DESC:
The following specification describes particularly the invention and in the manner in which it is to be performed:

SOLID STATE FORMS OF RESMETIROM AND PROCESSES FOR THEIR PREPARATION

FIELD OF THE INVENTION

The present application relates to crystalline forms R1, R2, R3, R4 and R5 of Resmetirom, their preparative methods and pharmaceutical compositions thereof. The present application provides amorphous form and amorphous solid dispersions of Resmetirom along with their preparative methods. The present application also provides crystalline form RL of lysine salt of Resmetirom along with its preparative methods.

BACKGROUND OF THE INVENTION
Resmetirom (MGL-3196) is a first-in-class, orally administered, small-molecule, liver-directed, thyroid hormone receptor (THR) ß-selective agonist., developed by Madrigal Pharmaceuticals and its partner Roche Holding AG/VIA. Resmetirom is currently in advanced clinical trials for the treatment of Non-Alcoholic Fatty Liver Disease. Resmetirom is chemically known as 2-(3,5-dichloro-4-{[6-oxo-5-(propan-2-yl)-1,6- dihydropyridazin-3-yl]oxy}phenyl)-3,5-dioxo-2,3,4,5- tetrahydro-1,2,4-triazine-6-carbonitrile.

US7452882B2 (herein after referred as US’882) first discloses Resmetirom along with the process for preparation thereof. WO2014043706A1 (herein after referred as WO’706) discloses crystalline Form I of Resmetirom. WO’ 706 also discloses solvate forms viz. MIBK solvate, Dihydrate and DMAc solvate. Further, WO2020010068A1 (herein after referred as WO’068) discloses various solvate forms Form B to Form ?. However, all these solvates were not stable and converts to Form I under different conditions.
New polymorphic forms, solvates and solid dispersions of a pharmaceutically useful compound or salts thereof 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, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Resmetirom.
SUMMARY OF THE INVENTION
First aspect of the present application relates to crystalline form R1 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 11.18, 12.48, 13.8, 15.02, 16.49 and 20.6 ± 0.2° 2?. In embodiments of the present application, crystalline form R1 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 5.59, 10.56, 22, 22.76, 26.69 and 27.78 ± 0.2° 2?.

Second aspect of the present application relates to crystalline form R1 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 1.

Third aspect of the present application relates to a process for preparing crystalline form R1 of Resmetirom; the process comprising;
a) providing a solution or suspension comprising Resmetirom and formic acid by mixing Resmetirom with formic acid optionally in presence of a solvent;
b) isolating crystalline form R1 of Resmetirom from the mixture of step a); and;
c) optionally, drying the isolated product at suitable temperature.
Fourth aspect, the present application provides a pharmaceutical composition comprising crystalline form R1 of Resmetirom and at least one pharmaceutically acceptable carrier.

Fifth aspect of the present application relates to crystalline form R2 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 9.04, 22.56 and 25.5 ± 0.2° 2?. In embodiments of the present application crystalline form R2 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 9.6, 15.9 and 26.4 ± 0.2° 2?.
Sixth aspect of the present application relates to crystalline form R2 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 2.

Seventh aspect of the present application relates to a process for preparing crystalline form R2 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and hexanoic acid by mixing Resmetirom with hexanoic acid optionally in presence of a solvent;
b) adding an anti-solvent;
c) isolating crystalline form R2 of Resmetirom from the mixture of step b); and;
c) optionally, drying the isolated product at suitable temperature.

Eighth, aspect, the present application provides a pharmaceutical composition comprising crystalline form R2 of Resmetirom and at least one pharmaceutically acceptable carrier.
Ninth aspect of the present application relates to crystalline form R3 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 13.18, 27.2,30 and 31.6 ± 0.2° 2?. In embodiments of the present application, crystalline form R3 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 9.68, 16.99 and 20.57 ± 0.2° 2?.

Tenth aspect of the present application relates to crystalline form R3 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 3.

Eleventh aspect of the present application relates to a process for preparing crystalline form R3 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and sulfolane by mixing Resmetirom with sulfolane optionally in presence of a solvent;
b) adding an anti-solvent;
c) isolating crystalline form R3 of Resmetirom from the mixture of step b); and;
c) optionally, drying the isolated product at suitable temperature.

Twelfth, aspect, the present application provides a pharmaceutical composition comprising crystalline form R3 of Resmetirom and at least one pharmaceutically acceptable carrier.

Thirteenth aspect of the present application relates to crystalline form R4 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.02, 8.9, 9.35 and 14.09 ± 0.2° 2?. In embodiments of the present application, crystalline form R4 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 16.88, 22.56 and 28.77 ± 0.2° 2?.

Fourteenth aspect of the present application relates to crystalline form R4 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 4.

Fifteenth aspect of the present application relates to a process for preparing crystalline form R4 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and butyric acid by mixing Resmetirom with butyric acid optionally in presence of a solvent;
b) adding an anti-solvent;
c) isolating crystalline form R4 of Resmetirom from the mixture of step b); and;
c) optionally, drying the isolated product at suitable temperature.

Sixteenth aspect of the present application provides a pharmaceutical composition comprising crystalline form R4 of Resmetirom and at least one pharmaceutically acceptable carrier.

Seventeenth aspect of the present application relates to crystalline form R5 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 12.0, 14.28, 15.5 and 22.43 ± 0.2° 2?. In embodiments of the present application, crystalline form R5 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 5.7, 10.6, 20.2, 21.09,21.44 and 28.82 ± 0.2° 2?.

Eighteenth aspect of the present application relates to crystalline form R5 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 5.

Ninteenth aspect of the present application relates to a process for preparing crystalline form R5 of Resmetirom; the process comprising;
a) providing a solution or suspension of Resmetirom in 1, 2-Dimethoxyethane;
b) isolating crystalline form R5 of Resmetirom from the mixture of step a); and;
c) optionally, drying the isolated product at suitable temperature.

Twentieth aspect, the present application provides a pharmaceutical composition comprising crystalline form R5 of Resmetirom and at least one pharmaceutically acceptable carrier.

Twenty fist aspect of the present application provides amorphous solid dispersion comprising resmetirom and one or more pharmaceutically acceptable excipient.

Twenty second aspect of the present application provides a process for preparation of amorphous solid dispersion comprising Resmetirom and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution comprising Resmetirom and one or more pharmaceutically acceptable excipients in a suitable solvent;
b) removing solvent from the solution obtained in step (a), and
c) recovering the solid dispersion of Resmetirom with one or more pharmaceutically acceptable excipients.

Twenty third aspect of the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Resmetirom and at least one pharmaceutically acceptable carrier.

Twenty fourth aspect of the present application provides a process for preparation of amorphous form of Resmetirom comprising;
a) providing a solution of Resmetirom in a suitable solvent;
b) removing solvent from the solution obtained in step (a), and
c) isolating the amorphous form of Resmetirom.

Twenty fifth aspect of the present application provides a pharmaceutical composition comprising amorphous form of Resmetirom and at least one pharmaceutically acceptable carrier.

Twenty sixth aspect of the present application relates to crystalline form RL of Lysine salt of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 18.42, 19.09 and 20.49 ± 0.2° 2?. In embodiments of the present application, crystalline form RL of Lysine salt of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 11.24 and 17.12 ± 0.2° 2?.

Twenty seventh aspect of the present application relates to crystalline form RL of Lysine salt of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 4.

Twenty eighth aspect of the present application relates to a process for preparing crystalline form RL of Lysine salt of Resmetirom; the process comprising;
a) providing a mixture of Resmetirom and Lysine in a suitable solvent;
b) isolating crystalline form RL of lysine salt of Resmetirom from the mixture of step a); and;
c) optionally, drying the isolated product at suitable temperature.

Twenty ninth aspect of the present application provides a composition comprising crystalline form RL of lysine salt of Resmetirom and one or more pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of crystalline from R1 of Resmetirom.
Figure 2 is powder X-ray diffraction pattern of crystalline from R2 of Resmetirom.
Figure 3 is powder X-ray diffraction pattern of crystalline from R3 of Resmetirom.
Figure 4 is powder X-ray diffraction pattern of crystalline from R4 of Resmetirom.
Figure 5 is powder X-ray diffraction pattern of crystalline from R5 of Resmetirom.
Figure 6 is powder X-ray diffraction pattern of amorphous solid dispersion of Resmetirom with eudragit.
Figure 7 is powder X-ray diffraction pattern of amorphous from of Resmetirom.
Figure 8 is powder X-ray diffraction pattern of crystalline from RL of lysin salt of Resmetirom.

DETAILED DESCRITPION
First aspect of the present application relates to crystalline form R1 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 11.18, 12.48, 13.8, 15.02, 16.49 and 20.6 ± 0.2° 2?. In embodiments of the present application, crystalline form R1 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 5.59, 10.56, 22, 22.76, 26.69 and 27.78 ± 0.2° 2?.

Second aspect of the present application relates to crystalline form R1 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 1.

Third aspect of the present application relates to a process for preparing crystalline form R1 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and formic acid by mixing Resmetirom with formic acid optionally in presence of a solvent;
b) isolating crystalline form R1 of Resmetirom from the mixture of step a); and;
c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a), the optional solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water.
In one of the embodiments of step a), any physical form of Resmetirom may be utilized, which may be crystalline or amorphous, for providing the suspension of Resmetirom in a solvent comprising formic acid. In another embodiment of step a), any physical form of Resmetirom may be utilized, which may be anhydrous or hydrate or solvate for providing the suspension of Resmetirom in a solvent comprising formic acid.
Isolation of crystalline form R1 of Resmetirom in step b) may be performed by any technique known in the art. Specifically, crystalline form R1 of Resmetirom may be isolated from the mixture of step a) by filtration followed by drying.
The resulting compound obtained in step (b) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures between RT to 75 °C or at a temperature of about 50 °C or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Fourth aspect of the present application relates to a pharmaceutical composition comprising crystalline form R1 of Resmetirom and one or more pharmaceutically acceptable excipient.

Fifth aspect of the present application relates to crystalline form R2 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 9.04, 22.56 and 25.5 ± 0.2° 2?. In embodiments of the present application crystalline form R2 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 9.6, 15.9 and 26.4 ± 0.2° 2?.

Sixth aspect of the present application relates to crystalline form R2 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 2.

Seventh aspect of the present application relates to a process for preparing crystalline form R2 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and hexanoic acid by mixing Resmetirom with hexanoic acid optionally in presence of a solvent;
b) adding an anti-solvent;
c) isolating crystalline form R2 of Resmetirom from the mixture of step b); and;
d) optionally, drying the isolated product at suitable temperature.

In embodiments of step a), the optional solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water.
In one of the embodiments of step a), any physical form of Resmetirom may be utilized, which may be crystalline or amorphous, for providing the suspension of Resmetirom in a solvent comprising formic acid. In another embodiment of step a), any physical form of Resmetirom may be utilized, which may be anhydrous or hydrate or solvate for providing the suspension of Resmetirom in a solvent comprising formic acid.
In embodiments of step b), the anti-solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water. In another embodiment of step b), the anti- solvent may be an ether solvent. In a specific embodiment, the anti-solvent is diisopropyl ether.

Isolation of crystalline form R2 of Resmetirom in step b) may be performed by any technique known in the art. Specifically, crystalline form R2 of Resmetirom may be isolated from the mixture of step a) by filtration followed by drying.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures between RT to 75 °C or at a temperature of about 50 °C or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Eighth, aspect, the present application provides a pharmaceutical composition comprising crystalline form R2 of Resmetirom and at least one pharmaceutically acceptable carrier.

Ninth aspect of the present application relates to crystalline form R3 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 13.18, 27.2,30 and 31.6 ± 0.2° 2?. In embodiments of the present application crystalline form R3 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 9.68, 16.99 and 20.57 ± 0.2° 2?.

Tenth aspect of the present application relates to crystalline form R3 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 3.

Eleventh aspect of the present application relates to a process for preparing crystalline form R3 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and sulfolane by mixing Resmetirom with sulfolane optionally in presence of a solvent;
b) adding an anti-solvent;
c) isolating crystalline form R3 of Resmetirom from the mixture of step b); and;
c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a), the optional solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water.
In one of the embodiments of step a), any physical form of Resmetirom may be utilized, which may be crystalline or amorphous, for providing the suspension of Resmetirom in a solvent comprising formic acid. In another embodiment of step a), any physical form of Resmetirom may be utilized, which may be anhydrous or hydrate or solvate for providing the suspension of Resmetirom in a solvent comprising formic acid.
In embodiments of step b), the anti-solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water. In a specific embodiment, the anti-solvent is water.

Isolation of crystalline form R3 of Resmetirom in step b) may be performed by any technique known in the art. Specifically, crystalline form R3 of Resmetirom may be isolated from the mixture of step a) by filtration followed by drying.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures between RT to 75 °C or at a temperature of about 50 °C or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours

Twelfth, aspect, the present application provides a pharmaceutical composition comprising crystalline form R3 of Resmetirom and at least one pharmaceutically acceptable carrier.

Thirteenth aspect of the present application relates to crystalline form R4 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.02, 8.9, 9.35 and 14.09 ± 0.2° 2?. In embodiments of the present application crystalline form R4 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 16.88, 22.56 and 28.77 ± 0.2° 2?.

Fourteenth aspect of the present application relates to crystalline form R4 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 4.

Fifteenth aspect of the present application relates to a process for preparing crystalline form R4 of Resmetirom; the process comprising;
a) providing a solution or a suspension comprising Resmetirom and butyric acid by mixing Resmetirom with butyric acid optionally in presence of a solvent;
b) adding an anti-solvent
c) isolating crystalline form R4 of Resmetirom from the mixture of step b); and;
c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a), the optional solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; hydrocarbon solvents like hexane, heptane and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water.
In one of the embodiments of step a), any physical form of Resmetirom may be utilized, which may be crystalline or amorphous, for providing the suspension of Resmetirom in a solvent comprising formic acid. In another embodiment of step a), any physical form of Resmetirom may be utilized, which may be anhydrous or hydrate or solvate for providing the suspension of Resmetirom in a solvent comprising formic acid.
In embodiments of step b), the anti-solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; hydrocarbon solvents like hexane, heptane and the like water. In a specific embodiment, the anti-solvent is heptane.

Isolation of crystalline form R4 of Resmetirom in step b) may be performed by any technique known in the art. Specifically, crystalline form R4 of Resmetirom may be isolated from the mixture of step a) by filtration followed by drying.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures between RT to 75 °C or at a temperature of about 50 °C or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Sixteenth aspect of the present application provides a pharmaceutical composition comprising crystalline form R4 of Resmetirom and at least one pharmaceutically acceptable carrier.

Seventeenth aspect of the present application relates to crystalline form R5 of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 12.0, 14.28, 15.5 and 22.43 ± 0.2° 2?. In embodiments of the present application, crystalline form R5 of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 5.7, 10.6, 20.2, 21.09,21.44 and 28.82 ± 0.2° 2?.

Eighteenth aspect of the present application relates to crystalline form R5 of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 5.

Nineteenth aspect of the present application relates to a process for preparing crystalline form R5 of Resmetirom; the process comprising;
a) providing a solution or suspension of Resmetirom in 1, 2-Dimethoxyethane;
b) isolating crystalline form R5 of Resmetirom from the mixture of step a); and;
c) optionally, drying the isolated product at suitable temperature.

In one of the embodiments of step a), any physical form of Resmetirom may be utilized, which may be crystalline or amorphous, for providing the suspension of Resmetirom in a solvent comprising formic acid. In another embodiment of step a), any physical form of Resmetirom may be utilized, which may be anhydrous or hydrate or solvate for providing a solution or suspension of Resmetirom in 1, 2-Dimethoxyethane.
Isolation of crystalline form R5 of Resmetirom in step b) may be performed by any technique known in the art. Specifically, crystalline form R5 of Resmetirom may be isolated from the mixture of step a) by filtration followed by drying.
The resulting compound obtained in step (b) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures between RT to 75 °C or at a temperature of about 50 °C or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Twentieth aspect of the present application relates to a pharmaceutical composition comprising crystalline form R5 of Resmetirom and one or more pharmaceutically acceptable excipient.

Twenty first aspect of the present application provides amorphous solid dispersion comprising Resmetirom and one or more pharmaceutically acceptable excipient.

Twenty second aspect of the present application provides a process for preparation of amorphous solid dispersion comprising Resmetirom and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution of Resmetirom and one or more pharmaceutically acceptable excipients in a suitable solvent;
b) removing solvent from the solution obtained in step (a), and
c) recovering the solid dispersion of Resmetirom with one or more pharmaceutically acceptable excipients.

Providing a solution in step (a) includes direct use of a reaction mixture containing resmetirom that is obtained in the course of its synthesis or dissolving resmetirom and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.
Any physical form of resmetirom may be utilized for providing the solution of step (a).
Suitable pharmaceutically acceptable excipients which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS). hydroxypropyl methylcellulose phthalate (HPMCP), HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates such as Eudragit L and Eudragit S, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
In a preferred embodiment, the pharmaceutically acceptable excipient is Eudragit in various mole ratios.
Suitable solvent of step a) may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water; mixture thereof. Preferably, suitable solvent is methanol.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art.
Step (c) involves recovering amorphous solid dispersion of resmetirom with one or more pharmaceutically acceptable excipient. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Resmetirom, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore, these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous Resmetirom or solid dispersion to control hygroscopicity and to improve stability.
Twenty third aspect of the present application provides a pharmaceutical composition comprising amorphous solid dispersion of resmetirom and at least one pharmaceutically acceptable carrier.

Twenty fourth aspect of the present application provides a process for preparation of amorphous form of resmetirom comprising;
a) providing a solution of resmetirom in a suitable solvent;
b) removing solvent from the solution obtained in step (a); and
c) isolating the amorphous form of Resmetirom.

Providing a solution in step (a) includes direct use of a reaction mixture containing resmetirom that is obtained in the course of its synthesis or dissolving resmetirom and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.
Any physical form of resmetirom may be utilized for providing the solution of step (a).
Suitable solvent of step a) may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water; mixture thereof. Preferably, suitable solvent is acetone.
After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
Step (b) involves removing solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art.
Step (c) involves recovering amorphous form of resmetirom. The said recovery can be achieved by using the processes known in the art.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Twenty fifth aspect of the present application provides a pharmaceutical composition comprising amorphous form of resmetirom and at least one pharmaceutically acceptable carrier.

Twenty sixth aspect of the present application relates to crystalline form RL of Lysine salt of Resmetirom characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 18.42, 19.09 and 20.49 ± 0.2° 2?. In embodiments of the present application, crystalline form RL of Lysine salt of Resmetirom is further characterized by its PXRD pattern having additional peaks located at about 11.24 and 17.12 ± 0.2° 2?.

Twenty seventh aspect of the present application relates to crystalline form RL of Lysine salt of Resmetirom characterized by a PXRD pattern substantially as illustrated in Figure 8.

Twenty eighth aspect of the present application relates to a process for preparing crystalline form RL of Lysine salt of Resmetirom; the process comprising;
a) providing a mixture of Resmetirom and Lysine in a suitable solvent;
b) isolating crystalline form RL of lysine salt of Resmetirom from the mixture of step a); and;
c) optionally, drying the isolated product at suitable temperature.
In embodiments of step a), the suitable solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water. Preferably the solvent is acetone.
In one of the embodiments of step a), any physical form of Resmetirom may be utilized, which may be crystalline or amorphous, for providing the suspension of Resmetirom in a solvent comprising formic acid. In another embodiment of step a), any physical form of Resmetirom may be utilized, which may be anhydrous or hydrate or solvate for providing the mixture of resmetirom and lysine in a solvent.
Isolation of crystalline form RL of Resmetirom lysine salt in step b) may be performed by any technique known in the art. Specifically, crystalline form RL of Resmetirom lysine salt may be isolated from the mixture of step a) by filtration followed by drying.
The resulting compound obtained in step (b) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures between RT to 75 °C or at a temperature of about 50 °C or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Resmetirom is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

Twenty ninth aspect of the present application provides a composition comprising crystalline form RL of lysine salt of resmetirom and one or more pharmaceutically acceptable excipient.

In an aspect of the present application the solid forms of Resmetirom and its salts of present application may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
The solid forms of Resmetirom and its salts of the present application is stable and has excellent physico-chemical properties. The solid forms of Resmetirom and its salts of the present application may be easily formulated into a pharmaceutical composition comprising Resmetirom.
Yet another aspect of the present application relates to a pharmaceutical composition comprising solid forms of Resmetirom and its slats and one or more pharmaceutically acceptable excipient.
Solid forms of Resmetirom and its slats of the present application with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

X-ray powder diffractograms of crystalline forms R1 and/or R2 and/or R3 and/or R4 of Resmetirom is recorded on PANalytical X-ray diffractometer, Model: panalytical empyrean. System description: CuK-Alpha 1 wavelength=1.5405980 Å, voltage 45 kV, current 40 mA. The diffractograms were collected over a 2? range of 3-40 °.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
A name used herein to characterize a crystalline form should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
In general, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?±0.2º) of 19.6º" means "having a diffraction peak at a diffraction angle (2?) of 19.4º to 19.8º. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES
Example-1: Preparation of crystalline form R1 of Resmetirom
A mixture of Resmetirom (1 g) and formic acid (5 mL) was stirred for 3 days at room temperature. The resulting mixture was dried at room temperature for 2.5 hours followed by drying under VTD dryer for 1 day at 50 °C to obtain the title compound. PXRD pattern is shown in Figure 1.

Example-2: Preparation of crystalline form R2 of Resmetirom
A mixture of Resmetirom (1 g) and hexanoic acid (2 mL) was stirred for 20 hours at room temperature. Diisopropyl ether (25 mL) was added to the above mixture and stirred for 2 hours at the same temperature. The solid was filtered under vacuum under nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours followed by drying at 50 °C for 12 hours using VTD drier to obtain the title compound. PXRD pattern is shown in Figure 2.

Example-3: Preparation of crystalline form R3 of Resmetirom
A mixture of Resmetirom (1 g) and sulolane (2 mL) was stirred for 20 hours at room temperature. Water (25 mL) was added to the above mixture and stirred for 1 hours at the same temperature. The reaction mixture was filtered under vacuum under nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours followed by drying at 50 °C for 12 hours using VTD drier to obtain the title compound. PXRD pattern is shown in Figure 3.

Example-4: Preparation of crystalline form R4 of Resmetirom
A mixture of Resmetirom (1 g) and butyric acid (5 mL) was stirred for 2 days at room temperature. Heptane (25 mL) was added to the above mixture and stirred for 2 hours at the same temperature. The reaction mixture was filtered under vacuum under nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours followed by drying at 50 °C for 12 hours using VTD drier to obtain the title compound. PXRD pattern is shown in Figure 4.

Example-5: Preparation of crystalline form R5 of Resmetirom
A mixture of Resmetirom (1 g) and 1,2-Dimethoxyethane (2.5 mL) was stirred for 24 hours at 40 °C. After 24 hours of stirring at 40 °C, the reaction mixture is cooled to 25 °C. The solid was filtered and dried at under VTD dryer for 2 days at 50 °C to obtain the title compound. PXRD pattern is shown in Figure 5.

Example-6: Preparation of amorphous solid dispersion of Resmetirom and Eudragit (1:2)
A mixture of Resmetirom (1.5 g) and eudragit (3 g) in methanol (500 mL) was heated 50 °C and stirred for 1 hour. The mixture was filtered and the resulting clear solution was subjected to spray drying at 70 °C. The resulting solid was further dried at 40 °C under VTD dryer for 18 hours to obtain the title compound. PXRD pattern is shown in Figure 6.

Example-7: Preparation of amorphous form of Resmetirom
A mixture of Resmetirom (3 g) and acetone (300 mL) was stirred for 2 hours at 40 °C. The mixture was filtered and the resulting clear solution was subjected to spray drying at 65 °C to obtain the title compound. PXRD pattern is shown in Figure 7.

Example-8: Preparation of crystalline form RL of Resmetirom
A mixture of Resmetirom (1.7 g) and lysine (0.58 g) in acetone (15 mL) was stirred for 2 days at room temperature. The resulting solid was filtered and dried at under VTD dryer for 3 hours at room temperature to obtain the title compound. PXRD pattern is shown in Figure 8.

Dated this 8th day of November 2023
Signature: ____________

Dr. B. Dinesh Kumar
Dr. Reddy’s Laboratories Limited.
,CLAIMS:We Claim:
1. A process for preparation of amorphous solid dispersion comprising Resmetirom and one or more pharmaceutically acceptable excipient; the process comprising;
a) providing a solution comprising Resmetirom and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture threreof;
b) removing solvent from the solution obtained in step (a), and
c) recovering the solid dispersion comprising Resmetirom and one or more pharmaceutically acceptable excipients.
2. The process as claimed in claim 1, where in pharmaceutically acceptable excipient is selected from one or more of co-povidone, HPMC and Eudragit.
3. The process as claimed in claim 1, where in the Resmetirom and pharmaceutically acceptable excipient ratio is varying from 1:1 to 1:3.
4. The process as claimed in claim 1, where the solvent is selected from methanol, isopropanol, acetone, methyl isobutyl ketone, diethyl ether, tetrahydrofuran, ethyl acetate, propyl acetate, water; mixture thereof.
5. A process for preparation of amorphous solid dispersion comprising Resmetirom and Eudragit; the process comprising;
d) providing a solution comprising Resmetirom and eudragit by dissolving in a suitable solvent or mixture threreof;
e) removing solvent from the solution obtained in step (a), and
f) recovering the solid dispersion comprising Resmetirom and eudragit.
6. Solid state forms of resmetirom selected from any one of a) Crystalline form R1; b) Crystalline form R2; c) Crystalline form R3; d) Crystalline form R4; e) Crystalline form R5; f) Amorphous solid dispersion of Resmetirom with eudragit; g) Crystalline form RL of lysine salt of Resmetirom.
7. A pharmaceutical composition comprising any of the solid forms of Resmetirom as claimed in claims 1-6, and a pharmaceutically acceptable carrier.