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WO2025083699A2 - Polymorphes de resmétirom et procédé associé - Google Patents

Polymorphes de resmétirom et procédé associé Download PDF

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Publication number
WO2025083699A2
WO2025083699A2 PCT/IN2024/052019 IN2024052019W WO2025083699A2 WO 2025083699 A2 WO2025083699 A2 WO 2025083699A2 IN 2024052019 W IN2024052019 W IN 2024052019W WO 2025083699 A2 WO2025083699 A2 WO 2025083699A2
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Prior art keywords
resmetirom
polymorph
drying
solid
temperature
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WO2025083699A3 (fr
Inventor
Arijit Das
Ramanaiah CHENNURU
Anjaneyaraju Indukuri
Manjunath BOLLINENI
Yerramnaidu BOTCHA
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Cipla Ltd
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Cipla Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to novel crystalline polymorphs of Resmetirom or its salts, hydrates, solvates and to process for preparation thereof.
  • Resmetirom is a selective agonist of thyroid hormone receptor-P which increases hepatic fat metabolism and reduces lipotoxicity.
  • Resmetirom is chemically 2-[3,5- dichloro-4-[(6-oxo-5-propan-2-yl-lH-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-l,2, 4- triazine -6-carbonitrile which has the structure;
  • Resmetirom is disclosed in International Publication No. WO 2007/009913.
  • the WIPO publication nos. WO 2014/043706, WO 2018/075650, WO 2020/010068, WO 2021/063367 relate to various crystalline forms and salts of Resmetirom.
  • Drug polymorphism refers to the existence of two or more crystal forms of the drug. A single molecule may give rise to a variety of polymorphs which have distinct crystal structure and physical properties such as the melting points, TGA, DSC, PXRD, NMR, IR spectrum.
  • the present invention provides novel crystalline polymorphs of Resmetirom or its salts, hydrates, solvates and to the process for preparation thereof.
  • the present invention provides novel crystalline forms of Resmetirom, wherein said polymorphs are selected from the group consisting of;
  • Resmetirom polymorph Form Cl that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 1 having the characteristic peaks at 5.80, 6.09, 6.50, 7.70, 9.60, 9.67, 11.59, 11.64, 13.40, 14.56, and 23.43 degrees ⁇ 29;
  • Resmetirom polymorph Form C2 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 2 having the characteristic peaks at 5.82, 6.07, 6.50, 7.70, 9.60, 11.59, 13.45 and 14.57 degree ⁇ 29;
  • Resmetirom polymorph Form C3 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 3 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ⁇ 29.
  • PXRD powder X-ray diffraction
  • Resmetirom polymorph Form C4 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 4 having the characteristic peaks at 6.40, 7.73, 23.86 and 25.27 degree ⁇ 29.
  • PXRD powder X-ray diffraction
  • the intended therapeutic use of the crystalline forms of Resmetiron is a selective agonist of thyroid hormone receptor-P, the most preferred crystalline forms is Resmetirom polymorph Form Cl and Resmetirom polymorph Form C3 or its salts, hydrates and solvates.
  • the polymorph is polymorph Form C3.
  • Resmetirom polymorph Form C3 is further characterized by DSC exhibiting a broad endothermic peak at 294.79°C and an endothermic peak with an onset at 335.18°C and at 336.32°C (Fig 5).
  • Resmetirom polymorph Form C3 is characterized by TGA exhibiting a weight loss of 0.598% (Fig 6).
  • the Resmetirom polymorph Form C3 post humidification exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 7 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ⁇ 29. This indicates that Form 3 is stable even after humidification.
  • PXRD powder X-ray diffraction
  • the present invention provides the salts of polymorphic Forms Cl, C2, C3 and C4, preferably the ammonium salts.
  • the present invention provides the ammonium salt of polymorph Form Cl characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 8.01, 9.60, 10.71, 13.74, 15.81, 18.01, 19.36, 21.88 and 24.46 degree ⁇ 29 (Fig 8).
  • XRPD powder X-ray diffraction
  • the present invention provides the ammonium salt of polymorph Form C2 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 5.81, 9.28, 11.64, 14.39, 25.48 and 29.0 degree ⁇ 29 (Fig 9).
  • XRPD powder X-ray diffraction
  • the present invention provides the ammonium salt of polymorph Form C3 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 7.03, 8.96, 16.88, 17.95, 23.53 and 24.32 degree ⁇ 29(Fig 10).
  • XRPD powder X-ray diffraction
  • Resmetirom polymorphic forms may be prepared from Resmetirom API or its amorphous form.
  • the processes of preparation of Resmetirom polymorphic forms include seeding.
  • the present invention encompasses the processes that convert different crystalline polymorphic forms of the present invention into one another as well as conversion of the ammonium salt of one polymorphic form as prepared to another.
  • the present invention relates to a process for preparing Resmetirom crystalline polymorph Forms Cl, C2, C3 and C4 comprising; i. Dissolving Resmetirom or its amorphous form in a solvent; ii. Optionally seeding with suitable Resmetirom polymorph; iii. Allowing to crystallize the suitable polymorph; and iv.
  • the crystalline Form is polymorph Form Cl prepared from Resmetirom or its amorphous form in presence of solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
  • the crystalline Form is polymorph Form C2 prepared by drying polymorph Form Cl by controlling the temperature and time;
  • the crystalline Form is polymorph Form C3 prepared from Resmetirom or its amorphous form or ammonia salt in presence of the solvent selected from lower alcohol or trifluoro acetic acid or by drying Form Cl by controlling the temperature and time;
  • the crystalline Form is polymorph Form C4 prepared by drying Form Cl by controlling the temperature and time. wherein one crystalline polymorph Form may be converted to another crystalline polymorph Form.
  • the present invention discloses a process for preparing ammonia salt of Resmetirom polymorph Form Cl, C2, C3 comprising; i. Suspending/ Dissolving Resmetirom or its salt in a solvent; ii. Adding ammonia dissolved in suitable solvent to obtain the product; wherein the ammonia salt of one crystalline polymorph Form may be converted to another crystalline polymorph Form.
  • the present invention provides a process for synthesis of Resmetirom polymorphic Form Cl comprising; i. Dissolving Resmetirom or its amorphous form in a suitable solvent; ii. optionally seeding with Resmetirom polymorph Form Cl; iii. Filtering and drying at a temperature ranging between 40°C to 80°C to obtain the desired product.
  • Resmetirom polymorph Form Cl is obtained from the solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
  • the present invention provides the preparation of ammonium salt of Resmetirom Form Cl comprising; i. Suspending Resmetirom in a solvent and alcoholic ammonia solution for a period of 10-35minutes; ii. Stirring the resulting suspension of step (i) for a period of 50-65mins at room temperature to obtain the solid; iii. Filtering the solid and drying to obtain the desired product.
  • the crystalline Resmetirom polymorph Form Cl or its ammonium salt is used for preparation of other polymorphic forms.
  • the present invention provides a process for preparation of Resmetirom polymorph Form C2 which comprises drying Resmetirom Form Cl, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 100°C to 120°C for a period of 7-10 hours.
  • ATD air tray dryer
  • the present invention provides the preparation of ammonium salt of Resmetirom Form C2 comprising; i. Suspending Resmetirom in a solvent at room temperature followed by adding alcoholic ammonia solution and stirring the mixture for a period of 40-100 minutes to obtain the solid; ii. Filtering the solid and drying to obtain the desired product.
  • the crystalline Resmetirom polymorph Form C2 or its ammonium salt is used for preparation of other polymorphic forms.
  • the present invention provides a process for preparation of Resmetirom polymorph Form C3 comprising drying Resmetirom Form Cl, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 180°C to 210°C for a period of 5-15minutes.
  • the present invention discloses a process for preparation of Resmetirom Form C3 from Resmetirom or its ammonium salt comprising; i. Dissolving Resmetirom in a solvent at room temperature and removing any undissolved particulate to obtain the clear solution; ii. Adding the clear solution of step (i) to the pre-chilled solvent followed by seeding with Resmetirom Form C3 at a temperature ranging between - 10°C to -15°C, stirring the resulted suspension at -5°C to -10°C to obtain the solid; and iii. Filtering the solid and drying to obtain the product.
  • the solvent for obtaining Resmetirom polymorphic Form C3 is selected from lower alcohol, preferably isobutanol or trifluoroacetic acid, the ammonia used in the process is dissolved in C1-C4 alcohol.
  • the Resmetirom polymorphic Form C3 may be obtained from ammonium salt of Resmetirom polymorphic Form Cl, Form C2 or Form C3.
  • the process for preparation of Resmetirom polymorphic Form C3 comprises; i. Suspending the ammonium salt of Resmetirom Form Cl or Form C2 or Form C3 in a solvent at a temperature ranging between -10°C to - 5°C and seeding with Resmetirom Form C3 seed at said temperature to obtain the slurry; ii. Adding Trifluoro acetic acid to the above slurry at a temperature ranging between -10°C to -5°C and stirring at said temperature until a solid is formed; iii.
  • the present invention provides a process for preparation of ammonium salt of Resmetirom Form C3 comprising; i. Suspending ammonium salt of Resmetirom Form Cl in a solvent at room temperature to obtain the slurry; ii. Heating the slurry at a temperature ranging between 40-45°C, stirring at said temperature and cooling to room temperature to obtain the solid; iii. Filtering the solid and drying to obtain the desired product.
  • the solvent for the process is selected from lower alcohols or esters, preferably the ester such as ethyl acetate.
  • the present invention provides a process for preparation of Resmetirom polymorph Form C4 comprising; i. Suspending Resmetirom Form Cl in a suitable solvent; and ii. Filtering, suck drying under vacuum followed by drying under vacuum at a temperature ranging between 65-90°C for a period of 10-12 hours to obtain the desired product.
  • the Resmetirom polymorphic Form C4 is obtained using the solvent selected from aliphatic or aromatic hydrocarbons; preferably aliphatic hydrocarbon.
  • the Resmetirom or its amorphous form used in the present invention are prepared by a process known in the art.
  • the present invention provides a pharmaceutical composition comprising the Resmetirom polymorphic Forms Cl, C2, C3 or C4 or its ammonium salt together with pharmaceutically acceptable excipients.
  • Fig 5 Depicts the DSC thermogram of Resmetirom polymorph Form C3
  • Fig 7 Depicts the PXRD of Resmetirom Form C3 post humidification.
  • Fig 8 Depicts the PXRD of the ammonia salt of Resmetirom polymorph Form Cl.
  • Fig 9 Depicts the PXRD of the ammonia salt of Resmetirom polymorph Form C2.
  • Fig 10 Depicts the PXRD of the ammonia salt of Resmetirom polymorph Form C3
  • any of the words “contains”, “containing”, “including,” “includes,” “comprising,” and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.
  • crystalline form “polymorphs” “polymorphic salt forms” used in the entire specification refer and mean a crystalline form of a substance that is distinct from another crystalline form but shares the same chemical formula.
  • the present invention is directed to novel polymorphs of Resmetirom or its salts, hydrates, solvates and to the process for preparation thereof.
  • the novel polymorphs of Resmetirom are obtained in the present invention by controlling the temperature and time which influences the properties of said polymorphs.
  • the present inventors further observed that various Resmetirom polymorphic Forms can be obtained either from Resmetirom or its salts or from amorphous form or can be prepared from the ammonium salt of its polymorphic forms.
  • the present invention provides a process for the preparation of various polymorphic Forms which are simple and industrially viable.
  • the present invention relates to novel crystalline forms of Resmetirom, wherein said polymorphs are selected from the group consisting of; Resmetirom polymorph Form Cl that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 1 having the characteristic peaks at 5.80, 6.09, 6.50, 7.70, 9.60, 9.67, 11.59, 11.64, 13.40, 14.56, and 23.43 degrees ⁇ 29;
  • PXRD powder X-ray diffraction
  • Resmetirom polymorph Form C2 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 2 having the characteristic peaks at 5.82, 6.07, 6.50, 7.70, 9.60, 11.59, 13.45 and 14.57 degree ⁇ 20;
  • Resmetirom polymorph Form C3 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 3 having the characteristic peaks at 6.53, 7.80, 11.89, 17.07, 23.49 and 24.10 degree ⁇ 29.
  • PXRD powder X-ray diffraction
  • Resmetirom polymorph Form C4 that exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 4 having the characteristic peaks at 6.40, 7.73, 23.86 and 25.27 degree ⁇ 29.
  • PXRD powder X-ray diffraction
  • the intended therapeutic use of the crystalline forms of Resmetiron is a selective agonist of thyroid hormone receptor-P, the most preferred crystalline forms is Resmetirom polymorph Form Cl and Resmetirom polymorph Form C3 or its salts, hydrates and solvates.
  • the present invention preferably relates to Resmetirom polymorph Form C3.
  • the Resmetirom polymorph Form C3 is further characterized by DSC exhibiting a broad endothermic peak at 294.79°C and an endothermic peak with an onset at 335.18°C and at 336.32°C (Fig 5).
  • Resmetirom polymorph Form C3 is characterized by TGA exhibiting a weight loss of 9.598% (Fig 6).
  • the Resmetirom polymorph Form C3 post humidification exhibits a powder X-ray diffraction (PXRD) pattern peaks substantially the same as depicted in Fig 7 having the characteristic peaks at 6.53, 7.89, 11.89, 17.97, 23.49 and 24.19 degree ⁇ 29. This indicates that Form 3 is stable even after humidification.
  • PXRD powder X-ray diffraction
  • the present invention relates to the salts of polymorphic Forms Cl, C2, C3 and C4, preferably the ammonium salts.
  • the present invention discloses the ammonium salt of polymorph Form Cl characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 8.91, 9.69, 19.71, 13.74, 15.81, 18.91, 19.36, 21.88 and 24.46 degree ⁇ 29 (Fig 8).
  • the present invention discloses the ammonium salt of polymorph Form C2 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 5.81, 9.28, 11.64, 14.39, 25.48 and 29.0 degree ⁇ 20 (Fig 9).
  • the present invention relates to the ammonium salt of polymorph Form C3 characterized by powder X-ray diffraction (XRPD) pattern having the characteristic peaks at 7.03, 8.96, 16.88, 17.95, 23.53 and 24.32 degree ⁇ 20(Fig 10).
  • XRPD powder X-ray diffraction
  • the present invention provides a method of synthesizing the various polymorphic forms of Resmetirom viz. Cl, C2, C3 and C4 as well as the preparation of its ammonium salts.
  • Resmetirom polymorphic forms may be prepared from Resmetirom API or its amorphous form.
  • the processes of preparation of Resmetirom polymorphic forms include seeding.
  • the present invention encompasses the processes that convert different crystalline polymorphic forms of the present invention into one another as well as conversion of the ammonium salt of one polymorphic form as prepared to another.
  • the present invention relates to a process for preparing the crystalline forms Cl, C2, C3 and C4 comprising; i. Dissolving Resmetirom or its amorphous form or its ammonia salt in a solvent; ii. Optionally seeding with suitable Resmetirom polymorph; iii. Allowing to crystallize the suitable polymorph; and iv. Filtering said polymorph; wherein a) The crystalline Form is polymorph Form Cl prepared from Resmetirom or its amorphous form in presence of solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
  • solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof.
  • the crystalline Form is polymorph Form C2 prepared by drying polymorph Form Cl by controlling the temperature and time; c) The crystalline Form is polymorph Form C3 prepared from Resmetirom or its amorphous form or ammonia salt in presence of the solvent selected from lower alcohol or trifluoro acetic acid or by drying Form Cl by controlling the temperature and time; d) The crystalline Form is polymorph Form C4 prepared by drying Form Cl by controlling the temperature and time. wherein one crystalline polymorph Form may be converted to another crystalline polymorph Form.
  • the present invention discloses a process for preparing ammonia salt of Resmetirom polymorph Form Cl, C2, C3 comprising; i. Suspending/ Dissolving Resmetirom or its salt in a solvent; ii. Adding ammonia dissolved in suitable solvent to obtain the product; wherein the ammonia salt of one crystalline polymorph Form may be converted to another crystalline polymorph Form.
  • the present invention relates to a process for preparation of Resmetirom polymorph Form Cl comprising; i. Dissolving Resmetirom or its amorphous form in a suitable solvent; ii. optionally seeding with Resmetirom polymorph Form Cl; iii. Filtering and drying at a temperature ranging between 40°C to 80°C to obtain the desired product.
  • Resmetirom or its amorphous form was dissolved in a solvent selected from C1-C4 alcohol, halogenated hydrocarbons such as chloroform, methylene dichloride (MDC) alone or mixtures thereof at a temperature ranging between 22-30°C and stirring the resultant suspension for 3-5 hours. Filtering the solid formed, suck drying under vacuum followed by drying at a temperature in the range of 40-85°C for about 10-15 hours to obtain Resmetirom polymorph Form Cl.
  • the present invention relates to the preparation of ammonium salt of Resmetirom Form Cl comprising; i. Suspending Resmetirom in a solvent and alcoholic ammonia solution for a period of 10-35minutes ; ii. Stirring the resulting suspension of step (i) for a period of 50-65mins at room temperature to obtain the solid ; iii. Filtering the solid and drying to obtain the desired product.
  • Resmetirom was suspended in the solvent selected from lower alcohol, preferably isobutanol followed by addition of alcoholic ammonia over a period of 15-35 minutes and stirring the resulting suspension for about 60mins at room temperature.
  • the resulting solid was filtered under nitrogen atmosphere and further suck dried to obtain the ammonium slat of Resmetirom polymorph Form Cl.
  • the crystalline polymorph Form Cl of Resmetirom or its ammonium salt is used for preparation of other polymorphic forms.
  • the present invention discloses a process for preparation of Resmetirom polymorph Form C2 comprising drying Resmetirom Form Cl, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 100°C to 120°C for a period of 7-10 hours.
  • ATD air tray dryer
  • the present invention relates to the preparation of ammonium salt of Resmetirom Form C2 comprising; i. Suspending Resmetirom in a solvent at room temperature followed by adding alcoholic ammonia solution and stirring the mixture for a period of 50-70 minutes to obtain the solid ; ii. Filtering the solid and drying to obtain the desired product.
  • the ammonium salt of Resmetirom Form C2 was prepared by suspending Resmetirom in lower alcohol selected from methanol, ethanol or isopropanol at room temperature and adding alcoholic ammonia and stirring the resulting suspension for a period of about 60 minutes at room temperature. Filtering the resulting solid, suck drying under vacuum followed by drying at a temperature in the range of 45-55°C to obtain the product.
  • the crystalline polymorph Form C2 of Resmetirom or its ammonium salt is used for preparation of other polymorphic forms.
  • the present invention relates to a process for preparation of Resmetirom polymorph Form C3 comprising drying Resmetirom Form Cl, prepared by the process of the present invention, in the air tray dryer (ATD) at a temperature ranging between 180°C to 210°C for a period of 5- 15minutes.
  • ATD air tray dryer
  • the present invention relates to a process for preparation of Resmetirom Form C3 comprising; i. Suspending Resmetirom in a solvent and alcoholic ammonia and stirring at room temperature to obtain the solid; ii. Filtering and drying the solid under nitrogen atmosphere to obtain Resmetirom ammonium salt; iii. Suspending Resmetirom ammonium salt of step (ii) into a mixture of pre- ccoled solvent and Resmetirom Form C3 seed at a temperature of -5°C followed by slow addition of trifluoroacetic acid at said temperature, stirring and slowly raising the temperature to 5-10°C and stirring to obtain the solid; iv. Filtering the solid of step (iii), washing and drying to obtain the desired product.
  • Resmetirom Ammonium salt as wet material was suspended in a mixture of pre-cooled lower alcohol, preferably isobutanol followed by seeding with Resmetirom Form C3 seed at -5°C.
  • To the resulting suspension was added slowly Trifluoro acetic acid at a temperature ranging between -10°C to - 5°C, stirring at said temperature, raising the temperature to 5-10°C and stirring at said temperature to obtain the solid.
  • Resmetirom was dissolved in a solvent selected from Trifluoro acetic acid at room temperature.
  • the undissolved particulate matter was removed and the clear solution was slowly added to prechilled solvent selected from lower alcohol, preferably isobutanol and Resmetirom Form 3 seed slurry at -10°C to -15°C.
  • the suspension was stirred at a temperature ranging between -5°C to -10°C for about 2-3 hours.
  • the solid obtained was filtered, suck dried under vacuum followed by further drying at a temperature ranging between 40-90°C for about 15-17 hours to obtain Resmetirom polymorph Form C3.
  • the present invention discloses the preparation of Resmetirom Form C3 comprising; i. Suspending the ammonium salt of Resmetirom Form Cl or Form C2 or Form C3 in a solvent at a temperature ranging between -10°C to -5°C and seeding with Resmetirom Form C3 seed at said temperature to obtain the slurry; ii. Adding Trifluoro acetic acid to the above slurry at a temperature ranging between -10°C to -5°C and stirring at said temperature until a solid is formed; iii. Filtering the solid, drying and washing to obtain the desired product.
  • ammonium salt of Resmetirom Form Cl or Form C2 or Form C3 was suspended in the solvent selected from lower alcohol, preferably isobutanol at about -5°C. This was followed by adding Resmetirom Form C3 seed into the above prechilled solvent and stirred at said temperature. Trifluoro acetic acid was then added to the slurry at about -5°C and stirred the resulted suspension for about an hour at said temperature. The solid formed was filtered and suck dried under vacuum.
  • the present invention relates to a process for preparation of ammonium salt of Resmetirom Form C3 comprising; i. Suspending ammonium salt of Resmetirom Form Cl in a solvent at room temperature to obtain the slurry; ii. Heating the slurry at a temperature ranging between 40-45°C, stirring at said temperature and cooling to room temperature to obtain the solid; iii. Filtering the solid and drying to obtain the desired product.
  • ammonium salt of Resmetirom Form Cl was suspended in the solvent such as ethyl acetate at room temperature and the slurry was heated to a temperature in the range of 40°C-45°C and stirred for about 180mins. The reaction mixture was cooled to room temperature. Filtered the resulted solid, suck dried under vacuum for about 30 min followed by drying at about 50°C for 3-5 hours obtain the ammonium salt of Resmetirom Form C3.
  • the present invention relates to a process for preparation of Resmetirom polymorph Form C4 comprising; i. Suspending Resmetirom Form Cl in a suitable solvent; and ii. Filtering, suck drying under vacuum followed by drying under vacuum at a temperature ranging between 65-90°C for a period of 10-12 hours to obtain the desired product.
  • Resmetirom polymorphic Form Cl was suspended in a solvent selected from aliphatic or aromatic hydrocarbon, preferably aliphatic hydrocarbon and stirred at room temperature. The resulting solid was filtered and suck dried under vacuum followed by drying at a temperature of about 80°C for a period of 10-12 hours to obtain Resmetirom Form C4.
  • Resmetirom polymorphic Forms Cl, C2, C3 and C4 or its ammonium salts are stable at all temperature conditions and humidity.
  • Resmetirom polymorphic Form 3 is stable at low temperature of 2-8°C, room temperature and at ACC (amorphous calcium carbonate) conditions.
  • Resmetirom polymorph Form C3 The stability data of Resmetirom polymorph Form C3 is given in the table below.
  • Resmetirom or its amorphous form used as the starting material in the present invention is prepared according to the processes known in the literature.
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising the Resmetirom polymorphic Forms Cl, C2, C3 or C4 or its ammonium salts together with pharmaceutically acceptable excipients.
  • Resmetirom (5.0 gm) amorphous form was suspended in a mixture of Chloroform (98.0 ml) and Methanol (2.0 ml) at room temperature and stirred the resulted suspension for 3 hours. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 80 °C for 6 hours to obtain the title compound.
  • Resmetirom (4.5 gm) was suspended in a mixture of Chloroform (88.2 ml) and Methanol (1.8 ml) along with 170 mg of Resmetirom Form Cl seed at room temperature and stirred the resulted suspension for 2 hours at room temperature. Filtered the resulted solid, suck dried under vacuum for 10 min followed by drying under vacuum at 80 °C for 10-12 hours to obtain the title compound.
  • Resmetirom (0.7gm) was suspended in methylene dichloride (MDC) (14 ml) along with 140 mg of Resmetirom Form Cl seed at 0-5°C and stirred the resulted suspension for 2 hours at 0-5°C. Filtered the resulted solid, suck dried under vacuum for 10 min followed by drying at 40 °C for 2 hours and at 60°C for 10-12 hours to obtain the title compound.
  • MDC methylene dichloride
  • Resmetirom (135. Ogm) was suspended in MDC (2025 ml) along with 2.7 g of Resmetirom Form Cl seed at 22-25°C and stirred the resulted suspension for 4 hours at 22-25°C. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 40 °C for 6 hours and at 60°C for 10-12 hours to obtain the title compound.
  • Resmetirom Form Cl obtained by any of the process of examples 1 to 4 was heated at 200 °C for 5-10 min to obtain the title compound.
  • Example 7 Process for preparation of Resmetirom Form C3 from Resmetirom Ammonia salt
  • Resmetirom 70gm was suspended in isobutanol (1400 ml) and added 70 ml of methanolic ammonia over a period of 15-30 min and stirred the resulted suspension for 60mins at room temperature. Filtered the resulted solid in Pressure Nutsche Filter (PNF) under nitrogen, suck dried under nitrogen for 30 min to obtain Resmetirom Ammonia salt. Above Resmetirom ammonia salt wet material was then suspended into a mixture of pre-cooled isobutanol (1050 ml) along with 3.5g of Resmetirom Form C3 seed at -5°C.
  • PNF Pressure Nutsche Filter
  • Resmetirom (10.0 gm) was dissolved in a Trifluoro acetic acid (50.0 ml) at room temperature. Any undissolved particulate were removed to obtain particle free solution and the resulted clear solution was slowly added to pre-chilled isobutanol (200ml) and Resmetirom Form C3 (0.5g) seed slurry at -10°C to -15°C. Stirred the resulted suspension for 2 hours at -5°C to -10°C. Filtered the solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 90°C for 15 hours to obtain the title compound.
  • Resmetirom 400gm was suspended in Isobutanol (3200 ml) and added 800 ml of Isobutanolic ammonia over a period of 15-30 min and stirred the resulted suspension for 60mins at room temperature. Added 800ml of Isobutanol and stirred the resulted suspension for 120mins at room temperature. Filtered the resulted solid in ANFD (agitated nutsche filter dryer) under nitrogen, suck dried under nitrogen for 120 min followed by drying at 50 °C for 2 hours to obtain Resmetirom Ammonia salt.
  • ANFD agitated nutsche filter dryer
  • Resmetirom ammonia salt wet material suspended into a mixture of precooled Isobutanol (6000 ml) along with 20 g of Resmetirom Form C3 seed at - 2°C.
  • To this resulted suspension slowly added Trifluoro acetic acid (320 ml) at - 2°C and stirred for 30min at 2°C and the raised temperature to 8-10°C and stirred at this temperature for lOhrs. Filtered the resulted solid, and bed washed with 400ml of Isobutanol, suck dried under vacuum for 60 min.
  • the wet material was again suspended in 4000 ml of Iso-butanol at 8-10°C and stirred for 1 hr at 8-10°C then filtered the material and suck dried the material under vacuum followed by drying at 30 °C for 2 hours and 40 °C for 6 hours and 60°C for 10 hours and 80°C for 5 hours.
  • Example 10 Process for preparation of Resmetirom Form C3 from ammonia salt of Resmetirom Form Cl
  • Resmetirom Form Cl (5.0 gm) was suspended in Isobutanol (75.0ml) at -5°C.
  • Resmetirom Form C3 (250 mg) seed was added into above prechilled Isobutanol solution and stirred for 5 min at -5°C.
  • Trifluoro acetic acid (1.8 ml) was added to the above slurry at -5°C and stirred the resulted suspension for 1 hour at -5°C. Filtered the solid, suck dried under vacuum for 30 min.
  • the wet material was further slurried in 50ml of Isobutanol at 0-5°C for Jackpot then filtered, suck dried under vacuum for 30 min followed by drying at 40°C for 3 hours and at 60 °C for 3 hours and then at 90 °C for 24 hours to obtain the title compound.
  • Example 11 Process for preparation of Resmetirom Form C3 from ammonia salt of Resmetirom Form C2
  • Resmetirom Form C2 (1.0 gm) was suspended in Isobutanol (15ml) at 10°C to 15°C.
  • Resmetirom Form C3 (50mg) seed was added into above prechilled Isobutanol solution and stirred for 5min at 10°C to 15°C.
  • Trifluoro acetic acid (0.35ml) was added to the above slurry at 10-15°C and stirred the resulted suspension for 2 hour at 10°C to 15°C. Filtered the solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 90 °C for 15 hours to obtain the title compound.
  • Example 12 Process for preparation of Resmetirom Form C3 from ammonia salt of Resmetirom Form C3
  • Resmetirom Form C3 (1.3gm) was suspended in Isobutanol (22.5ml) at 10°C to 15°C and added Resmetirom Form C3 (75mg) into the above slurry and stirred for 5min at 10°C to 15°C.
  • Trifluoro acetic acid (0.52ml) was added to the above slurry at 10-15°C and stirred the resulted suspension for 4 hours at 10°C to 15°C. Filtered the solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours and at 90°C for 15 hours to obtain the title compound.
  • Resmetirom 70gm was suspended in Isobutanol (1400 ml) and added 70 ml of Methanolic ammonia over a period of 15-30 min and stirred the resulted suspension for 60mins at room temperature. Filtered the resulted solid in PNF under nitrogen, suck dried under nitrogen for 30 min to obtain the title compound. Yield: 68.5 gram
  • Resmetirom (5.0 gm) was suspended in Methanol (20 ml) at room temperature and added 5.0 ml Methanolic ammonia and stirred the resulted suspension for 60mins at room temperature. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 50 °C for 4 hours obtain the title compound.
  • Ammonia salt of Resmetirom Form Cl (4.0 gm) was suspended in Ethyl acetate (40 ml) at room temperature, Heated the slurry to 40 ⁇ 5°C and stirred for 180 mins at this temperature then cooled to the room temperature. Filtered the resulted solid, suck dried under vacuum for 30 min followed by drying at 50°C for 4 hours to obtain the title compound.
  • Resmetirom Form Cl prepared by any of the process of examples 1 to 4 was suspended in 4ml of n-Heptane and stirred for 3 hours at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne les nouveaux polymorphes de resmétirom ou ses sels, hydrates, solvates et leur procédé de préparation.
PCT/IN2024/052019 2023-10-16 2024-10-08 Polymorphes de resmétirom et procédé associé Pending WO2025083699A2 (fr)

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WO2014043706A1 (fr) 2012-09-17 2014-03-20 Madrigal Pharmaceuticals, Inc. Procédé de synthèse d'analogues de l'hormone thyroïdienne et de ses polymorphes
WO2018075650A1 (fr) 2016-10-18 2018-04-26 Madrigal Pharmaceuticals, Inc. Méthodes de traitement de troubles hépatiques ou de troubles lipidiques avec un agoniste thr-bêta
WO2020010068A1 (fr) 2018-07-02 2020-01-09 Madrigal Pharmaceuticals, Inc. Formes solides de 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phényl)-3,5-dioxo-2,3,4,5-tétrahydro-1,2,4-triazine-6-carbonitrile
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CN114787153A (zh) * 2019-12-26 2022-07-22 苏州科睿思制药有限公司 一种Resmetirom晶型及其制备方法和用途
AU2021341182A1 (en) * 2020-09-10 2023-04-27 Crystal Pharmaceutical (Suzhou) Co., Ltd. Crystal form of resmetirom, preparation method therefor, and use thereof
CN114907327A (zh) * 2021-02-10 2022-08-16 杭州领业医药科技有限公司 Resmetirom的晶型及其制备方法和用途
CN115124515A (zh) * 2021-04-16 2022-09-30 杭州领业医药科技有限公司 Resmetirom的晶型及其制备方法
CN119143733A (zh) * 2023-06-14 2024-12-17 四川弘远药业有限公司 一种甲状腺激素受体激动剂的晶型及其制备方法和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007009913A1 (fr) 2005-07-21 2007-01-25 F. Hoffmann-La Roche Ag Derives de pyridazinone utilises comme agonistes du recepteur de l'hormone thyroidienne
WO2014043706A1 (fr) 2012-09-17 2014-03-20 Madrigal Pharmaceuticals, Inc. Procédé de synthèse d'analogues de l'hormone thyroïdienne et de ses polymorphes
WO2018075650A1 (fr) 2016-10-18 2018-04-26 Madrigal Pharmaceuticals, Inc. Méthodes de traitement de troubles hépatiques ou de troubles lipidiques avec un agoniste thr-bêta
WO2020010068A1 (fr) 2018-07-02 2020-01-09 Madrigal Pharmaceuticals, Inc. Formes solides de 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phényl)-3,5-dioxo-2,3,4,5-tétrahydro-1,2,4-triazine-6-carbonitrile
WO2021063367A1 (fr) 2019-09-30 2021-04-08 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation

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