Solid-state forms of resmetirom and processes for preparation thereof

Abstract

The present application relates to a various novel crystalline forms of 2- [3,5-dichloro -4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy) phenyl]-3,5- dioxo- 2,3,4,5-tetrahydro [1,2,4] triazine-6-carbonitrile represented by the following structural formula-1, which is referred to as Resmetirom. The present application also relates to process for the preparation of various novel crystalline polymorphic forms of compound of formula-1.

Description

[0001] Solid-state forms of Resmetirom and processes for preparation thereof

[0002] Related Applications:

[0003] This application claims the benefit of priority to our Indian patent application number 202441001088 filed on Jan 05, 2024, disclosures of all of which is incorporated by reference in their entirety.

[0004] Field of the invention:

[0005] The present application relates to a novel crystalline forms of 2-[3,5-dichloro- 4-(5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5- tetrahydro[l,2,4]triazine-6-carbonitrile represented by the following structural formula- 1 , which is referred to as Resmetirom.

[0006] Formula- 1.

[0007] Background of the invention:

[0008] 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yloxy)phenyl]- 3,5-dioxo-2,3,4,5-tetrahydro[l,2,4]triazine-6-carbonitrile or 2-[3,5-Dichloro-4-((6- oxo-5-(propan-2-yl)- l,6-dihydropyridazin-3-yl)oxy)phenyl]-3,5-dioxo-2, 3,4,5- tetrahydro-l,2,4-triazine-6-carbonitrile, commonly known as Resmetirom, is approved by the US FDA under the brand name REZDIFFRA. It is a thyroid hormone receptor-beta (THR-beta) agonist indicated, in conjunction with diet and exercise, for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (stages F2 to F3 fibrosis).

[0009]

[0010] US. Patent number 7452882 describes a method of making Resmetirom and its intermediates.

[0011] W02014043706A1 describes the crystalline form I, hydrate form, DMAC solvate and MIBK solvate of Resmetirom.

[0012] There is a still develop further solid-state forms or polymorphs of Resmetirom to meet the pharmaceuticals requirements.

[0013] Discovering new solid-state forms / polymorphic forms, solvates of a pharmaceutical product can provide materials having desirable physicochemical properties. New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.

[0014] Furthermore, solid-state study of an active pharmaceutical ingredient aims to widen the variety of polymorphs that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.

[0015] Brief summary of the invention:

[0016] The first embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-Ml and process for the preparation thereof.

[0017] The second embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-M2 and process for the preparation thereof.

[0018] The third embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-M3 and process for the preparation thereof.

[0019] The fourth embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-M4 and process for the preparation thereof.

[0020] The fifth embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-M5 and process for the preparation thereof.

[0021] The sixth embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-M6 and process for the preparation thereof.

[0022] The seventh embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-M7 and process for the preparation thereof.

[0023] Brief description of the drawings:

[0024] Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of form-Ml of Resmetirom.

[0025] Figure-2: Illustrates the PXRD pattern of form- M2 of Resmetirom.

[0026] Figure-3: Illustrates the PXRD pattern of form-M3 of Resmetirom.

[0027] Figure-4: Illustrates the PXRD pattern of form-M4 of Resmetirom.

[0028] Figure-5: Illustrates the PXRD pattern of form-M5 of Resmetirom.

[0029] Figure-6: Illustrates the PXRD pattern of form-M6 of Resmetirom.

[0030] Figure-7: Illustrates the PXRD pattern of form-M7 of Resmetirom.

[0031] Detailed description of the invention:

[0032] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid-state NMR spectra. As is well known in the art, the graphical data potentially provides additional technical information to further define the respective solid-state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.

[0033] As used herein, the term “isolated” in reference to crystalline polymorph of Resmetirom of the present disclosure corresponds to a crystalline polymorph of Resmetirom that is physically separated from the reaction mixture in which it is formed.

[0034] The term “about” refers to a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

[0035] A crystal form of Resmetirom referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Resmetirom characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0036] The first embodiment of the present invention provides crystalline form-Ml of Resmetirom of formula- 1. In the first aspect of the first embodiment, wherein the crystalline form-M 1 of Resmetirom is characterized by its PXRD peaks at about 10.6°, 11.0° and 12.7° ± 0.2° 26.

[0037] In the second aspect of the first embodiment, wherein the crystalline form-M 1 of Resmetirom is characterized by its PXRD peaks at about 10.6°, 11.0° and 12.7° ± 0.2° 26 and having one or more additional peaks selected from at about 16.2°, 11.5°, 16.9°, 18.8°, 21.1°, 22.4° and 24.2° ± 6.2° 26.

[0038] In the third aspect of the first embodiment, wherein the crystalline form-M 1 of Resmetirom of formula- 1 is characterized by a PXRD pattern substantially as depicted in figure- 1.

[0039] In the fourth aspect of the first embodiment of the present invention provides a process for the preparation of crystalline form-M 1 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in a mixture of acetic acid and solvent, b) isolating crystalline form-M 1 of Resmetirom of formula- 1, wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with a mixture acetic acid and a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M 1 of Resmetirom of formula- 1 in step-b) by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture and crystallization.

[0040] The second embodiment of the present invention provides crystalline form- M2 of Resmetirom of formula- 1.

[0041] In the first aspect of the second embodiment, wherein the crystalline form-M2 of Resmetirom characterized by its PXRD peaks at about 5.6°, 6.4°, 7.7°, 15.1° and 23.7° ± 6.2°. In the second aspect of the second embodiment, wherein the crystalline form- M2 of Resmetirom is characterized by its PXRD peaks at about 5.0°, 6.4°, 7.7°, 15.1° and 23.7° ± 0.2° and having one or more additional peaks selected from at about 10.1°, 12.1°, 14.3°, 17.8°, 19.6° and 21.8° ± 0.2° 26.

[0042] In the third aspect of the second embodiment, wherein the crystalline form- M2 of Resmetirom of formula- 1 is characterized by a PXRD pattern substantially as depicted in figure-2.

[0043] In the fourth aspect of the second embodiment of the present invention provides a process for the preparation of crystalline form-M2 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in solvent, b) isolating crystalline form- M2 of Resmetirom of formula- 1 ; wherein the solvent in step-a) is cyclohexanol; providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with a cyclohexanol at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M2 of Resmetirom of formula- 1 in step-b) is by combining with another solvent is selected from methyl tertiary butyl ether, n-heptane, n-hexane, diisopropyl ether, diethyl ether, cyclohexane and mixtures thereof.

[0044] In the fifth aspect of the second embodiment, wherein the crystalline form-M2 of Resmetirom is polymorphically stable up to one year.

[0045] The third embodiment of the present invention provides crystalline form-M3 of Resmetirom of formula- 1.

[0046] In the first aspect of the third embodiment, wherein the crystalline form-M3 of Resmetirom is characterized by its peaks at about 6.9°, 8.6°, 11.5°, 13.9°, 24.7° and 30.2° ± 0.2° 20. In the second aspect of the third embodiment, wherein crystalline form-M3 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.6°, 11.5°, 13.9°, 24.7° and 30.2° ± 0.2° 20 and having one or more additional peaks selected from at about 9.8°, 10.3°, 10.7°, 12.2°, 15.7°, 17.4°, 17.9°, 18.7°, 21.6°, 22.7°, 26.7° and 28.5° ± 0.2° 20.

[0047] In the third aspect of the third embodiment, wherein the crystalline form-M3 of Resmetirom of formula- 1 is characterized by a PXRD pattern substantially as depicted in figure-3.

[0048] In the fourth aspect of the third embodiment of the present invention provides process for the preparation of crystalline form-M3 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in cyclohexanol, b) isolating crystalline form-M3 of Resmetirom of formula- 1 ; wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with a cyclohexanol at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M3 of Resmetirom of formula- 1 in step-b) is by combining with an anti-solvent; wherein anti-solvent is selected from n-heptane, n-hexane, cyclohexane and the like.

[0049] The fourth embodiment of the present invention provides crystalline form-M4 of Resmetirom of formula- 1.

[0050] In the first aspect of the fourth embodiment, wherein the crystalline form-M4 is characterized by its PXRD peaks at about 3.9°, 18.3° and 19.0°± 0.2° 20.

[0051] In the second aspect of the fourth embodiment, wherein the crystalline form- M4 of Resmetirom is characterized by its PXRD peaks at about 3.9°, 18.3° and 19.0°± 0.2° 20 and having one or more additional peaks selected from at about 9.6°, 11.9°, 13.2°, 14.9°, 15.2°, 16.9°, 17.6°, 19.7°, 21.8°, 23.9°, 25.2°, 25.7°, 29.8° and 36.9° ± 0.2° 26.

[0052] In the third aspect of the fourth embodiment, wherein the crystalline form-M4 of Resmetirom of formula- 1 is characterized by a PXRD pattern substantially as depicted in figure-4.

[0053] In the fourth aspect of the fourth embodiment of the present invention provides a process for the preparation of crystalline form-M4 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in acetic acid, b) isolating crystalline form-M4 of Resmetirom of formula- 1 ; wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with an acetic acid at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M4 of Resmetirom of formula- 1 in step-b) is by combining with an anti-solvent; wherein anti-solvent is selected from n-heptane, n-hexane, cyclohexane and the like.

[0054] The fifth embodiment of the present invention provides crystalline form-M5 of Resmetirom of formula- 1.

[0055] In the first aspect of the fifth embodiment, wherein the crystalline form-M5 of Resmetirom is characterized by its PXRD peaks at peaks at about 6.4°, 7.5°, 8.2° and 9.5° ± 0.2° 20.

[0056] In the second aspect of the fifth embodiment, wherein crystalline form-M5 of Resmetirom is characterized by its PXRD peaks at about 6.4°, 7.5°, 8.2° and 9.5° ± 0.2° 20 and having one or more additional peaks selected from at about 10.0°, 11.5°, 16.1°, 18.8°, 19.4°, 20.5°, 21.7°, 23.2°, 24.7° and 27.2° ± 0.2° 20.

[0057] In the third aspect of the fifth embodiment, wherein the crystalline form-M5 of Resmetirom of formula- 1 is characterized by a PXRD pattern substantially as depicted in figure-5.

[0058] In the fourth aspect of the fifth embodiment of the present invention provides a process for the preparation of crystalline form-M5 of Resmetirom of formula- 1 comprising: a) contacting Resmetirom with Isonicotinamide in acetonitrile solvent, b) optionally filtering the obtained mixture in step-a), c) isolating crystalline form-M5 of Resmetirom of formula- 1 ; wherein contacting Resmetirom with isonicotinamide in acetonitrile in step-a) can be carried out at a suitable temperature ranging from about 25°C to reflux temperature; isolating crystalline form-M5 of Resmetirom of formula- 1 in step-b) is by cooling the mixture to lower temperatures followed by filtration of the mixture.

[0059] In the fifth aspect of the fifth embodiment, wherein the crystalline form-M5 of Resmetirom is polymorphically stable up to one year.

[0060] The sixth embodiment of the present invention provides crystalline form-M6 of Resmetirom of formula- 1.

[0061] In the first aspect of the sixth embodiment, wherein the crystalline form-M6 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.5°, 11.2° and 14.5°± 0.2° 26.

[0062] In the second aspect of the sixth embodiment, wherein the crystalline form- M6 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.5°, 11.2° and 14.5°± 0.2° 26 and having one or more additional peaks selected from at about 10.6°, 12.1°, 13.9°, 15.3°, 15.9°, 16.4°, 17.2°, 17.9°, 19.6°, 19.9°, 21.4°, 22.4°, 25.1°, 27.5°, 29.9° and 32.4°± 0.2° 26.

[0063] In the third aspect of the sixth embodiment, wherein the crystalline form-M6 of Resmetirom of formula- 1 is characterized by a PXRD pattern substantially as depicted in Figure-6. In the fourth aspect of the sixth embodiment of the present invention provides a process for the preparation of crystalline form-M6 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in mixture of acetonitrile and tetrahydrofuran, b) isolating crystalline form-M6 of Resmetirom of formula- 1. wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with the mixture of acetonitrile and tetrahydrofuran at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M6 of Resmetirom of formula- 1 in step-b) is by cooling the mixture to lower temperatures followed by filtration of the mixture.

[0064] In the fifth aspect of the sixth embodiment, wherein the crystalline form-M6 of Resmetirom is polymorphically stable up to one year.

[0065] The seventh embodiment of the present invention provides crystalline form- M7 of Resmetirom of formula- 1.

[0066] In the first aspect of the seventh embodiment, wherein the crystalline form- M7 of Resmetirom is characterized by its PXRD peaks at about 9.1°, 9.5°, 10.5°, 10.8° and 23.0° ± 0.2° 26.

[0067] In the second aspect of the seventh embodiment, wherein the crystalline form- M7 of Resmetirom is characterized by its PXRD peaks at about 9.1°, 9.5°, 10.5°, 10.8° and 23.0° ± 0.2° 26 and having one or more additional peaks selected from at about 11.9°, 15.7°, 17.3°, 18.8°, 19.5°, 21.5°, 24.3°, 24.9° and 28.8° ± 0.2° 26.

[0068] In the third aspect of the seventh embodiment, wherein the crystalline form- M7 of Resmetirom of formula- 1 characterized by a PXRD pattern substantially as depicted in figure-7.

[0069] In the fourth aspect of the seventh embodiment of the present invention provides a process for the preparation of crystalline form-M7 of Resmetirom of formula- 1 comprising: a) suspending Resmetirom in isobutyl acetate, b) filtering the mixture obtained in step-a) to provide crystalline form-M7 of Resmetirom of formula- 1.

[0070] In the fifth aspect of the seventh embodiment, wherein the crystalline form- M7 of Resmetirom is polymorphically stable up to one year.

[0071] The eighth embodiment provides crystalline forms obtained according to the present invention such as crystalline form-Ml, form-M2, Form-M3, Form-M4, Form- M5, Form-M6 and form-M7 of Resmetirom of formula- 1 used for the preparation of various pharmaceutical formulations.

[0072] The ninth embodiment of the present invention provides pharmaceutical composition comprising crystalline form selected from one or more of form-Ml, form-M2, Form-M3, Form-M4, Form-M5, Form-M6 and form-M7 of Resmetirom of the present invention and at least one pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0073] The tenth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of crystalline forms of Resmetirom obtained according to the present invention.

[0074] The eleventh embodiment of the present invention discloses a method for treating a patient in need thereof. The method involves administering a therapeutically effective amount of crystalline forms, obtained in accordance with the present invention. Crystalline forms obtained according to the present invention utilized in the treatment of various conditions, including but not limited to: (a) a method for treating resistance to thyroid hormone (RTH) syndrome; (b) a method for treating non-alcoholic steatohepatitis; (c) a method for treating familial hypercholesterolemia; (d) a method for treating fatty liver disease; and (e) a method for treating dyslipidemia.

[0075] Crystalline form-Ml, form-M2, Form-M3, Form-M4, Form-M5, Form-M6 and form-M7 of Resmetirom produced by various processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin / cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling / micronization may be performed before drying or after drying of the product.

[0076] Crystalline forms of Resmetirom obtained according to the present invention has particle size distribution as characterized by 90% particles having particle size (D90) less than about 100 pm, preferably less than about 50 pm, 50% particles having particle size (D50) less than about 50 pm, preferably less than about 20 pm and 10% particles having particle size (D10) less than about 30 pm, preferably less than about 10 pm.

[0077] Micronized Crystalline forms of Resmetirom obtained according to the present invention has particle size distribution as characterized by 90% particles having particle size (D90) less than about 20 pm, 50% particles having particle size (D50) less than about 10 pm and 10% particles having particle size (D10) less than about 5 pm.

[0078] Resmetirom used as an input for the preparation of crystalline forms of Resmeitrom can be obtained according to the process described in IN 202341029959 or by the process described in the literature or within the common general knowledge of person skilled in art. P-XRD Method of Analysis:

[0079] The PXRD analysis of the compound of formula- 1 of the present invention is carried out by using BRUKER / D8 ADVANCE or BRUKER / D2 PHASER diffractometer using CuKa radiation of wavelength 1.5406A0.

[0080] The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as an illustration only and hence, should not be construed as a limitation on the scope of the invention.

[0081] Examples:

[0082] Example-1: Preparation of crystalline form-Ml of Resmetirom

[0083] Dissolved Resmetirom (0.5 g) in the mixture of acetic acid (12 ml) and ethyl acetate (18 ml) at 40-50°C, cooled the obtained solution to 25-30°C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound.

[0084] Yield: 300 mg. PXRD of the obtained compound is illustrated in figure- 1.

[0085] Example-2: Preparation of crystalline form-M2 of Resmetirom

[0086] Dissolved Resmetirom (0.5 g) in cyclohexanol (45 ml) at 60-70°C and filtered for particle free. Obtained filtrate is added to the methyl tertiary butyl ether (80 ml) at 25- 30°C and stirred at the same temperature. Cyclohexane (100 ml) added to the mixture at 25-30°C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound.

[0087] Yield: 230 mg. PXRD of the obtained compound is illustrated in figure-2.

[0088] Example-3: Preparation of crystalline form-M3 of Resmetirom

[0089] Dissolved Resmetirom (0.5 g) in cyclohexanol (45 ml) at 60-70°C, cooled the obtained solution to 25-30°C and filtered for particle free. Obtained filtrate is added to cyclohexane (80 ml) at 25-30°C and stirred at the same temperature. Filtered the solid and dried to get the title compound.

[0090] Yield: 330 mg. PXRD of the obtained compound is illusstrated in figure-3.

[0091] Example-4: Preparation of crystalline form-M4 of Resmetirom Dissolved Resmetirom (0.5 g) in acetic acid (7 ml) at 70-80°C. Obtained solution is added to cyclohexane (60 ml) at 25-30°C and stirred. The mixture was cooled to 0- 5°C and stirred the mixture at the same temperature. The mixture was heated to 35- 40°C and stirred. Filtered the solid and dried to get the title compound.

[0092] Yield: 300 mg. PXRD of the obtained compound is illustrated in figure-4.

[0093] Example-5: Preparation of crystalline form-M5 of Resmetirom

[0094] Dissolved Resmetirom (0.5 g) and isonicotinamide (0.286 g) in acetonitrile (12 ml) at 75-85 °C and filtered for particle free at the same temperature. Obtained filtrate is cooled to 25-30°C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound.

[0095] Yield: 375 mg. PXRD of the obtained compound is illustrated in figure-5.

[0096] Example-6: Preparation of crystalline form-M6 of Resmetirom

[0097] Dissolved Resmetirom (0.3 g) in a mixture (1: 1) of acetonitrile and tetrahydrofuran (6.0 ml) at 55-65°C and filtered for particle free at the same temperature. Obtained filtrate is cooled to 25-30°C and stirred at the same temperature. Filtered the solid and dried to get the title compound.

[0098] Yield: 205 mg. PXRD of the obtained compound is illustrated in figure-6.

[0099] Example-7: Preparation of crystalline form-M7 of Resmetirom

[0100] A mixture of isobutyl acetate (15.0 ml) and Resmetirom (0.3 g) is stirred at 25-30°C. Filtered the solid and dried to get the title compound.

[0101] Yield: 220 mg. PXRD of the obtained compound is illustrated in figure-7.

Claims

Claims1. A crystalline form-M2 of Resmetirom of formula- 1Formula- 1. is characterized by its PXRD peaks at about 5.0°, 6.4°, 7.7°, 15.1° and 23.7° ± 0.2° 26.

2. The crystalline form-M2 of Resmetirom is characterized by its PXRD peaks at about 5.0°, 6.4°, 7.7°, 15.1° and 23.7° ± 0.2° and having one or more additional peaks selected from about 10.1°, 12.1°, 14.3°, 17.8°, 19.6° and 21.8° ± 0.2° 20.

3. The crystalline form-M2 according to claim 1 is characterized by a PXRD pattern substantially as depicted in figure-2.

4. The process for the preparation of crystalline form-M2 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in a solvent, b) isolating crystalline form-M2 of Resmetirom of formula- 1.

5. The process according to claim 4, wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with a solvent at a temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M2 of Resmetirom of formula- 1 in step-b) is by combining with another solvent is selected from methyl tertiary butyl ether, n-heptane, n-hexane, diisopropyl ether, diethyl ether, cyclohexane andmixtures thereof.

6. The process according to claim 4, wherein the solvent in step-a) is cyclohexanol.

7. A crystalline form-Ml of Resmetirom is characterized by its PXRD peaks at about 10.6°, 11.0° and 12.7° ± 0.2° 26.

8. The crystalline form-Ml of Resmetirom is characterized by its PXRD peaks at about 10.6°, 11.0° and 12.7° ± 0.2° 26 and having one or more additional peaks selected from at about 16.2°, 11.5°, 16.9°, 18.8°, 21.1°, 22.4° and 24.2° ± 6.2° 26.

9. The crystalline form-Ml according to claim 7 is characterized by a PXRD pattern substantially as depicted in figure- 1.

16. A process for the preparation of crystalline form-Ml of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in a mixture of acetic acid and solvent, b) isolating crystalline form-Ml of Resmetirom of formula- 1.

11. The process according to the claim 16, wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with a mixture acetic acid and a solvent at a temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-Ml of Resmetirom of formula- 1 in step-b) by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture and crystallization.

12. A crystalline form-M3 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.6°, 11.5°, 13.9°, 24.7° and 36.2° ± 6.2° 26.

13. The crystalline form-M3 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.6°, 11.5°, 13.9°, 24.7° and 30.2° ± 0.2° 20 and having one or more additional peaks selected from at about 9.8°, 10.3°, 10.7°, 12.2°, 15.7°, 17.4°, 17.9°, 18.7°, 21.6°, 22.7°, 26.7° and 28.5° ± 0.2° 20.

14. The crystalline form-M3 according to claim 12 is characterized by a PXRD pattern substantially as depicted in figure-3.

15. A crystalline form-M4 of Resmetirom is characterized by its PXRD peaks at about 3.9°, 18.3° and 19.0°± 0.2° 20.

16. The crystalline form-M4 of Resmetirom is characterized by its PXRD peaks at about 3.9°, 18.3° and 19.0°± 0.2° 20 and having one or more additional peaks selected from at about 9.6°, 11.9°, 13.2°, 14.9°, 15.2°, 16.9°, 17.6°, 19.7°, 21.8°, 23.9°, 25.2°, 25.7°, 29.8° and 36.9° ± 0.2° 20.

17. The crystalline form-M4 according to claim 15 is characterized by a PXRD pattern substantially as depicted in figure-4.

18. A crystalline form-M5 of Resmetirom is characterized by its PXRD peaks at about 6.4°, 7.5°, 8.2° and 9.5° ± 0.2° 20.

19. The crystalline form-M5 of Resmetirom is characterized by its PXRD peaks at about 6.4°, 7.5°, 8.2° and 9.5° ± 0.2° 20 and having one or more additional peaks selected from at about 10.0°, 11.5°, 16.1°, 18.8°, 19.4°, 20.5°, 21.7°, 23.2°, 24.7° and 27.2° ± 0.2° 20.

20. The crystalline form-M5 according to claim 18 is characterized by a PXRD pattern substantially as depicted in figure-5.

21. The process for the preparation of crystalline form-M5 of Resmetirom offormula- 1 comprising: a) contacting Resmetirom with Isonicotinamide in acetonitrile, b) optionally filtering the obtained mixture in step-a), c) isolating crystalline form-M5 of Resmetirom of formula- 1.

22. The process according to claim 21, wherein contacting Resmetirom with isonicotinamide in acetonitrile in step-a) can be carried out at a temperature ranging from about 25 °C to reflux temperature; isolating crystalline form-M5 of Resmetirom of formula- 1 in step-b) is by cooling the mixture to lower temperatures followed by filtration of the mixture.

23. A crystalline form-M6 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.5°, 11.2° and 14.5°± 0.2° 26.

24. The crystalline form-M6 of Resmetirom is characterized by its PXRD peaks at about 6.9°, 8.5°, 11.2° and 14.5°± 0.2° 26 and having one or more additional peaks selected from about 16.6°, 12.1°, 13.9°, 15.3°, 15.9°, 16.4°, 17.2°, 17.9°, 19.6°, 19.9°, 21.4°, 22.4°, 25.1°, 27.5°, 29.9° and 32.4°± 6.2° 26.

25. The crystalline form-M6 according to claim 23 is characterized by a PXRD pattern substantially as depicted in Figure-6.

26. The process for the preparation of crystalline form-M6 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in mixture of acetonitrile and tetrahydrofuran, b) isolating crystalline form-M6 of Resmetirom.

27. The process according to the claim 26, wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by combining Resmetirom with the mixture of acetonitrile and tetrahydrofuran at a temperature ranging fromabout 25°C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M6 of Resmetirom of formula- 1 in step-b) is by cooling the mixture to lower temperatures followed by filtration of the mixture.

28. A crystalline form-M7 of Resmetirom is characterized by its PXRD peaks at about 9.1°, 9.5°, 10.5°, 10.8° and 23.0° ± 0.2° 26.

29. The crystalline form-M7 of Resmetirom is characterized by its PXRD peaks at about 9.1°, 9.5°, 10.5°, 10.8° and 23.0° ± 0.2° 26 and having one or more additional peaks selected from about 11.9°, 15.7°, 17.3°, 18.8°, 19.5°, 21.5°, 24.3°, 24.9° and 28.8° ± 6.2° 26.

36. The crystalline form-M7 according to claim 28 is characterized by a PXRD pattern substantially as depicted in figure-7.

31. The process for the preparation of crystalline form-M7 of Resmetirom of formula- 1 comprising: a) suspending Resmetirom in isobutyl acetate, b) isolating the mixture obtained in step-a) to provide crystalline form-M7 of Resmetirom of formula- 1.

32. The crystalline form-Ml, form-M2, Form-M3, Form-M4, Form-M5, Form-M6 and form-M7 of Resmetirom of formula- 1 obtained according to the preceding claims used for the preparation of various pharmaceutical formulations.

33. The pharmaceutical composition comprising crystalline form selected from one or more of form-Ml, form-M2, Form-M3, Form-M4, Form-M5, Form-M6 and form-M7 of Resmetirom according the preceding claims and at least one pharmaceutically acceptable excipient.

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