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. Formula-1. 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 Indian Patent Application Nos. 202441005789, filed on Jan 29, 2024, and 202441077212, filed on Oct 11, 2024, the disclosures of all of which are 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] Formula- 1.

[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-M8 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-M9 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-MIO and process for the preparation thereof.

[0019] The fourth embodiment of the present invention provides a process for the micronization of crystalline Resmetirom of formula- 1.

[0020] The fifth embodiment of the present invention provides a novel crystalline form of Resmetirom compound of formula- 1, hereinafter designated as crystalline form-Mll 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-M12 and process for the preparation thereof.

[0022] The seventh embodiment of the present invention provides a novel crystalline form of Resmetirom with orotic acid.

[0023] Brief description of the drawings:

[0024] Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline of form-M8 of Resmetirom.

[0025] Figure-2: Illustrates the powder X-Ray diffraction pattern of crystalline of form-M9 of Resmetirom.

[0026] Figure-3: Illustrates the powder X-Ray diffraction pattern of crystalline of form-MIO of Resmetirom obtained according to example-3.

[0027] Figure-4: Illustrates the powder X-Ray diffraction pattern of crystalline of form-Ml l of Resmetirom.

[0028] Figure-5: Illustrates the powder X-Ray diffraction pattern of crystalline of form-M12 of Resmetirom.

[0029] Figure-6: Illustrates the powder X-Ray diffraction pattern of crystalline form of Resmetirom with orotic acid.

[0030] Figure-7: Illustrates the powder X-Ray diffraction pattern of crystalline of form-MIO of Resmetirom obtained according to example-4.

[0031] Figure-8: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline of form-MIO of Resmetirom {before micronization} prepared according to example-8.

[0032] Figure-9: Illustrates the PXRD pattern of crystalline of form-MIO of Resmetirom {after micronization} prepared according to example-8.

[0033] Figure-10: Illustrates the PXRD pattern of crystalline of form-MIO of Resmetirom {before micronization} prepared according to example-9.

[0034] Figure-11: Illustrates the PXRD pattern of micronized crystalline of form-MIO of Resmetirom {after micronization} prepared according to example-9.

[0035] Figure-12: Illustrates the PXRD pattern of crystalline of form-MIO of Resmetirom {before micronization} prepared according to example- 10.

[0036] Figure-13: Illustrates the PXRD pattern of micronized crystalline of form-MIO of Resmetirom {after micronization} prepared according to example- 10.

[0037] Figure-14: Illustrates the PXRD pattern of crystalline of form-MIO of Resmetirom prepared according to example- 11.

[0038] Detailed description of the invention:

[0039] 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.

[0040] 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.

[0041] 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.

[0042] The “solvent” used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N- methylpyrrolidone (NMP) and mixtures thereof; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and mixtures thereof; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane- 1,2- diol, propane- 1,2-diol, cyclohexanol and mixtures thereof; “polar solvents” such as water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.

[0043] The first embodiment of the present invention provides a crystalline form-M8 of Resmetirom of formula- 1.

[0044] In the first aspect of the first embodiment provides a crystalline form-M8 of Resmetirom of formula- 1 characterized by its PXRD pattern as illustrated in figure- 1.

[0045] In the second aspect of the first embodiment of the present invention provides a process for the preparation of crystalline form-M8 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in an alcohol solvent, b) combining an obtained solution in step-a) with an ether solvent, c) isolating crystalline form-M8 of Resmetirom of formula- 1 , wherein providing a solution of Resmetirom in a solvent in step-a) can be carried out by dissolving Resmetirom in a solvent selected from an alcohol solvent; at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M8 of Resmetirom of formula- 1 in step-c) by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture or crystallization or adding anti-solvent is selected from hydrocarbon solvent.

[0046] The second embodiment of the present invention provides a crystalline form- M9 of Resmetirom of formula- 1.

[0047] In the first aspect of the second embodiment provides a crystalline form-M9 of Resmetirom of formula- 1 characterized by its PXRD pattern as illustrated in figure-2.

[0048] In the second aspect of the second embodiment of the present invention provides a process for the preparation of crystalline form-M9 of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in acetic acid, b) combing the obtained solution in step-a) with an hydrocarbon solvent, c) isolating crystalline form-M9 of Resmetirom of formula- 1 , wherein providing a solution of Resmetirom in step-a) can be carried out by dissolving Resmetirom in acetic acid at a suitable temperature ranging from about 25 °C to reflux temperature or solution in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form-M9 of Resmetirom of formula- 1 in step-c) by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture; optionally the obtained compound in step-c) is further slurrying in ether solvent.

[0049] The third embodiment of the present invention provides a crystalline form- M10 of Resmetirom of formula- 1.

[0050] In the first aspect of the third embodiment provides a crystalline form-MIO of Resmetirom of formula- 1 characterized by its PXRD peaks at about 4.9°, 6.3°, 7.6° and 9.1° ± 0.2° 26.

[0051] In the second aspect of the third embodiment provides a crystalline form-MIO of Resmetirom of formula-1 characterized by its PXRD peaks at about 6.3°, 7.6° and 9.1° ± 0.2° 20.

[0052] In the third aspect of the third embodiment provides a crystalline form-MIO of Resmetirom of formula-1 characterized by its PXRD peaks at about 6.3°, 7.6° and 9.1°± 0.2° 20 and further comprising one or more additional peaks selected from at about 4.9°, 12.0°, 19.4°, 23.4°, 23.7°, 24.0° and 26.2° ± 20.

[0053] In the fourth aspect of the third embodiment provides a crystalline form-MIO of Resmetirom of formula-1 characterized by its PXRD peaks at about 6.3°, 7.6° and 9.1°± 0.2° 20 and further comprising one or more additional peaks selected from at about 4.9°, 12.0°, 19.4°, 22.6°, 23.4°, 23.7°, 24.0°, 25.1°, and 26.2° ± 20.

[0054] In the fifth aspect of the third embodiment provides a crystalline form-MIO of Resmetirom of formula- 1 characterized by its PXRD pattern as illustrated in figure-3 or figure-7 to 14.

[0055] In the sixth aspect of the third embodiment of the present invention provides a process for the preparation of crystalline form-MIO of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in a mixture of alcohol solvent and nitrile solvent or ketone solvent, b) isolating crystalline form-MIO of Resmetirom of formula- 1, wherein providing a solution of Resmetirom in step-a) can be carried out by dissolving Resmetirom in the mixture of alcohol solvents and nitrile solvents or ketone 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-MIO 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 or crystallization or combining with anti-solvent is selected from ether solvent, hydrocarbon solvent and mixtures thereof; the solution obtained in step-a) optionally combining with the seed crystals of crystalline form-MIO of Resmetirom in a solvent at a suitable temperature; wherein the seed crystals obtained according to the process described in the present invention.

[0056] In eighth aspect of third embodiment, Crystalline form-MIO 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.

[0057] In ninth aspect of third embodiment provides an accelerated and long-term stability data of crystalline form-MIO of Resmetirom is outlined in Table- 1 as follows:

[0058] Table- 1

[0059] The fourth embodiment of the present invention provides a process for the micronization of crystalline Resmetirom of formula- 1.

[0060] In the first aspect of the fourth embodiment, the micronization of crystalline form is performed by milling (and / or re-milling) using a jet-milling process with feed rates between 1 and 5 kg / cm2and milling pressures between 2.0 and 7.0 kg / cm2.

[0061] In the second aspect of the fourth embodiment, Micronized Crystalline form of Resmetirom [herein also referred as Crystalline form {after micronization}] 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.

[0062] In the third aspect of the fourth embodiment, wherein the crystalline form is form-MIO of Resmetirom of formula- 1.

[0063] The fifth embodiment of the present invention provides a crystalline form- M 11 of Resmetirom of formula- 1.

[0064] In the first aspect of the fifth embodiment provides a crystalline form-Mll of Resmetirom of formula- 1 characterized by its PXRD characteristic peaks at about 5.4°, 5.7°, 10.9° and 16.2° ± 0.2° 20 and further characterized PXRD characteristic peaks at about 8.7°, 11.5°, 19.5° and 21.7° ± 0.2° 20.

[0065] In the second aspect of the fifth embodiment provides a crystalline form-Mll of Resmetirom of formula- 1 characterized by its PXRD pattern as illustrated in figure-5.

[0066] In the third aspect of the fifth embodiment of the present invention provides a process for the preparation of crystalline form-Mll of Resmetirom of formula- 1 comprising: a) providing a solution of Resmetirom in a mixture of alcohol and ketone solvents, b) combining with an anti-solvent to the obtained solution in step-a), c) isolating crystalline form-Mll of Resmetirom of formula- 1 , wherein providing a solution of Resmetirom in step-a) can be carried out by dissolving Resmetirom in the mixture of alcohol solvents and ketone solvents 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 11 of Resmetirom of formula- 1 in step-b) by filtering the obtained solid from the mixture or by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture .

[0067] The sixth embodiment of the present invention provides a crystalline form- Ml of Resmetirom of formula- 1.

[0068] In the first aspect of the sixth embodiment provides a crystalline form-M 12 of Resmetirom of formula- 1 characterized by its PXRD characteristic peaks at about 5.4°, 8.3°, 10.8°, 15.4° and 16.9° ± 0.2° 20 and further characterized PXRD characteristic peaks at about 13.9°, 18.0°, 19.1°, 19.9° and 23.8° ± 0.2° 20.

[0069] In the second aspect of the fifth embodiment provides a crystalline form-M 12 of Resmetirom of formula- 1 characterized by its PXRD pattern as illustrated in figure-5.

[0070] The seventh embodiment of the present invention provides a crystalline form of Resmetirom with orotic acid.

[0071] In the first aspect of the seventh embodiment provides a crystalline form of Resmetirom with orotic acid characterized by its PXRD characteristic peaks at about 10.4°, 15.9°, 22.1°, 23.8 and 28.4° ± 0.2° 20 and further characterized PXRD characteristic peaks at about 15.3°, 17.4°, 24.7° and 26.5° ± 0.2° 20. In the second aspect of the seventh embodiment provides a crystalline form of Resmetirom with orotic acid characterized by its PXRD pattern as illustrated in figure-6.

[0072] In the third aspect of the seventh embodiment of the present invention provides a process for the preparation of crystalline form of Resmetirom with orotic acid comprising: a) providing a mixture of Resmetirom with orotic acid in a solvent, b) isolating crystalline form of Resmetirom with orotic acid, wherein providing a mixture of Resmetirom in a solvent in step-a) can be carried out by contacting Resmetirom with orotic acid in a solvent which is same as defined above and at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent or a mixture in step-a) can also be obtained from the synthetic process in which Resmetirom is prepared; isolating crystalline form of Resmetirom with orotic acid in step-b) by filtering the obtained solid from the mixture or by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture.

[0073] The eighth embodiment provides crystalline forms obtained according to the present invention such as crystalline form-M8, Form-M9, Form-MIO, Form-Mil, Form-M12 of Resmetirom of formula- 1 and crystalline form of Resmetirom with orotic acid used for the preparation of various pharmaceutical formulations.

[0074] The ninth embodiment of the present invention provides pharmaceutical composition comprising crystalline form selected from one or more of crystalline form-M8, Form-M9, Form-MIO, Form-Mil, Form-M12 of Resmetirom of formula-1 and crystalline form of Resmetirom with orotic acid 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.

[0075] The tenth embodiment of the present invention discloses a method for treating a patient in need thereof. The method involves administering a therapeutically effective amount of Resmetirom crystalline forms, obtained in accordance with the present invention. These crystalline forms are 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.

[0076] Crystalline form-M8, Form-M9, Form-MIO, Form-Mil, Form-M12 of Resmetirom of formula- 1 and crystalline form of Resmetirom with orotic acid 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.

[0077] Resmetirom used as an input for the preparation of crystalline forms of Resmeitrom can be obtained according to the process described in our co-pending application IN202341029959 or by the process described in the literature or the common general knowledge of person skilled in art.

[0078] Particle size measurement:

[0079] The particle size distribution analysis was carried out by using a Malvern Mastersizer 3000 instrument.

[0080] P-XRD Method of Analysis: 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.

[0081] 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.

[0082] Examples:

[0083] Example-1: Preparation of crystalline form-M8 of Resmetirom

[0084] Dissolved Resmetirom (2 g) in cyclohexanol (172 ml) at 60-70°C, cooled the obtained solution to 25-30°C and added to methyl tertiary butyl ether (240 ml). Partially distilled off the solvent from the mixture. Obtained solution is added to a cyclohexane (240 ml) at 25-30°C and stirred at the same temperature. Filtered the solid and dried to get the title compound.

[0085] Yield: 1.2 g. PXRD of pattern the obtained compound is illustrated in figure- 1.

[0086] Example-2: Preparation of crystalline form-M9 of Resmetirom

[0087] Dissolved Resmetirom (2 g) in a mixture of acetic acid (70 ml) at 50-60°C and stirred at the same temperature. Filtered the solution for particle free, obtained filtrate is added to cyclohexane (600 ml) at 25-30°C and stirred at the same temperature. Filtered the solid, added the obtained solid to methyl tertiary butyl ether (120 ml) at 25-30°C and stirred at the same temperature. Filtered the solid and dried to get the title compound.

[0088] Yield: 1.4 g. PXRD pattern of the obtained compound is illustrated in figure-2.

[0089] Example-3: Preparation of crystalline form-MIO of Resmetirom

[0090] A mixture of Resmetirom (5 g) and isopropanol (175 ml) was heated to 60-70°C; acetone (50 ml) added to it and stirred at the same temperature. Filtered the solution for particle free. Obtained filtrate is added to cyclohexane (450 ml) at 25-30°C and stirred at the same temperature. Filtered the solid and dried to get the title compound. Yield: 3.6 g. PXRD pattern of the obtained compound is illustrated in figure-3. Example-4: Preparation of crystalline form-MIO of Resmetirom

[0091] Dissolved Resmetirom (2 g) in the mixture of n-butanol (25 ml) and acetonitrile (25 ml) at 70-80°C. Filtered the solution for particle free. Obtained filtrate is cooled to 0- 10°C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound.

[0092] Yield: 995 mg. PXRD pattern of the obtained compound is illustrated in figure-7.

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

[0094] A mixture of Resmetirom (500 mg) in isopropanol (5 ml) heated to 55-65°C, acetone (5 ml) added to it and stirred at the same temperature. Filtered the solution for particle free, obtained filtrate is added to n-heptane (30 ml) at 25-30°C and stirred at the same temperature. Filtered the solid and dried to get the title compound.

[0095] Yield: 380 mg. PXRD pattern of the obtained compound is illustrated in figure-4.

[0096] Example-6: Preparation of crystalline form-M12 of Resmetirom

[0097] Dissolved Resmetirom (300 mg) in acetone (18 ml) at 40-50°C and stirred at the same temperature. n-Heptane added to the reaction mixture at 40-50°C and stirred at the same temperature. Cooled the mixture to 25-30°C and stirred at the same temperature. Filtered the precipitated solid and to get the title compound.

[0098] Yield: 210 mg. PXRD pattern of the obtained compound is illustrated in figure-5.

[0099] Example-7: Preparation of crystalline form of Resmetirom with orotic acid

[0100] A mixture of Resmetirom (300 mg), orotic acid (108 mg) and n-heptane (18 ml) stirred at 25-30°C for 3 hours. Filtered the solid and dried to get the title compound. Yield: 238 mg. PXRD pattern of the obtained compound is illustrated in figure-6.

[0101] General Procedure: Preparation of crystalline form-MIO of Resmetirom

[0102] Dissolved Resmetirom in the mixture of n-butanol (11 Volumes) and acetonitrile (11 Volumes) at 70-80°C. Filtered the solution for particle free. Obtained filtrate is cooled to 0-10°C and stirred at the same temperature. Filtered the precipitated solid, washed with n-butanol and dried to get the title compound.

[0103] General Procedure: Micronization of crystalline form-MIO of Resmetirom:

[0104] Crystalline Form-MIO of Resmetirom was subjected to micronization using a micronizer, and the resulting compound was characterized as shown in the below table -2:

[0105] Table-2

[0106] Example-11: Preparation of crystalline form-MIO of Resmetirom

[0107] Dissolved Resmetirom (110 g) in the mixture of n-butanol (1210 ml) and acetonitrile (1210 ml) at 70-80°C. Filtered the solution. Obtained filtrate is slowly added to the pre-cooled solution of seeds crystals of Form-MIO of Resmetirom (5.5 g) in n- butanol (330 ml) at 0-10°C and stirred at the same temperature. Filtered the precipitated solid, washed with n-butanol and dried to get the title compound.

[0108] Yield: 48.8 g; PXRD pattern of the obtained compound is illustrated in figure-14.

Claims

Claims1. A crystalline form-M 10 of Resmetirom of formula- 1Formula- 1 is characterized by its PXRD peaks at about 6.3°, 7.6° and 9.1° ± 0.2° 20.

2. The crystalline form-M 10 of Resmetirom is characterized by its PXRD peaks at about 6.3°, 7.6° and 9.1°± 0.2° 20 and further comprising one or more additional peaks selected from at about 4.9°, 12.0°, 19.4°, 23.4°, 23.7°, 24.0° and 26.2° ± 20.

3. The crystalline form of Resmetirom according to claim 1, further characterized by its XRPD pattern substantially as shown in Figures 3 and 7 to 14.

4. A process for the preparation of crystalline form-M 10 of Resmetirom comprising: a) providing a solution of Resmetirom in a mixture of alcohol solvent and nitrile solvent or ketone solvent, b) isolating crystalline form-M 10 of Resmetirom.

5. The process according to claim 5, wherein isolating crystalline form-M 10 of Resmetirom in step-b) by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture or crystallization or combining with anti-solvent is selected from ether solvent, hydrocarbon solvent and mixtures thereof.

6. A Resmetirom having a particle size distribution as characterized by 90% particles having particle size (D90) less than about 50 pm.

7. A Resmetirom according to claim 6, wherein the Resmetirom is in crystalline form MIO.

8. A micronized Resmetirom having a particle size distribution as characterized by 90% particles having particle size (D90) less than about 20 pm.

9. A micronized Resmetirom according to claim 8, wherein the Resmetirom is in crystalline form MIO.

10. The crystalline form-MIO of Resmetirom obtained according to the preceding claims used for the preparation of various pharmaceutical formulations.

11. The pharmaceutical composition comprising crystalline form-MIO of Resmetirom according the preceding claims and at least one pharmaceutically acceptable excipient.

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