Solid state forms of resmetirom

Abstract

The present disclosure encompasses solid state forms of Resmetirom and pharmaceutical compositions thereof.

Description

Attorney Docket: API079-W001 (2222-215 PCT)SOLID STATE FORMS OF RESMETIROMCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, Indian Provisional Application No. 202411074390 filed on October 1, 2024, Indian Provisional Application No. 202511025634, filed on March 20, 2025, and Indian Provisional Application No. 202511092738, filed on September 26, 2025. The entire contents of each of the foregoing applications are incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses solid state forms of Resmetirom and pharmaceutical compositions thereof.BACKGROUND OF THE DISCLOSURE

[0003] Resmetirom, 2-[3,5-dichloro-4-[(6-oxo-5-propan-2-yl-lH-pyridazin-3- yl)oxy]phenyl]-3,5-dioxo-l,2,4-triazine-6-carbonitrile, has the following chemical structure:

[0004] Resmetirom is a thyroid hormone receptor (THR) [3-selective agonist, and it is developed for the treatment of for non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias.

[0005] The compound is described in International Publication No. WO 2007 / 009913. The entire contents of the foregoing publication is incorporated by reference herein. International Publication Nos. WO 2014 / 043706, WO 2018 / 075650, WO 2020 / 010068, WO 2021 / 063367,Attorney Docket: API079-W001 (2222-215 PCT)WO 2021 / 129465, WO 2022 / 052822, WO2022 / 086894, W02022 / 171200, CN115124515A, IN202241066042, US2024 / 0423993, WO 2025 / 011259, IN 202311058349, CN119613386, WO 2025 / 083699, WO2025 / 146705, WO2025 / 171032, WO2025172958, CN118772117, CN119143733, CN119019375, IN202411074390 and CN119954780 relate to crystalline forms and salts of Resmetirom. The entire contents of each of the foregoing publications is incorporated by reference herein.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (“XRD”) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0007] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0008] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physicalAttorney Docket: API079-W001 (2222-215 PCT) stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Resmetirom.SUMMARY OF THE DISCLOSURE

[0009] The present disclosure provides crystalline polymorphs of Resmetirom, and pharmaceutical compositions thereof. The crystalline polymorphs can be used to prepare other solid state forms of Resmetirom, Resmetirom salts and / or co-crystals thereof and their solid state forms.

[0010] The present disclosure also provides uses of any one of said solid state forms of Resmetirom or in the preparation of other solid state forms of Resmetirom or salts or co-crystals thereof.

[0011] The present disclosure provides any one of the crystalline forms of Resmetirom for use in medicine, including for the treatment of non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and / or associated dyslipidemias.

[0012] The present disclosure also encompasses the use of any one or a combination of the crystalline polymorphs of Resmetirom of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising any one of the crystalline polymorphs of Resmetirom according to the present disclosure.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one of the crystalline polymorphs of Resmetirom with at least one pharmaceutically acceptable excipient.

[0015] The crystalline polymorphs of Resmetirom as defined herein and the pharmaceutical compositions or formulations of any one of the crystalline polymorphs of Resmetirom may be used as medicaments, particularly for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and / or associated dyslipidemias.

[0016] The present disclosure also provides methods of treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and / or associated dyslipidemias, by administering a therapeutically effective amount of any one of the crystalline polymorphs of Resmetirom of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from non-alcoholic steatohepatitisAtorney Docket: API079-W001 (2222-215 PCT)(NASH), non-alcoholic faty liver disease (NAFLD) and / or associated dyslipidemias or otherwise in need of the treatment.

[0017] The present disclosure also provides uses of any one of the crystalline polymorphs of Resmetirom of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., non-alcoholic steatohepatitis (NASH), non-alcoholic faty liver disease (NAFLD) and / or associated dyslipidemias.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows an X-ray powder diffraction (“XRPD”) patern of crystalline isobutanol solvate form RT1 of Resmetirom obtained from Example 1 procedure A.

[0019] Figure 1A shows an XRPD patern of crystalline isobutanol solvate form RT1 of Resmetirom obtained from Example 1 procedure C.

[0020] Figure 2 shows an XRPD patern of desolvated form RT2 of Resmetirom.

[0021] Figure 2A shows an XRPD patern of desolvated form RT2 of Resmetirom obtained from Example 1 procedure C.

[0022] Figure 3 shows an XRPD patern of isobutanol solvate form RT3 of Resmetirom.

[0023] Figure 4 shows an XRPD patern of crystalline isobutanol solvate form RT4 of Resmetirom.

[0024] Figure 5 shows an XRPD patern of form RT5 of Resmetirom.DETAILED DESCRIPTION OF THE DISCLOSURE

[0025] The present disclosure also provides uses of any one of said solid state forms of Resmetirom or in the preparation of other solid state forms of Resmetirom or salts or co-crystals thereof.

[0026] Solid state properties of Resmetirom and crystalline polymorphs thereof can be influenced by controlling the conditions under which Resmetirom and crystalline polymorphs thereof are obtained in solid form.

[0027] The solid state forms of Resmetirom as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.

[0028] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to meanAttorney Docket: API079-W001 (2222-215 PCT) that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. For example, polymorphically pure Resmetirom form RT1 means that the solid state form is substantially free of other solid state forms of Resmetirom; and polymorphically pure Resmetirom form RT4 means that the solid state form is substantially free of other solid state forms of Resmetirom. Thus, a crystalline polymorph of Resmetirom or a salt described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Resmetirom, salt or cocrystal. In some embodiments of the disclosure, the described crystalline polymorph of Resmetirom, salt or cocrystal may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Resmetirom.

[0029] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorph of Resmetirom, of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0030] 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 ofAttorney Docket: API079-W001 (2222-215 PCT) graphical data are characterizing the same crystal form or two different crystal forms. 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.

[0031] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Resmetirom relates to a crystalline form of Resmetirom which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0032] The term "desolvate" is used herein to describe a morphic form resulting from a solvent being substantially removed from a solvate, typically by heat, vacuum, or both. In some embodiments, at least 75% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 80% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 85% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 90% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 95% by weight of the solvent is removed from the solvate to form a desolvate. In some embodiments, at least 99% by weight of the solvent is removed from the solvate to form a desolvate.

[0033] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0034] 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.

[0035] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are optionally measured using CuKa radiation, X = 1.5418 A, typically at a temperature of 25 ± 3°C.

[0036] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., theAttorney Docket: API079-W001 (2222-215 PCT) room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25 °C.

[0037] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mb of the solvent. In another context, the term "v / v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mb of solvent X was added.

[0038] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0039] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0040] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0041] The solid state forms of Resmetirom as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.

[0042] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of any other compounds" refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w / w) or less, about 5% (w / w) or less, about 4% (w / w) or less, about 3% (w / w) or less, about 2% (w / w) or less, about 1.5% (w / w) or less, about 1% (w / w) or less, about 0.8% (w / w) or less, about 0.6% (w / w) or less, about 0.4% (w / w) or less, about 0.2% (w / w) or less, about 0.1% (w / w) or less, or about 0% of any other compound as measured, for example, by HPLC. Alternatively, a chemically pure or purified compound or a compound that is substantially freeAttorney Docket: API079-W001 (2222-215 PCT) of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC. Thus, pure or purified Resmetirom, described herein as substantially free of any compounds would be understood to contain greater than about 90% (w / w), greater than about 95% (w / w), greater than about 96% (w / w), greater than about 97% (w / w), greater than about 98% (w / w), greater than about 98.5% (w / w), greater than about 99% (w / w), greater than about 99.2% (w / w), greater than about 99.4% (w / w), greater than about 99.6% (w / w), greater than about 99.8% (w / w), greater than about 99.9% (w / w), or about 100% of the subject Resmetirom,. Alternatively, pure or purified Resmetirom, described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2% area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Resmetirom.

[0043] The present disclosure includes a crystalline isobutanol solvate of Resmetirom. In embodiments, the crystalline isobutanol solvate of Resmetirom is designated form RT1. Crystalline isobutanol solvate form RT1 of Resmetirom may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 or Figure 1A; an X-ray powder diffraction pattern having peaks at 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0044] Crystalline isobutanol solvate Form RT1 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having peaks at 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 13.7, 24.0 and 19.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0045] Crystalline isobutanol solvate Form RT1 of Resmetirom may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.3, 8.8, 13.7, 14.4, 19.9, 21.0 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0046] Crystalline isobutanol solvate Form RT1 of Resmetirom as described in any aspect or embodiment may be further characterized by an X-ray powder diffraction pattern having anAttorney Docket: API079-W001 (2222-215 PCT) absence of peaks at any one, two, or three of: 3.8 to 4.8 degrees 2-theta ± 0.2 degrees 2-theta; 7.2 to 7.4 degrees 2-theta ± 0.2 degrees 2-theta; and / or 9.3 to 9.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0047] In any aspect or embodiment of the present disclosure, crystalline isobutanol solvate Form RT1 of Resmetirom is isolated. Particularly, crystalline isobutanol solvate Form RT1 of Resmetirom according to any aspect or embodiment of the disclosure may be isolated.

[0048] In any aspect or embodiment crystalline isobutanol solvate Form RT1 of Resmetirom may be polymorphically pure.

[0049] In embodiments, crystalline isobutanol solvate Form RT1 may contain about 3% to about 8%, of isobutanol by weight, as determined by TGA. In embodiments, crystalline isobutanol solvate Form RT1 may contain about 4% to about 7%, of isobutanol by weight, as determined by TGA.

[0050] Crystalline isobutanol solvate Form RT1 of Resmetirom may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1 or Figure 1A, and combinations thereof.

[0051] According to any aspect or embodiment the present disclosure, crystalline isobutanol solvate Form RT1 of Resmetirom may be prepared by a process comprising: (a) crystallization of the isobutanol solvate of Resmetirom from a mixture comprising isobutanol and 2-methoxyethanol and addition of an antisolvent, or (b ) crystallization of the isobutanol solvate of Resmetirom from a mixture comprising isobutanol and methyl tert-butyl ether and an antisolvent; or (c) crystallization of the isobutanol solvate of Resmetirom from a mixture comprising isobutanol, methyl tert-butyl and water and an antisolvent.

[0052] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom wherein the process comprises crystallization of isobutanol solvate Form RT1 of Resmetirom from a mixture comprising isobutanol and 2-methoxyethanol and addition of an antisolvent. The antisolvent may be an C5-C8 alkane, preferably heptane.

[0053] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom wherein the process comprises:(i) providing a solution of Resmetirom in the a mixture comprising isobutanol and 2- methoxyethanol, optionally at a temperature of about 60 °C to about 75 °C;(ii) optionally filtering the solution;Attorney Docket: API079-W001 (2222-215 PCT)(iii) optionally cooling the solution to about -15°C to about -5 °C;(iv) adding n-heptane;(v) optionally warming the reaction to a temperature of about 10 °C to about 20 °C;(vi) optionally maintain the solution at a temperature of about 10 °C to about 20 °C for about 1 to about 4 hours.(vii) optionally isolating the solid formed.

[0054] Crystalline isobutanol solvate Form RT1 of Resmetirom may alternatively be prepared by a process comprising combining a solution of Resmetirom in isobutanol, methyl tert-butyl ether, and water, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane. The mixture may be seeded with Form RT1 or form RT2 of Resmetirom prior to combining with the antisolvent. The solution of Resmetirom in isobutanol, methyl tert-butyl ether and water may be heated to a temperature of: about 40°C to about 80°C, or about 50°C to about 75°C, or about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C, and filtered prior to combining with the antisolvent. The solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, may be cooled to a temperature of: about 15°C to about 45°C, about 18°C to about 40°C, about 22°C to about 42°C, about 25°C to about 40°C, about 28°C to about 38°C, or about 30°C to about 35°C. The solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, may be combined with the antisolvent at a temperature of: about 15°C to about 35°C, about 18°C to about 30°C, about 22°C to about 28°C, about 24°C to about 26°C, or about 25°C, to form a mixture. The resulting mixture may be cooled, preferably to a temperature of: about -10°C to about 10°C, about -5°C to about 5°C, about -2°C to about 2°C, or about 0°C. The cooled mixture may be stirred, preferably for a period of: about 30 minutes to about 14 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 4 hours to about 8 hours, or about 5 hour to about 7 hours.

[0055] The isobutanol solvate of Resmetirom Form RT1 may be isolated, preferably by filtration, centrifugation or decantation, more preferably by filtration.

[0056] In embodiments, the crystalline isobutanol solvate of Resmetirom is designated form RT3. Crystalline isobutanol solvate form RT3 of Resmetirom may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 18.6, 22.0 and 25.0 degrees 2-theta± 0.2 degrees 2-theta; and combinations ofthese data.

[0057] Crystalline isobutanol solvate Form RT3 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 18.6, 22.0 andAttorney Docket: API079-W001 (2222-215 PCT)25.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 12.4, 23.5 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0058] Crystalline isobutanol solvate Form RT3 of Resmetirom may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 9.9, 12.4, 14.2, 18.6, 22.0, 23.5, 25.0 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0059] In any aspect or embodiment, crystalline isobutanol solvate Form RT3 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having an absence of peaks at any one, two, three or four of: 3.8 to 6.2 degrees 2-theta ± 0.2 degrees 2- theta; 7.3 to 7.6 degrees 2-theta ± 0.2 degrees 2-theta; 9.1 to 9.4 degrees 2-theta ± 0.2 degrees 2-theta; and / or 12.7 to 13.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] In any aspect or embodiment of the present disclosure, crystalline isobutanol solvate Form RT3 of Resmetirom is isolated. Particularly, crystalline isobutanol solvate Form RT3 of Resmetirom according to any aspect or embodiment of the disclosure may be isolated.

[0061] In any aspect or embodiment crystalline isobutanol solvate Form RT3 of Resmetirom may be polymorphically pure.

[0062] In embodiments, crystalline isobutanol solvate Form RT3 may contain about 10% to about 18%, preferably about 13% to about 16% of isobutanol by weight, as determined by TGA. In embodiments, crystalline isobutanol solvate Form RT3 may contain about 11% to about 17% of isobutanol by weight, as determined by TGA.

[0063] Crystalline isobutanol solvate Form RT3 of Resmetirom may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 9.9, 14.2, 18.6, 22.0 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0064] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline isobutanol solvate Form RT3 of Resmetirom wherein the process comprises crystallization of isobutanol solvate Form RT3 of Resmetirom from isobutanol.

[0065] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline isobutanol solvate Form RT3 of Resmetirom wherein the process comprises:(i) providing a solution of Resmetirom in isobutanol, optionally at a temperature of about 50 °C to about 75 °C;(ii) optionally filtering the solution;(iii) optionally cooling the solution to about -10°C to about 10 °C;Attorney Docket: API079-W001 (2222-215 PCT)(vi) optionally maintain the solution at a temperature of about -10 °C to about 10 °C for about 6 to about 24 hours.(vii) optionally isolating the solid formed;

[0066] The present disclosure provides a desolvated crystalline polymorph of Resmetirom designated Form RT2. The desolvated crystalline Form RT2 of Resmetirom may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2 or Figure 2A; an X-ray powder diffraction pattern having peaks at 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern having peaks at 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta and combinations of these data.

[0067] Desolvated crystalline Form RT2 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having peaks at 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two three or four additional peaks selected from 19.0, 11.7, 14.7 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0068] Desolvated crystalline Form RT2 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having peaks at 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two three or four additional peaks selected from 19.0, 11.7, 14.7 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] Desolvated crystalline Form RT2 of Resmetirom may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.8, 9.6, 16.2 and 19.0 degrees 2-theta ± 0.2 degrees 2-theta or an X-ray powder diffraction pattern having peaks at 6. 1, 7.8, 9.6, 16.2 and 19.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0070] Alternatively, desolvated crystalline form RT2 of Resmetirom may be characterized by an X-ray powder diffraction pattern having peaks at 7.8, 9.6, 16.2 and 11.7 degrees 2-theta ± 0.2 degrees 2-theta or an X-ray powder diffraction pattern having peaks at 6. 1, 7.8, 9.6, 16.2 and 11.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0071] Alternatively, desolvated crystalline form RT2 of Resmetirom may be characterized by an X-ray powder diffraction pattern having peaks at 7.8, 9.6, 16.2 and 14.7 degrees 2-theta ± 0.2 degrees 2-theta or an X-ray powder diffraction pattern having peaks at 6. 1, 7.8, 9.6, 16.2 and 14.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0072] Alternatively, desolvated crystalline form RT2 of Resmetirom may be characterized by an X-ray powder diffraction pattern having peaks at 7.8, 9.6, 16.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta or an X-ray powder diffraction pattern having peaks at 6. 1, 7.8, 9.6, 16.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)

[0073] Desolvated crystalline Form RT2 of Resmetirom may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.8, 9.6, 11.7, 14.7, 16.2, 19.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta or an X-ray powder diffraction pattern having peaks at 6.1, 7.8, 9.6, 11.7, 14.7, 16.2, 19.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] Form RT2 of Resmetirom according to any aspect or embodiment may be further characterized by an X-ray diffraction pattern having an absence of peaks at any one or more of: 3.8 to 5.4 degrees 2-theta; 8.3 to 9.1 degrees 2-theta± 0.2 degrees 2-theta, 4.5 to 5.4 degrees 2-theta ± 0.2 degrees 2-theta; 8.3 to 9.1 degrees 2-theta ± 0.2 degrees 2-theta; 10.2 to 11.2 degrees 2-theta ± 0.2 degrees 2-theta; 10.5 to 11.0 degrees 2-theta ± 0.2 degrees 2-theta; and / or 12.6 to 13.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0075] In any aspect or embodiment of the present disclosure, de solvated crystalline Form RT2 of Resmetirom is isolated. Particularly, desolvated crystalline Form RT2 of Resmetirom according to any aspect or embodiment of the disclosure may be isolated.

[0076] In any aspect or embodiment desolvated crystalline Form RT2 of Resmetirom may be polymorphically pure.

[0077] Desolvated crystalline Form RT2 of Resmetirom may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern having peaks at 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta an XRPD pattern as depicted in Figure 2 or Figure 2A, and combinations thereof.

[0078] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline form RT2 of Resmetirom, wherein the process comprises preparing crystalline isobutanol solvate, preferably Form RT1 of Resmetirom according to the present disclosure and drying it under vacuum to obtain form RT2 of Resmetirom.

[0079] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline form RT2 of Resmetirom wherein the process comprises crystallization of isobutanol solvate, preferably Form RT1 of Resmetirom from a mixture comprising isobutanol and 2-methoxyethanol, addition of an antisolvent, wherein the antisolvent may be an C5-C8 alkane, preferably heptane, isolating the obtained solid and drying under vacuum. The process may include a step of seeding with an isobutanol solvate, preferably form RTl.

[0080] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline form RT2 of Resmetirom wherein the process comprises crystallization of isobutanol solvate, preferably Form RT1 of Resmetirom from a mixtureAttorney Docket: API079-W001 (2222-215 PCT) comprising isobutanol and methyl-tert butyl ether (designated MTBE), addition of an antisolvent, wherein the antisolvent may be an C5-C8 alkane, preferably heptane, isolating the obtained solid and drying under vacuum. The process may include a step of seeding with an isobutanol solvate, preferably form RT1.

[0081] Crystalline Form RT2 of Resmetirom may alternatively be prepared by a process comprising combining a solution of Resmetirom in isobutanol, methyl tert-butyl ether, and water, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane. The mixture may be seeded with Form RT1 or Form RT2 of Resmetirom prior to combining with the antisolvent. The solution of Resmetirom in isobutanol, methyl tert-butyl ether and water may be heated to a temperature of: about 40°C to about 80°C, or about 50°C to about 75°C, or about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C, and fdtered prior to combining with the antisolvent. The solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, may be cooled to a temperature of: about 15°C to about 45°C, about 18°C to about 40°C, about 22°C to about 42°C, about 25°C to about 40°C, about 28°C to about 38°C, or about 30°C to about 35°C. The solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, may be combined with the antisolvent at a temperature of: about 15°C to about 35°C, about 18°C to about 30°C, about 22°C to about 28°C, about 24°C to about 26°C, or about 25°C, to form a mixture. The resulting mixture may be cooled, preferably to a temperature of: about -10°C to about 10°C, about -5°C to about 5°C, about -2°C to about 2°C, or about 0°C. The cooled mixture may be stirred, preferably for a period of: about 30 minutes to about 14 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 4 hours to about 8 hours, or about 5 hour to about 7 hours. The obtained solid may be isolated, preferably by fdtration, centrifugation or decantation and preferably by filtration and dried to obtain form RT2.

[0082] According to any aspect or embodiment the process for preparing Resmetirom formRT1 may comprise:(i) providing a solution of Resmetirom in the a mixture comprising isobutanol and 2- methoxyethanol or solution in 2-methoxy ethanol then adding isobutnaol, optionally at a temperature of about 60 °C to about 75 °C;(ii) optionally filtering the solution;(iii) optionally cooling the solution to about -15°C to about -5 °C;(iv) adding n-heptane;(v) optionally warming the reaction to a temperature of about 10 °C to about 20 °C;Attorney Docket: API079-W001 (2222-215 PCT)(vi) optionally maintain the solution at a temperature of about 10 °C to about 20 °C for about 1 to about 4 hours.(vii) isolating the solid formed; and(viii) drying the obtained wet solid under vacuum to obtain anhydrous form RT2.

[0083] According to any aspect or embodiment the process for preparing Resmetirom form RT2 may comprise:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and 2- methoxyethanol or providing a solution in 2-methoxy ethanol then adding isobutnaol, optionally at a temperature of about 60 °C to about 75 °C;(ii) optionally filtering the solution;(iii) optionally cooling the solution to about -15°C to about -5 °C;(iv) adding n-heptane;(v) optionally warming the reaction to a temperature of about 10 °C to about 20 °C;(vi) optionally maintain the solution at a temperature of about 10 °C to about 20 °C for about 1 to about 4 hours.(vii) isolating the solid formed; and(viii) drying the obtained wet solid under vacuum to obtain anhydrous form RT2.

[0084] According to any aspect or embodiment the process for preparing Resmetirom form RT1 may comprise:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and methyl tertbutyl ether, optionally at a temperature of about 50 °C to about 70 °C, preferably at about 60 °C;(ii) optionally filtering the solution;(iii) optionally seeding the solution with isobutanol solvate crystals, preferably crystals of form RTl;(iv) optionally cooling the solution to about 20°C to about 25 °C;(v) optionally reducing the reaction volume;(vi) adding n-heptane;(vii) optionally cooling the reaction to a temperature of about 0 °C to about 5 °C;(viii) optionally maintain the solution at a temperature of about 0 °C to about 5 °C for about 1 to about 4 hours; and(ix) isolating the solid formed.

[0085] According to any aspect or embodiment form RT1 formed by the processes of the present disclosure may be converted to afford form RT2 by drying.Attorney Docket: API079-W001 (2222-215 PCT)According to any aspect or embodiment the process for preparing Resmetirom form RT2 may comprise:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and methyl tertbutyl ether, optionally at a temperature of about 50 °C to about 70 °C, preferably at about 60 °C;(ii) optionally filtering the solution;(iii) optionally seeding the solution with isobutanol solvate crystals, preferably crystals of form RTl;(iv) optionally cooling the solution to about 20°C to about 25 °C;(v) optionally reducing the reaction volume;(vi) adding n-heptane;(vii) optionally cooling the reaction to a temperature of about 0 °C to about 5 °C;(viii) optionally maintain the solution at a temperature of about 0 °C to about 5 °C for about 1 to about 4 hours.(ix) isolating the solid formed; and(viii) drying the obtained wet solid under vacuum to obtain anhydrous form RT2.

[0086] According to any aspect or embodiment, step (vii) may be carried out, preferably by filtration, decantation or centrifuge, more preferably by filtration.

[0087] The process may further comprise combining the obtained Resmetirom form RT2 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0088] The present disclosure includes a crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom. In embodiments, the crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom is designated form RT4. Crystalline tetrahydrofurfuryl alcohol solvate form RT4 of Resmetirom may be characterized by data selected from one or more of the following: an X- ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0089] Crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 12.0, 15.6 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0090] Crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.8, 12.0, 13.6, 15.6, 17.6, 24.8, 26.0 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)

[0091] Crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom may be alternatively characterized by an X-ray powder diffraction pattern having an absence of peaks at any one, two three, or four of: 3.8 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta; and / or at 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta and / or 7.3 to 9.0 degrees 2-theta ± 0.2 degrees 2- theta; and / or 12.5 to 13.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0092] In any aspect or embodiment of the present disclosure, crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom is isolated. Particularly, Crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom according to any aspect or embodiment of the disclosure may be isolated.

[0093] In any aspect or embodiment crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom may be polymorphically pure.

[0094] In embodiments, crystalline tetrahydrofurfuryl alcohol solvate Form RT4 may contain about 17% to about 21%, of tetrahydrofurfuryl alcohol by weight, as determined by TGA. Alternatively, crystalline tetrahydrofurfuryl alcohol solvate Form RT4 may contain about 16% to about 20%, of tetrahydrofurfuryl alcohol by weight, as determined by TGA.

[0095] Crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0096] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom wherein the process comprises crystallization of tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom from a solution of Resmetirom in tetrahydrofurfuryl alcohol and addition of an antisolvent or addition of the Resmetirom solution to the antisolvent. The antisolvent may be an C5-C8 alkane, preferably cyclohexane.

[0097] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom wherein the process comprises:(i) providing a solution of Resmetirom in tetrahydrofurfuryl alcohol optionally at a temperature of about 50 °C to about 75 °C;(ii) optionally cooling the solution to room temperature;(iii) optionally filtering the solution;(iv) adding the solution into an C5-C8 alkane, preferably cyclohexane;(vi) optionally maintaining the solution under stirring for about 1 to about 7 hours; andAttorney Docket: API079-W001 (2222-215 PCT)(vii) optionally isolating the solid formed.

[0098] The present disclosure provides a crystalline polymorph of Resmetirom designated Form RT5. The crystalline Form RT5 of Resmetirom may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 5.1, 6.4, 7.9, 12.3 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0099] Crystalline Form RT5 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having peaks at 5.1, 6.4, 7.9, 12.3 and 23.9degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two orthree additional peaks selected from 14.4, 18.0 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0100] Crystalline Form RT5 of Resmetirom may be alternatively characterized by an X- ray powder diffraction pattern having peaks at 5.1, 6.4, 7.9, 12.3, 14.4, 18.0, 23.9 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0101] According to any aspect or embodiment, crystalline Form RT5 of Resmetirom may be further characterized by an X-ray powder diffraction pattern having an absence of peaks at any one, two, three, or four of: 3.8 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta; and / or 5.6 to 5.8 degrees 2-theta ± 0.2 degrees 2-theta; and / or 8.6 to 9.5 degrees 2-theta ± 0.2 degrees 2- theta; and / or 11.0 to 11.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0102] In any aspect or embodiment of the present disclosure, crystalline Form RT5 of Resmetirom may be anhydrous.

[0103] In any aspect or embodiment of the present disclosure, crystalline Form RT5 of Resmetirom is isolated. Particularly, crystalline Form RT5 of Resmetirom according to any aspect or embodiment of the disclosure may be isolated.

[0104] In any aspect or embodiment crystalline Form RT5 of Resmetirom may be polymorphically pure.

[0105] Crystalline Form RT5 of Resmetirom may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 5.1, 6.4, 7.9, 12.3 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5, and combinations thereof.

[0106] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline form RT5 of Resmetirom, wherein the process comprises preparing crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom according to the present disclosure, suspending it in an ether solvent and drying it under vacuum to obtain formAttorney Docket: API079-W001 (2222-215 PCT)RT5 of Resmetirom. The ether solvent may preferably be diisopropylether (DIPE) or methyl tert-butyl ether (MTBE).

[0107] According to any aspect or embodiment the present disclosure provides a process for preparing crystalline form RT5 of Resmetirom wherein the process comprises crystallization of tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom from a solution of tetrahydrofurfuryl alcohol and Resmetirom, suspending it in an ether solvent and drying it under vacuum to obtain form RT5 of Resmetirom. The ether solvent may preferably be diisopropylether (DIPE) or methyl tert-butyl ether (MTBE) .According to any aspect or embodiment the process for preparing Resmetirom form RT5 may comprise:(i) providing a solution of Resmetirom in tetrahydrofurfuryl alcohol optionally at a temperature of about 50 °C to about 75 °C;(ii) optionally cooling the solution to room temperature;(iii) optionally filtering the solution;(iv) adding the solution into an C5-C8 alkane, preferably cyclohexane;(v) optionally maintaining the solution under stirring for about 1 to about 7 hours;(vi) isolating the solid formed;(vii) suspending the material isolated in step (vi) in an ether solvent, preferably diisopropylether or methyl tert-butyl ether and maintaining the suspension under stirring for about 1 to about 72 hours;(viii) isolating the solid; and(ix) drying under vacuum to obtain anhydrous form RT5.

[0108] According to any aspect or embodiment, step (viii) may be carried out, preferably by filtration, decantation or centrifuge, more preferably by filtration.

[0109] The process may further comprise combining the obtained Resmetirom form RT5 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0110] The present disclosure encompasses a process for preparing other solid state forms of Resmetirom, Resmetirom salts and solid state forms, or cocrystals thereof. The process includes preparing any one of the solid state forms of Resmetirom by the processes of the present disclosure, and converting that form to a different form of Resmetirom or the salts, or cocrystals thereof.

[0111] The present disclosure provides the above described crystalline polymorphs of Resmetirom or the salt thereof for use in the preparation of pharmaceutical compositions comprising Resmetirom.Attorney Docket: API079-W001 (2222-215 PCT)

[0112] The present disclosure also encompasses the use of any one of the crystalline polymorphs of Resmetirom of the present disclosure for the preparation of pharmaceutical compositions of any one of the crystalline polymorphs of Resmetirom or the salt thereof and / or solid state forms thereof.

[0113] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one of the crystalline polymorphs of Resmetirom or combination thereof of the present disclosure with at least one pharmaceutically acceptable excipient.

[0114] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Resmetirom or the salt thereof of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0115] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0116] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0117] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium,Attorney Docket: API079-W001 (2222-215 PCT) crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0118] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0119] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0120] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0121] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0122] In liquid pharmaceutical compositions of the present invention, Resmetirom and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0123] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0124] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer,Attorney Docket: API079-W001 (2222-215 PCT) carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[0125] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0126] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0127] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0128] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0129] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0130] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and / or sorbitol, an opacifying agent and / or colorant.

[0131] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0132] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and thenAttorney Docket: API079-W001 (2222-215 PCT) screened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0133] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0134] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[0135] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0136] A pharmaceutical formulation of Resmetirom can be administered. Resmetirom may be formulated for administration to a mammal, in embodiments to a human, by injection. Resmetirom can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0137] The crystalline polymorph of Resmetirom and the pharmaceutical compositions and / or formulations of Resmetirom of the present disclosure can be used as medicaments, particularly for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and / or associated dyslipidemias.

[0138] The present disclosure also provides methods of treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and / or associated dyslipidemias by administering a therapeutically effective amount of the crystallineAttorney Docket: API079-W001 (2222-215 PCT) polymorphs of Resmetirom of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0139] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Powder X-ray Diffraction ("XRPD") method

[0140] X-ray diffraction was performed on X-Ray powder diffractometer:BrukerD8 Advance; CuKa radiation (X = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.Measurement parameters:Scan range: 2 - 40 degrees 2-theta;Scan mode: continuous;Step size: 0.05 degrees;Time per step: 0.5 s;Sample spin: 30 rpm;Sample holder: PMMA specimen holder ring with silicon low background holder.SS-NMR method

[0141] The spectra were recorded using BRUKER AVANCE III HD US / WB spectrometer at 11.7 T with 3.2 mm probe head. The spectra were recorded at room temperature and the frictional heating of the spinning samples was compensated.

[0142] The13C CP / MAS NMR spectra employing cross-polarization were acquired using the standard cross-polarization pulse scheme at spinning frequency of 15 kHz. The duration of cross-polarization spin-lock pulse was 2 ms, and the spectral width was 300 ppm with the resonance frequency offset 100 ppm.EXAMPLESPreparation of starting materials

[0143] Resmetirom can be prepared according to methods known from the literature, for example according to the disclosure in International publication no. WO 2007 / 009913.Attorney Docket: API079-W001 (2222-215 PCT)Example 1: Preparation of Resmetirom crystal Form RT1 and form RT2Procedure A

[0144] Resmetirom (1.0g) was dissolved in mixture of Isobutanol (120mL) and 2- methoxyethanol (lOmL) at about 65-70°C under stirring and a clear solution was obtained. The hot clear solution was filtered through 0.45 micron filter. The particle free solution was transferred to 250mL round bottom flask. The solution was cooled under stirring to -10°C. Added n-Heptane (lOOmL) to the solution at about -10°C, under stirring and after 15min the temperature was raised at about 15 °C. The reaction mass maintained for 2.0 hours at about 15°C under stirring. The precipitated white solid was filtered and suck dry for 15min at about 25°C. The obtained solid was analyzed by XRPD and designated as Form RT1 of Resmetirom. The XRPD pattern of Form RT1 is presented in Figure 1.

[0145] The Form RT1 was dried under vacuum at about 55 °C for 2hr. The obtained dry solid was analyzed by XRPD and the XRPD pattern is presented in Figure 2.Procedure B

[0146] Resmetirom (1.0g) was dissolved in 2-methoxyethanol (8mL) at about 65-70°C under stirring. The clear solution was obtained then Isobutanol (40mL) was added to the hot 2- methoxyethanol solution at about 50-55°C and the obtained solution was filtered through 0.45 micron filter. The solution was cooled to -10°C under stirring, n-Heptane (50mL) was added to the solution at about -10°C, and after 15 min the temperature was raised at about 15 °C. The reaction mass maintained for 2.0 hours at about 15°C under stirring. The precipitated white solid was filtered and suck dry for about 15min at about 25 °C. The obtained solid was analyzed by XRPD and identified as Form RT1 of Resmetirom.

[0147] The Form RT1 was dried under vacuum at about 55 °C for 2hr. The obtained dry solid was analyzed by XRPD and identified as Form RT2 of Resmetirom.Procedure C

[0148] Resmetirom (10g) was dissolved in 350 ml (isobutanol- MTBE 1: 1) solvent mixture at about 60°C and added charcoal (1g, 10%w / w) and maintained under stirring for one hour at 60°C. Reaction mixture was filtered through hyflo and washed with (isobutanol- MTBE 1: 1) 50 ml. The clear solution was Seeded with Form RT1, obtained according to procedure A or procedure B, (0.1g) and slowly cooled down to 20-25°C, over about 30 minutes and allowed to stir for 2hrs. Reaction mixture was subjected to distillation under reduced pressure at about 60°C and reduced the reaction volume to about 175 ml under vacuum, n-heptane (50 ml) was added into the concentrated reaction mixture maintained at 0-5 °C for 60 minutes. The reaction mixture was filtered and washed with heptane 50mlx3. The obtained solid was analyzed byAtorney Docket: API079-W001 (2222-215 PCT)XRPD and identified as Form RT1 of Resmetirom. The XRPD patern of obtained is presented in Figure 1A.

[0149] The obtained solid was further dried under vacuum oven at about 60°C for 4 hrs and then dried at 80°C for 13 hrs. The obtained solid was analyzed by XRD and identified as Form RT2 of Resmetirom. The XRPD patern of obtained is presented in Figure 2A.Procedure D

[0150] Resmetirom (25g) was added in a solvent mixture (Isobutanol (500ml)+MTBE (500ml)+water (3 ml)) at about 25°C. The reaction mixture was heated up to 60°C and stirred for 15-20 minutes and obtained a clear solution. Filtered and clear solution was transferred in a 2L Reactor with Tj about 30°C. The clear reaction mixture was seeded with 5% form RT2 (1.25g) at about 33°C (Tr). The reaction mixture was stirred at about 25°C for 1 hour. Then added n-heptane (500 ml) at about 25°C and after 10 minutes cool down to 0°C and maintain under stirring for another 6.5 hours. The reaction mixture was filtered and washed with heptane (50 mlx3). Wet cake was 16.9g (analyzed by XRD and characterized as Form RT1). Further the wet cake was suck dry at 25 °C for 7 hours (RH 29-34%). The sample was tube milled at about 25000 rpm for one minute and kept for drying in vacuum oven.

[0151] The sample was dried in vacuum oven at about 80°C under vacuum for about 8 hours (Form RT2) further dried in VTD at about 110°C under vacuum for 4 hours. Sample was cooled down to room temperature (25°C) and obtained solid was Form RT2 (yield: 14,8 g).Example 2: Preparation of Resmetirom crystal Form RT3Procedure A

[0152] Resmetirom (0.03g) was dissolved in Isobutanol (3 ml), at about 60-65°C. The clear solution was cooled down to 0-5°C and maintained under stirring for about 18 hours. Filtered and suck dried under vacuum for about 15 minutes. The obtained solid was further dried in vacuum oven at about 60°C / 2 hours. The obtained solid was analyzed by XRD and designated as Form RT3 of Resmetirom. The XRPD patern of Form RT3 is presented in Figure 3.Example 3: Preparation of Resmetirom crystal Form RT4Procedure A

[0153] Resmetirom (0.2g) was dissolved in Tetrahydrofurfiiryl alcohol (1 ml) at about 25°C and filtered through 0.45 micron filter to remove any undissolved particulate. The clear solution was slowly added into cyclohexane (4 ml) at about 25°C. The reaction mixture wasAttorney Docket: API079-W001 (2222-215 PCT) maintained under stirring for about 6 hrs, filtered and suck dried for about 15 minutes. The obtained solid was analyzed by XRD and designated as Form RT4 of Resmetirom. The XRPD pattern of Form RT4 is presented in Figure 4.Procedure B

[0154] Resmetirom (20g) was dissolved in Tetrahydrofurfuryl alcohol (100 ml) at about 60°C. cooled down to room temperature then filtered through 0.45 micron filter to remove any undissolved particulate. The clear solution was slowly added into cyclohexane (500 ml) at about 25 °C. The reaction mixture was maintained under stirring for about 6 hrs. filtered and suck dried for about 30 minutes. The obtained solid was analyzed by XRD and designated as Form RT4 of Resmetirom.Example 4: Preparation of Resmetirom crystal Form RT5Procedure A

[0155] Resmetirom (form RT4, 0.02g) was suspended in Diisopropylether (DIPE, 2 ml) at about 25°C. The slurry mass was maintained under stirring for 48hrs at 25°C. The reaction mixture was filtered and suck dried for 10 minutes. The obtained solid was further dried under vacuum in vacuum oven at about 60°C / 4 hours. The obtained solid was analyzed by XRD and designated as Form RT5 of Resmetirom. The XRPD pattern of Form RT5 is presented in Figure 5.Procedure B

[0156] Resmetirom (form RT4, 15g) was suspended in methyl-tert butyl ether (MTBE, 600 ml) at about 25°C. The slurry mass was maintained under stirring for 24hrs at about 25°C. The reaction mixture was filtered and suck dried for 30 minutes. The obtained solid was further dried under vacuum in vacuum oven at about 60°C / 6 hours. The obtained solid was analyzed by XRD and designated as Form RT5 of Resmetirom.Attorney Docket: API079-W001 (2222-215 PCT)

[0157] Further aspects and embodiments of the present disclosure are set out in the numbered Clause Group A below, and Clause Group B below:CLAUSE GROUP A1. Crystalline isobutanol solvate of Resmetirom.2. Crystalline isobutanol solvate of Resmetirom according to Clause 1, designated form RT1, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 or Figure 1A; an X-ray powder diffraction pattern having peaks at: 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2- theta; and combinations of these data.3. Crystalline isobutanol solvate of Resmetirom according to Clause 1 or Clause 2, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from: 13.7, 24.0 and 19.9 degrees 2-theta ± 0.2 degrees 2-theta.4. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2 and 3, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.3, 8.8, 13.7, 14.4, 19.9, 21.0 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.5. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, and4, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.8 to 4.8 degrees 2-theta ± 0.2 degrees 2-theta.6. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, and5, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 7.2 to 7.4 degrees 2-theta ± 0.2 degrees 2-theta.7. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, and 6, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 9.3 to 9.7 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)8. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, and 7, which is isolated.9. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5,6, 7, and 8, which is polymorphically pure.10. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6,7, 8, and 9, which is substantially free of any other solid state forms of Resmetirom isobutanol solvate, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom isobutanol solvate.11. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, and 10, which is substantially free of any other crystalline forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline forms of Resmetirom.12. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, which is substantially free of amorphous Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of amorphous Resmetirom.13. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, which is substantially free of any other solid state forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom.14. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, which contains about 3% to about 8% of isobutanol by weight.Attorney Docket: API079-W001 (2222-215 PCT)15. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, which contains about 4% to about 7% of isobutanol by weight.16. A process for preparing the crystalline isobutanol solvate of Resmetirom as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, comprising: (a) crystallization of the isobutanol solvate of Resmetirom from a mixture comprising isobutanol and 2- methoxyethanol and an antisolvent, or (b) crystallization of the isobutanol solvate of Resmetirom from a mixture comprising isobutanol and methyl tert-butyl ether and an antisolvent; or (c) crystallization of the isobutanol solvate of Resmetirom from a mixture comprising isobutanol, methyl tert-butyl and water and an antisolvent.17. A process according to Clause 16, wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane.18. A process according to any of Clauses 16 and 17, comprising crystallization from a mixture comprising isobutanol and 2-methoxyethanol and an antisolvent, wherein the process comprises combining a solution of Resmetirom in isobutanol and 2-methoxyethanol, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane.19. A process according to any of Clauses 16, 17 and 18, wherein the v / v ratio of isobutanol to 2-methoxyethanol is: about 2: 1 to about 20: 1, about 3: 1 to about 18: 1, about 4: 1 to about 15: 1, about 4: 1 to about 13: 1, or about 5: 1 to about 12: 1.20. A process according to any of Clauses 16, 17, 18, and 19, wherein the v / v ratio of antisolvent to the solution of isobutanol and 2-methoxyethanol is: about 1 :2 to about 2: 1, about 1: 1.8 to about 1.8: 1, about 1: 1.5 to about 1.5: 1, about 1: 1.4 to about 1: 0.8, or about 1: 1.2 to about 1:0.9.21. A process according to any of Clauses 18, 19 and 20, wherein the solution of Resmetirom in isobutanol and 2-methoxyethanol is heated to a temperature of about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, about 55°C to about 70°C, and filtering.Attorney Docket: API079-W001 (2222-215 PCT)22. A process according to any of Clauses 18, 19, 20, and 21, wherein the solution of Resmetirom in isobutanol and 2-methoxyethanol is cooled to a temperature of: about -20°C to about 15°C, about -15°C to about 10°C, about -15°C to about 5°C, about -15°C to about 0°C, or about -15°C to about -5°C, or about -10°C.23. A process according to any of Clauses 18, 19, 20, 21, and 22, wherein the cooled solution of Resmetirom in isobutanol and 2-methoxyethanol is combined with the antisolvent at a temperature of: about -20°C to about 5°C, about -15°C to about 5°C, about -15°C to about 0°C, or about -15°C to about -5°C, or about -10°C.24. A process according any of Clauses 18, 19, 20, 21, 22, and 23, wherein the antisolvent is added to the solution of Resmetirom in isobutanol and 2-methoxyethanol to form a mixture.25. A process according to any of Clauses 18, 19, 20, 21, 22, 23, and 24, wherein the mixture is stirred for a period of: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes, or about 15 minutes.26. A process according to any of Clauses 23, 24 and 25, wherein the mixture is maintained at a temperature of: about 8°C to about 25°C, about 10°C to about 20°C, about 12°C to about 18°C, or about 15°C.27. A process according to any of Clauses 18, 19, 20, 21, 22, 23, 24, 25, and 26, wherein the mixture is stirred for a period of: about 30 minutes to about 8 hours, about 45 minutes to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, or about 2 hours, preferably with stirring.28. A process according to any of Clauses 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27, wherein the isobutanol solvate of Resmetirom is isolated, preferably by fdtration, centrifugation or decantation, more preferably by fdtration.29. A process according to Clauses 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28, wherein the isobutanol solvate of Resmetirom is dried under fdtration, preferably for: about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes, about 10 minutes to about 20 minutes, or about 15 minutes.Attorney Docket: API079-W001 (2222-215 PCT)30. A process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom according to any of Clauses 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, wherein the process comprises:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and 2- methoxyethanol, optionally at a temperature of about 60 °C to about 75 °C;(ii) optionally filtering the solution;(iii) optionally cooling the solution to about -15°C to about -5 °C;(iv) adding n-heptane;(v) optionally warming the reaction to a temperature of about 10 °C to about 20 °C;(vi) optionally maintain the solution at a temperature of about 10 °C to about 20 °C for about 1 to about 4 hours.(vii) optionally isolating the solid formed.31. A process according to any of Clauses 16 and 17, comprising crystallization from a mixture comprising isobutanol and methyl tert-butyl ether and an antisolvent, wherein the process comprises combining a solution of Resmetirom in isobutanol and methyl tert-butyl ether, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane.32. A process according to any Clause 31, wherein the solution of Resmetirom in isobutanol and methyl tert-butyl ether is seeded with Form RT1 of Resmetirom isobutanol solvate prior to combining with the antisolvent.33. A process according to any of Clauses 16, 17, 31, and 32, wherein the v / v ratio of isobutanol to methyl tert-butyl ether is: about 5: 1 to about 0.5: 1, about 4: 1 to about 0.7: 1, about 3: 1 to about 0.8: 1, about 2: 1 to about 0.7: 1, about 1.5: 1 to about 0.9: 1, or about 1:2: 1 to about 0.95: 1, or about 1;1.34. A process according to any of Clauses 16, 17, 31, 32, and 33, wherein the v / v ratio of antisolvent to the isobutanol and methyl tert-butyl ether is: about 1 : 10 to about 5: 1, about 1 : 8 to about 2: 1, about 1 :6 to about 1: 1, about 1:5 to about 1 : 15 , or about 1:4 to about 1 :25, about 1:4 to about 1:3, or about 1:3.5.Attorney Docket: API079-W001 (2222-215 PCT)35. A process according to any of Clauses 16, 17, 31, 32, 33, and 34, wherein antisolvent is added to the solution of Resmetirom in isobutanol and methyl tert-butyl ether, preferably at a temperature of: about -10°C to about 15°C, about -5°C to about 10°C, or about 0°C to about 5 °C, to form a mixture.36. A process according to Clause 35, wherein the mixture is maintained for a period of: about 10 minutes to about 4 hours, about 20 minutes to about 3 hours, about 45 minutes to about 2 hours, or about 60 minutes, optionally with stirring.37. A process according to any of Clauses 16, 17, 31, 32, 33, 34, 35, and 36, wherein the isobutanol solvate of Resmetirom is isolated, preferably by fdtration, centrifugation or decantation, more preferably by fdtration.38. A process according to any of Clauses 16, 17, 31, 32, 33, 34, 35, 36, and 37, wherein the isobutanol solvate of Resmetirom is dried under fdtration, preferably for: about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes, about 10 minutes to about 20 minutes, or about 15 minutes.39. A process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom, according to any of Clauses 16, 17, 31, 32, 33, 34, 35, 36, 37, and 38, wherein the process comprises:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and methyl tertbutyl ether, optionally at a temperature of about 60°C to about 75°C;(ii) optionally stirring the solution with charcoal, and filtering;(iii) optionally seeding the solution with Form RT1 of Resmetirom;(iv) optionally cooling the solution, preferably to a temperature of about 20°C to about 25°C;(v) optionally concentrating the solution;(vi) adding n-heptane to form a mixture;(vii) optionally stirring the mixture, preferably at a temperature of 0°C to about 5°C, preferably for about 30 minutes to about 4 hours.(viii) optionally isolating the solid formed.Attorney Docket: API079-W001 (2222-215 PCT)40. A process according to any of Clauses 16 and 17, comprising crystallization from a mixture comprising isobutanol, methyl tert-butyl and water and an antisolvent, wherein the process comprises combining a solution of Resmetirom in isobutanol, methyl tert-butyl ether, and water, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5- C8 alkane, more preferably n-heptane.41. A process according to any of Clauses 16, 17 and 40, wherein the solution of Resmetirom in isobutanol, methyl tert-butyl ether, and water is seeded with Form RT1 or form RT2 of Resmetirom prior to combining with the antisolvent.42. A process according to any of Clauses 16, 17, 40, and 41, wherein the v / v ratio of isobutanol to methyl tert-butyl ether is: about 5: 1 to about 1:5, about 4: 1 to about 1:4, about 3: 1 to about 1:3, about 2: l to about 1:2, about 1.5: 1 to about 1: 1.5, about 1.2: 1 to about 1: 1.2, about 1.1 : 1 to about 1 : 1.1, or 1 : 1.43. A process according to any of Clauses 16, 17, 40, 41, and 42, wherein water is used in an amount (vol% of total solvent mixture) of: about 0.05% to about 5%, 0.05% to about 3%, about 0.08% to about 2%, about 0. 1% to about 1%, about 0. 1% to about 0.6%, about 0.1% to about 0.5%, about 0. 15% to about 0.4%, about 0.2% to about 0.35%, or about 0.3%.44. A process according to any of Clauses 16, 17, 40, 41, 42, and 43, wherein the v / v ratio of antisolvent to the mixture of isobutanol, methyl tert-butyl ether and water is: about 2: 1 to about 1:5, about 1.5: 1 to about 1:4, about 1.2: 1 to about 1: 1:3, about 1.3: 1 to about 1:2.5, about 1: 1 to about 1:2.4, or about 1: 1.5 to about 1:2.3, or about 1: 1.8 to about 1:2.2, or about 1:2.1.45. A process according to any of Clauses 16, 17, 40, 41, 42, 43, and 44, wherein the solution of Resmetirom in isobutanol, methyl tert-butyl ether and water is heated to a temperature of: about 40°C to about 80°C, or about 50°C to about 75°C, or about 50°C to about 70°C, about 55 °C to about 65 °C, or about 60°C, and fdtering.46. A process according to any of Clauses 16, 17, 40, 41, 42, 43, 44, and 45, wherein the solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, is cooled to a temperature of: about 15°C to about 45°C, about 18°C to about 40°C, about 22°C to about 42°C, about 25°C to about 40°C, about 28°C to about 38°C, or about 30°C to about 35°C.Attorney Docket: API079-W001 (2222-215 PCT)47. A process according to any of Clauses 16, 17, 40, 41, 42, 43, 44, 45, and 46, wherein the solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, is combined with the antisolvent at a temperature of: about 15°C to about 35°C, about 18°C to about 30°C, about 22°C to about 28°C, about 24°C to about 26°C, or about 25°C, to form a mixture.48. A process according any of Clauses 16, 17, 40, 41, 42, 43, 44, 45, 46, and 47, wherein the mixture of Resmetirom in isobutanol, methyl tert-butyl ether, water, and antisolvent is cooled, preferably to a temperature of: about -10°C to about 10°C, about -5°C to about 5°C, about -2°C to about 2°C, or about 0°C.49. A process according to Clause 48, wherein the mixture is stirred for a period of: about 30 minutes to about 14 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 4 hours to about 8 hours, or about 5 hour to about 7 hours.50. A process according to any of Clauses 16, 17, 40, 41, 42, 43, 44, 45, 46, 47, 48 and 49, wherein the isobutanol solvate of Resmetirom is isolated, preferably by fdtration, centrifugation or decantation, more preferably by filtration.51. A process according to Clauses 16, 17, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, wherein the isobutanol solvate of Resmetirom is dried under filtration, preferably for: about 1 hour to about 12 hours, about 2 hours to about 11 hours, about 4 hours to about 10 hours, about 5 hours to about 8 hours, or about 7 hours.52. A process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom according to any of clauses 16, 17, 49, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, wherein the process comprises:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and methyl tertbutyl ether and water;(ii) optionally heating the solution, preferably to a temperature of: about 50°C to about 70°C, and filtering;(iii) optionally seeding with form RT2 of Resmetirom, preferably at a temperature of about 25 °C to about 35 °C,(iv) adding n-heptane to form a mixture;Attorney Docket: API079-W001 (2222-215 PCT)(v) optionally stirring the mixture, preferably at a temperature of -5°C to about 5°C, preferably for about 1 hour to about 8 hours.(vii) optionally isolating the solid formed.53. Crystalline isobutanol solvate of Resmetirom according to Clause 1, designated form RT3, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at: 9.9, 14.2, 18.6, 22.0 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.54. Crystalline isobutanol solvate of Resmetirom according to any of Clause 1 and Clause 53, which is characterized by an X-ray powder diffraction pattern having peaks at: 9.9, 14.2, 18.6, 22.0 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from: 12.4, 23.5 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.55. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 53 and 54, which is characterized by an X-ray powder diffraction pattern having peaks at: 9.9, 12.4, 14.2, 18.6, 22.0, 23.5, 25.0 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.56. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54 and55, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at: 3.8 to 6.2 degrees 2-theta ± 0.2 degrees 2-theta.57. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54 55, and 56, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at: 7.3 to 7.6 degrees 2-theta ± 0.2 degrees 2-theta.58. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54 55,56, and 57, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at: 9. 1 to 9.4 degrees 2-theta ± 0.2 degrees 2-theta.59. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54 55, 56, 57, and 58, which is characterized by an X-ray powder diffraction pattern having an absence of peaks at: 12.7 to 13.2 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)60. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54, 55, 56, 57, 58, and 59, which is isolated.61. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54, 55, 56, 57, 58, 59, and 60, which is polymorphically pure.62. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54, 55, 56, 57, 58, 59, 60, and 61, which is substantially free of any other crystalline forms of Resmetirom isobutanol solvate, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline forms of Resmetirom isobutanol solvate.63. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54, 55, 56, 57, 58, 59, 60, 61, and 62, which is substantially free of any other solid state forms of Resmetirom isobutanol solvate, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom isobutanol solvate.64. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, and 63, which is substantially free of amorphous Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of amorphous Resmetirom.65. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, and 64, which is substantially free of any other solid state forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom.66. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, and 65, which contains about 10% to about 18% ofisobutanol by weight.Attorney Docket: API079-W001 (2222-215 PCT)67. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, and 66, which contains about 11% to about 17% of isobutanol by weight.68. Crystalline isobutanol solvate of Resmetirom according to any of Clauses 1, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, and 67, which contains about 13% to about 16% of isobutanol by weight.69. A process for preparing crystalline isobutanol solvate of Resmetirom as defined in any of Clauses 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, and 68, comprising crystallization of isobutanol solvate Form RT3 of Resmetirom from isobutanol.70. A process according to Clause 69, comprising cooling a solution of Resmetirom in isobutanol.71. A process according to any of Clause 69 and 70, comprising:(i) providing a solution of Resmetirom in isobutanol;(ii) optionally filtering the solution;(iii) optionally cooling the solution;(vi) optionally maintaining the solution for about 6 to about 24 hours; and(vii) optionally isolating the solid formed.72. A process according to any of Clauses 71, wherein the solution of Resmetirom in isobutanol in step (i) is heated to a temperature of: about 40°C to about 80°C, or about 50°C to about 75°C, or about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C to about 65°C.73. A process according to any of Clauses 71 and 72, wherein the solution in step (iii) is cooled to a temperature of: about -20°C to about 15°C, or about -15°C to about 10°C, about - 10°C to about 10°C, about -5°C to about 10°C, or about 0°C to about 5°C74. A process according to any of Clauses 71, 72, and 73, wherein the solution in step (vi) is stirred for about 8 to about 20 hours, or about 18 hours.Attorney Docket: API079-W001 (2222-215 PCT)75. A process according to any of Clauses 71, 72, 73, and 74, wherein the crystalline Form RT3 of Resmetirom is isolated, preferably by fdtration, centrifugation or decantation, more preferably by fdtration.76. A process according to any of Clauses 71, 72, 73, 74, and 75, wherein the crystalline Form RT3 of Resmetirom is dried, preferably under vacuum.77. A process according to any of Clauses 71, 72, 73, 74, 75, and 76, wherein the crystalline Form RT3 of Resmetirom is dried under vacuum at a temperature of: about 40°C to about 80°C, or about 50°C to about 75°C, or about 50°C to about 70°C, about 55°C to about 65°C, or about 60°C.78. A crystalline form of Resmetirom, designated Form RT2, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2 or Figure 2A; or an X-ray powder diffraction pattern having peaks at: 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta.79. A crystalline form of Resmetirom according to Clause 78, which is characterized by: an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta.80. A crystalline form of Resmetirom according to any of Clauses 78 and 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two three or four additional peaks selected from: 19.0, 11.7, 14.7 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.81. A crystalline form of Resmetirom according to Clause 78, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 19.0 degrees 2-theta ± 0.2 degrees 2-theta.82. A crystalline form of Resmetirom according to any of Clause 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and 19.0 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)83. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 11.7 degrees 2-theta ± 0.2 degrees 2-theta.84. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and11.7 degrees 2-theta ± 0.2 degrees 2-theta.85. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 14.7 degrees 2-theta ± 0.2 degrees 2-theta.86. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and14.7 degrees 2-theta ± 0.2 degrees 2-theta.87. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.88. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.89. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 11.7, 14.7, 16.2, 19.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.90. A crystalline form of Resmetirom according to any of Clauses 78 and Clause 79, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 11.7, 14.7, 16.2, 19.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)91. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90, which is further characterized by an X-ray diffraction pattern having an absence of peaks at: 3.8 to 5.4 degrees 2-theta.92. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, and 91, which is further characterized by an X-ray diffraction pattern having an absence of peaks at: 8.3 to 9.1 degrees 2-theta ± 0.2 degrees 2-theta.93. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, and 92, which is further characterized by an X-ray diffraction pattern having an absence of peaks at: 4.5 to 5.4 degrees 2-theta ± 0.2 degrees 2-theta.94. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, and 93, which is further characterized by an X-ray diffraction pattern having an absence of peaks at: 8.3 to 9.1 degrees 2-theta ± 0.2 degrees 2-theta.95. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, which is further characterized by an X-ray diffraction pattern having an absence of peaks at: 10.2 to 11.2 degrees 2-theta ± 0.2 degrees 2- theta.96. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, and 95, which is further characterized by an X-ray diffraction pattern having an absence of peaks at: 10.5 to 11.0 degrees 2-theta ± 0.2 degrees 2- theta.97. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, and 96, which is further characterized by an X- ray diffraction pattern having an absence of peaks at: 12.6 to 13.1 degrees 2-theta ± 0.2 degrees 2-theta.98. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, and 97, which is further characterized by anAtorney Docket: API079-W001 (2222-215 PCT)X-ray diffraction patern having an absence of peaks at: 12.8 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta.99. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, and 98, which is further characterized by an X-ray diffraction patern having an absence of peaks at: 15.2 to 15.5 degrees 2-theta ± 0.2 degrees 2-theta.100. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99, which is further characterized by an X-ray diffraction patern having an absence of peaks at: 16.5 to 16.7 degrees 2-theta ± 0.2 degrees 2-theta.101. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100, which is further characterized by an X-ray diffraction patern having an absence of peaks at: 22.7 to 23.0 degrees 2-theta ± 0.2 degrees 2-theta.102. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and 101, which is isolated.103. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, and 102, which is polymorphically pure.104. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99. 100, 101, 102, and 103, which is substantially free of any other crystalline forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline forms of Resmetirom.105. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, and 104, which is substantially free of amorphous Resmetirom, preferably containing: about 20% (w / w) or less,Attorney Docket: API079-W001 (2222-215 PCT) about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of amorphous Resmetirom.106. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, and 105, which is substantially free of any other solid state forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom.107. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, and 105, which is an anhydrous form, preferably containing: less than 15% by weight, less than 10% by weight, less than 5% by weight, or less than 1% by weight, of water or any solvent in a defined, stoichiometric amount within the crystal.108. A crystalline form of Resmetirom according to any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, and 107, which is a desolvate form; preferably wherein the crystalline form contains less than 15% by weight of isobutanol, less than 10% by weight of isobutanol, less than 5% isobutanol, or less than 1% isobutanol.109. A process for preparing a crystalline form of Resmetirom as defined in any of Clauses 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, and 108, comprising drying a crystalline isobutanol solvate of Resmetirom.110. A process according to Clause 109, wherein the crystalline isobutanol solvate of Resmetirom is as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15.111. A process according to any of Clauses 109 and 110, comprising drying the crystalline isobutanol solvate of Resmetirom under vacuum.Attorney Docket: API079-W001 (2222-215 PCT)112. A process according to any of Clauses 109, 110 and 111, wherein the drying is carried under vacuum at a temperature of: about 40°C to about 140°C, or about 45°C to about 130°C, or about 50°C to about 125°C, about 55°C to about 105°C, or about 55°C to about 110°C.113. A process according to any of Clauses 109, 110, 111, and 112, wherein the drying is carried out for a period of time of: about 1 hour to about 20 hours, about 2 hours to about 18 hours, or about 2 hours to about 14 hours.114. A process according to any of Clauses 109, 110, 111, 112, and 113, wherein the isobutanol solvate of Resmetirom is prepared according to a process as defined in any of Clauses 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52.115. A process according to any of Clauses 109, 110, 111, 112, 113, and 114, wherein the product contains less than 15% by weight of isobutanol, less than 10% by weight of isobutanol, less than 5% isobutanol, or less than 1% isobutanol.116. A crystalline form of Resmetirom, which is obtainable by the process of any of Clauses 109, 110, 111, 112, 113, 114, and 115.117. A process according to any of Clauses 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 69, 70, 71, 72, 73, 74, 75, 107, 108, 109, 110, 111, 112, 113, 114, and 115, which further comprises combining the isobutanol solvate of Resmetirom, or Resmetirom with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.118. A process for preparing other solid state forms of Resmetirom, Resmetirom salts and solid state forms, or cocrystals thereof, comprising preparing a product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, and 116, and converting the product to a different form of Resmetirom or a salt, or a cocrystal thereof.Attorney Docket: API079-W001 (2222-215 PCT)119. Use of a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105,106, 107, 108, and 116, in the preparation of pharmaceutical compositions comprising Resmetirom, or any crystalline polymorph of Resmetirom or a salt thereof and / or solid state forms thereof.120. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, and 116, and at least one pharmaceutically acceptable excipient.121. A process for preparing a pharmaceutical composition as defined in Clause 108, comprising a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,107, 108, and 116, with at least one pharmaceutically acceptable excipient.122. Use of a crystalline product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, and 116, or a pharmaceutical composition as defined in Clause 120, for the preparation of a medicament.123. Use of a crystalline product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, and 116, or a pharmaceutical composition as defined in Clause 120, for the preparation of a medicament for the treatment of non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFUD) and / or associated dyslipidemias.124. A method of treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFUD) and / or associated dyslipidemias by administering a therapeutically effectiveAttorney Docket: API079-W001 (2222-215 PCT) amount of a crystalline product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, and 116, or a pharmaceutical composition as defined in Clause 120, to a subject in need of the treatment.Attorney Docket: API079-W001 (2222-215 PCT)CLAUSE GROUP B1. A crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom.2. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to Clause 1, which is designated form RT4, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X- ray powder diffraction pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.3. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to Clause 1 or Clause 2, which is characterized by an X-ray powder diffraction pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 12.0, 15.6 and 27.4 degrees 2-theta ± 0.2 degrees 2- theta.4. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2 and 3, which is characterized by an X-ray powder diffraction pattern having peaks at 6.8, 12.0, 13.6, 15.6, 17.6, 24.8, 26.0 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.5. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, and 4, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.8 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta.6. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, and 5, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta.7. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, and 6, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 7.3 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)8. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, and 7, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 12.5 to 13.1 degrees 2-theta ± 0.2 degrees 2-theta.9. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, 7, and 8, which is isolated.10. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, and 9, which is polymorphically pure.11. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, and 10, which is substantially free of any other solid state forms of Resmetirom tetrahydrofurfuryl alcohol solvate, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom tetrahydrofurfuryl alcohol solvate.12. Crystalline tetrahydrofurfuryl alcohol solvate according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, which is substantially free of any other crystalline forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline forms of Resmetirom.13. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, which is substantially free of amorphous Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of amorphous Resmetirom.14. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 2, 3, 4, 5, 6, 7, 8, and 9, which is substantially free of any other solid state forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom.Attorney Docket: API079-W001 (2222-215 PCT)15. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, which contains about 17% to about 21%, of tetrahydrofurfuryl alcohol by weight.16. Crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Clauses 1. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15, which contains about 16% to about 20%, of tetrahydrofurfuryl alcohol by weight.17. A process for preparing a crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, wherein the process comprises crystallization of the tetrahydrofurfuryl alcohol solvate of Resmetirom from a mixture comprising tetrahydrofurfuryl alcohol an antisolvent.18. A process according to Clause 17, wherein the antisolvent is a C5-C8 alkane, preferably cyclohexane.19. A process according to any of Clauses 17 and 18, which comprises combining a solution of Resmetirom in tetrahydrofurfuryl alcohol with the antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, preferably cyclohexane.20. A process according to Clause 19, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is added to the antisolvent; or wherein the antisolvent is added to the solution of Resmetirom in tetrahydrofurfuryl alcohol,21. A process according to Clause 19 or Clause 20, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is added to the antisolvent.22. A process according to any of Clauses 17, 18, 19, 20 and 21, wherein the v / v ratio of antisolvent to tetrahydrofurfuryl alcohol is: about 1: 1 to about 10: 1, about 2: 1 to about 8: 1, about 2.5: 1 to about 7: 1, about 3: 1 to about 6: 1, about 3.5: 1 to about 5.5: 1, or about 4: 1 to about 5: 1.Attorney Docket: API079-W001 (2222-215 PCT)23. A process according to any of Clauses 19, 20, 21, and 22, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is heated to a temperature of: about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, or about 60°C, and filtering.24. A process according to Clause 23, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is cooled to a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C.25. A process according to any of Clauses 19, 20, 21, 22, 23, or 24, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is combined with the antisolvent at a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C, preferably by addition of the solution of Resmetirom in tetrahydrofurfuryl alcohol to the antisolvent.26. A process according to any of Clauses 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the mixture is stirred for a period of: about 1 hour to about 12 hours, about 2 hours to about 10 hour, about 3 hours to about 8 hours, about 5 hours to about 7 hours, or about 6 hours.27. A process according to any of Clauses 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26, wherein the mixture is maintained at a temperature of: about 10°C to about 35 °C, about 15 °C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C.28. A process according to any of Clauses 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27, wherein the crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom is isolated, preferably by filtration, centrifugation or decantation, more preferably by filtration.29. A process according to Clauses 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28, wherein the crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom is dried under filtration, preferably for: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 45 minutes, or about 15 minutes to about 30 minutes.30. A process for preparing a crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, comprising:Attorney Docket: API079-W001 (2222-215 PCT)(i) providing a solution of Resmetirom in tetrahydrofurfuryl alcohol;(ii) optionally cooling the solution;(iii) optionally filtering the solution;(iv) adding the solution into an C5-C8 alkane to form a mixture;(vi) optionally maintaining the mixture under stirring.(vii) optionally isolating the solid formed.31. A process according to Clause 30, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol in step (i) is at a temperature of about 50°C to about 75°C.32. A process according to any of Clauses 30 and 31, wherein the solution of Resmetirom in tetrahydrofufurylalcohol in step (ii) is cooled to room temperature.33. A process according to any of Clauses 30, 31, and 32, wherein the C5-C8 alkane is cyclohexane.34. A process according to any of Clauses 30, 31, 32, or 33, wherein step (vi) comprises maintaining the mixture under stirring for about 1 to about 7 hours.35. A crystalline polymorph of Resmetirom, designated Form RT5, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 5.1, 6.4, 7.9, 12.3 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.36. Crystalline Form RT5 of Resmetirom according to Clause 35, which is characterized by an X-ray powder diffraction pattern having peaks at 5. 1, 6.4, 7.9, 12.3 and 23.9 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 14.4, 18.0 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.37. Crystalline Form RT5 of Resmetirom according to Clause and or Clause 36, which is characterized by an X-ray powder diffraction pattern having peaks at 5. 1, 6.4, 7.9, 12.3, 14.4, 18.0, 23.9 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)38. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36 and 37, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.8 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta.39. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, and 38, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 5.6 to 5.8 degrees 2-theta ± 0.2 degrees 2-theta.40. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, and39, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 8.6 to 9.5 degrees 2-theta ± 0.2 degrees 2-theta.41. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 36, 38, 39, and 40, which is further characterized by an X-ray powder diffraction pattern having an absence of peaks at 11.0 to 11.5 degrees 2-theta ± 0.2 degrees 2-theta.42. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, 39,40, and 41, which is anhydrous.43. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, 39, 40, 41, and 42, which is isolated.44. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, 39, 40, 41, 42, and 43, which is polymorphically pure.45. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44, which is substantially free of any other crystalline forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other crystalline forms of Resmetirom.46. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, and 45, which is substantially free of amorphous Resmetirom, preferablyAttorney Docket: API079-W001 (2222-215 PCT) containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of amorphous Resmetirom.47. Crystalline Form RT5 of Resmetirom according to any of Clauses 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46, which is substantially free of any other solid state forms of Resmetirom, preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other solid state forms of Resmetirom.48. A process for preparing crystalline form RT5 of Resmetirom as defined in any of Clauses 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, comprising stirring a suspension of crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16, in an ether solvent, isolating the solid, and drying.49. A process according to Clause 48, wherein the ether is a C4 to C8 ether, preferably a C4 to C7 ether, or a C4 to C6 ether, and particularly a C5 to C6 ether.50. A process according to Clause 49, wherein the ether is diisopropylether or methyl tertbutyl ether.51. A process according to any of Clauses 48, 49 and 50, wherein the ether solvent is used in an amount of: about 10 ml to about 160 ml, about 20 ml to about 140 ml, about 30 ml to about 120 ml, or about 40 ml to about 100 ml, per gram of Resmetirom.52. A process according to any of Clauses 48, 49, 50, and 51, wherein the mixture is carried out at a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C.53. A process according to any of Clauses 48, 49, 50, 51, and 52, wherein the mixture is stirred for a period of: about 2 hours to about 72 hours, about 8 hours to about 60 hours, about 12 hours to about 54 hours, about 18 hours to about 50 hours, or about 24 hours to about 48 hours.Attorney Docket: API079-W001 (2222-215 PCT)54. A process according to any of Clauses 48, 49, 50, 51, 52, and 53, wherein the solid is isolated by fdtration, centrifugation or decantation, more preferably by fdtration.55. A process according to Clauses 48, 49, 50, 51, 52, 53, and 54, wherein the solid is dried under fdtration, preferably for: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 45 minutes, or about 10 minutes to about 30 minutes.56. A process according to any of Clauses 48, 49, 50, 51, 52, 53, 54, and 55, wherein the solid is dried or further dried under reduced pressure.57. A process according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, and 56, wherein the solid is dried or further dried under reduced pressure at a temperature of: about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, or about 60°C.58. A process according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, and 57, wherein the solid is dried or further dried under reduced pressure at a temperature of: about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, or about 60°C.59. A process according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, and 58, wherein the solid is dried or further dried for a period of: about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, or about 4 hours to about 6 hours.60. A process according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, and 59, wherein the process comprises preparing crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom by a process according to any of Clauses 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 31, 32, 33, and 34, suspending the crystalline Form RT4 in an ether solvent, isolating and drying under vacuum to obtain form RT5 of Resmetirom.61. A process according to any of Clauses 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60, wherein the process comprises crystallization of tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom from a solution of tetrahydrofurfuryl alcohol and Resmetirom, suspending the Form RT4 in an ether solvent and drying under vacuum to obtain form RT5 of Resmetirom.Attorney Docket: API079-W001 (2222-215 PCT)62. A process according to any of Clauses 60 and 61, wherein the ether solvent is diisopropylether (DIPE) or methyl tert-butyl ether (MTBE).63. A process for preparing crystalline Resmetirom form RT5 as defined in any of Clauses 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, comprising:(i) providing a solution of Resmetirom in tetrahydrofurfiiryl alcohol, optionally at a temperature of about 50°C to about 75°C;(ii) optionally cooling the solution to Room temperature;(iii) optionally filtering the solution;(iv) adding the solution into an C5-C8 alkane, preferably cyclohexane;(v) optionally maintaining the solution under stirring for about 1 to about 7 hours;(vi) isolating the solid formed;(vii) suspending the solid isolated in step (vi) in an ether solvent, preferably diisopropylether or methyl tert-butyl ether, and maintaining the suspension under stirring for about 1 to about 72 hours;(viii) isolating the solid and(ix) drying under vacuum to obtain anhydrous form RT5.64. A process according to Clause 63, wherein step (viii) is carried out by filtration, decantation or centrifuge, more preferably by filtration.65. A process according to any of Clauses 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, and 64, which further comprises combining the tetrahydrofurfiiryl alcohol solvate of Resmetirom, or Resmetirom, with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.66. A process for preparing other solid state forms of Resmetirom, Resmetirom salts and solid state forms, or cocrystals thereof, comprising preparing a product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, and converting the product to a different form of Resmetirom or a salt, or a cocrystal thereof.Attorney Docket: API079-W001 (2222-215 PCT)67. Use of a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, in the preparation of pharmaceutical compositions comprising Resmetirom, or any crystalline polymorph of Resmetirom or a salt thereof and / or solid state forms thereof.68. A pharmaceutical composition comprising a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, and at least one pharmaceutically acceptable excipient.69. A process for preparing a pharmaceutical composition as defined in Clause 68, comprising a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, with at least one pharmaceutically acceptable excipient.70. Use of a crystalline product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, or a pharmaceutical composition as defined in Clause 68, for the preparation of a medicament.71. Use of a crystalline product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, or a pharmaceutical composition as defined in Clause 68, for the preparation of a medicament for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFUD) and / or associated dyslipidemias.72. A method of treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFUD) and / or associated dyslipidemias by administering a therapeutically effective amount of a crystalline product as defined in any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47, or a pharmaceutical composition as defined in Clause 68, to a subject in need of the treatment.

Claims

Attorney Docket: API079-W001 (2222-215 PCT)CLAIMS1. Crystalline isobutanol solvate of Resmetirom.

2. The crystalline isobutanol solvate of Resmetirom according to Claim 1, designated form RT1, which is characterized by data selected from one or more of the following: an X- ray powder diffraction pattern substantially as depicted in Figure 1 or Figure 1A; an X-ray powder diffraction pattern having peaks at: 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

3. The crystalline isobutanol solvate of Resmetirom according to Claim 1 or Claim 2, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.3, 8.8, 14.4 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from: 13.7, 24.0 and 19.9 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline isobutanol solvate of Resmetirom according to any of Claims 1, 2 and3, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.3, 8.8, 13.7, 14.4, 19.9, 21.0 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline isobutanol solvate of Resmetirom according to any of Claims 1, 2, 3, or4, which is isolated, and / or which is polymorphically pure.

6. A process for preparing the crystalline isobutanol solvate of Resmetirom as defined in any of Claims 1, 2, 3, 4, and 5, comprising: (a) crystallization of the crystalline isobutanol solvate of Resmetirom from a mixture comprising isobutanol and 2-methoxyethanol and an antisolvent, or (b) crystallization of the crystalline isobutanol solvate of Resmetirom from a mixture comprising isobutanol and methyl tert-butyl ether and an antisolvent; or (c) crystallization of the crystalline isobutanol solvate of Resmetirom from a mixture comprising isobutanol, methyl tert-butyl and water and an antisolvent.

7. The process according to Claim 6, wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane.Attorney Docket: API079-W001 (2222-215 PCT)8. The process according to any of Claims 6 or 7, comprising crystallization from a mixture comprising isobutanol and 2-methoxyethanol and an antisolvent, wherein the process comprises combining a solution of Resmetirom in isobutanol and 2-methoxyethanol, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane.

9. The process according to any of Claims 6, 7 or 8, wherein the v / v ratio of isobutanol to 2-methoxyethanol is: about 2: 1 to about 20: 1, about 3: 1 to about 18: 1, about 4: 1 to about 15: 1, about 4: 1 to about 13: 1, or about 5: 1 to about 12: 1.

10. The process according to any of Claims 6, 7, 8, or 9, wherein the v / v ratio of antisolvent to the solution of isobutanol and 2-methoxyethanol is: about 1:2 to about 2: 1, about 1: 1.8 to about 1.8: 1, about 1: 1.5 to about 1.5: 1, about 1: 1.4 to about 1: 0.8, or about 1: 1.2 to about 1:0.9.

11. The process according to any of Claims 8, 9, or 10, wherein the solution of Resmetirom in isobutanol and 2-methoxyethanol is heated to a temperature of about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, about 55°C to about 70°C, and filtering.

12. The process according to any of Claims 8, 9, 10, or 11, wherein the solution of Resmetirom in isobutanol and 2-methoxyethanol is cooled to a temperature of: about -20°C to about 15°C, about -15°C to about 10°C, about -15°C to about 5°C, about -15°C to about 0°C, or about -15°C to about -5°C, or about -10°C.

13. The process according to any of Claims 8, 9, 10, 11, or 12, wherein the cooled solution of Resmetirom in isobutanol and 2-methoxyethanol is combined with the antisolvent at a temperature of: about -20°C to about 5°C, about -15°C to about 5°C, about -15°C to about 0°C, or about -15°C to about -5°C, or about -10°C.

14. The process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom according to any of Claims 8, 9, 10, 11, 12, or 13, wherein the process comprises:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and 2- methoxyethanol, optionally at a temperature of about 60 °C to about 75 °C;(ii) optionally filtering the solution;Attorney Docket: API079-W001 (2222-215 PCT)(iii) optionally cooling the solution to about -15°C to about -5 °C;(iv) adding n-heptane;(v) optionally warming the reaction to a temperature of about 10 °C to about 20 °C;(vi) optionally maintain the solution at a temperature of about 10 °C to about 20 °C for about 1 to about 4 hours; and(vii) optionally isolating the solid formed.

15. The process according to any of Claims 6 or 7, comprising crystallization from a mixture comprising isobutanol and methyl tert-butyl ether and an antisolvent, wherein the process comprises combining a solution of Resmetirom in isobutanol and methyl tert-butyl ether, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, more preferably n-heptane.

16. The process according to any of Claims 6, 7, or 15, wherein the v / v ratio of isobutanol to methyl tert-butyl ether is: about 5: 1 to about 0.5: 1, about 4: 1 to about 0.7: 1, about 3: 1 to about 0.8: 1, about 2: 1 to about 0.7: 1, about 1.5: 1 to about 0.9: 1, or about 1:2: 1 to about 0.95: 1, or about 1;1.

17. The process according to any of Claims 6, 7, 15, or 16, wherein the v / v ratio of antisolvent to the isobutanol and methyl tert-butyl ether is: about 1 : 10 to about 5: 1, about 1 : 8 to about 2: 1, about 1 :6 to about 1: 1, about 1:5 to about 1 : 15 , or about 1:4 to about 1 :25, about 1:4 to about 1:3, or about 1 :3.5.

18. The process according to any of Claims 6, 7, 15, 16, or 17, wherein antisolvent is added to the solution of Resmetirom in isobutanol and methyl tert-butyl ether, preferably at a temperature of: about -10°C to about 15°C, about -5°C to about 10°C, or about 0°C to about 5 °C, to form a mixture.

19. The process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom, according to any of Claims 6, 7, 15, 16, 17, or 18, wherein the process comprises:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and methyl tertbutyl ether, optionally at a temperature of about 60°C to about 75°C;(ii) optionally stirring the solution with charcoal, and filtering;(iii) optionally seeding the solution with Form RT1 of Resmetirom;Attorney Docket: API079-W001 (2222-215 PCT)(iv) optionally cooling the solution, preferably to a temperature of about 20°C to about 25°C;(v) optionally concentrating the solution;(vi) adding n-heptane to form a mixture;(vii) optionally stirring the mixture, preferably at a temperature of 0°C to about 5°C, preferably for about 30 minutes to about 4 hours; and(viii) optionally isolating the solid formed.

20. The process according to any of Claims 6 or 7, comprising crystallization from a mixture comprising isobutanol, methyl tert-butyl and water and an antisolvent, wherein the process comprises combining a solution of Resmetirom in isobutanol, methyl tert-butyl ether, and water, with an antisolvent, to form a mixture, preferably wherein the antisolvent is a C5- C8 alkane, more preferably n-heptane.

21. The process according to any of Claims 6, 7, or 20, wherein the v / v ratio of isobutanol to methyl tert-butyl ether is: about 5: 1 to about 1:5, about 4: 1 to about 1:4, about 3: 1 to about 1:3, about 2: 1 to about 1:2, about 1.5: 1 to about 1: 1.5, about 1.2: 1 to about 1: 1.2, about 1.1: 1 to about 1: 1.1, or 1: 1.

22. The process according to any of Claims 6, 7, 20, or 21, wherein water is used in an amount (vol% of total solvent mixture) of: about 0.05% to about 5%, 0.05% to about 3%, about 0.08% to about 2%, about 0. 1% to about 1%, about 0.1% to about 0.6%, about 0. 1% to about 0.5%, about 0.15% to about 0.4%, about 0.2% to about 0.35%, or about 0.3%.

23. The process according to any of Claims 6, 7, 20, 21, or 22, wherein the v / v ratio of antisolvent to the mixture of isobutanol, methyl tert-butyl ether and water is: about 2: 1 to about 1:5, about 1.5: 1 to about 1:4, about 1.2: 1 to about 1: 1:3, about 1.3: 1 to about 1:2.5, about 1: 1 to about 1 :2.4, or about 1 : 1.5 to about 1:2.3, or about 1 : 1.8 to about 1:2.2, or about 1:2.1.

24. The process according to any of Claims 6, 7, 20, 21, 22, or 23, wherein the solution of Resmetirom in isobutanol, methyl tert-butyl ether and water, is combined with the antisolvent at a temperature of: about 15°C to about 35°C, about 18°C to about 30°C, about 22°C to about 28°C, about 24°C to about 26°C, or about 25°C, to form a mixture.Attorney Docket: API079-W001 (2222-215 PCT)25. The process according any of Claims 6, 7, 20, 21, 22, 23, or 24, wherein the mixture of Resmetirom in isobutanol, methyl tert-butyl ether, water, and antisolvent is cooled, preferably to a temperature of: about -10°C to about 10°C, about -5°C to about 5°C, about -2°C to about 2°C, or about 0°C.

26. The process for preparing crystalline isobutanol solvate Form RT1 of Resmetirom according to any of Claims 6, 7, 20, 21, 22, 23, 24, or 25, wherein the process comprises:(i) providing a solution of Resmetirom in a mixture comprising isobutanol and methyl tertbutyl ether and water;(ii) optionally heating the solution, preferably to a temperature of: about 50°C to about 70°C, and filtering;(iii) optionally seeding with form RT2 of Resmetirom, preferably at a temperature of about 25 °C to about 35 °C,(iv) adding n-heptane to form a mixture;(v) optionally stirring the mixture, preferably at a temperature of -5°C to about 5°C, preferably for about 1 hour to about 8 hours; and(vii) optionally isolating the solid formed.

27. The crystalline isobutanol solvate of Resmetirom according to Claim 1, designated form RT3, which is characterized by data selected from one or more of the following: an X- ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at: 9.9, 14.2, 18.6, 22.0 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

28. The crystalline isobutanol solvate of Resmetirom according to any of Claim 1 and Claim 27, which is characterized by an X-ray powder diffraction pattern having peaks at: 9.9, 14.2, 18.6, 22.0 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from: 12.4, 23.5 and 29.0 degrees 2-theta ± 0.2 degrees 2- theta.

29. The crystalline isobutanol solvate of Resmetirom according to any of Claims 1, 27 and 28, which is characterized by an X-ray powder diffraction pattern having peaks at: 9.9, 12.4, 14.2, 18.6, 22.0, 23.5, 25.0 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)30. The crystalline isobutanol solvate of Resmetirom according to any of Claims 27, 28, or 29, which is isolated.

31. The crystalline isobutanol solvate of Resmetirom according to any of Claims 27, 28, 29, or 30, which is polymorphically pure.

32. The process for preparing crystalline isobutanol solvate of Resmetirom as defined in any of Claims 27, 28, 29, 30, or 31, comprising crystallization of isobutanol solvate Form RT3 of Resmetirom from isobutanol, preferably comprising cooling a solution of Resmetirom in isobutanol.

33. The process according to Claim 32, comprising:(i) providing a solution of Resmetirom in isobutanol;(ii) optionally filtering the solution;(iii) optionally cooling the solution;(vi) optionally maintaining the solution for about 6 to about 24 hours; and(vii) optionally isolating the solid formed.

34. A desolvate crystalline form of Resmetirom, designated Form RT2, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2 or Figure 2A; or an X-ray powder diffraction pattern having peaks at: 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta.

35. The crystalline form of Resmetirom according to Claim 34, which is characterized by: an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta.

36. The crystalline form of Resmetirom according to any of Claims 34 or 35 which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6 and 16.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two three or four additional peaks selected from: 19.0, 11.7, 14.7 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)37. The crystalline form of Resmetirom according to Claim 34, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 19.0 degrees 2-theta ± 0.2 degrees 2-theta.

38. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and 19.0 degrees 2-theta ± 0.2 degrees 2-theta.

39. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 11.7 degrees 2-theta ± 0.2 degrees 2-theta.

40. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and11.7 degrees 2-theta ± 0.2 degrees 2-theta.

41. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 14.7 degrees 2-theta ± 0.2 degrees 2-theta.

42. The crystalline form of Resmetirom according to any of Claims 34 and Claim 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and14.7 degrees 2-theta ± 0.2 degrees 2-theta.

43. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 16.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

44. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 16.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API079-W001 (2222-215 PCT)45. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 7.8, 9.6, 11.7, 14.7, 16.2, 19.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

46. The crystalline form of Resmetirom according to any of Claims 34 or 35, which is characterized by an X-ray powder diffraction pattern having peaks at: 6.1, 7.8, 9.6, 11.7, 14.7, 16.2, 19.0 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

47. The crystalline form of Resmetirom according to any of Claims 34, 35, 36, 37, 38, 39, 40. 41, 42, 43, 44, 45, and 46, which is isolated.

48. The crystalline form of Resmetirom according to any of Claims 34, 35, 36, 37, 38, 39, 40. 41, 42, 43, 44, 45, 46, and 47, which is polymorphically pure.

49. A process for preparing a crystalline form of Resmetirom as defined in any of Claims 34, 35, 36, 37, 38, 39, 40. 41, 42, 43, 44, 45, or 46, comprising drying a crystalline isobutanol solvate of Resmetirom.

50. The process according to Claim 49, wherein the crystalline isobutanol solvate of Resmetirom is as defined in any of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15.

51. The process according to any of Claims 49 or 50, comprising drying the crystalline isobutanol solvate of Resmetirom under vacuum.

52. The process according to any of Claims 49, 50, or 51, wherein the drying is carried under vacuum at a temperature of: about 40°C to about 140°C, or about 45°C to about 130°C, or about 50°C to about 125°C, about 55°C to about 105°C, or about 55°C to about 110°C.

53. The process according to any of Claims 49, 50, 51, or 52, wherein the drying is carried out for a period of time of: about 1 hour to about 20 hours, about 2 hours to about 18 hours, or about 2 hours to about 14 hours.

54. A crystalline tetrahydrofurfiiryl alcohol solvate of Resmetirom.Attorney Docket: API079-W001 (2222-215 PCT)55. The crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to Claim 54, which is designated form RT4, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

56. The crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to Claims 54 or 55, which is characterized by an X-ray powder diffraction pattern having peaks at 6.8, 13.6, 17.6, 24.8 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 12.0, 15.6 and 27.4 degrees 2-theta ± 0.2 degrees 2- theta; or which is characterized by an X-ray powder diffraction pattern having peaks at 6.8, 12.0, 13.6, 15.6, 17.6, 24.8, 26.0 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.

57. The crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Claims 54, 55, and 56, which is isolated.

58. The crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Claims 54, 55, 56, or 57, which is polymorphically pure.

59. The crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom according to any of Claims 54, 55, 56, 57, or 58, which contains about 17% to about 21%, of tetrahydrofurfuryl alcohol by weight.

60. A process for preparing a crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom as defined in any of Claims 54, 55, 56, 57, 58, or 59, wherein the process comprises crystallization of the tetrahydrofurfuryl alcohol solvate of Resmetirom from a mixture comprising tetrahydrofurfuryl alcohol an antisolvent.

61. The process according to Claim 60, wherein the antisolvent is a C5-C8 alkane, preferably cyclohexane.

62. The process according to any of Claims 60 or 61, which comprises combining a solution of Resmetirom in tetrahydrofurfuryl alcohol with the antisolvent, to form a mixture, preferably wherein the antisolvent is a C5-C8 alkane, preferably cyclohexane.Attorney Docket: API079-W001 (2222-215 PCT)63. The process according to Claim 62, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is added to the antisolvent; or wherein the antisolvent is added to the solution of Resmetirom in tetrahydrofurfuryl alcohol,64. The process according to Claim 62 or 63, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is added to the antisolvent.

65. The process according to any of Claims 60, 61, 62, 63, or 64, wherein the v / v ratio of antisolvent to tetrahydrofurfuryl alcohol is: about 1: 1 to about 10: 1, about 2: 1 to about 8: 1, about 2.5: 1 to about 7: 1, about 3: 1 to about 6: 1, about 3.5: 1 to about 5.5: 1, or about 4: 1 to about 5: 1.

66. The process according to any of Claims 62, 63, 64, or 65, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is heated to a temperature of: about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, or about 60°C, and filtering.

67. The process according to Claim 66, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is cooled to a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C.

68. The process according to any of Claims 62, 63, 64, 65, 66, or 67, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol is combined with the antisolvent at a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C, preferably by addition of the solution of Resmetirom in tetrahydrofurfuryl alcohol to the antisolvent.

69. The process according to any of Claims 62, 63, 64, 65, 66, 67, or 68, wherein the mixture is stirred for a period of: about 1 hour to about 12 hours, about 2 hours to about 10 hour, about 3 hours to about 8 hours, about 5 hours to about 7 hours, or about 6 hours.

70. The process according to any of Claims 62, 63, 64, 65, 66, 67, 68, or 69, wherein the mixture is maintained at a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C.Attorney Docket: API079-W001 (2222-215 PCT)71. The process according to any of Claims 62, 63, 64, 65, 66, 67, 68, 69, or 70, wherein the crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom is isolated, preferably by fdtration, centrifugation or decantation, more preferably by fdtration.

72. The process according to Claims 62, 63, 64, 65, 66, 67, 68, 68, 70, or 71, wherein the crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom is dried under filtration, preferably for: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 45 minutes, or about 15 minutes to about 30 minutes.

73. The process for preparing a crystalline tetrahydrofurfuryl alcohol solvate of Resmetirom as defined in any of Claims 54, 55, 56, 57, 58, or 59, comprising:(i) providing a solution of Resmetirom in tetrahydrofurfuryl alcohol optionally at a temperature of about 50 °C to about 75 °C;(ii) optionally cooling the solution, preferably to room temperature;(iii) optionally filtering the solution;(iv) adding the solution into an C5-C8 alkane to form a mixture, preferably cyclohexane;(vi) optionally maintaining the solution mixture under stirring, preferably for about 1 to about 7 hours; and(vii) optionally isolating the solid formed.

74. The process according to Claim 73, wherein the solution of Resmetirom in tetrahydrofurfuryl alcohol in step (i) is at a temperature of about 50°C to about 75°C.

75. The process according to any of Claims 73 or 74, wherein the solution of Resmetirom in tetrahydrofufurylalcohol in step (ii) is cooled to room temperature.

76. The process according to any of Claims 73, 74, or 75, wherein the C5-C8 alkane is cyclohexane.

77. The process according to any of Claims 73, 74, 75, or 76, wherein step (vi) comprises maintaining the mixture under stirring for about 1 to about 7 hours.Attorney Docket: API079-W001 (2222-215 PCT)78. A crystalline polymorph of Resmetirom, designated Form RT5, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 5.1, 6.4, 7.9, 12.3 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

79. The crystalline Form RT5 of Resmetirom according to Claim 78, which is characterized by an X-ray powder diffraction pattern having peaks at 5.1, 6.4, 7.9, 12.3 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 14.4, 18.0 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta; or which is characterized by an X-ray powder diffraction pattern having peaks at 5. 1, 6.4, 7.9, 12.3, 14.4, 18.0, 23.9 and 25.4 degrees 2-theta ± 0.2 degrees 2-theta.

80. The crystalline Form RT5 of Resmetirom according to any of Claims 78 or 79, which is anhydrous, or which is a desolvate.

81. The crystalline Form RT5 of Resmetirom according to any of Claims 78, 79 or 80, which is isolated.

82. The crystalline Form RT5 of Resmetirom according to any of Claims 78, 79, 80, or 81, which is polymorphically pure.

83. A process for preparing crystalline form RT5 of Resmetirom as defined in any of Claims 78, 79, 80, 81, or 82, comprising stirring a suspension of crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom as defined in any of Claims 54, 55, 56, 57, 58, and 59, in an ether solvent, isolating the solid, and drying.

84. The process according to Claim 83, wherein the ether is a C4 to C8 ether, preferably a C4 to C7 ether, or a C4 to C6 ether, and particularly a C5 to C6 ether; and more preferably wherein the ether is diisopropylether or methyl tert-butyl ether.

85. The process according to any of Claims 83 or 84, wherein the ether solvent is used in an amount of: about 10 ml to about 160 ml, about 20 ml to about 140 ml, about 30 ml to about 120 ml, or about 40 ml to about 100 ml, per gram of Resmetirom.Attorney Docket: API079-W001 (2222-215 PCT)86. The process according to any of Claims 83, 84 or 85, wherein the stirring is carried out at a temperature of: about 10°C to about 35°C, about 15°C to about 30°C, about 18°C to about 28°C, or about 25°C to about 28°C, or about 25°C.

87. The process according to any of Claims 83, 84, 85 or 86, wherein the mixture is stirred for a period of: about 2 hours to about 72 hours, about 8 hours to about 60 hours, about 12 hours to about 54 hours, about 18 hours to about 50 hours, or about 24 hours to about 48 hours.

88. The process according to any of Claims 83, 84, 85, 86, or 87, wherein the solid is isolated by fdtration, centrifugation or decantation, more preferably by fdtration.

89. The process according to Claims 83, 84, 85, 86, 87, or 88, wherein the solid is dried under fdtration, preferably for: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 10 minutes to about 45 minutes, or about 10 minutes to about 30 minutes.

90. The process according to any of Claims 83, 84, 85, 86, 87, 88, or 89, wherein the solid is dried or further dried under reduced pressure.

91. The process according to any of Claims 83, 84, 85, 86, 87, 88, 89, or 90, wherein the solid is dried or further dried under reduced pressure at a temperature of: about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, or about 60°C.

92. The process according to any of Claims 83, 84, 85, 86, 87, 88, 89, 90, or 91, wherein the solid is dried or further dried under reduced pressure at a temperature of: about 40°C to about 90°C, or about 50°C to about 80°C, or about 50°C to about 75°C, or about 60°C.

93. The process according to any of Claims 83, 84, 85, 86, 87, 88, 89, 90, 91, or 92, wherein the solid is dried or further dried for a period of: about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 7 hours, or about 4 hours to about 6 hours.

94. The process according to any of Claims 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, or 93, wherein the process comprises preparing crystalline tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom by a process according to any of Claims 60, 61, 62, 63, 64, 65, 66, 67,Attorney Docket: API079-W001 (2222-215 PCT)68, 69, 70, 71, 72, 73, 74, 75, 76, or 77, suspending the crystalline Form RT4 in an ether solvent, isolating and drying under vacuum to obtain form RT5 of Resmetirom.

95. The process according to any of Claims 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, or 93, and 94, wherein the process comprises crystallization of tetrahydrofurfuryl alcohol solvate Form RT4 of Resmetirom from a solution of tetrahydrofurfuryl alcohol and Resmetirom, suspending the Form RT4 in an ether solvent and drying under vacuum to obtain form RT5 of Resmetirom.

96. The process according to any of Claims 94 or 95, wherein the ether solvent is diisopropylether (DIPE) or methyl tert-butyl ether (MTBE).

97. The process for preparing crystalline Resmetirom form RT5 as defined in any of Claims 78, 79, 80, 81, or 82, comprising:(i) providing a solution of Resmetirom in tetrahydrofurfuryl alcohol, optionally at a temperature of about 50°C to about 75°C;(ii) optionally cooling the solution to Room temperature;(iii) optionally filtering the solution;(iv) adding the solution into an C5-C8 alkane, preferably cyclohexane;(v) optionally maintaining the solution under stirring for about 1 to about 7 hours(vi) isolating the solid formed;(vii) suspending the solid isolated in step (vi) in an ether solvent, preferably diisopropylether or methyl tert-butyl ether, and maintaining the suspension under stirring for about 1 to about 72 hours;(viii) isolating the solid and(ix) drying under vacuum to obtain anhydrous form RT5.

98. The process according to Claim 97, wherein step (viii) is carried out by filtration, decantation or centrifuge, more preferably by filtration.

99. The process according to any of Claims 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 32, 33, 49, 50, 51, 52, 53, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 83, 84, 85, 86, 87. 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, or 98, whichAttorney Docket: API079-W001 (2222-215 PCT) further comprises combining the Resmetirom with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

100. A process for preparing other solid state forms of Resmetirom, Resmetirom salts and solid state forms, or cocrystals thereof, comprising preparing a product as defined in any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, and converting that form to a different form of Resmetirom or a salt, or a cocrystal thereof.

101. Use of a crystalline product according to any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, in the preparation of pharmaceutical compositions comprising Resmetirom, or any crystalline polymorph of Resmetirom or a salt thereof and / or solid state forms thereof.

102. A pharmaceutical composition comprising a crystalline product according to any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, and at least one pharmaceutically acceptable excipient.

103. A process for preparing a pharmaceutical composition as defined in Claim 102, comprising a crystalline product according to any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, with at least one pharmaceutically acceptable excipient.

104. Use of a crystalline product as defined in any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, or a pharmaceutical composition as defined in Claim 102, for the preparation of a medicament.

105. Use of a crystalline product as defined in any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, or a pharmaceutical composition as defined in Claim 102, for the preparation of a medicament for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFUD) and / or associated dyslipidemias.Attorney Docket: API079-W001 (2222-215 PCT)106. A method of treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and / or associated dyslipidemias by administering a therapeutically effective amount of a crystalline product as defined in any of Claims 1, 2, 3, 4, 5, 27, 28, 29, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 54, 55, 56, 57, 58, 59, 78, 80, 81, or 82, or a pharmaceutical composition as defined in Claim 102, to a subject in need of the treatment.

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