Process for the preparation and purification of crystalline resmetirom

Abstract

The present invention relates to an efficient process for the preparation and purification of crystalline resmetirom. More specifically, the present invention relates to an operationally simple process for controlling / limiting the interference of impurities in purity of the crystalline resmetirom in accordance with ICH guidelines. Further, the present invention relates to an efficient process for the preparation of resmetirom Form I.

Description

[0001] PROCESS FOR THE PREPARATION AND PURIFICATION OF CRYSTALLINE

[0002] RESMETIROM

[0003] CROSS REFERENCE

[0004] This application claims the benefit of priority of our Indian patent application IN202411025945 filed on March 29, 2024 and IN202411046749 filed on June 18, 2024, which are incorporated herein by reference.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to an efficient process for the preparation and purification of crystalline resmetirom. More specifically, the present invention relates to an operationally simple process for controlling / limiting the interference of impurities in purity of the crystalline resmetirom in accordance with ICH guidelines. Further, the present invention relates to an efficient process for the preparation of resmetirom Form I.

[0007] BACKGROUND OF INVENTION

[0008] Resmetirom (MGL-3196) is a potent and selective thyroid hormone receptor [THR] 0 agonist for the treatment of non-alcoholic steatohepatitis (NASH) by increasing hepatic fat metabolism and reducing lipotoxicity. Specifically, resmetirom, chemically known as 2-(3,5-dichloro-4-((5- isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy) phenyl)-3,5-dioxo-2, 3,4, 5-tetrahydro- 1,2,4- triazine-6-carbonitrile is selective THR0 agonist in vitro, and in preclinical NASH models in vivo it reduced hepatic steatosis and is represented by formula I as given below:

[0009] As of before, there is no approved treatment for non-alcoholic steatohepatitis (NASH) which can lead to progressive liver diseases like fibrosis, cirrhosis and hepatocellular carcinoma. On 14thMarch 2024, U.S. Food and Drug Administration (FDA) have approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. The synthesis of pyridazinone derivative, MGL-3196, is first time described in a patent family, W02007 / 009913, by Hoffman-La-Roche, as shown in scheme below:

[0010] In one of the specific example, the process comprises the steps of condensation of 4-amino-2,6- dichlorophenol with 3,6, dichloro-4-isopropylpyridazine in presence of an inorganic base to produce 4- (6-chloro-5-isopropylpyridazin-3-yloxy)-3,5-dichlorobenzenamine, which is further oxidized in presence of sodium acetate / acetic acid to obtain a 6-(4-amino-2,6-dichlorophenoxy)-4- isopropyl pyridazin-3(2H)-one. Subsequently, the resulting derivative is diazotized using sodium nitrite and hydrochloric acid in acetic acid / water or water and then condensed with N- acetylcyanothiourea in the presence of sodium acetate or pyridine in water to yield ethyl(Z)-(2- cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazine ylidene)acetyl)carbamate, herein refers as substituted pyridazinone intermediate. The substituted pyridazinone intermediate undergoes intra-cyclization by means of sodium acetate and acetic acid at room temperature and then the reaction mixture is heated to 120°C. At this time, the reaction is cooled to 0°C, diluted with water and stirred for 30 minutes.

[0011] Finally, the resulting solid is filtered and rinsed with water followed by petroleum ether and the obtained solid is air dried for 30 minutes. Thereafter, the solid is taken in hot acetonitrile and the resulting mixture is treated with neutral decolorizing carbon, filtered through celite and again rinsed with acetonitrile. The yellow filtrate is concentrated under vacuum to obtain a solid material. The solid material is triturated with hot acetonitrile, cooled and diluted with water and filtered. The solid is again triturated with hot acetonitrile, filtered and rinsed with acetonitrile, water and petroleum ether. At last, the solid is collected and dried under vacuum oven at 80°C to isolate resmetirom. However, the said publication fails to teach whether resmetirom disclosed therein is crystalline, amorphous, a specific polymorph, or a mixture of polymorphic forms. The said publication is also silent about the purity of the resmetirom. Moreover, the process involves a large quantity of acetonitrile that results in an enormous volume of solvent, which is usually difficult to handle during bulk production. It has been observed by the present inventors that upon repetition of the above process, the content of residual solvent (acetonitrile) in the final product obtained are quite high than the permissible limits as specified in International Conference for Harmonization (ICH) guidelines. Since acetonitrile is a class 2 solvent and as per regulatory guidelines, class 2 solvents should be limited in pharmaceutical products. For example, for Class 2 solvents, the content of acetonitrile should be not higher than 410 ppm, the content of tetrahydrofuran (THF) should not be higher than 720 ppm, the content of 1,4-dioxane should not be higher than 380 ppm and the content of methanol should not be higher than 3,000 ppm.

[0012] Another PCT publication WO 2014 / 043706 discloses an anhydrous crystalline Form I, dihydrate, a methyl isobutyl ketone (MIBK) solvate, a dimethylacetamide solvate and a hydrate of resmetirom. Among them, Form I is the most thermodynamically pure polymorphic form as the other solvates such as methyl isobutyl ketone solvate and the dimethylacetamide solvate are not suitable for medicinal purpose and it may cause a problem of safety to a patient due to the presence of higher level of toxic solvents i.e. methyl isobutyl ketone and dimethylacetamide. The crystalline Form I have been prepared through formation of dimethylacetamide (DMAc) solvate and methyl isobutyl ketone (MIBK) solvate of resmetirom. Firstly, the crude product which is obtained by intracyclization of substituted pyridazinone intermediate is converted into dimethylacetamide solvate having a HPLC purity of 93.67% and then into dihydrate having a HPLC purity of 96.4%. Finally, the dihydrate of crude resmetirom is purified via formation of methyl isobutyl ketone (MIBK) solvate, wherein solvate has a HPLC purity of 98.5% and need one more purification through the solvent which is selected from ethanol, isopropanol, methyl isobutyl ketone and a combination for the conversion of MIBK solvate to Form I of resmetirom having a HPLC purity of 99.6%.

[0013] The major shortcoming of said synthetic route is that multiple purifications have been performed via formation of different solvates to achieve the desired purity and polymorph. On the contrary, these multiple purifications via solvate formation requires maximum use of utilities, prolonged hours for intermittent operations and tedious isolation procedures to prepare pure Form I of resmetirom, thereby making process unfeasible at industrial scale. In another PCT publication WO 2020 / 010068A1 by Hoffman-La-Roche, different polymorphic forms, co-crystals, salts and amorphous solid dispersions of resmetirom have been disclosed. This polymorphic form includes solvates, desolvates and mixtures of polymorphic forms either with solvates or desolvates. However, the processes described in the said PCT publication suffer from several disadvantages such as lack of reproducibility and polymorphic forms are found to be either mixture or contaminated with other polymorphic forms and solvated forms, thereby making an impure form which is not suitable for pharmaceutical formulations and therapeutic use thereof.

[0014] In one another PCT publication WO 2021 / 129465 by Crystal Pharmaceutical, a crystalline form CSIV of resmetirom have been unveiled. As per one of the specified examples, acetonitrile is added to the weighed resmetirom and then stirred at room temperature for three days to form a suspension. Afterwards, the suspension is centrifuged to obtain a solid. The obtained solid is then dried under vacuum at 100 °C for 3.5 hours to obtain desired CSIV form of resmetirom.

[0015] In another PCT publication WO 2022 / 052822 by Crystal Pharmaceutical, crystalline form CSVI of resmetirom have been disclosed, wherein the process of preparing said crystalline form CSVI comprises the steps of, adding acetonitrile / mixture of acetonitrile and water in weighed resmetirom. Then, the mixture is stirred at room temperature for 4 days. The obtained solid is separated from the mixture by filtration and subsequently dried at 40°C for 15.5 hours to obtain the crystalline form CSVI of the present disclosure.

[0016] In both of the above mentioned PCT publications by Crystal Pharmaceutical, the major drawbacks of preparing crystalline forms involve use of large volume of acetonitrile, extended days for the isolation of desired crystalline forms of resmetirom. However, the use of large volume of acetonitrile and prolonged days for the isolation makes the process unviable for industrial scale.

[0017] Another PCT publication WO 2022 / 086894 divulges several polymorphic forms of resmetirom and its salts. Moreover, in one of the specified examples, procedure to prepare form 20 of resmetirom has been reported, wherein acetonitrile (132 volumes) is added to resmetirom (500 mg) to obtain slurry. The slurry is magnetically stirred at 80°C over a period of 30 minutes to obtain a cloudy solution, thereafter the solution is filtered. Then, the filtered clear solution is again magnetically stirred at room temperature for 18 hours to obtain a solid precipitate. The solid is then separated by filtration and dried in vacuum at 45°C for 72 hours to obtain the desired crystalline form 20 of resmetirom. However, the use of excess quantities of solvent requires maximum use of utilities, thereby making the process cumbersome and tedious.

[0018] Several PCT publications WO 2021 / 063367, WO 2022 / 171200 disclose different crystalline forms of resmetirom such as CSI, and form 3 respectively. One another Chinese publication CN115124515 unveils crystalline forms 4, 7 and 9 of resmetirom which are acetone, 1, 4-dioxane and butanone solvates respectively.

[0019] Most of the prior arts as cited above reveal different crystalline forms of resmetirom. Amongst those different crystalline forms, most of them are solvates and are not suitable for use in medicine. Forms CSI, CSIV / CSV and CSVI are non-solvates or substantially free of solvents. However, the process disclosed for the preparation of these forms have poor reproducibility, involves use of large volume of solvents (specifically class 2 solvent), prolonged reaction times, tedious isolation procedures, thereby making the processes commercially unviable.

[0020] It is well known in the art that different crystalline forms can be obtained due to the differences in crystallization solvents and methods, e.g., crystallization temperature, cooling rate, stirring or standing, and that different crystalline forms may have different stability and solubility, sometimes even different in vivo bioavailability. Accordingly, it is necessary to obtain a pure crystalline form which is thermodynamically stable in the development of a drug, and the method of making such crystalline form should be simple and easily reproducible commercially.

[0021] In order to overcome the aforementioned drawbacks associated in the prior art processes, there is a need in the art to provide an industrially viable process for the preparation of crystalline form. Despite of several polymorphic forms reported in the literature, there is a need to provide a crystalline form of resmetirom and its process for preparation thereof, and converting it to thermodynamically stable pure resmetirom Form I, which provide opportunity to improve the characteristics of a pharmaceutically acceptable dosage form of the drug with a targeted release profile or other desired characteristics. Keeping this in mind, the present invention aims to provide an efficient process, wherein impurities, known or unknown have been controlled as per ICH guidelines for the preparation of resmetirom Form I. Mild conditions along with a simple process need to be opted to control the content of residual solvents, minimize the formation of the impurities or by-products and synthesize a novel crystalline form and its conversion to resmetirom Form I with high purity and stability throughout its shelf-life. OBJECT OF THE INVENTION

[0022] The principal object of the present invention is to provide an efficient process for the preparation and purification of crystalline form and its conversion to resmetirom form I that overcomes the limitations of prior art methods i.e. use of large volume of solvents, multiple use of utilities, prolonged reaction time for intermittent operations and tedious isolation procedures.

[0023] Another object of the present invention is to provide an industrially viable process for the preparation of crystalline form and its conversion to resmetirom form I in high purity, wherein the level of impurities [organic, inorganic, reaction intermediates, residual solvent] have been controlled as per ICH guidelines.

[0024] Yet one another object of the present invention is to provide a process for the preparation of pure resmetirom Form I which is free from other polymorphic forms.

[0025] Yet another object of the present invention is to provide an industrially advantageous process for the preparation of crystalline form and its conversion to resmetirom form I, which would be operationally simple, cost-effective and suitable at commercial scale.

[0026] Yet another object of the present invention is to provide an industrially advantageous novel crystalline form of resmetirom.

[0027] SUMMARY OF INVENTION

[0028] Accordingly, the present invention provides an industrially advantageous process for the preparation and purification of crystalline resmetirom, wherein the crystalline form is stable and substantially free from impurities.

[0029] In an embodiment, the present invention provides a process for the purification of crystalline resmetirom of formula I,

[0030] Formula I the process comprising the steps of: i. dissolving crude resmetirom in a suitable organic solvent, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. cooling the solution obtained in step (ii), iv. isolating the pure crystalline resmetirom.

[0031] In another embodiment, the present invention provides a process for the purification of resmetirom wherein all impurities are controlled as per ICH guidelines, the process comprising the steps of: i. dissolving crude resmetirom in a mixture of suitable organic solvent and water, ii. cooling the solution obtained in step (i), iii. isolating the pure crystalline resmetirom.

[0032] Yet another embodiment, the present invention provides novel crystalline forms of resmetirom.

[0033] Yet another embodiment, the present invention provides novel crystalline form M of resmetirom.

[0034] In one another embodiment the present invention provides a process for the preparation of novel crystalline Form M of resmetirom of formula I, the process comprising the steps of: i. dissolving crude resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. cooling the solution obtained in step (ii), iv. isolating the novel crystalline Form M of resmetirom.

[0035] In one another embodiment the present invention provides a process for the preparation of resmetirom Form I of formula I, the process comprising the steps of: i. dissolving resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. cooling the solution obtained in step (ii), iv. isolating the novel crystalline Form M of resmetirom, v. converting crystalline Form M to resmetirom Form I.

[0036] In one another embodiment of the present invention is to provide a process for the preparation of pure resmetirom Form I of formula I, the process comprising the steps of: i. adding crystalline Form M of resmetirom in a suitable organic solvent, ii. heating the reaction mass obtained in step (i) to reflux temperature of the solvent, iii. cooling the solution obtained in step (ii), iv. isolating the pure resmetirom Form I.

[0037] In another embodiment, the present invention provides a process for the preparation of resmetirom Form I, the process comprising the steps of: i. providing resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. optionally cooling the solution obtained in step (ii), iv. isolating the novel crystalline Form M of resmetirom, v. converting crystalline Form M to resmetirom Form I.

[0038] In another embodiment, the present invention provides a process for the preparation of pure resmetirom Form I of formula I, the process comprising the steps of: i. drying crystalline Form M of resmetirom at temperature above 100°C, ii. isolating the pure resmetirom Form I. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 : X-ray powder diffractogram (XRPD) of crystalline form of resmetirom [Form M] .

[0040] Figure 2: X-ray powder diffractogram (XRPD) of crystalline form of resmetirom [Form M].

[0041] Figure 3: X-ray powder diffractogram (XRPD) of crystalline form of resmetirom. [Form M].

[0042] Figure 4: X-ray powder diffractogram (XRPD) of resmetirom Form I.

[0043] Figure 5: X-ray powder diffractogram (XRPD) of resmetirom Form I.

[0044] Figure 6: X-ray powder diffractogram (XRPD) of resmetirom Form I.

[0045] Figure 7 : X-ray powder diffractogram (XRPD) of resmetirom Form I.

[0046] DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention provides a process for the preparation and purification of crystalline resmetirom of formula I, wherein removal of impurities have been achieved and controlled by using a benign solvent system and an operationally simple process. Further the present invention provides a process for the preparation of resmetirom Form I, wherein limit of impurities, formation of different and undesired crystalline forms, have been controlled through an operationally simple and reproducible process.

[0048] The term “substantially free” herein means resmetirom having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC.

[0049] As used herein, the term ‘crude’ represents a compound having impurities greater than the limits specified as per ICH guidelines, in particular having any known impurity greater than about 0.15% by area percentage of HPLC or any unknown impurity greater than about 0.10% by area percentage of HPLC. As used herein, the term “pure” refers to a crystalline form substantially free from different and undesired crystalline forms, and wherein the level of impurities either known or unknown impurities and limit of residual solvent are controlled as per ICH guidelines. Further the term “pure” represents a compound having purity greater than 99.00% w / w by HPLC, preferably greater than 99.50% w / w by HPLC and any individual known impurity present in an amount less than 0.15% w / w by HPLC, any unknown impurity presents in an amount of less than 0.10% w / w by HPLC, and total impurities present in an amount less than 0.50% w / w by HPLC. As used herein, the term “stable” represents a compound which is stable when stored at stability condition as per ICH stability guidelines. As used herein the term “impurities” refers to an unwanted substance that may be organic or inorganic substance, reaction intermediates and residual solvent, which differs from resmetirom and thereby lowers the purity of resmetirom.

[0050] As used herein the term “residual solvent” refers to a solvent which had previously been associated with or intact with the lattice of chemical compound, for example because the solvent was used in processing the chemical compound such as in any reaction, any synthesis, any prior precipitation or crystallization, or any other situation where the chemical compound came into contact with the solvent, wherein the "solvent" can be a single solvent or a solvent mixture.

[0051] As used herein the term “thermodynamically stable” refers to chemical stability, wherein not more than 0.5% w / w of total related substances are formed on storage at accelerated conditions of stability at 40° C. and 75% relative humidity or at 25° C. and 60% relative humidity for a period of at least three months.

[0052] As used herein, the term “reproducibility” means that process described in the present invention when followed produces a stable crystalline form which is substantially free from impurities and produces a product of a specified quality on a consistent basis.

[0053] As used herein, the term “ambient temperature” represents a temperature range of 25°C ± 5°C. As used herein, the term ‘partially’ represents a percentage of recovery of solvent in the range of 60 to 90% from the solution.

[0054] As used herein, the term “micronization” refers to the process of reducing the average diameter of a solid material’s particles. Usually, the term micronization is used when the particles that are produced are only a few micrometres (typically less than 10 mm) in diameter. Traditional micronization techniques are based on the use of friction to reduce particle size. Such methods include milling and grinding. Reduction in particle size may also take place as a result of collision and impact of the particles to each other.

[0055] As used herein, “reflux temperature” means” the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. In one embodiment of the present invention provides a process for the preparation and purification of crystalline resmetirom. The process comprises dissolving crude resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water. Thereafter, the solution can be stirred for 15 minutes to 90 minutes at reflux temperature of the solvent, preferably 15 minutes to 60 minutes.

[0056] The crude resmetirom used herein may be either any polymorphic form of resmetirom such as crystalline, or amorphous, solvated, desolvated, anhydrous or hydrated form which can be prepared by the process either given in the prior art or in the present invention.

[0057] The “suitable organic solvent” used in above reaction can be selected from but are not limited to "alcohol solvents" such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, tertbutanol, ethane- 1,2-diol, propane- 1,2-diol and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "polar solvent" such as water; or their mixtures.

[0058] Preferably, the organic solvent used herein may be alcohol, more preferably the solvent may be methanol. Organic solvents, specifically alcohol, can be used 4 to 40 times of volume, preferably 5- 35 times volume of resmetirom, for purpose of dissolution. However, the use of solvent for the dissolution may be varied based on solubility of the organic solvent in resmetirom.

[0059] Optionally, the solution can be concentrated by partially recovery of solvent under vacuum, wherein solvent can be recovered from the solution up to 60 to 90 percent of the solvent used for dissolution. Preferably, solvent can be recovered from 65 to 85 percent of solvent subjected for the partially recovery. Thereafter, the reaction mass can be subjected for cooling to an ambient temperature. After cooling, the resulting reaction mass may be subsequently stirred for a few minutes to few hours for complete crystallization, preferably, stirred for 15 minutes to 90 minutes, more preferably, 15 minutes to 60 minutes. Preferably, the mixture of solvents used for the dissolution of resmetirom can be selected from a mixture of alcohol and a polar solvent i.e., water. Preferably, the solvent used can be a mixture of methanol and water. In a mixture of organic solvent and water, the specific ratio of solvents can be utilized to achieve dissolution of resmetirom. The mixture of organic solvent and water in a ratio of 7 to 11: 1 to 2 (v / v). Preferably, mixture of organic solvent and water in a ratio of 9:1 (v / v) can be used. Specifically, the solution can be prepared in methanol and water by stirring at 60-70°C for 15 minutes to 60 minutes. Thereafter, the reaction mass can be subjected for cooling to an ambient temperature. After cooling, the resulting reaction mass may be subsequently stirred for a few minutes to few hours for complete crystallization.

[0060] Alternatively, the present invention provides a process for the preparation of resmetirom Form I. The process comprises providing resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water and can be stirred for few minutes to few hours at ambient temperature. Thereafter, the reaction mass can be subjected optionally to cooling to below ambient temperature and the resulting reaction mass may be subsequently stirred for 1-2 hours.

[0061] Afterwards, the crystallized solid can be isolated by using techniques known in the art such as filtration, centrifugation etc. The filtration can be done using pressure filtration, gravity filtration, vacuum filtration, and other techniques that are familiar to those skilled in the art. Finally, the resulting material obtained after filtration can be dried at 65-75°C for about 16-24 hours to obtain highly pure resmetirom substantially free from impurities as per ICH guidelines namely, novel crystalline Form M of resmetirom.

[0062] The preferable drying temperature can be 60-70°C and preferably, the solid can be dried for 16-24 hours and more preferably for 20-24 hours. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.

[0063] The resulting pure crystalline resmetirom of formula I of present invention have purity of greater than 99.0 %, preferably 99.50 % and more preferably 99.60% and all impurities have been reduced to less than 0.5% w / w by HPLC. It is advantageous to prepare crystalline resmetirom of formula I via using process of the present invention, as the process leads to results in purity of greater than 99.0%, preferably 99.50 % and more preferably 99.60% and any individual known impurity 0.15% and unknown ^0.10% as per ICH guidelines. Specifically, the present invention provides a purification process to reduce the level of des- monochloro impurity, namely, ethyl (Z)-(2-(2-(3-chloro-4-((5-isopropyl-6-oxo-l,6-dihydro pyridazin-3-yl)oxy)phenyl)hydrazineylidene)-2-cyanoacetyl) carbamate of formula II and some unknown impurities, specifically at RRT 1.05-1.10.

[0064] Formula II

[0065] According to the invention it is also unexpectedly found that a good reproducibility of the crystalline resmetirom of formula I in terms of purity can be obtained by electing the process sequences as given in the present invention wherein purification process is enough capable to reduce / eliminate the level of impurities rather than the use of purification by forming multiple solvates.

[0066] In one another embodiment, the present invention provides a crystalline form resmetirom of formula I as depicted in Figure- 1, Figure-2 and Figure 3.

[0067] The resulting crystalline form of resmetirom can be anhydrous or hydrate such as, hemihydrate or monohydrate or dihydrate in nature. Anhydrous form may have contained water content less than 1 % by weight. The hydrate form may have contained water content either in less than 2 % by weight for hemihydrate or less than 4% by weight for monohydrate and around 7 % for dihydrate.

[0068] The crystalline form namely Form M of resmetirom encompassed by the present invention may be characterized by at least one of differential scan calorimetry (DSC), Karl Fisher or thermogravimetric analysis (TGA) or X-Ray power diffraction (XRD).

[0069] In another embodiment, the present invention provides a process for the preparation of resmetirom Form I. The process comprises of dissolving resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water. Thereafter, the solution can be stirred for 15 minutes to 90 minutes at reflux temperature of the solvent, preferably 15 minutes to 60 minutes.

[0070] The resmetirom used herein may be either of crude resmetirom or any polymorphic form of resmetirom such as crystalline, or amorphous, solvated, desolvated, anhydrous or hydrated form which can be prepared by the process either given in the prior art or in the present invention. The “suitable organic solvent” used in above reaction can be selected from but are not limited to "alcohol solvents" such as methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, tertbutanol, ethane- 1,2-diol, propane- 1,2-diol and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "polar solvent" such as water ; or their mixtures.

[0071] Preferably, the organic solvent used herein may be alcohol, more preferably the solvent may be methanol. Organic solvents, specifically alcohol, can be used 4 to 40 times of volume, preferably 5- 35 times volume of resmetirom, for purpose of dissolution. However, the use of solvent for the dissolution may be varied based on solubility of the organic solvent in resmetirom.

[0072] The mixture of solvents used for the dissolution of resmetirom can be selected from a mixture of alcohol and a polar solvent i.e., water. Preferably, the solvent used can be a mixture of methanol and water. In a mixture of organic solvent and water, the specific ratio of solvents can be utilized to achieve dissolution of resmetirom. The mixture of organic solvent and water in a ratio of 7 to 11 : 1 to 2 (v / v). Preferably, mixture of organic solvent and water in a ratio of 9:1 (v / v) can be used.

[0073] Optionally, the solution can be concentrated by partially recovery of solvent under vacuum, wherein solvent can be recovered from the solution up to 60% to 90% of the solvent used for dissolution. Preferably, solvent can be recovered from 65% to 85% percent of solvent subjected for the partially recovery. Thereafter, the reaction mass can be subjected for cooling to an ambient temperature. After cooling, the resulting reaction mass may be subsequently stirred for a few minutes to few hours for complete crystallization, preferably, stirred for 15 minutes to 90 minutes, more preferably, 15 minutes to 60 minutes.

[0074] Alternatively, the present invention provides a process for the preparation of resmetirom Form I. The process comprises taking resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water and can be stirred for few minutes to few hours at ambient temperature. Thereafter, the reaction mass can be subjected optionally to cooling to below ambient temperature and the resulting reaction mass may be subsequently stirred for 1-2 hours.

[0075] Afterwards, the crystallized solid can be isolated by using techniques known in the art such as filtration, centrifugation etc. The filtration can be done using pressure filtration, gravity filtration, vacuum filtration, and other techniques that are familiar to those skilled in the art. Finally, the resulting material obtained after filtration can be dried at 65-75°C for about 16-24 hours to obtain novel crystalline Form M of resmetirom.

[0076] The preferable drying temperature can be 60-70°C and preferably, the solid can be dried for 16-24 hours and more preferably for 20-24 hours. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.

[0077] The crystalline form M is pure and is an inventive part of the invention. It is advantageous to prepare form M and convert it to pure resmetirom Form I in consistent and reproducible manner.

[0078] Furthermore, the present invention provides a process for the conversion of Form M to resmetirom Form I which is the most thermodynamically stable form of resmetirom.

[0079] In one another embodiment, the present invention provides an efficient process for the preparation of pure resmetirom Form I. The process comprises of adding crystalline Form M of resmetirom in a suitable solvent. Thereafter, the reaction mass can be heated to reflux temperature of the solvent. The solution can be stirred for 15 minutes to 90 minutes, preferably 15 minutes to 60 minutes.

[0080] The “suitable solvent” used in above reaction can be selected from but are not limited to "aliphatic nitrile solvents" such as acetonitrile, isobutyronitrile, chloroacetonitrile, propionitrile, and malononitrile and the like. Preferably, the organic solvent used herein may be acetonitrile.

[0081] Further, the reaction mass can be subjected to cooling at an ambient temperature. Subsequently after cooling, the resulting reaction mass can be stirred for a few minutes to few hours for complete crystallization. Preferably, reaction mass may be stirred for 15 minutes to 90 minutes, more preferably, 15 minutes to 60 minutes. Afterwards, the resulting crystalline compound can be isolated by using techniques known in the art such as filtration, centrifugation etc. The filtration can be done using pressure filtration, gravity filtration, vacuum filtration, and other techniques that are familiar to those skilled in the art. Finally, the resulting material obtained after filtration can be dried at 65-75°C for about 24-36 hours to obtain pure resmetirom Form I. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.

[0082] In one another embodiment, the present invention provides one another process for the preparation of resmetirom Form I. The process comprises heating or drying resmetirom (crude or any other form) at a temperature greater than 100°C for few minutes to few hours. It is advantageous to dry at a temperature of 100-160°C for consistently obtaining resmetirom Form I. Preferably the drying may be carried out at 110-150°C for 1-5 hours.

[0083] Preferably, the process comprises heating or drying resmetirom form M at a temperature greater than 100°C for few minutes to few hours. It is advantageous to dry at a temperature of 100-160°C for consistently obtaining resmetirom Form I. Preferably the drying may be carried out at 110-150°C for 1-5 hours.

[0084] In preferred embodiment of the present invention, pure resmetirom Form I obtained as a crystalline form is substantially free from different and undesired crystalline forms, and wherein the level of impurities either known (^0.15%) or unknown impurities (^0.10%) and limit of residual solvent are controlled as per ICH guidelines.

[0085] In another preferred embodiment of the present invention, resmetirom Form I obtained herein can be micronized to obtain the desired particle size which can be utilized to improve the characteristics for pharmaceutical formulations and therapeutic use thereof. The particle size of resmetirom Form I d90 can be in the range of 1 pm to 50 pm, preferably 1 to 30 pm, more preferably 1 to 10 pm.

[0086] Further, the resulting crystalline resmetirom and resmetirom Form I provided by the present invention can be used in the preparation of THR-P selective agonist drugs. Furthermore, the resulting crystalline resmetirom and resmetirom Form I provided by the present invention can be utilized in the preparation of drugs for the treatment of nonalcoholic steatohepatitis (NASH) and heterozygous familial hypercholesterolemia (HeFH). In an embodiment, the resulting crystalline resmetirom forms can be used to prepare pharmaceutical composition which comprises an effective therapeutic amount of crystalline form of resmetirom and a pharmaceutically acceptable carrier or adjuvant. The pharmaceutical composition of crystalline resmetirom can be used to prepare dosage forms such as tablet, hard gelatin capsules, soft gelatin capsules, injection solutions and sachets.

[0087] In yet another embodiment of the present invention, the crude resmetirom of formula I can be prepared by the method as reported in the product patent US 7,452,882 or by the process as given in the present specification. The process for the preparation of resmetirom comprises condensation of 4-amino-2,6-dichlorophenol with 3,6-dichloropyridazine in the presence of potassium carbonate to produce 4-(6-chloro-5-isopropylpyridazin-3-yloxy)-3,5-dichlorobenzenamine, which is further oxidized in presence of sodium acetate / acetic acid to obtain 6-(4-amino-2,6-dichlorophenoxy)-4- isopropylpyridazin-3(2H)-one. Subsequently, the said compound is diazotized using sodium nitrite and hydrochloric acid in acetic acid / water and condensed with A-cyanoacetylurethane in the presence of sodium acetate or pyridine in water to yield ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5- isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate, which undergoes intra-cyclization by means of sodium acetate and acetic acid to yield a resmetirom.

[0088] Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

[0089] EXAMPLES:

[0090] Example 1: Preparation of crude resmetirom [Repetition of process of W02007 / 009913 Al]

[0091] Ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazineylidene)acetyl)carbamate (3.49g) was taken in glacial acetic acid (72ml) and sodium acetate (2.94g) at room temperature. The reaction mixture was heated to 120°C for 1.5 hours. At this time, the reaction was cooled to 0°C, diluted with water and stirred for 30 minutes. The resulting solid was filtered and rinsed with water followed by petroleum ether. The solid was air dried for 30 minutes. The solid was then diluted with hot acetonitrile (250ml). The resulting red mixture was treated with neutral decolorizing carbon, filtered through celite and rinsed with acetonitrile (IL) until no UV active material eluted. The yellow filtrate was concentrated under reduced pressure and triturated with hot acetonitrile (50ml), cooled for 15 minutes, diluted with water (100ml) and filtered. The solid was triturated again with hot acetonitrile (10ml), filtered and rinsed with acetonitrile, water, and petroleum ether. The solids were collected and dried under high vacuum overnight and then dried in a vacuum oven at 80°C overnight to afford crude resmetirom having acetonitrile content = 51,863 ppm.

[0092] Example 2: Preparation of crude resmetirom

[0093] Ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate (100g) was taken in N,N-dimethylacetamide (200ml) along with sodium acetate (90g). Thereafter, the reaction mass was heated at 105-115°C and stirred till complete dissolution. Subsequently, the reaction mass was cooled to 20-30°C followed by addition of water (1000ml), tetrahydrofuran (500ml) & ethyl acetate (450ml) to extract the material from the reaction mass. Then, the obtained reaction mass was washed with brine solution followed by recovery of the solvent under vacuum at temperature 60-70°C. Finally, acetonitrile (400ml) was added to the residue followed by stirring and recovery of solvent at 60- 70°C. Again, acetonitrile (750ml) was added to the residue and refluxed for 30 minutes, cooled to 20-30°C, stirred for 1 hour and filtered the resulting solid at 20-30°C. The solid was dried at 60- 70°C under vacuum to get crude resmetirom (88.4g) having acetonitrile content = 520 ppm.

[0094] Example 1: Purification of resmetirom

[0095] Resmetirom (10g) having HPLC purity [w / w]= 99.32%; single highest impurity= 0.23% at RRT 1.10; des-monochloro impurity= 0.14% was dissolved in methanol (350 ml) and the solution was stirred for 30 minutes at reflux temperature. Thereafter, the resulting mixture was concentrated under vacuum till 50 ml of methanol was left. The resulting mass was then cooled to 20-30°C and stirred for 60 minutes. Finally, the reaction mass was filtered and dried at 60-70°C to get pure crystalline resmetirom (8g) having HPLC purity [w / w]= 99.64%; impurity at RRT 1.10= 0.09%; des-monochloro impurity=not detected. The X-ray diffraction of the product was shown in Figure 1.

[0096] Example 2: Purification of resmetirom.

[0097] Resmetirom (10g) having HPLC purity [w / w]= 97.68%; impurity= 0.24% at RRT 1.06; des- monochloro impurity= 0.77% was dissolved in methanol (350 ml) and the solution was stirred for 30 minutes at reflux temperature. Thereafter, the resulting mixture was concentrated under vacuum till 100ml of volume of methanol was left and then stirred for 60 minutes. The resulting mass was then cooled to 20-30°C and stirred for 1 hour. Finally, the reaction mass was filtered and dried at 60- 70°C to get pure crystalline resmetirom having HPLC purity [w / w]= 99.77%; impurity at RRT 1.09= 0.04%; des-monochloro impurity= 0.06%.

[0098] Example 3: Purification of resmetirom

[0099] Resmetirom (10g) having HPLC purity [w / w]= 98.68%; single highest impurity= 0.35% at RRT 1.05; des-monochloro impurity= 0.20% was dissolved in methanol (50 ml) and the solution was stirred for 30 minutes at reflux temperature. The resulting solution was then cooled to 20-30°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get pure crystalline resmetirom (7.4g) having HPLC purity [w / w]= 99.82%; impurity at RRT 1.05= 0.04%; des-monochloro impurity= 0.04%. The X-ray diffraction of the product was shown in Figure 2.

[0100] Example 4: Purification of resmetirom

[0101] Resmetirom (10g) having HPLC purity [w / w]= 98.58%; single highest impurity= 0.35% at RRT 1.05; des-monochloro impurity= 0.20% was dissolved in methanol (50 ml) and the solution was stirred for 30 minutes at reflux temperature. The resulting solution was then cooled to 20-30°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get pure crystalline resmetirom (7.4g) having HPLC purity[w / w]= 99.85%; impurity at RRT 1.05= not detected; des-monochloro impurity= 0.02%.

[0102] Example 5: Purification of resmetirom

[0103] Resmetirom (10g) having HPLC purity [w / w]= 98.90%; single highest impurity= 0.27% at RRT 1.05; des-monochloro impurity= 0.71% was dissolved in a mixture of methanol and water (9:1, 160 ml) and the solution was stirred for 30 minutes at reflux temperature. The resulting solution was then cooled to 40-50°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get pure crystalline resmetirom having HPLC purity [w / w]= 99.55%; impurity at RRT 1.05= 0.09%; des-monochloro impurity= not detected. The X-ray diffraction of the product was shown in Figure 3. Example 6: Purification of resmetirom

[0104] Resmetirom (10g) having HPLC purity [w / w]= 98.58%; single highest impurity= 0.35% at RRT 1.05; des-monochloro impurity= 0.20% was dissolved in a mixture of methanol and water (9:1, 160 ml) and the solution was stirred for 30 minutes at reflux temperature. The resulting solution was then cooled to 40-50°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get pure crystalline resmetirom having HPLC purity [w / w]= 99.82%; impurity at RRT 1.05= not detected; des-monochloro impurity= 0.03%.

[0105] Example 7: Purification of resmetirom

[0106] Resmetirom (10g) having HPLC purity [w / w]= 98.58%; single highest impurity= 0.35% at RRT 1.05; des-monochloro impurity= 0.20% was dissolved in a mixture of methanol and water (9:1, 160 ml) and the solution was stirred for 30 minutes at reflux temperature. The resulting solution was then cooled to 40-50°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get pure crystalline resmetirom having HPLC purity [w / w]= 99.77%; impurity at RRT 1.05= not detected; des-monochloro impurity= 0.02%.

[0107] Example 8: Purification of resmetirom

[0108] Resmetirom (3.75 kg) having HPLC purity [w / w] = 99.22%; impurity at RRT 1.05= 0.17%; des- monochloro impurity= 0.02% was dissolved in methanol (18.75 L) and the solution was stirred for 2 hours at 25-30°C. The resulting solution was then cooled to 10-20°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get 2.70 kg pure crystalline resmetirom having HPLC purity [w / w]=99.64%; impurity at RRT 1.05= not detected; des- monochloro impurity= 0.02%.

[0109] Example 9: Preparation of crystalline Form M of resmetirom

[0110] Crude resmetirom (10g) was dissolved in methanol (350ml) and the solution was stirred for 30 minutes at reflux temperature. Thereafter, the resulting mixture was concentrated under vacuum till 100ml of volume of methanol was left and then stirred for 60 minutes. The resulting mass was then cooled to 20-30°C and stirred for 1 hour. Finally, the reaction mass was filtered and dried at 60- 70°C to get crystalline Form M of resmetirom. The X-ray diffraction of the product was shown in Figure 2. Example 10: Preparation of crystalline Form M of resmetirom

[0111] Resmetirom (10g) was dissolved in a mixture of methanol and water (9: 1, 160 ml) and the solution was stirred for 30 minutes at reflux temperature. The resulting solution was then cooled to 40-50°C and stirred for 1 hour. Thereafter, the reaction mass was filtered and dried at 60-70°C to get pure crystalline Form M of resmetirom. The X-ray diffraction of the product was shown in Figure 3.

[0112] Example 11: Preparation of resmetirom Form I

[0113] Resmetirom (285g) was taken in acetonitrile (1710ml) and the reaction mass was stirred for 1 hour at reflux temperature. Thereafter, the reaction mass was cooled to 20-30°C and stirred for 1 hour. Finally, the reaction mass was filtered and the resulting solid was dried at 60-70°C for 24-36 hours to get pure resmetirom Form I (248g) having acetonitrile content: 128 ppm. The X-ray diffraction of the product was shown in Figure 4.

[0114] Example 12: Preparation of resmetirom Form I

[0115] Crystalline Form M of resmetirom (277g) was taken in acetonitrile (1662ml) and the reaction mass was stirred for 1 hour at reflux temperature. Thereafter, the reaction mass was cooled to 20-30°C and stirred for 1 hour. Finally, the resulting mass was filtered and wet cake was dried at 60-70°C for 24-36 hours to obtain resmetirom Form I (236g) having acetonitrile content: 176 ppm and X-ray diffraction of the product was shown in Figure 5.

[0116] Example 13: Preparation of resmetirom Form I

[0117] Crystalline Form M of resmetirom (3.8Kg) was taken in acetonitrile (22.8L) and the reaction mass was stirred for 1 hour at reflux temperature. Thereafter, the reaction mass was cooled to 20-30°C and stirred for 1 hour. Finally, the reaction mixture was filtered and resulting solid compound was dried at 60-70°C for 24-36 hours to obtain pure resmetirom Form I (3.0Kg) having acetonitrile content: 228 ppm. The X-ray diffraction of the product was shown in Figure 6.

[0118] Example 14: Preparation of resmetirom Form I

[0119] Crude Resmetirom (15.30 Kg) was taken in a mixture of methanol and water (9: 1, 245 L) and the solution was stirred for two hours at 20-30°C. Then the resulting mass was filtered and dried at 60- 70°C under vacuum to get pure resmetirom (crystalline Form M). Thereafter, crystalline Form M of resmetirom was taken in acetonitrile (92 L) and the reaction mass was stirred for 1 hour at a reflux temperature. Subsequently, the resulting mass was cooled to 20-30°C and stirred further for 1 hour and filtered. The resulting solid compound was dried at 60-70°C for 24-36 hours to get pure resmetirom Form I.

[0120] Example 15: Preparation of resmetirom Form I

[0121] Crystalline form M of resmetirom (15g) was dried at 110°C in an oven for 3 hours to obtain resmetirom form I. The X-ray diffraction of the product was shown in Figure 7.

[0122] Example 16: Preparation of resmetirom Form I

[0123] Crystalline form M of resmetirom (20g) was dried at 150°C in an oven for 3 hours to obtain resmetirom form I.

[0124] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

Claims

CLAIMS1. A process for the purification of crystalline resmetirom of formula I,Formula Ithe process comprising the steps of: i. dissolving crude resmetirom in a suitable organic solvent, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. cooling the solution obtained in step (ii), iv. isolating the pure crystalline resmetirom.

2. The process as claimed in claim 1, wherein organic solvent in step (i) is selected from an alcohol solvent, ether solvent, ester solvent, polar-aprotic solvent, nitrile solvent or mixture thereof.

3. The process as claimed in claim 2, wherein an alcohol solvent is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; ether solvent is selected from dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and the like; ester solvent is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; polar-aprotic solvent is selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; ketone solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvent is selected from acetonitrile, propionitrile, isobutyronitrile and the like; or their mixtures thereof.

4. A process for the preparation of resmetirom form I of formula I,the process comprising the steps of: i. dissolving resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. cooling the solution obtained in step (ii), iv. isolating the novel crystalline Form M of resmetirom, v. converting crystalline Form M to resmetirom Form I.

5. The process as claimed in claim 4, wherein organic solvent in step (i) is selected from an alcohol solvent, ether solvent, ester solvent, polar-aprotic solvent, nitrile solvent or mixture thereof.

6. Crystalline Form M of resmetirom.

7. A process for the preparation of crystalline Form M of resmetirom of formula I,the process comprising the steps of: i. dissolving resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. cooling the solution obtained in step (ii), iv. isolating the novel crystalline Form M of resmetirom.

8. The process as claimed in claim 7, wherein organic solvent in step (i) is selected from an alcohol solvent, ether solvent, ester solvent, polar-aprotic solvent, nitrile solvent or mixture thereof.

9. A process for the preparation of Form I of resmetirom of formula I,the process comprising the steps of: i. adding crystalline Form M of resmetirom in a suitable organic solvent, ii. heating the reaction mass obtained in step (i) to reflux temperature of the solvent, iii. cooling the solution obtained in step (ii), iv. isolating the pure resmetirom Form I.

10. The process as claimed in claim 9, wherein organic solvent in step (i) is selected from an aliphatic nitrile solvent.

11. A process for the preparation of resmetirom Form I,the process comprising the steps of: i. providing resmetirom in a suitable organic solvent or in a mixture of suitable organic solvent and water, ii. optionally, partially recovering of the solvent from the solution obtained in step (i), iii. optionally cooling the solution obtained in step (ii), iv. isolating the novel crystalline Form M of resmetirom, v. converting crystalline Form M to resmetirom Form I.

12. A process for the preparation of pure resmetirom Form I of formula I,the process comprising the steps of: i. drying crystalline Form M of resmetirom at temperature above 100°C, ii. isolating the pure resmetirom Form I.

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