DESC:FIELD OF THE INVENTION

The present invention provides an amorphous form of Resmetirom and process for preparation thereof. This invention also provides amorphous solid dispersion and premix of Resmetirom. The present invention also provides pharmaceutical compositions containing the same.

BACKGROUND OF THE INVENTION

Resmetirom is a thyroid hormone receptor (THR) ß-selective agonist in development for the treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis and its structural formula is:

There remains a need for additional solid-state form of Resmetirom having good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

OBJECT OF THE INVENTION

Object of the present invention is to provide solid form of Resmetirom.

Another object of the present invention is to provide an amorphous form of Resmetirom.

Another object of the present invention is to provide a process for the preparation of amorphous form of Resmetirom.
Another object of the present invention is to provide amorphous solid dispersion of Resmetirom with at least one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a process for the preparation of amorphous solid dispersion of Resmetirom with at least one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a premix of Resmetirom with at least one pharmaceutically acceptable carrier.

Another object of the present invention is to provide a process for the preparation of a premix of Resmetirom with at least pharmaceutically acceptable carrier.

SUMMARY OF THE INVENTION

An aspect of the present invention is to provide solid form of Resmetirom.

Another aspect of the present invention provides an amorphous form of Resmetirom.

Another aspect of the present invention provides a stable amorphous form of Resmetirom.

In another aspect, the present invention provides a process for the preparation of a stable amorphous form of Resmetirom, comprising the steps of;
a) providing a solution of Resmetirom in one or more suitable solvents; and
b) isolating the stable amorphous form of Resmetirom.

In another aspect, the present invention provides a process for the preparation of a stable amorphous form of Resmetirom, comprising the steps of;
a) providing a solution of Resmetirom in one or more suitable solvents; and
b) adding suitable amount of anti-solvent to the solution of Resmetirom at suitable temperature to obtain stable amorphous product.

Another aspect of the present invention provides a process for the preparation of stable amorphous form of Resmetirom, comprising the steps of;
a) providing a solution of Resmetirom in one or more solvents;
b) lyophilizing the solution obtained in step a); and
c) isolating the stable amorphous form of Resmetirom.

In another aspect, the present invention provides a process for the preparation of amorphous Resmetirom, comprising the steps of;
a) milling/grinding Resmetirom under suitable milling conditions; and
b) isolating the amorphous form of Resmetirom.

In another embodiment, the present invention provides a process for the preparation of a stable amorphous form of Resmetirom, comprising the steps of:
a) providing a solution of Resmetirom in one or more solvents;
b) adding suitable pharmaceutically acceptable acid to obtain pharmaceutically acceptable salt of Resmetirom;
c) adding suitable base to the solution of step b); and
d) isolating the stable amorphous form of Resmetirom.

In another embodiment, the pharmaceutically acceptable acid used in the present invention is selected from hydrochloric acid, sulphuric acid, acetic acid, oxalic acid, formic acid and tartaric acid.

In another embodiment, the suitable base used in the present invention is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, ammonia, sodium carbonate and sodium bicarbonate.

In another aspect, the present invention provides amorphous solid dispersion of Resmetirom with at least one pharmaceutically acceptable carrier or polymer.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Resmetirom, comprising the steps of:
a) providing a solution of Resmetirom in a suitable solvent;
b) adding a solution of at least one pharmaceutically acceptable carrier in a suitable solvent to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of Resmetirom.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Resmetirom, comprising the steps of:
a) providing a solution of Resmetirom in a suitable solvent;
b) adding at least one pharmaceutically acceptable carrier to step a); and
c) isolating to get amorphous solid dispersion of Resmetirom.

Another aspect of the present invention provides a premix of Resmetirom with at least one pharmaceutically acceptable carrier.

In another aspect, the present invention provides a process for the preparation of a premix of Resmetirom, comprising the steps of:
a) adding Resmetirom to at least one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of Resmetirom either by removal of solvent from solution of step b) or by isolating the solid mass of step a).

In another aspect, the present invention provides a process for the preparation of a premix of Resmetirom, wherein said process comprises grinding of Resmetirom with at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: Represents the X-Ray Powder Diffraction (XRPD) pattern of the stable amorphous form of Resmetirom of the present invention (initial).
Figure 2: Represents the X-Ray Powder Diffraction (XRPD) pattern of the stable amorphous form of Resmetirom of the present invention that is exposed for a period of 12 months at 25°C /60% RH.

DETAILED DESCRIPTION OF THE INVENTION

The terms “amorphous or stable amorphous " is interchangeable and indicate that the Resmetirom is present in substantially amorphous state and is substantially free from any other form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Substantially pure amorphous” denotes that at least 90%, preferably at least 95%, more preferably at least 99% of the Resmetirom is amorphous. In other words, “substantially free from any other form” preferably means that the amorphous form does not contain detectable amounts, of any other portions of Resmetirom e.g. measurable upon X-ray powder diffraction analysis and/or Differential scanning calorimetry, and preferably the any other form is less than about 5% w/w of the amorphous form.

The term “stable” as used herein refers to physical stability and/or chemical stability of the active agent in the composition, wherein changes in the drug assay values and/or impurities content are less than about 10%, during stability study storage of the composition at 25° C. and 60% relative humidity (RH), or 30° C. and 65% RH, or 40° C. and 75% RH, for durations such as initial, 1, 3, 6, 12, 18, or 24 months.

As used herein, the term “pharmaceutically acceptable excipient/carrier/polymer” means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

As used herein, the term “Solid dispersion” is used herein refers to the dispersion of one or more active ingredients in an inert polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Solid dispersion consists of two or more components, generally a polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve. A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a polymer or carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the polymer dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles. Further, the term "stable solid dispersion" as used in the context of the present invention, denotes a state where most of the Resmetirom, preferably 90%, 95% or all of the Resmetirom of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer/ carrier matrix. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.

The term "premix" is used herein to describe combinations of Resmetirom and at least one pharmaceutically acceptable carrier, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy. In embodiments, the drug is considered as being uniformly or non-uniformly distributed over surfaces of carrier particles. In other embodiments, the premixes are considered to be in the nature of molecular dispersions, or solid solutions. Simple mixtures of powdered ingredients will not constitute premixes.

The terms “pharmaceutically acceptable salt” or “salt” are used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like; The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, or selenium, and the like; benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The “suitable solvent” as used in the context of the present invention, is selected from the group comprising of, but not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water and mixture thereof. Preferably, methanol, acetonitrile, dichloromethane, ethanol, isopropanol, acetone, tetrahydrofuran, water and mixtures thereof.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

In a main embodiment, the present invention provides a solid form of Resmetirom.

In another main embodiment, the present invention provides an amorphous form of Resmetirom.

In another main embodiment, the present invention provides a stable amorphous form of Resmetirom.

In another embodiment, the present invention provides a stable amorphous form of Resmetirom, wherein said Resmetirom is stable after exposure to 40 °C/75% RH for a period of six months or 25°C /60% RH., for a period of at least 12 months.

In another embodiment, the present invention provides a stable amorphous form of Resmetirom, wherein the amorphous form does not convert to any other solid form when stored at a temperature of up to about 40ºC and at a relative humidity of about 25% to about 75% for about initial, 1 month, 3 months, 6 months, and 12 months or more.

Stability study of amorphous form:
In an embodiment, the experimental results of stability test of stable amorphous form of resmetirom are shown in Table below:
Time 25±2°C/60±5% RH 40±2°C/75±5% RH
HPLC purity (%) PXRD HPLC purity (%) PXRD
Initial 99.50 Complies 99.50 Complies
1st month 99.50 Complies 99.40 Complies
3rd month 99.45 Complies 99.35 Complies
6th month 99.40 Complies 99.30 Complies
12th month 99.30 Complies 99.30 Complies

In another embodiment, the present invention provides Resmetirom having less than 0.1% of one or more of any impurity as measured by HPLC.

In a further embodiment, the stable amorphous form of Resmetirom has a purity of at least about 98% by area percentage of HPLC, preferably at least 99% by area percentage of HPLC, more preferably at least 99.5% by area percentage of HPLC, most preferably at least 99.8% by area percentage of HPLC.

In another embodiment, the present invention provides a process for the preparation of stable amorphous form of Resmetirom, comprising the steps of:
a) providing a solution of Resmetirom in one or more suitable solvents; and
b) isolating the stable amorphous form of Resmetirom.

In another embodiment, the present invention provides a process for the preparation of a stable amorphous form of Resmetirom, comprising the steps of;
a) preparing a solution of Resmetirom in one or more solvents;
b) optionally stirring the reaction mixture as obtained in step a) for suitable time at suitable temperature;
c) optionally filtering the reaction mixture as obtained in step b); and
d) isolating the stable amorphous form of Resmetirom by removal of the solvent.

In another embodiment, solution of Resmetirom may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.

Moreover, drying may 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 may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the present invention provides a process for the preparation of amorphous form of Resmetirom, comprising the steps of:
a) milling/grinding Resmetirom under suitable milling conditions; and
b) isolating the amorphous form of Resmetirom.

In another embodiment, the present invention provides a process for the preparation of a stable amorphous form of Resmetirom, comprising the steps of:
a) providing a solution of Resmetirom in a solvent;
b) lyophilizing/spray drying the solution obtained in step a); and
c) isolating the stable amorphous form of Resmetirom.

Another aspect of the present invention provides a process for the preparation of stable amorphous form of Resmetirom, comprising the steps of;
a) providing a solution of Resmetirom in one or more solvents;
b) stirring the reaction mixture as obtained in step a) for suitable time at suitable temperature;
c) lyophilizing the solution obtained in step b); and
d) isolating the stable amorphous form of Resmetirom.

In another embodiment, the amorphous form of Resmetirom, obtained after lyophilization, is isolated by a process such as drying at room temperature, drying under vacuum, or by any known conventional method. Moreover, drying may 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 may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the present invention provides a process for the preparation of stable amorphous form of Resmetirom, comprising:
(a) contacting Resmetirom in one or more solvents to obtain a solution; and
(b) obtaining stable amorphous form of Resmetirom by removal of the solvent.

In one more embodiment, the present invention provides a substantially pure amorphous form of Resmetirom, wherein said amorphous form is substantially free from any other form.

In one more embodiment, amorphous form thus obtained is substantially free from solvent used in its preparation. In general, the stable amorphous form of Resmetirom, is substantially free from residual solvents.

The term “substantially free” means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example, but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%.

In an embodiment, the residue solvent content in stable amorphous of resmetirom is given in the table below:
Residual solvent Amount (ppm) (Example 1)
Methanol 578
Ethanol 0.0
Acetone 3507
Ethyl acetate 0.0
Tetahydrofuran 0.0

In another embodiment, the present application provides pharmaceutical composition comprising amorphous form of Resmetirom, and at least one pharmaceutically acceptable excipient.

The present invention provides a stable solid dispersion of Resmetirom suitable for powder handling and downstream processes. A stable solid dispersion of Resmetirom of the present application was surprisingly found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.

In another embodiment, the present invention provides an amorphous solid dispersion of Resmetirom, with at least one pharmaceutically acceptable carrier or polymer.

In the present invention, the solid dispersion technology is used for dispersing water insoluble Resmetirom monomolecularly in a solid state into an inert carrier. The technology specifically includes a solvent process, a fusion process, and a mixed-grinding process.

The solvent process either comprises dissolving a water insoluble Resmetirom and a water-soluble polymer, i.e. the carrier, in an organic solvent capable of dissolving both and removing the solvent by evaporation or comprises dissolving the Resmetirom in an organic solvent, dispersing the solution in the carrier and removing the solvent by evaporation to provide the desired solid dispersion.

The fusion process either comprises heating the Resmetirom and the water-soluble polymer together by utilizing the phenomenon of melting point depression, cooling the melt to solidify and pulverizing the resulting solid to provide the desired solid dispersion, or comprises dissolving the Resmetirom in a comparatively low-melting water-soluble polymer under heating, cooling the resulting solution to solidify and pulverizing the solid to provide the desired solid dispersion.

The mixed-grinding technology, in which the water insoluble Resmetirom and the water-soluble polymer are mix-ground or roll-mixed without heating. It is considered that various factors arising from mechanical manipulation, such as lattice defect or lattice modulation, increases in specific surface area and surface energy and so on, enhances the activity of the solid phase to encourage transition of the Resmetirom to an amorphous state and, hence, dispersion of the Resmetirom in this amorphous state into the carrier.

Accordingly, in an embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of Resmetirom or salt thereof, comprising the steps of:
a) providing a solution of Resmetirom in a suitable solvent;
b) adding at least one pharmaceutically acceptable carrier or polymer to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of Resmetirom.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Resmetirom, comprising the steps of:
a) preparing a solution of Resmetirom with one or more pharmaceutically acceptable carriers in one or more solvents; and
b) optionally stirring the reaction mixture as obtained in step a); and
c) optionally filtering the reaction mixture as obtained in step b); and
d) isolating to get amorphous solid dispersion of Resmetirom by removal of the solvent.

In another embodiment, the Resmetirom and the pharmaceutically acceptable carriers may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein comprises amorphous Resmetirom, and the carrier present in weight ratios ranging from about 1:99 to about 99:1.

Preferably, the ratio is about 50:50. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable carrier or polymer.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of Resmetirom is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove colour, insoluble materials, improve clarity of the solution, and/or remove impurities absorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of Resmetirom, comprising the steps of:
a) heating Resmetirom in presence of at least one pharmaceutically acceptable carrier or polymer to get a solution;
b) cooling the solution; and
c) isolating to get amorphous solid dispersion of Resmetirom.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of Resmetirom, wherein said Resmetirom is mixed with pharmaceutically acceptable water-soluble polymer at ambient temperature.

In preferred embodiment, the present invention provides a simple process which comprises mixing a water insoluble Resmetirom and a water-soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, making the water insoluble Resmetirom as amorphous in nature to thereby yield a solid dispersion insuring very high solubility and bioavailability which have never been achieved by any dry process heretofore known.

In another embodiment, Resmetirom as used for preparing amorphous solid dispersion, can be either crystalline, amorphous or mixture in nature.

In preferred embodiment, the solid dispersion is a substance obtained by dispersing Resmetirom into a carrier in a mono-molecular state. In this dispersion, the Resmetirom remains in a completely amorphous state. Generally, the amorphous form is in a higher energetic state compared to the any other and is therefore expected to have a higher absorptivity.

In another embodiment, the present application provides a pharmaceutical composition comprising a stable solid dispersion of Resmetirom or pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable excipient.

In an embodiment, the present application provides a stable solid dispersion of Resmetirom, with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.

In one another embodiment, the present invention provides a premix of Resmetirom with at least one pharmaceutically acceptable polymer and/or carrier.

In one another embodiment, the present invention provides a process for the preparation of a premix of Resmetirom, comprising the steps of:
a) adding Resmetirom to at least one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of Resmetirom either by removal of solvent from solution of step b) or by isolating the solid mass of step a).

In another embodiment, the present application provides a pharmaceutical composition comprising a premix of Resmetirom, together with at least one pharmaceutically acceptable excipient.

In another embodiment, a solution of Resmetirom used to prepare amorphous solid dispersion/ premix/ amorphous form of Resmetirom, may be prepared by dissolving Resmetirom in a suitable solvent or by taking the reaction mixture containing Resmetirom directly.

In an embodiment, a solution of Resmetirom in a suitable solvent can be prepared at any suitable temperature, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In an embodiment, a solution of Resmetirom in a suitable solvent may be filtered to make it clear, free of unwanted particles. In an embodiment, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.

In preferred embodiments, removal of solvent at any stage of preparation of amorphous form/ solid dispersion/ premix of Resmetirom may include, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, flash evaporation, rotational dying, agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization, and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at a temperature of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In preferred embodiment, stable amorphous form of Resmetirom may be combined with carrier either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Resmetirom and at least one pharmaceutically acceptable carrier.

In another embodiment, stable amorphous form of Resmetirom may be combined with the carrier by evaporating the suspension or solution of stable amorphous form of Resmetirom and at least one pharmaceutically acceptable carrier.

In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolate, and cross-linked styrene divinyl benzene or any other carrier at any aspect of present application.

In an embodiment, at least one pharmaceutically acceptable carrier may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other carrier at any aspect of present application.

The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Resmetirom with a suitable non-polymeric carrier by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.

Stable amorphous form or stable solid dispersion or premix of Resmetirom, may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another embodiment, the amorphous solid dispersion of Resmetirom, is characterized by particle size distribution of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

In another embodiment, the amorphous form of Resmetirom, is characterized by particle size distribution wherein, d90 is between 0.1µm to 200 µm, specifically d90 is between 2.0 µm to 150µm.

Powder X-ray Diffraction was recorded on an X-Ray powder diffractometer PANalytical X’Pert3; K-Alpha1 [Å] (l = 1.54060 Å); X'Celerator detector. Prior to analysis, sufficient quantity of powder sample was grinded gently in a mortar with pestle. Finally, grinded simple was filled in to the groove of the sample holder uniformly and the XRPD graph was recorded within the 2? range of 3 to 40.

Thermogravimetric analysis was performed on Perkin Elmer Pyris 1 TGA and platinum sample pan was loaded onto the hang down wire and waited till the balance become stable and TGA curve was recorded in the temperature range of 30oC to 400oC (100 oC/minute) with air flow 50mL/minute.

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 application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example 1: Preparation of amorphous form of Resmetirom.
Charged 1000 ml of acetone to the 20 g of Resmetirom, stirred at RT to get cleared, then filtered through 0.45 µm filter aid and washed with 20 ml of acetone. Obtained solution charged to spray dryer (Buchi B-290 Mini Spray Dryer) to get amorphous compound as off-white powder. Yield: 15 g, Purity: 99.5% by HPLC.

Example-2: Preparation of amorphous form of Resmetirom
Charged 1300 ml of acetonitrile to the 20 g of Resmetirom, stirred at RT to get cleared, then filtered through 0.45 µm filter aid and washed with 20 ml of acetonitrile. Obtained solution charged to spray dryer (Buchi B-290 Mini Spray Dryer) to get amorphous compound as off-white powder. Yield: 16 g, Purity: 99.4% by HPLC.

Example-3: Preparation of amorphous form of Resmetirom
Charged 160 ml of Methanol, 1440 ml of dichloromethane to the 20 g of Resmetirom, stirred at RT to get cleared then filtered through 0.45 µm filter aid and washed with 20 ml of 10% methanol: dichloromethane. Obtained solution charged to spray dryer (Buchi B-290 Mini Spray Dryer) to get amorphous compound as off-white powder. Yield: 17 g, Purity: 99.4% by HPLC.

Example-4: Preparation of amorphous form of Resmetirom
Charged 200 ml of Tetrahydrofuran to the 20 g of Resmetirom, stirred at RT to get cleared then filtered through 0.45 µm filter aid and washed with 20 ml Tetrahydrofuran. Obtained solution charged to Spray Dryer (Buchi B-290 Mini Spray Dryer) to get amorphous compound as off-white powder. Yield: 16.2 g, Purity: 99.5% by HPLC.

Example-5: Preparation of amorphous solid dispersion of Resmetirom with Eudragit (Grade: L-100)
A mixture of Resmetirom (1.2 g) and Eudragit (Grade: L-100) (1.2 g) was dissolved in methanol (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get the title compound. Yield: 2.3g.

Example 6: Preparation of amorphous solid dispersion of Resmetirom with hydroxypropylcellulose and lactose
To a mixture of hydroxypropylmethylcellulose (1g), low-substituted hydroxypropylcellulose (2.5g) and lactose (4.2 g) were added a solution of Resmetirom (1.2 g) in absolute ethanol and after stirring, the ethanol was evaporated in vacuo to get a solid dispersion. Yield: 7.5g.

Example 7: Preparation of amorphous solid dispersion of Resmetirom with PVP K-90
Resmetirom (1 g) was dissolved in ethanol (50 mL) at 25°C to make a solution, to this was added PVP K-90 (0.8 g) with stirring and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 55°C to obtain the title compound. Yield: 1.5g.

Example 8: Preparation of Resmetirom and lactose monohydrate premix.
Resmetirom (200 mg) and lactose monohydrate (100 mg) was dissolved in a mixture of acetone (20 mL) and ethanol (10 mL) at 40 °C. The solution was filtered to make it particle-free. The solvent was evaporated under vacuum at 175 rpm and at 50 °C. The solid was dried at 50 °C for 15 minutes to provide the title compound. Yield: 300g

Dated 28th Day of August, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer
,CLAIMS:We Claim:

1. A stable amorphous form of Resmetirom, characterized by data selected from one or more of the following:
a) the amorphous form of Resmetirom is stable when exposed to a relative humidity of 75% at 40 °C or a relative humidity of 60% at 25° C for a period of 12 months;
b) an X ray powder diffraction spectrum (XRPD) as depicted in Figure 1; or
c) having a purity of about 99% or more by area percentage of high-performance liquid chromatography (HPLC).

2. A process for the preparation of stable amorphous compound as claimed in claim 1, comprising the steps of:
a) preparing a solution by dissolving the Resmetirom in one or more solvents to obtain a solution;
b) isolating the stable amorphous form of Resmetirom;

3. A process for the preparation of stable amorphous compound as claimed in claim 1, comprising the steps of:
a) preparing a solution by dissolving the Resmetirom in a solvent;
b) lyophilizing the solution obtained in step a); and
c) isolating the stable amorphous form of Resmetirom.

4. A stable amorphous solid dispersion comprising Resmetirom, and one or more pharmaceutically acceptable carriers selected from hydroxypropylmethyl cellulose, low-substituted hydroxypropylcellulose, hydroxyethyl cellulose, cellulose acetate phthalate, carboxy methyl ethyl cellulose, Eudragit (Grade: L-100), povidone, polyvinylpyrrolidone (PVP), lactose, sorbitol and mixtures thereof.

5. A process for the preparation of stable amorphous solid dispersion as claimed in claim 4, comprising Resmetirom, and one or more pharmaceutically acceptable carriers, comprising the steps of:
a) preparing a solution of Resmetirom in a suitable solvent; and
b) adding at least one pharmaceutically acceptable carrier or polymer to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of Resmetirom.

6. A stable premix of Resmetirom or its pharmaceutically acceptable salts with at least one pharmaceutically acceptable carrier selected from lactose monohydrate, sorbitol, xylitol, and mannitol.

7. A process for preparing a stable premix as claimed in claim 6, comprising Resmetirom with one or more pharmaceutically acceptable excipients, comprising the steps of:
a) adding Resmetirom to at least one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of Resmetirom either by isolating the solid mass of step a) or by removal of solvent from solution of step b).

8. The process as claimed in preceding claims, wherein the solvent is selected from methanol, ethanol, isopropanol, butanol, pentanol, acetone, methyl isobutyl ketone, hexane, heptane, toluene, octane, water and mixtures thereof.

Dated 28th Day of August, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer