DESC:FIELD OF THE INVENTION
The present invention relates to novel crystalline polymorphs of Resmetirom or its salts, hydrates, solvates and to process for preparation thereof.

BACKGROUND OF THE INVENTION
Resmetirom, is a selective agonist of thyroid hormone receptor-ß which increases hepatic fat metabolism and reduces lipotoxicity. Resmetirom is chemically 2-[3,5-dichloro-4-[(6-oxo-5-propan-2-yl-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-l,2, 4- triazine -6-carbonitrile which has the structure;

Resmetirom is disclosed in International Publication No. WO 2007/009913. The WIPO publication nos. WO 2014/043706, WO 2018/075650, WO 2020/010068, WO 2021/063367 relate to various crystalline forms and salts of Resmetirom.
Drug polymorphism refers to the existence of two or more crystal forms of the drug. A single molecule may give rise to a variety of polymorphs which have distinct crystal structure and physical properties such as the melting points, TGA, DSC, PXRD, NMR, IR spectrum.
Developing new polymorphs of the pharmaceutical actives possessing desirable properties such as ease of handling, ease of processing, improved stability, ease of purification provide an opportunity to provide the pharmaceutical actives with improved pharmaceutical activity.
Thus a need persists in the art to provide novel polymorphs of Resmetirom that fulfill the desired improved characteristic of the drug.

SUMMARY OF THE INVENTION
In view of the above, the present invention provides novel crystalline polymorphs of Resmetirom or its salts, hydrates, solvates and to the process for preparation thereof.
Accordingly, the present invention provides novel crystalline forms of Resmetirom, wherein said polymorphs are selected from the group consisting of;
Resmetirom polymorph Form C1 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 1 having the characteristic peaks at 5.80, 6.09, 6.50, 7.70, 9.60, 9.67, 11.59, 11.64, 13.40, 14.56, and 23.43 degrees ±2?;
Resmetirom polymorph Form C2 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 2 having the characteristic peaks at 5.82, 6.07, 6.50, 7.70, 9.60, 11.59, 13.45 and 14.57 degree ±2?;
Resmetirom polymorph Form C3 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 3 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ±2?.
Resmetirom polymorph Form C4 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 4 having the characteristic peaks at 6.40, 7.73, 23.86 and 25.27 degree ±2?.
In an aspect, the intended therapeutic use of the crystalline forms of Resmetiron is a selective agonist of thyroid hormone receptor-ß, the most preferred crystalline forms is Resmetirom polymorph Form C1 and Resmetirom polymorph Form C3 or its salts, hydrates and solvates.
In a most preferred aspect, the polymorph is polymorph Form C3.
In another aspect, the Resmetirom polymorph Form C3 is further characterized by DSC exhibiting a broad endothermic peak at 204.79°C and an endothermic peak with an onset at 335.18°C and at 336.32°C (Fig 5).
In yet another aspect, Resmetirom polymorph Form C3 is characterized by TGA exhibiting a weight loss of 0.598% (Fig 6).
In yet another aspect, the Resmetirom polymorph Form C3 post humidification exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 7 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ±2?. This indicates that Form 3 is stable even after humidification.
In another aspect, the present invention provides the salts of polymorphic Forms C1, C2, C3 and C4, preferably the ammonium salts.
Accordingly, the present invention provides the ammonium salt of polymorph Form C1 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 8.01, 9.60, 10.71, 13.74, 15.81, 18.01, 19.36, 21.88 and 24.46 degree ±2? (Fig 8).
In yet another aspect, the present invention provides the ammonium salt of polymorph Form C2 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 5.81, 9.28, 11.64, 14.39, 25.48 and 29.0 degree ±2? (Fig 9).
In another aspect, the present invention provides the ammonium salt of polymorph Form C3 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 7.03, 8.96, 16.88, 17.95, 23.53 and 24.32 degree ±2?(Fig 10).
In another aspect, the present invention provides a method of synthesizing the various polymorphic forms of Resmetirom viz. C1, C2, C3 and C4 as well as the preparation of its ammonium salts.
The various Resmetirom polymorphic forms may be prepared from Resmetirom API or its amorphous form. In alternate aspects, the processes of preparation of Resmetirom polymorphic forms include seeding.
In another preferred aspect, the present invention encompasses the processes that convert different crystalline polymorphic forms of the present invention into one another as well as conversion of the ammonium salt of one polymorphic form as prepared to another.
In an embodiment, the present invention relates to a process for preparing Resmetirom crystalline polymorph Forms C1, C2, C3 and C4 comprising;
i. Dissolving Resmetirom or its amorphous form in a solvent;
ii. Optionally seeding with suitable Resmetirom polymorph;
iii. Allowing to crystallize the suitable polymorph; and
iv. Filtering said polymorph;
wherein
a) The crystalline Form is polymorph Form C1 prepared from Resmetirom or its amorphous form in presence of solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
b) The crystalline Form is polymorph Form C2 prepared by drying polymorph Form C1 by controlling the temperature and time;
c) The crystalline Form is polymorph Form C3 prepared from Resmetirom or its amorphous form or ammonia salt in presence of the solvent selected from lower alcohol or trifluoro acetic acid or by drying Form C1 by controlling the temperature and time;
d) The crystalline Form is polymorph Form C4 prepared by drying Form C1 by controlling the temperature and time.
wherein one crystalline polymorph Form may be converted to another crystalline polymorph Form.

In another aspect, the present invention discloses a process for preparing ammonia salt of Resmetirom polymorph Form C1, C2, C3 comprising;
i. Suspending/ Dissolving Resmetirom or its salt in a solvent;
ii. Adding ammonia dissolved in suitable solvent to obtain the product;
wherein the ammonia salt of one crystalline polymorph Form may be converted to another crystalline polymorph Form.
Accordingly, in an aspect, the present invention provides a process for synthesis of Resmetirom polymorphic Form C1 comprising;
i. Dissolving Resmetirom or its amorphous form in a suitable solvent;
ii. optionally seeding with Resmetirom polymorph Form C1;
iii. Filtering and drying at a temperature ranging between 40°C to 80°C to obtain the desired product.
In an aspect, Resmetirom polymorph Form C1 is obtained from the solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
In yet another aspect, the present invention provides the preparation of ammonium salt of Resmetirom Form C1 comprising;
i. Suspending Resmetirom in a solvent and alcoholic ammonia solution for a period of 10-35minutes;
ii. Stirring the resulting suspension of step (i) for a period of 50-65mins at room temperature to obtain the solid;
iii. Filtering the solid and drying to obtain the desired product.
In another aspect, the crystalline Resmetirom polymorph Form C1 or its ammonium salt is used for preparation of other polymorphic forms.
In another aspect, the present invention provides a process for preparation of Resmetirom polymorph Form C2 which comprises drying Resmetirom Form C1, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 100°C to 120°C for a period of 7-10 hours.
In another aspect, the present invention provides the preparation of ammonium salt of Resmetirom Form C2 comprising;
i. Suspending Resmetirom in a solvent at room temperature followed by adding alcoholic ammonia solution and stirring the mixture for a period of 40-100 minutes to obtain the solid;
ii. Filtering the solid and drying to obtain the desired product.
In another aspect, the crystalline Resmetirom polymorph Form C2 or its ammonium salt is used for preparation of other polymorphic forms.
In yet another aspect, the present invention provides a process for preparation of Resmetirom polymorph Form C3 comprising drying Resmetirom Form C1, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 180°C to 210°C for a period of 5-15minutes.
In another aspect, the present invention discloses a process for preparation of Resmetirom Form C3 from Resmetirom or its ammonium salt comprising;
i. Dissolving Resmetirom in a solvent at room temperature and removing any undissolved particulate to obtain the clear solution;
ii. Adding the clear solution of step (i) to the pre-chilled solvent followed by seeding with Resmetirom Form C3 at a temperature ranging between -10°C to -15°C, stirring the resulted suspension at -5°C to -10°C to obtain the solid; and
iii. Filtering the solid and drying to obtain the product.
OR
i. Suspending Resmetirom in a solvent and adding ammonia solution, optionally seeding, and stirring at room temperature to obtain the solid;
ii. Filtering and drying the solid under nitrogen atmosphere to obtain Resmetirom ammonium salt;
iii. Suspending Resmetirom ammonium salt of step (ii) into a mixture of pre-cooled solvent and Resmetirom Form C3 seed at a temperature of -5°C followed by slow addition of trifluoroacetic acid at said temperature, stirring and slowly raising the temperature to 5-10°C and stirring to obtain the solid;
iv. Filtering the solid of step (iii), washing and drying to obtain the desired product.
In an aspect, the solvent for obtaining Resmetirom polymorphic Form C3 is selected from lower alcohol, preferably isobutanol or trifluoroacetic acid. the ammonia used in the process is dissolved in C1-C4 alcohol.
In yet another aspect, the Resmetirom polymorphic Form C3 may be obtained from ammonium salt of Resmetirom polymorphic Form C1, Form C2 or Form C3.
Accordingly, the process for preparation of Resmetirom polymorphic Form C3 comprises;
i. Suspending the ammonium salt of Resmetirom Form C1 or Form C2 or Form C3 in a solvent at a temperature ranging between -10°C to -5°C and seeding with Resmetirom Form C3 seed at said temperature to obtain the slurry;
ii. Adding Trifluoro acetic acid to the above slurry at a temperature ranging between -10°C to -5°C and stirring at said temperature until a solid is formed;
iii. Filtering the solid, drying and washing to obtain the desired product
The solvent for the process is selected from lower alcohol, preferably isobutanol.
In yet another aspect, the present invention provides a process for preparation of ammonium salt of Resmetirom Form C3 comprising;
i. Suspending ammonium salt of Resmetirom Form C1 in a solvent at room temperature to obtain the slurry;
ii. Heating the slurry at a temperature ranging between 40-45°C, stirring at said temperature and cooling to room temperature to obtain the solid;
iii. Filtering the solid and drying to obtain the desired product.
The solvent for the process is selected from lower alcohols or esters, preferably the ester such as ethyl acetate.
In another aspect, the present invention provides a process for preparation of Resmetirom polymorph Form C4 comprising;
i. Suspending Resmetirom Form C1 in a suitable solvent; and
ii. Filtering, suck drying under vacuum followed by drying under vacuum at a temperature ranging between 65-90°C for a period of 10-12 hours to obtain the desired product.
In an aspect, the Resmetirom polymorphic Form C4 is obtained using the solvent selected from aliphatic or aromatic hydrocarbons; preferably aliphatic hydrocarbon.
In another aspect, the Resmetirom or its amorphous form used in the present invention are prepared by a process known in the art.
In yet another aspect, the present invention provides a pharmaceutical composition comprising the Resmetirom polymorphic Forms C1, C2, C3 or C4 or its ammonium salt together with pharmaceutically acceptable excipients.

DESCRIPTION OF THE FIGURES
Fig 1: Depicts PXRD of Resmetirom polymorph Form C1
Fig 2: Depicts the PXRD of Resmetirom polymorph Form C2
Fig 3: Depicts the PXRD of Resmetirom polymorph Form C3
Fig 4: Depicts the PXRD of Resmetirom polymorph Form C4
Fig 5: Depicts the DSC thermogram of Resmetirom polymorph Form C3
Fig 6: Depicts the TGA of Resmetirom polymorph Form C3
Fig 7: Depicts the PXRD of Resmetirom Form C3 post humidification.
Fig 8: Depicts the PXRD of the ammonia salt of Resmetirom polymorph Form C1.
Fig 9: Depicts the PXRD of the ammonia salt of Resmetirom polymorph Form C2.
Fig 10: Depicts the PXRD of the ammonia salt of Resmetirom polymorph Form C3

DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in its preferred and optional embodiments however should not be construed to limit the scope of the invention.
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.

Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

The terms “crystalline form” “polymorphs” “polymorphic salt forms” used in the entire specification refer and mean a crystalline form of a substance that is distinct from another crystalline form but shares the same chemical formula.
The present invention is directed to novel polymorphs of Resmetirom or its salts, hydrates, solvates and to the process for preparation thereof. The novel polymorphs of Resmetirom are obtained in the present invention by controlling the temperature and time which influences the properties of said polymorphs. The present inventors further observed that various Resmetirom polymorphic Forms can be obtained either from Resmetirom or its salts or from amorphous form or can be prepared from the ammonium salt of its polymorphic forms. Thus the present invention provides a process for the preparation of various polymorphic Forms which are simple and industrially viable.
In an embodiment, the present invention relates to novel crystalline forms of Resmetirom, wherein said polymorphs are selected from the group consisting of;
Resmetirom polymorph Form C1 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 1 having the characteristic peaks at 5.80, 6.09, 6.50, 7.70, 9.60, 9.67, 11.59, 11.64, 13.40, 14.56, and 23.43 degrees ±2?;
Resmetirom polymorph Form C2 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 2 having the characteristic peaks at 5.82, 6.07, 6.50, 7.70, 9.60, 11.59, 13.45 and 14.57 degree ±2?;
Resmetirom polymorph Form C3 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 3 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ±2?.
Resmetirom polymorph Form C4 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 4 having the characteristic peaks at 6.40, 7.73, 23.86 and 25.27 degree ±2?.
In an embodiment, the intended therapeutic use of the crystalline forms of Resmetiron is a selective agonist of thyroid hormone receptor-ß, the most preferred crystalline forms is Resmetirom polymorph Form C1 and Resmetirom polymorph Form C3 or its salts, hydrates and solvates.
In an embodiment, the present invention preferably relates to Resmetirom polymorph Form C3.
In another aspect, the Resmetirom polymorph Form C3 is further characterized by DSC exhibiting a broad endothermic peak at 204.79°C and an endothermic peak with an onset at 335.18°C and at 336.32°C (Fig 5).
In yet another aspect, Resmetirom polymorph Form C3 is characterized by TGA exhibiting a weight loss of 0.598% (Fig 6).
In yet another aspect, the Resmetirom polymorph Form C3 post humidification exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 7 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ±2?. This indicates that Form 3 is stable even after humidification.
In another preferred embodiment, the present invention relates to the salts of polymorphic Forms C1, C2, C3 and C4, preferably the ammonium salts.
Accordingly, the present invention discloses the ammonium salt of polymorph Form C1 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 8.01, 9.60, 10.71, 13.74, 15.81, 18.01, 19.36, 21.88 and 24.46 degree ±2? (Fig 8).
In yet another embodiment, the present invention discloses the ammonium salt of polymorph Form C2 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 5.81, 9.28, 11.64, 14.39, 25.48 and 29.0 degree ±2? (Fig 9).
In yet another embodiment, the present invention relates to the ammonium salt of polymorph Form C3 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 7.03, 8.96, 16.88, 17.95, 23.53 and 24.32 degree ±2?(Fig 10).
In another embodiment, the present invention provides a method of synthesizing the various polymorphic forms of Resmetirom viz. C1, C2, C3 and C4 as well as the preparation of its ammonium salts.
The various Resmetirom polymorphic forms may be prepared from Resmetirom API or its amorphous form. In alternate aspects, the processes of preparation of Resmetirom polymorphic forms include seeding.
In another preferred embodiment, the present invention encompasses the processes that convert different crystalline polymorphic forms of the present invention into one another as well as conversion of the ammonium salt of one polymorphic form as prepared to another.
In an embodiment, the present invention relates to a process for preparing the crystalline forms C1, C2, C3 and C4 comprising;
i. Dissolving Resmetirom or its amorphous form or its ammonia salt in a solvent;
ii. Optionally seeding with suitable Resmetirom polymorph;
iii. Allowing to crystallize the suitable polymorph; and
iv. Filtering said polymorph;
wherein
a) The crystalline Form is polymorph Form C1 prepared from Resmetirom or its amorphous form in presence of solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
b) The crystalline Form is polymorph Form C2 prepared by drying polymorph Form C1 by controlling the temperature and time;
c) The crystalline Form is polymorph Form C3 prepared from Resmetirom or its amorphous form or ammonia salt in presence of the solvent selected from lower alcohol or trifluoro acetic acid or by drying Form C1 by controlling the temperature and time;
d) The crystalline Form is polymorph Form C4 prepared by drying Form C1 by controlling the temperature and time.
wherein one crystalline polymorph Form may be converted to another crystalline polymorph Form.

In another aspect, the present invention discloses a process for preparing ammonia salt of Resmetirom polymorph Form C1, C2, C3 comprising;
i. Suspending/ Dissolving Resmetirom or its salt in a solvent;
ii. Adding ammonia dissolved in suitable solvent to obtain the product;
wherein the ammonia salt of one crystalline polymorph Form may be converted to another crystalline polymorph Form.
In an embodiment, the present invention relates to a process for preparation of Resmetirom polymorph Form C1 comprising;
i. Dissolving Resmetirom or its amorphous form in a suitable solvent;
ii. optionally seeding with Resmetirom polymorph Form C1;
iii. Filtering and drying at a temperature ranging between 40°C to 80°C to obtain the desired product.
Accordingly, Resmetirom or its amorphous form was dissolved in a solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof at a temperature ranging between 22-30°C and stirring the resultant suspension for 3-5 hours. Filtering the solid formed, suck drying under vacuum followed by drying at a temperature in the range of 40-85°C for about 10-15 hours to obtain Resmetirom polymorph Form C1.
In yet another embodiment, the present invention relates to the preparation of ammonium salt of Resmetirom Form C1 comprising;
i. Suspending Resmetirom in a solvent and alcoholic ammonia solution for a period of 10-35minutes ;
ii. Stirring the resulting suspension of step (i) for a period of 50-65mins at room temperature to obtain the solid ;
iii. Filtering the solid and drying to obtain the desired product.
Accordingly, Resmetirom was suspended in the solvent selected from lower alcohol, preferably isobutanol followed by addition of alcoholic ammonia over a period of 15-35 minutes and stirring the resulting suspension for about 60mins at room temperature. The resulting solid was filtered under nitrogen atmosphere and further suck dried to obtain the ammonium slat of Resmetirom polymorph Form C1.
In another embodiment, the crystalline polymorph Form C1 of Resmetirom or its ammonium salt is used for preparation of other polymorphic forms.
In another embodiment, the present invention discloses a process for preparation of Resmetirom polymorph Form C2 comprising drying Resmetirom Form C1, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 100°C to 120°C for a period of 7-10 hours.
In another embodiment, the present invention relates to the preparation of ammonium salt of Resmetirom Form C2 comprising;
i. Suspending Resmetirom in a solvent at room temperature followed by adding alcoholic ammonia solution and stirring the mixture for a period of 50-70 minutes to obtain the solid ;
ii. Filtering the solid and drying to obtain the desired product.
In an embodiment, the ammonium salt of Resmetirom Form C2 was prepared by suspending Resmetirom in lower alcohol selected from methanol, ethanol or isopropanol at room temperature and adding alcoholic ammonia and stirring the resulting suspension for a period of about 60 minutes at room temperature. Filtering the resulting solid, suck drying under vacuum followed by drying at a temperature in the range of 45-55°C to obtain the product.
In yet another embodiment, the crystalline polymorph Form C2 of Resmetirom or its ammonium salt is used for preparation of other polymorphic forms.
In yet another embodiment, the present invention relates to a process for preparation of Resmetirom polymorph Form C3 comprising drying Resmetirom Form C1, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 180°C to 210°C for a period of 5-15minutes.
In another embodiment, the present invention relates to a process for preparation of Resmetirom Form C3 comprising;
i. Suspending Resmetirom in a solvent and alcoholic ammonia and stirring at room temperature to obtain the solid;
ii. Filtering and drying the solid under nitrogen atmosphere to obtain Resmetirom ammonium salt;
iii. Suspending Resmetirom ammonium salt of step (ii) into a mixture of pre-ccoled solvent and Resmetirom Form C3 seed at a temperature of -5°C followed by slow addition of trifluoroacetic acid at said temperature, stirring and slowly raising the temperature to 5-10°C and stirring to obtain the solid;
iv. Filtering the solid of step (iii), washing and drying to obtain the desired product.
Accordingly, the process comprises of suspending Resmetirom in a solvent selected from lower alcohol, preferably isobutanol followed by addition of alcoholic ammonia over a period of 15-30 mins and stirring the resulted suspension for about 60mins at room temperature. Filtering the resulted solid under nitrogen atmosphere and suck drying to obtain Resmetirom Ammonium salt.
The above obtained Resmetirom Ammonium salt as wet material was suspended in a mixture of pre-cooled lower alcohol, preferably isobutanol followed by seeding with Resmetirom Form C3 seed at -5°C. To the resulting suspension was added slowly Trifluoro acetic acid at a temperature ranging between -10°C to -5°C, stirring at said temperature, raising the temperature to 5-10°C and stirring at said temperature to obtain the solid. Filtering the solid, washing with lower alcohol, preferably isobutanol, suck drying under vacuum for about 40 mins. Washing the dried material several times with the solvent, filtering and drying at a temperature ranging between 40°C-90°C to obtain Resmetirom Form C3.
In yet another embodiment, Resmetirom polymorph Form C3 is prepared by the process comprising;
i. Dissolving Resmetirom in a solvent at room temperature and removing any undissolved particulate to obtain the clear solution;
ii. Adding the clear solution of step (i) to the pre-chilled solvent followed by seeding with Resmetirom Form C3 at a temperature ranging between -10°C to -15°C, stirring the resulted suspension at -5°C to -10°C to obtain the solid;
iii. Filtering the solid and drying to obtain the product.
As per the process steps described above, Resmetirom was dissolved in a solvent selected from Trifluoro acetic acid at room temperature. The undissolved particulate matter was removed and the clear solution was slowly added to pre-chilled solvent selected from lower alcohol, preferably isobutanol and Resmetirom Form 3 seed slurry at -10°C to -15°C. The suspension was stirred at a temperature ranging between -5°C to -10°C for about 2-3 hours. The solid obtained was filtered, suck dried under vacuum followed by further drying at a temperature ranging between 40-90°C for about 15-17 hours to obtain Resmetirom polymorph Form C3.
In yet another embodiment, the present invention discloses the preparation of Resmetirom Form C3 comprising;
i. Suspending the ammonium salt of Resmetirom Form C1 or Form C2 or Form C3 in a solvent at a temperature ranging between -10°C to -5°C and seeding with Resmetirom Form C3 seed at said temperature to obtain the slurry;
ii. Adding Trifluoro acetic acid to the above slurry at a temperature ranging between -10°C to -5°C and stirring at said temperature until a solid is formed;
iii. Filtering the solid, drying and washing to obtain the desired product.
Accordingly, ammonium salt of Resmetirom Form C1 or Form C2 or Form C3 was suspended in the solvent selected from lower alcohol, preferably isobutanol at about -5°C. This was followed by adding Resmetirom Form C3 seed into the above prechilled solvent and stirred at said temperature. Trifluoro acetic acid was then added to the slurry at about -5°C and stirred the resulted suspension for about an hour at said temperature. The solid formed was filtered and suck dried under vacuum. The wet material was further slurried in the solvent, isobutanol, at 0-5°C, filtered, suck dried under vacuum and further dried stepwise at a temperature in the range of 40°C-90°C for a period of 3-24 hours to obtain Resmetirom Form C3.
In yet another embodiment, the present invention relates to a process for preparation of ammonium salt of Resmetirom Form C3 comprising;
i. Suspending ammonium salt of Resmetirom Form C1 in a solvent at room temperature to obtain the slurry;
ii. Heating the slurry at a temperature ranging between 40-45°C, stirring at said temperature and cooling to room temperature to obtain the solid;
iii. Filtering the solid and drying to obtain the desired product.

In the process, ammonium salt of Resmetirom Form C1 was suspended in the solvent such as ethyl acetate at room temperature and the slurry was heated to a temperature in the range of 40°C-45°C and stirred for about 180mins. The reaction mixture was cooled to room temperature. Filtered the resulted solid, suck dried under vacuum for about 30 min followed by drying at about 50°C for 3-5 hours obtain the ammonium salt of Resmetirom Form C3.
In an embodiment, the present invention relates to a process for preparation of Resmetirom polymorph Form C4 comprising;
i. Suspending Resmetirom Form C1 in a suitable solvent; and
ii. Filtering, suck drying under vacuum followed by drying under vacuum at a temperature ranging between 65-90°C for a period of 10-12 hours to obtain the desired product.
Accordingly, Resmetirom polymorphic Form C1 was suspended in a solvent selected from aliphatic or aromatic hydrocarbon, preferably aliphatic hydrocarbon and stirred at room temperature. The resulting solid was filtered and suck dried under vacuum followed by drying at a temperature of about 80°C for a period of 10-12 hours to obtain Resmetirom Form C4.

In an embodiment, the Resmetirom polymorphic Forms C1, C2, C3 and C4 or its ammonium salts are stable at all temperature conditions and humidity.Resmetirom polymorphic Form 3 is stable at low temperature of 2-8°C, room temperature and at ACC (amorphous calcium carbonate) conditions.

The stability data of Resmetirom polymorph Form C3 is given in the table below.
In an embodiment, Resmetirom or its amorphous form used as the starting material in the present invention is prepared according to the processes known in the literature.
In another embodiment, the present invention discloses a pharmaceutical composition comprising the Resmetirom polymorphic Forms C1, C2, C3 or C4 or its ammonium salts together with pharmaceutically acceptable excipients.
The following 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.
Example 1: Process for preparation of Resmetirom Form C1:
Resmetirom (5.0 gm) amorphous form was suspended in a mixture of Chloroform (98.0 ml) and Methanol (2.0 ml) at room temperature and stirred the resulted suspension for 3 hours. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 80 °C for 6 hours to obtain the title compound.
Yield: Dry weight: 3.5 gram
Example2:
Resmetirom (4.5 gm) was suspended in a mixture of Chloroform (88.2 ml) and Methanol (1.8 ml) along with 170 mg of Resmetirom Form C1 seed at room temperature and stirred the resulted suspension for 2 hours at room temperature. Filtered the resulted solid, suck dried under vacuum for 10 min followed by drying under vacuum at 80 °C for 10-12 hours to obtain the title compound.
Yield: Dry weight: 3.4 gram
Example3:
Resmetirom (0.7gm) was suspended in methylene dichloride (MDC) (14 ml) along with 140 mg of Resmetirom Form C1 seed at 0-5°C and stirred the resulted suspension for 2 hours at 0-5°C. Filtered the resulted solid, suck dried under vacuum for 10 min followed by drying at 40 °C for 2 hours and at 60°C for 10-12 hours to obtain the title compound.
Yield: Dry weight: 0.5 gram
Example 4:
Resmetirom (135.0gm) was suspended in MDC (2025 ml) along with 2.7 g of Resmetirom Form C1 seed at 22-25°C and stirred the resulted suspension for 4 hours at 22-25°C. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 40 °C for 6 hours and at 60°C for 10-12 hours to obtain the title compound.
Yield: Dry weight: 128 grams
Example 5: Process for preparation of Resmetirom Form C2 from C1:
Resmetirom Form C1 obtained by any of the process of examples 1 to 4 was dried at 120°C in ATD for 8 hours to obtain the title compound.
Example 6: Process for preparation of Resmetirom Form C3 from Form C1:
Resmetirom Form C1 obtained by any of the process of examples 1 to 4 was heated at 200 °C for 5-10 min to obtain the title compound.
Example 7: Process for preparation of Resmetirom Form C3 from Resmetirom Ammonia salt
Resmetirom (70gm) was suspended in isobutanol (1400 ml) and added 70 ml of methanolic ammonia over a period of 15-30 min and stirred the resulted suspension for 60mins at room temperature. Filtered the resulted solid in Pressure Nutsche Filter (PNF) under nitrogen, suck dried under nitrogen for 30 min to obtain Resmetirom Ammonia salt.
Above Resmetirom ammonia salt wet material was then suspended into a mixture of pre-cooled isobutanol (1050 ml) along with 3.5g of Resmetirom Form C3 seed at -5°C. To this resulted suspension was slowly added Trifluoro acetic acid (24.6 ml) at -5°C and stirred for 1 hour at -5°C and raised the temperature to 5-10°C and stirred at this temperature for 2hrs. Filtered the resulted solid, and bed washed with 70ml of isobutanol, suck dried under vacuum for 40 min. The wet material was again suspended in 700ml of iso-butanol at 10-15°C and stirred for 1 hr at 10-15°C then filtered the material and suck dried the material under vacuum followed by drying at 40°C for 2 hours and at 60°C for 10-12 hours and 90°C for 28-30 hours to obtain the title compound.
Yield: 42.0gm
Example 8: Process for preparation of Resmetirom Form C3 from Resmetirom
Resmetirom (10.0 gm) was dissolved in a Trifluoro acetic acid (50.0 ml) at room temperature. Any undissolved particulate were removed to obtain particle free solution and the resulted clear solution was slowly added to pre-chilled isobutanol (200ml) and Resmetirom Form C3 (0.5g) seed slurry at -10°C to -15°C. Stirred the resulted suspension for 2 hours at -5°C to -10°C. Filtered the solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 90°C for 15 hours to obtain the title compound.
Yield: Dry weight: 9.2 gram
Example 9: Process for the preparation of Resmetirom Form C3
Resmetirom (400gm) was suspended in Isobutanol (3200 ml) and added 800 ml of Isobutanolic ammonia over a period of 15-30 min and stirred the resulted suspension for 60mins at room temperature. Added 800ml of Isobutanol and stirred the resulted suspension for 120mins at room temperature. Filtered the resulted solid in ANFD (agitated nutsche filter dryer) under nitrogen, suck dried under nitrogen for 120 min followed by drying at 50 °C for 2 hours to obtain Resmetirom Ammonia salt.
Above Resmetirom ammonia salt wet material suspended into a mixture of pre-cooled Isobutanol (6000 ml) along with 20 g of Resmetirom Form C3 seed at -2°C. To this resulted suspension slowly added Trifluoro acetic acid (320 ml) at -2°C and stirred for 30min at 2°C and the raised temperature to 8-10°C and stirred at this temperature for 10hrs. Filtered the resulted solid, and bed washed with 400ml of Isobutanol, suck dried under vacuum for 60 min. The wet material was again suspended in 4000 ml of Iso-butanol at 8-10°C and stirred for 1 hr at 8-10°C then filtered the material and suck dried the material under vacuum followed by drying at 30 °C for 2 hours and 40 °C for 6 hours and 60°C for 10 hours and 80°C for 5 hours.
Above Resmetirom material jet milled with 2kg feeding pressure and 3kg milling pressure by using auto feeder followed by further drying at 60 °C for 1 hours and at 90 °C for about 15 hours to obtain the title compound.
Yield: Dry weight: 280 grams

Example 10: Process for preparation of Resmetirom Form C3 from ammonia salt of Resmetirom Form C1
Ammonia salt of Resmetirom Form C1 (5.0 gm) was suspended in Isobutanol (75.0ml) at -5°C. Resmetirom Form C3 (250 mg) seed was added into above prechilled Isobutanol solution and stirred for 5 min at -5°C. Trifluoro acetic acid (1.8 ml) was added to the above slurry at -5°C and stirred the resulted suspension for 1 hour at -5°C. Filtered the solid, suck dried under vacuum for 30 min. The wet material was further slurried in 50ml of Isobutanol at 0-5°C for 1hr then filtered, suck dried under vacuum for 30 min followed by drying at 40°C for 3 hours and at 60 °C for 3 hours and then at 90 °C for 24 hours to obtain the title compound.
Yield: Dry weight: 3.6 gram
Example 11: Process for preparation of Resmetirom Form C3 from ammonia salt of Resmetirom Form C2
Ammonia salt of Resmetirom Form C2 (1.0 gm) was suspended in Isobutanol (15ml) at 10°C to 15°C. Resmetirom Form C3 (50mg) seed was added into above prechilled Isobutanol solution and stirred for 5min at 10°C to 15°C. Trifluoro acetic acid (0.35ml) was added to the above slurry at 10-15°C and stirred the resulted suspension for 2 hour at 10°C to 15°C. Filtered the solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 90 °C for 15 hours to obtain the title compound.
Yield: Dry weight: 0.8 gram

Example 12: Process for preparation of Resmetirom Form C3 from ammonia salt of Resmetirom Form C3
Ammonia salt of Resmetirom Form C3 (1.3gm) was suspended in Isobutanol (22.5ml) at 10°C to 15°C and added Resmetirom Form C3 (75mg) into the above slurry and stirred for 5min at 10°C to 15°C. Trifluoro acetic acid (0.52ml) was added to the above slurry at 10-15°C and stirred the resulted suspension for 4 hours at 10°C to 15°C. Filtered the solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 90°C for 15 hours to obtain the title compound.
Yield: Dry weight: 1.0 gram
Processes for the preparation of Ammonia salt of Resmetirom
Example 13: Process for the preparation of Ammonia salt of Resmetirom Form C1
Resmetirom (70gm) was suspended in Isobutanol (1400 ml) and added 70 ml of Methanolic ammonia over a period of 15-30 min and stirred the resulted suspension for 60mins at room temperature. Filtered the resulted solid in PNF under nitrogen, suck dried under nitrogen for 30 min to obtain the title compound.
Yield: 68.5 gram
Example 14: Process for the preparation of Ammonia salt of Resmetirom Form C2
Resmetirom (5.0 gm) was suspended in Methanol (20 ml) at room temperature and added 5.0 ml Methanolic ammonia and stirred the resulted suspension for 60mins at room temperature. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours obtain the title compound.
Yield: 4.3 gram
Example 15: Process for the preparation of Ammonia salt of Resmetirom Form C3
Ammonia salt of Resmetirom Form C1 (4.0 gm) was suspended in Ethyl acetate (40 ml) at room temperature, Heated the slurry to 40±5°C and stirred for 180 mins at this temperature then cooled to the room temperature. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 50°C for 4 hours to obtain the title compound.
Yield: 3.7 gram
Example 16: Process for preparation of Resmetirom Form C4:
200 mg of Resmetirom Form C1 prepared by any of the process of examples 1 to 4 was suspended in 4ml of n-Heptane and stirred for 3 hours at room temperature. Filtered the resulted solid and suck dry under vacuum for 10 min followed by drying at 80 °C under vacuum for 10-12 hrs to obtain the title compound.
Example 17: Stability data
Resmetirom Form C3 (6 months stability)
Limits Description XRD purity
Initial Yellowish brown colour solid Crystalline pattern observed 99.95
40°C/75%RH (1st month) Yellowish brown colour solid Comparable with initial
99.95
40°C/75%RH (3rd month) Yellowish brown colour solid Comparable with initial
99.96
40°C/75%RH (6th months) Yellowish brown colour solid Comparable with initial
99.89
25°C/60%RH (1st month) Yellowish brown colour solid Comparable with initial
99.95
25°C/60%RH (3rd month) Yellowish brown colour solid Comparable with initial
99.95
25°C/60%RH (6th month) Yellowish brown colour solid Comparable with initial
99.89
2-8°C (1st month) Yellowish brown colour solid Comparable with initial
99.95
2-8°C (3rd month) Yellowish brown colour solid Comparable with initial
99.96
2-8°C (6th months) Yellowish brown colour solid Comparable with initial
99.89

It will be understood that the above description is intended to be illustrative and not restrictive. The embodiments will be apparent to those in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description but should instead be determined by the appended claims along with full scope of equivalents to which such claims are entitled.
,CLAIMS:
1. Crystalline polymorphs of Resmetirom or its salts, hydrates or solvates thereof selected from the group consisting of;
Resmetirom polymorph Form C1 that exhibits a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 5.80, 6.09, 6.50, 7.70, 9.60, 9.67, 11.59, 11.64, 13.40, 14.56, and 23.43 degrees ±2?;
Resmetirom polymorph Form C2 that exhibits a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 5.82, 6.07, 6.50, 7.70, 9.60, 11.59, 13.45 and 14.57 degree ±2?;
Resmetirom polymorph Form C3 that exhibits a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ±2?;
Resmetirom polymorph Form C3 post humidification that exhibits a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ±2?;
Resmetirom polymorph Form C4 that exhibits a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 6.40, 7.73, 23.86 and 25.27 degree ±2?.

2. The crystalline polymorph as claimed in claim 1, wherein the polymorph is polymorph C1.

3. The crystalline polymorph as claimed in claim 1, wherein the polymorph is polymorph C3 further characterized by;
i. DSC exhibiting a broad endothermic peak at 204.79°C and an endothermic peak with an onset at 335.18°C and at 336.32°C;
ii. TGA exhibiting a weight loss of 0.598%.

4. A process for preparing the crystalline polymorphic Forms C1, C2, C3 and C4 as claimed in any one of the preceding claims 1-3, comprising;
i. Dissolving Resmetirom or its amorphous form in a solvent;
ii. Optionally seeding with suitable Resmetirom polymorph;
iii. Allowing to crystallize the suitable polymorph; and
iv. Filtering said polymorph;
wherein
a) The crystalline Form is polymorph Form C1 prepared from Resmetirom or its amorphous form in presence of solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
b) The crystalline Form is polymorph Form C2 prepared by drying polymorph Form C1 by controlling the temperature and time;
c) The crystalline Form is polymorph Form C3 prepared from Resmetirom or its amorphous form or ammonia salt in presence of the solvent selected from lower alcohol or trifluoro acetic acid or by drying Form C1 by controlling the temperature and time;
d) The crystalline Form is polymorph Form C4 prepared by drying Form C1 by controlling the temperature and time;
wherein one crystalline polymorph Form may be converted to another crystalline polymorph Form.
5. A process for preparing ammonia salt of Resmetirom polymorph Form C1, C2, C3 in any one of the preceding claims 1-3, comprising;
i. Suspending/ Dissolving Resmetirom or its salt in a solvent;
ii. Adding alcoholic ammonia to obtain the product;
wherein the ammonia salt of one crystalline polymorph Form may be converted to another crystalline polymorph Form.
6. The process for preparing crystalline Resmetirom polymorphic Form C1 as claimed in claim 4, comprising;
i. Dissolving Resmetirom or its amorphous form in a solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof;
ii. Optionally seeding with Resmetirom polymorph Form C1;
iii. Filtering and drying at a temperature ranging between 40°C to 80°C to obtain the desired product.

7. The process for preparing ammonia salt of Resmetirom polymorphic Form C1 as claimed in claim 5, comprising;
i. Suspending Resmetirom in a solvent selected from lower alcohols such as isobutanol and alcoholic ammonia solution for a period of 10-35minutes;
ii. Stirring the resulting suspension of step (i) for a period of 50-65mins at room temperature to obtain the solid;
iii. Filtering the solid and drying to obtain the desired product.

8. A process for preparing Resmetirom polymorphic Form C2 comprising drying Resmetirom Form C1 obtained by the process as claimed in claim 5 in the air tray dryer (ATD) at a temperature ranging between 100°C to 120°C for a period of 7-10 hours;
OR
i. Suspending Resmetirom in a solvent at room temperature followed by adding alcoholic ammonia solution and stirring the mixture for a period of 50-70 minutes to obtain the solid;
ii. Filtering the solid and drying to obtain the desired product.

9. A process for preparing ammonia salt of Resmetirom polymorphic Form C2 as claimed in claim 5, comprising;
i. Suspending Resmetirom in a solvent at room temperature followed by adding alcoholic ammonia solution and stirring the mixture for a period of 50-70 minutes to obtain the solid ;
ii. Filtering the solid and drying to obtain the desired product.

10. A process for preparing Resmetirom polymorphic Form C3 comprising drying Resmetirom Form C1 obtained by the process as claimed in claim 5 in the air tray dryer (ATD) at a temperature ranging between 180°C to 210°C for a period of 5-15minutes.

11. A process for preparing Resmetirom Form C3 as claimed in claim 4 comprising;
i. Dissolving Resmetirom in a solvent at room temperature and removing any undissolved particulate to obtain the clear solution;
ii. Adding the clear solution of step (i) to the pre-chilled solvent followed by seeding with Resmetirom Form C3 at a temperature ranging between -10°C to -15°C, stirring the resulted suspension at -5°C to -10°C to obtain the solid; and
iii. Filtering the solid and drying to obtain the product.
OR
i. Suspending Resmetirom in a solvent and alcoholic ammonia and stirring at room temperature to obtain the solid;
ii. Filtering and drying the solid under nitrogen atmosphere to obtain Resmetirom ammonium salt;
iii. Suspending Resmetirom ammonium salt of step (ii) into a mixture of pre-ccoled solvent and Resmetirom Form C3 seed at a temperature of -5°C followed by slow addition of trifluoroacetic acid at said temperature, stirring and slowly raising the temperature to 5-10°C and stirring to obtain the solid;
iv. Filtering the solid of step (iii), washing and drying to obtain the desired product.

12. The process as claimed in claim 11, wherein the solvent is selected from lower alcohol, preferably isobutanol or trifluoroacetic acid.

13. A process for preparing ammonium salt of Resmetirom polymorphic Form C3 as claimed in claim 5, comprising;
i. Suspending ammonium salt of Resmetirom Form C1 in a solvent selected from lower alcohols or esters, preferably the ester such as ethyl acetate at room temperature to obtain the slurry;
ii. Heating the slurry at a temperature ranging between 40-45°C, stirring at said temperature and cooling to room temperature to obtain the solid;
iii. Filtering the solid and drying to obtain the desired product.

14. A process for preparing Resmetirom polymorphic Form C3 as claimed in claim 5, comprising;
i. Suspending the ammonium salt of Resmetirom Form C1 in a solvent selected from lower alcohol, preferably isobutanol at a temperature ranging between -10°C to -5°C and seeding with Resmetirom Form C3 seed at said temperature to obtain the slurry;
ii. Adding Trifluoro acetic acid to the above slurry at a temperature ranging between -10°C to -5°C and stirring at said temperature until a solid is formed;
iii. Filtering the solid, drying and washing to obtain the desired product.

15. A process for preparing Resmetirom polymorph Form C4 as claimed in claim 4, comprising;
i. Suspending Resmetirom Form C1 in a solvent selected from aliphatic or aromatic hydrocarbons; preferably aliphatic hydrocarbon; and
ii. Filtering, suck drying under vacuum followed by drying under vacuum at a temperature ranging between 65-90°C for a period of 10-12 hours to obtain the desired product.

16. The process as claimed in claim 15, wherein the solvent is n-heptane.

17. A pharmaceutical composition comprising Resmetirom polymorphic Forms C1, C2, C3 or C4 or its salts as claimed in any one of the preceding claims together with pharmaceutically acceptable excipients.