1, WO2022052822A1, WO2022086894A1, W02022171200A1 and CN115124515A patent publication also discloses number of crystalline Forms and co-crystals of Resmetirom.

[0012] A new crystalline form of a compound may possess physical properties that differ from, and are advantageous over, those of other known crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.

[0013] The discovery of new crystalline form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product such as Resmetirom. Further, there is a need in the art for a commercially scalable process for the preparation of amorphous Resmetirom with high purity and yields. Hence the main object of the present invention is to provide novel crystalline form of Resmetirom and also a process for the preparation of amorphous Resmetirom with high yield and purity which is easily scalable to commercial scale. of the invention:

[0014] Accordingly, the present invention provides novel crystalline form of Resmetirom, process for its preparation and pharmaceutical compositions comprising the same.

[0015] The present invention also provides amorphous Resmetirom, process for its preparation and pharmaceutical composition comprising the same. The novel crystalline form of Resmetirom of the present invention has advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability.

[0016] In one aspect, the present invention provides crystalline form of Resmetirom characterized by a powder X-ray diffractogram that comprises one or more peaks at about 5.0, 6.4, 7.8, 12.1, 14.4, 15.1, 20.0, 24.0, 25.3 and 26.4 degrees 20±0.2 degrees 20, herein designated as Crystalline Form Ml.

[0017] In another aspect, the present invention provides Crystalline Form Ml of Resmetirom further characterized by a powder X-ray diffractogram that comprises one or more additional peaks at about 12.9, 14.0, 16.7, 20.8, 27.6 and 28.2 degrees 20±0.2 degrees 20.

[0018] In another aspect, the present invention provides Crystalline Form Ml of Resmetirom characterized by a powder X-ray diffractogram substantially as shown in Figure 1 or Figure 2.

[0019] In another aspect, the present invention provides Crystalline Form Ml of Resmetirom characterized by a Differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.

[0020] In another aspect, the present invention provides Crystalline Form Ml of Resmetirom characterized by a Thermo gravimetric analysis (TGA) thermogram substantially as shown in Figure 4.

[0021] In another aspect, the present invention provides Crystalline Form Ml of Resmetirom characterized by any one or more of the following; i. powder X-ray diffractogram that comprises one or more peaks at about 5.0, 6.4, 7.8, 12.1, 14.4, 15.1, 20.0, 24.0, 25.3 and 26.4 degrees 20±O.2 degrees 20; ii. powder X-ray diffractogram substantially as shown in Figure 1 or Figure 2; iii. differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3; or iv. thermo gravimetric analysis (TGA) thermogram substantially as shown in Figure 4. In another aspect, the present invention provides a process for the preparation of Crystalline Form Ml of Resmetirom, which comprises; a) suspending or dissolving Resmetirom in a suitable solvent or mixture of solvents, b) stirring the step a) suspension or a solution for a sufficient period of time; and c) isolating the Crystalline Form Ml of Resmetirom.

[0022] In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises; a) providing a solution of Resmetirom in one or more suitable solvent, b) removing the solvent from step a) solution or optionally adding suitable anti-solvent to step a) solution; and c) isolating the amorphous Resmetirom.

[0023] In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises: a) providing a solution of Resmetirom in one or more suitable solvent, b) subjecting the step a) solution to spray-drying; and c) isolating the amorphous Resmetirom.

[0024] In another aspect, the present invention provides stable amorphous Resmetirom characterized by having an X-ray powder diffraction pattern substantially as shown in Figure 5.

[0025] In a further aspect, the present invention provides a pharmaceutical composition comprising Crystalline Form Ml of Resmetirom or amorphous Resmetirom of the present invention and at least one pharmaceutically acceptable excipient.

[0026] Figure-1 shows an X-ray powder diffraction pattern of the Crystalline Form Ml of Resmetirom obtained as per Example 1.

[0027] Figure-2 shows an X-ray powder diffraction pattern of the Crystalline Form Ml of Resmetirom obtained as per Example 3. Figure-3 shows a Differential scanning calorimetry thermogram of the Crystalline Form Ml of Resmetirom.

[0028] Figure-4 shows a Thermogravimetric analysis thermogram of the Crystalline Form Ml of Resmetirom.

[0029] Figure-5 shows an X-ray powder diffraction pattern of amorphous Resmetirom.

[0030] The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (Instrument name Bruker D8 Advance) with measured using CuKa radiation of wavelength 1.54066A0step size of 0.012° / min; scan range of 3-40° A.

[0031] Differential scanning calorimetry (DSC) data in the present disclosure were recorded on a Perkin Elmer (Model-DSC 4000) at a heating rate of 10.0°C / min in the temperature range of from 25°C to 350°C.

[0032] Thermo gravimetric analysis (TGA) data in the present disclosure were recorded on a Perkin Elmer (TGA-4000) at a heating rate of 10°C / min in the temperature range of from 25°C to 300°C.

[0033] Detailed description of the invention:

[0034] Accordingly, the present invention provides novel crystalline and amorphous form of Resmetirom, process for their preparation; and pharmaceutical compositions comprising the same.

[0035] The novel crystalline form of Resmetirom of the present invention has advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability.

[0036] In one aspect, the present invention provides crystalline form of Resmetirom characterized by a powder X-ray diffractogram that comprises one or more peaks at about 5.0, 6.4, 7.8, 12.1, 14.4, 15.1, 20.0, 24.0, 25.3 and 26.4 degrees 20±0.2 degrees 20, herein designated as crystalline Form Ml. In another aspect, the present invention provides crystalline form Ml of Resmetirom further characterized by a powder X-ray diffractogram that comprises one or more additional peaks at about 12.9, 14.0, 16.7, 20.8, 27.6 and 28.2 degrees 20±0.2 degrees 20.

[0037] In another aspect, the present invention provides crystalline form Ml of Resmetirom characterized by a powder X-ray diffractogram substantially as shown in Figure 1 or Figure 2.

[0038] In another aspect, the present invention provides crystalline form Ml of Resmetirom characterized by a Differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3.

[0039] In an embodiment, the crystalline form Ml of Resmetirom of the present invention is further characterized by a DSC thermogram showing endothermic peaks at about 334°C to 337±3°C.

[0040] In another aspect, the present invention provides crystalline form Ml of Resmetirom characterized by a Thermo gravimetric analysis (TGA) thermogram substantially as shown in Figure 4.

[0041] In another aspect, the present invention provides a process for the preparation of Crystalline Form Ml of Resmetirom, which comprises; a) suspending or dissolving Resmetirom in a suitable solvent or mixture of solvents; b) stirring the step a) suspension or a solution for a sufficient period of time; and c) isolating the crystalline Form Ml of Resmetirom.

[0042] The step a) of the forgoing process involves suspending or dissolving Resmetirom in a suitable solvent selected from ether solvents such as ethyl ether, methyl ter-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran, dioxane and the like; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; chloro solvents such as dichloromethane, chloroform and the like; ester solvents such as ethyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene, cyclohexane, n-hexane, n-heptane and the like; or mixture of these solvents; preferably ether solvents and more preferably methyl ter-butyl ether (MTBE); at a suitable temperature of about 10°C to about reflux temperature of the solvent used; preferably at about 20°C to about 30°C; and the obtained suspension or a solution was stirred for a sufficient period of time till complete formation of crystalline material at a suitable temperature; preferably for 4-6 hrs at about 20°C to about 30°C; then isolation of Crystalline Form Ml of Resmetirom in step c) is carried out by methods known in the art; for example; filtration followed by drying at a suitable temperature.

[0043] In a specific embodiment, the present invention provides a process for the preparation of Crystalline Form Ml of Resmetirom, which comprises: a) suspending Resmetirom or its alcohol solvate in methyl tertiary-butyl ether (MTBE) at a suitable temperature of about 20°C to about 30°C, b) stirring the step a) suspension for a sufficient period of time at a suitable temperature of about 20°C to about 30°C; and c) isolating the Crystalline Form Ml of Resmetirom by filtration followed by drying.

[0044] The crystalline Form Ml of Resmetirom obtained above further dried. The drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; the drying may be carried out at a suitable temperature, for example less than about 70°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or any other suitable time period.

[0045] The starting Resmetirom material used herein in the present invention for the preparation of Crystalline Form Ml of Resmetirom may be any crystalline, amorphous or other forms of Resmetirom, like solvates and / or hydrates; and the same can be prepared by the methods known in the art.

[0046] The present invention is based in part on the unexpected finding that the new Crystalline Form disclosed herein possesses advantageous physicochemical properties which render their processing as medicaments beneficial. The new Crystalline Form of the present invention has adequate stability characteristics enabling their incorporation into a variety of different formulations particularly suitable for pharmaceutical utility. The Crystalline Form Ml of Resmetirom of the present invention exists in anhydrous or a solvated form. In an embodiment, the Crystalline Form Ml of Resmetirom of the present invention exists as a methyl t-butyl ether solvated form.

[0047] The Crystalline Form Ml of Resmetirom of the present invention having water content less than 1% w / w; preferably less than 0.8% w / w.

[0048] The Crystalline Form Ml of Resmetirom of the present invention may readily be incorporate into pharmaceutical compositions for immediate or delayed or modified release for the treatment of non-alcoholic steatohepatitis (NASH).

[0049] In an embodiment, the Crystalline Form Ml of Resmetirom of the present invention having purity greater than 99% by HPLC; preferably greater than 99.9% by HPLC.

[0050] In an embodiment, the Crystalline Form Ml of Resmetirom of the present invention used as an intermediary for the preparation of other known polymorphic forms such as crystalline or amorphous form of Resmetirom.

[0051] In another aspect, the present invention provides a pharmaceutical composition comprising Crystalline Form Ml of Resmetirom of the present invention and at least one pharmaceutically acceptable excipient.

[0052] In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises; a) providing a solution of Resmetirom in one or more suitable solvent, b) removing the solvent from step a) solution or optionally adding suitable anti-solvent to step a) solution; and c) isolating the amorphous Resmetirom.

[0053] The step a) of the forgoing process involves providing a solution of Resmetirom in one or more suitable solvent is carried out by dissolving Resmetirom in a suitable solvent at a suitable temperature of about 10°C to about reflux temperature of the solvent used; or utilizing the reaction mixture comprising Resmetirom obtained directly during the course of synthesis. The suitable solvent used herein may selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and / or mixtures thereof; preferably alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol and the like; and ketone solvent selected from acetone, methyl isobutyl ketone, methyl ethylketone and the like; more preferably mixture of methanol and acetone.

[0054] The removal of solvent from the step a) solution is carried out by known techniques such as distillation, spray drying, agitated thin film drying (“ATFD”), and freeze drying. Alternatively, the suitable anti-solvent in which Resmetirom is not soluble added to step a) solution to precipitate out Resmetirom.

[0055] Then isolation of amorphous Resmetirom is carried out by the methods known in the art depends on step b) method; for example, separating the amorphous form by way of decantation, filtration, filtration under vacuum, centrifugation and other methods known in the art or taking out the obtained amorphous solid followed by drying; or by adding a suitable solvent to the amorphous solid obtained after removal of the solvent by distillation and separating the amorphous form by way of decantation, filtration, filtration under vacuum, centrifugation and other methods known in the art; wherein the suitable solvent is the one in which Resmetirom is insoluble.

[0056] In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises: a) providing a solution of Resmetirom in one or more suitable solvent, b) subjecting the step a) solution to spray-drying; and c) isolating the amorphous Resmetirom.

[0057] The step a) of the forgoing process involves providing a solution of Resmetirom in one or more suitable solvent is carried out by dissolving Resmetirom in a suitable solvent at a suitable temperature of about 10°C to about reflux temperature of the solvent used; or utilizing the reaction mixture comprising Resmetirom obtained directly during the course of synthesis. The suitable solvent may selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and / or mixtures thereof; preferably alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol and the like; and ketone solvent selected from acetone, methyl isobutyl ketone, methyl ethylketone and the like; more preferably mixture of methanol and acetone.

[0058] The step b) of the forgoing process involves subjecting the step a) solution to spray-drying at a suitable temperature from about 30°C to about 80°C. Then isolation of amorphous Resmetirom is carried out by taking out the obtained amorphous solid followed by drying.

[0059] The amorphous Resmetirom obtained above may be further dried in suitable driers known in the art, for examples tray drier, dried under vacuum and / or in a Fluid Bed Drier to achieve the desired LOD levels.

[0060] In another aspect, the present invention provides stable amorphous Resmetirom, having an X-ray powder diffraction pattern substantially as shown in Figure 5.

[0061] In another aspect, the present invention provides stable amorphous Resmetirom having purity of greater than 99% by HPLC.

[0062] In another aspect, the present invention provides pharmaceutical composition comprising amorphous Resmetirom prepared according to the present invention and having one or more pharmaceutically acceptable excipients.

[0063] The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water. The term “amorphous” as applied to a compound refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”).

[0064] The following examples are set forth to aid the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

[0065] Example-1: Preparation of Crystalline Form of Resmetirom (Form Ml):

[0066] To a clean and dry RBF, Resmetirom (3 g) and methyl t-butyl ether (150 ml) were added at 20-30°C and the obtained suspension was stirred for 4 hrs at the same temperature. The obtained solid was filtered off, washed with methyl t-butylether and dried in a vacuum tray drier at 20-30°C to get the title compound. Yield: 1.5 g.

[0067] The PXRD pattern of obtained crystalline Form Ml of Resmetirom is set forth in Figure 1.

[0068] Example-2: Preparation of Crystalline Form of Resmetirom (Form Ml):

[0069] The title compound prepared in a similar manner to example 1 except that ethanol solvate of Resmetirom is used as input in the place of Resmetirom.

[0070] Example-3: Preparation of Crystalline Form of Resmetirom (Form Ml):

[0071] To a clean and dry RBF, Resmetirom methanol solvate (50 g) and methyl t-butyl ether (2500 ml) were added at 20-30°C and the obtained suspension was stirred for 4 hrs at the same temperature. The obtained solid was filtered off, washed with methyl t-butyl ether and dried in a vacuum tray drier at 60-70°C to get the title compound.

[0072] Yield: 35 g; M.C: 0.73%;

[0073] Purity by HPLC: 99.95 %.

[0074] The PXRD pattern of obtained crystalline Form Ml of Resmetirom is set forth in Figure 2. Example-4: Preparation of Crystalline Form of Resmetirom (Form Ml):

[0075] To a clean and dry RBF, Resmetirom (50 g) and methyl t-butyl ether (2500 ml) were added at 20-30°C and the obtained suspension was stirred for 4 hrs at the same temperature. The obtained solid was filtered off, washed with methyl t-butyl ether and dried in a vacuum tray drier at 60-70°C to get the title compound.

[0076] The PXRD pattern of obtained crystalline Form Ml of Resmetirom as set forth in Figure 2.

[0077] Example-5: Stability of Crystalline Form of Resmetirom (Form Ml):

[0078] The crystalline form Ml of the present invention in appropriate quantity placed under the conditions mentioned in the below table for stability study purpose and after completion of the respective time period, the crystal form status of the samples analyzed by PXRD, which results are as shown below:

[0079] The above result shows that crystalline Form Ml of the present invention is stable for at least 4 weeks under the above mentioned closed conditions; and stable for at least 48 hrs under the open conditions. Based on, the crystalline Form Ml can be stable under long term and accelerated conditions. Example-6: Preparation of amorphous Resmetirom:

[0080] Resmetirom (20 g) was dissolved in methanol (200 ml) and acetone (200 ml) at 25-30°C and the obtained solution was filtered through 0.2 microns filter. The filtrate was subject to spray drying in a spray dryer (Model: Lab Model PE- 1.5 A; Make: M / s Prathik Enterprises) at inlet temperature of 80°C through steam with feed rate of 8 ml / min at 1 kg / cm2Nitrogen pressure applied for feeding. After completion of spray dryer, cooled to room temperature, collected the material from the chamber and analyzed.

[0081] Purity: 99.5% by HPLC.

[0082] The PXRD pattern of obtained amorphous Resmetirom is set forth in Figure 5.

[0083] Example-7: Stability of Amorphous Resmetirom:

[0084] The Amorphous Form of the present invention in appropriate quantity placed under the conditions mentioned in the below table for stability study purpose and after completion of the respective time period, the amorphous form of the samples analyzed by PXRD, which results are as shown below:

[0085] The above result shows that amorphous form of the present invention is stable for at least 4 weeks under the above mentioned closed conditions; and stable for at least 1 week under the open conditions. Based on, the amorphous form can be stable under long term and accelerated conditions.

Claims

WE CLAIM:

1. A crystalline Form Ml of Resmetirom characterized by a powder X-ray diffractogram that comprises peaks at about 5.0, 6.4, 7.8, 12.1, 14.4, 15.1, 20.0, 24.0, 25.3 and 26.4 degrees 20±0.2 degrees 20.

2. The crystalline Form Ml of Resmetirom as claimed in claim 1, further characterized by a powder X-ray diffractogram that comprises one or more additional peaks at about 12.9, 14.0, 16.7, 20.8, 27.6 and 28.2 degrees 20±0.2 degrees 20.

3. The crystalline Form Ml of Resmetirom of claim 1 characterized by a powder X-ray diffractogram substantially as shown in Figure 1 or Figure 2.

4. The crystalline Form Ml of Resmetirom of claim 1 characterized by a Differential scanning calorimetry (DSC) theromogram substantially as shown in Figure 3.

5. The crystalline Form Ml of Resmetirom of claim 1 characterized by a Thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 4.

6. The crystalline Form Ml of Resmetirom as claimed in claim 1, further characterized by a DSC thermogram showing endothermic peaks at about 334°C to 337±3°C.

7. A crystalline form Ml of Resmetirom characterized by any one or more of the following; i. powder X-ray diffractogram that comprises one or more peaks at about 5.0, 6.4, 7.8, 12.1, 14.4, 15.1, 20.0, 24.0, 25.3 and 26.4 degrees 20±0.2 degrees 20; ii. powder X-ray diffractogram substantially as shown in Figure 1 or Figure 2; iii. differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 3; or iv. thermo gravimetric analysis (TGA) thermogram substantially as shown in Figure 4.

8. A process for the preparation of Crystalline Form Ml of Resmetirom, which comprises;a) suspending or dissolving Resmetirom in a suitable ether solvent or mixture of solvents; b) stirring the step a) suspension or a solution for a sufficient period of time; and c) isolating the Crystalline Form Ml of Resmetirom.

9. The process as claimed in claim 8, wherein the suitable ether solvent in step a) is selected from ethyl ether, methyl ter-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran, dioxane and / or mixtures thereof.

10. The process as claimed in claim 8, wherein the step a) is carried out at a temperature of about 20°C to about 40°C; the stirring in step b) is carried out for 4-6 hours at a temperature of about 20°C to about 40°C; and the isolation in step c) is carried out by filtration followed by drying.

11. The process for the preparation of Crystalline Form Ml of Resmetirom as claimed in claim 1, comprises: a) suspending Resmetirom in methyl tertiary-butyl ether (MTBE) at a suitable temperature of about 20°C to about 30°C, b) stirring the step a) suspension for a sufficient period of time at a suitable temperature of about 20°C to about 30°C; and c) isolating the Crystalline Form Ml of Resmetirom by filtration followed by drying.

12. The Crystalline Form Ml of Resmetirom as claimed in any of the proceeding claims having purity greater than 99% by HPLC.

13. A pharmaceutical composition comprising Crystalline Form Ml of Resmetirom as claimed in claim 1 and at least one pharmaceutically acceptable excipient.

14. A process for the preparation of amorphous Resmetirom, which comprises; a) providing a solution of Resmetirom in one or more suitable solvent, b) removing the solvent from step a) solution or optionally adding suitable antisolvent to step a) solution; and c) isolating the amorphous Resmetirom.

15. The process as claimed in claim 14, wherein the suitable solvent in step a) is selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and / or mixtures thereof.

16. The process as claimed in claim 14, wherein in step b) the removal of solvent from the step a) solution is carried out by distillation, spray drying, agitated thin film drying (“ATFD”) or freeze drying.

17. A process for the preparation of amorphous Resmetirom, which comprises: a) providing a solution of Resmetirom in one or more suitable solvent, b) subjecting the step a) solution to spray-drying; and c) isolating the amorphous Resmetirom.

18. The process as claimed in claim 17, wherein the suitable solvent in step a) is selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and / or mixtures thereof.

19. The process as claimed in claim 17, wherein the suitable solvent is mixture of methanol and acetone.

20. The stable amorphous Resmetirom obtained according to claim 15 or claim 17 having purity greater than 99% by HPLC.

21. Stable amorphous Resmetirom characterized by a powder X-ray diffractogram substantially as shown in Figure 5.

22. A pharmaceutical composition comprising an amorphous Resmetirom as claimed in claim 21 and at least one pharmaceutically acceptable excipient.

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