DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of amorphous Resmetirom and pharmaceutical composition comprising the amorphous Resmetirom.

BACKGROUND OF THE INVENTION:
Resmetirom is a selective agonist of thyroid hormone receptor-ß which increases hepatic fat metabolism and reduces lipotoxicity. Resmetirom recently approved by USFDA and indicated in conjunction with diet and exercise for the treatment of adults with non-cirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis. Resmetirom is commercially available under the brand name of REZDIFFRA. Resmetirom is chemically known as 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4] triazine-6-carbonitrile and is structurally represented by the following formula I:

Formula I
Resmetirom and process for its preparation was first disclosed in US7452882B2. There is no characteristic data for Resmetirom in this patent.

The US9266861B2 patent discloses crystalline anhydrous Form I of Resmetirom, which is obtained by converting Resmetirom dimethylacetamide solvate to dihydrate form then to MIBK solvate and finally converted into anhydrous Form I.

US20210122740A1 discloses different solvates of Resmetirom including methanol solvate, ethanol solvate and acetone solvate and an amorphous solid dispersion of Resmetirom. Further, WO2021063367A1, WO2021129465A1, WO2022052822A1, WO2022086894A1, WO2022171200A1 and CN115124515A patent publication also discloses number of crystalline Forms and co-crystals of Resmetirom.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may resulted in the difference in their in vivo bioavailability.

There is a need in the art for a commercially scalable process for the preparation of amorphous Resmetirom with high purity and yields. Hence the main objective of the present invention is to provide a process for the preparation of amorphous Resmetirom with high yield and purity which is easily scalable to commercial scale.

SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for the preparation of amorphous Resmetirom with high yield and purity, which is commercially scalable.

In one aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises;
a) providing a solution of Resmetirom in one or more suitable solvent,
b) removing the solvent from step a) solution or optionally adding suitable anti-solvent to the step a) solution; and
c) isolating the amorphous Resmetirom.

In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises:
a) providing a solution of Resmetirom in one or more suitable solvent,
b) subjecting the step a) solution to spray-drying; and
c) isolating the amorphous Resmetirom.

In another aspect, the present invention provides stable amorphous Resmetirom having purity of greater than 99% by HPLC.

In another aspect, the present invention provides stable amorphous Resmetirom characterized by having an X-ray powder diffraction pattern substantially as shown in Figure-1.

In another aspect, the present invention provides pharmaceutical composition comprising amorphous Resmetirom prepared according to the present invention and having one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1 shows an X-ray powder diffraction pattern of amorphous Resmetirom.

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (Instrument name Bruker D8 Advance) with measured using CuKa radiation of wavelength 1.54066A° step size of 0.012°/min; scan range of 3-40°A.

DETAILED DESCRIPTION OF THE INVENTION:
The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.

The term “amorphous” as applied to a compound refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (“glass transition”).

In one aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises;
a) providing a solution of Resmetirom in one or more suitable solvent,
b) removing the solvent from step a) solution or optionally adding suitable anti-solvent to the step a) solution; and
c) isolating the amorphous Resmetirom.

The starting Resmetirom compound may be prepared as per the process disclosed in US7452882B2. Further the starting Resmetirom may be in any form such as a crude, crystalline, solvated forms known in the art or the reaction mixture comprising Resmetirom obtained directly during the course of synthesis.

The step a) of the forgoing process involves providing a solution of Resmetirom in one or more suitable solvent and is carried out by dissolving Resmetirom in a suitable solvent at a suitable temperature of about 10°C to about reflux temperature of the solvent used; preferably at about 20°C to about 40°C; or utilizing the reaction mixture comprising Resmetirom obtained directly during the course of synthesis. The suitable solvent may selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof; preferably the alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol and the like; and the ketone solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; more preferably mixture of methanol and acetone.

The removal of solvent from the step a) solution is carried out by known techniques such as distillation, spray drying, agitated thin film drying (“ATFD”), and freeze drying. Alternatively, the suitable anti-solvent in which Resmetirom is not soluble added to step a) solution to precipitate out Resmetirom.

Then isolation of amorphous Resmetirom is carried out by the methods known in the art and depends on the step b) method; for example, separating the amorphous form by way of decantation, filtration, filtration under vacuum, centrifugation and other methods known in the art or taking out the obtained amorphous solid followed by drying; or by adding a suitable solvent to the amorphous solid obtained after removal of the solvent by distillation and separating the amorphous form by way of decantation, filtration, filtration under vacuum, centrifugation and other methods known in the art; wherein the suitable solvent is the one in which Resmetirom is insoluble.

In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, which comprises:
a) providing a solution of Resmetirom in one or more suitable solvent,
b) subjecting the step a) solution to spray-drying; and
c) isolating the amorphous Resmetirom.

The step a) of the forgoing process involves providing a solution of Resmetirom in one or more suitable solvent and is carried out by dissolving Resmetirom in a suitable solvent at a suitable temperature of about 10°C to about reflux temperature of the solvent used; preferably at about 20°C to about 40°C; or utilizing the reaction mixture comprising Resmetirom obtained directly during the course of synthesis. The suitable solvent may selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof; preferably the alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol and the like; and the ketone solvent selected from acetone, methyl isobutyl ketone, methyl ethylketone and the like; more preferably mixture of methanol and acetone.

The step b) of the forgoing process involves subjecting the step a) solution to spray-drying at a suitable temperature of about 30°C to about 90°C; preferably at about 65°C to about 80°C. Then isolation of amorphous Resmetirom is carried out by taking out the obtained amorphous solid followed by drying.

The amorphous Resmetirom obtained above may be further dried in a suitable dryer known in the art, for examples tray dryer, dried under vacuum and/or in a Fluid Bed Dryer to achieve the desired LOD levels.

In another aspect, the present invention provides stable amorphous Resmetirom having purity of greater than 99% by HPLC.

In another aspect, the present invention provides stable amorphous Resmetirom, having an X-ray powder diffraction pattern substantially as shown in Figure-1.

The amorphous Resmetirom of the present invention has advantageous properties selected from at least one of: chemical purity, flowability, solubility, stability - such as storage stability.

In another aspect, the present invention provides pharmaceutical composition comprising amorphous Resmetirom prepared according to the present invention and having one or more pharmaceutically acceptable excipients.
Examples:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1:
Preparation of amorphous Resmetirom:
Resmetirom (20 g) was dissolved in methanol (200 ml) and acetone (200 ml) at 25-30°C and the obtained solution was filtered through 0.2 microns filter. The filtrate was subject to spray drying in a spray dryer (Model: Lab Model PE-1.5A; Make: M/s Prathik Enterprises) at inlet temperature of 80°C through steam with feed rate of 8 ml/min at 1 kg/cm2 Nitrogen pressure applied for feeding. After the completion of spray dryer, cooled to room temperature, collected the material from the chamber and analyzed.
Purity: 99.5% by HPLC
The PXRD pattern of obtained amorphous Resmetirom is set forth in Fig.1.

Example-2:
Stability of Amorphous Resmetirom:
The Amorphous Resmetirom of the present invention in appropriate quantity placed under the conditions mentioned in the below table for stability study purpose and after completion of the respective time period, the Amorphous form of the samples analyzed by PXRD, which results are as shown below:
Test condition Time Period Final Form Remarks
2-8°C; closed 1 week Amorphous No change
25±2°C / 60±5% RH; closed Amorphous No change
2-8°C; closed 2 weeks Amorphous No change
25±2°C / 60±5% RH; closed Amorphous No change
2-8°C; closed
4 weeks Amorphous No change
25±2°C / 60±5% RH; closed Amorphous No change
60± 2°C; Open 24 hours Amorphous No change
60± 2°C; Open 48 hours Amorphous No change
60± 2°C; Open 1 week Amorphous No change

The above result shows that Resmetirom amorphous form of the present invention is stable for at least 4 weeks under the above mentioned closed conditions; and stable for at least 1 week under the open conditions. Based on, the Resmetirom amorphous form of the present invention can be stable under long term and accelerated conditions.
,CLAIMS:WE CLAIM:
1. A process for the preparation of amorphous Resmetirom, which comprises;
a) providing a solution of Resmetirom in one or more suitable solvent,
b) removing the solvent from step a) solution or optionally adding suitable anti-solvent to the step a) solution; and
c) isolating the amorphous Resmetirom.

2. The process as claimed in claim 1, wherein the suitable solvent in step a) is selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof.

3. The process as claimed in claim 1, wherein the suitable solvent is a mixture of methanol and acetone.

4. The process as claimed in claim 1, wherein in step b) the removal of solvent from the step a) solution is carried out by distillation, spray drying, agitated thin film drying (“ATFD”) or freeze drying.

5. A process for the preparation of amorphous Resmetirom, which comprises:
a) providing a solution of Resmetirom in one or more suitable solvent,
b) subjecting the step a) solution to spray-drying; and
c) isolating the amorphous Resmetirom.

6. The process as claimed in claim 5, wherein the suitable solvent in step a) is selected from alcohols, ketones, nitriles, chloro solvents, ethers, esters and/or mixtures thereof.

7. The process for the preparation of amorphous Resmetirom as claimed in claim 5, comprises;
a) providing a solution of Resmetirom in a mixture of methanol and acetone at a suitable temperature of about 20°C to about 40°C,
b) subjecting the step a) solution to spray-drying at a suitable temperature of about 65°C to about 80°C; and
c) isolating the amorphous Resmetirom.

8. The amorphous Resmetirom obtained according to any of the preceding claim is stable and having purity greater than 99% by HPLC.

9. Stable amorphous Resmetirom characterized by a powder X-ray diffractogram substantially as shown in Figure 1.

10. The pharmaceutical composition comprising amorphous Resmetirom as claimed in the preceding claims and at least one pharmaceutically acceptable excipient.