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US-12616701-B2 - Solid state forms of Resmetirom

US12616701B2US 12616701 B2US12616701 B2US 12616701B2US-12616701-B2

Abstract

The present disclosure encompasses solid state forms of Resmetirom, in embodiments crystalline polymorphs of Resmetirom, processes for preparation thereof, and pharmaceutical compositions thereof.

Inventors

  • Polina Lapido
  • Jenny Goldshtein
  • Vitaly Krimer
  • Doron RUDIK

Assignees

  • ASSIA CHEMICAL INDUSTRIES LTD.

Dates

Publication Date
20260505
Application Date
20211019

Claims (20)

  1. 1 . Crystalline Resmetirom: caffeine.
  2. 2 . The crystalline Resmetirom: caffeine according to claim 1 , which is a co-crystal.
  3. 3 . The crystalline Resmetirom: caffeine according to claim 1 , which is a salt.
  4. 4 . The crystalline Resmetirom: caffeine according to claim 1 , designated form RC2-A, which is characterized by data selected from one or more of the following: i) an XRPD pattern having peaks at 6.0, 6.8, 10.4, 11.2 and 16.4 degrees 2-theta±0.2 degrees 2-theta; ii) an XRPD pattern as depicted in FIG. 24 ; iii) a solid state 13 C NMR spectrum with characteristic peaks at 139.5, 118.8, 106.7, 34.0 and 29.6 ppm=0.2 ppm; iv) a solid state 13 C NMR spectrum having the following chemical shift absolute differences from reference peak at 161.0 ppm±1 ppm: 21.4, 42.2, 54.3, 127.0 and 131.4 ppm=0.1 ppm; v) a solid state 13 C NMR spectrum substantially as depicted in FIG. 34 , 35 or 36 ; and vi) combinations of these data.
  5. 5 . The crystalline Resmetirom: caffeine according to claim 4 , designated form RC2-A, characterized by the XRPD pattern having peaks at 6.0, 6.8, 10.4, 11.2 and 16.4 degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 14.6, 15.6, 17.8, 19.5 and 26.9 degrees two theta±0.2 degrees two theta.
  6. 6 . The crystalline Resmetirom: caffeine according to claim 4 , which is characterized by an X-ray powder diffraction pattern having peaks at 6.0, 6.8, 10.4, 11.2, 14.6, 15.6, 16.4, 17.8, 19.5 and 26.9 degrees 2-theta±0.2 degrees 2-theta.
  7. 7 . The crystalline Resmetirom: caffeine according to claim 4 , wherein the molar ratio of Resmetirom and caffeine is 1:1.
  8. 8 . The crystalline Resmetirom: caffeine according to claim 4 , which is an anhydrous form.
  9. 9 . The crystalline Resmetirom: caffeine according to claim 4 , which contains no more than about 20% of any other crystalline forms of Resmetirom:caffeine or crystalline Resmetirom: caffeine salt.
  10. 10 . The crystalline Resmetirom: caffeine according to claim 4 , designated form RC2-A which contains no more than about 20% of amorphous Resmetirom:caffeine or Resmetirom: caffeine salt.
  11. 11 . The crystalline Resmetirom: caffeine according to claim 1 , designated form RC2-B, which is characterized by data selected from one or more of the following: i) an XRPD pattern having peaks at 8.9, 10.6, 11.2, 14.5 and 17.1 degrees 2-theta±0.2 degrees 2-theta; ii) an XRPD pattern as depicted in FIG. 25 ; iii) a solid state 13 C NMR spectrum with characteristic peaks at 145.9, 142.7, 108.7, 33.5 and 28.1 ppm±0.2 ppm; iv) a solid state 13 C NMR spectrum having the following chemical shift absolute differences from reference peak at 161.1 ppm±1 ppm: 15.2, 18.45, 52.4, 127.6 and 133.0 ppm±0.1 ppm; v) a solid state 13 C NMR spectrum substantially as depicted in FIG. 37 , 38 or 39 ; and vi) combinations of these data.
  12. 12 . The crystalline Resmetirom: caffeine according to claim 11 , designated form RC2-B, characterized by the XRPD pattern having peaks at 8.9, 10.6, 11.2, 14.5 and 17.1 degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three or four additional peaks selected from 14.9, 20.0, 21.9, 24.5 and 28.2 degrees two theta±0.2 degrees two theta.
  13. 13 . The crystalline Resmetirom: caffeine according to claim 11 , which is characterized by an X-ray powder diffraction pattern having peaks at 8.9, 10.6, 11.2, 14.5, 14.9, 17.1, 20.0, 21.9, 24.5 and 28.2 degrees 2-theta±0.2 degrees 2-theta.
  14. 14 . The crystalline Resmetirom: caffeine according to claim 11 , wherein the molar ratio of Resmetirom and caffeine is 1:1.
  15. 15 . The crystalline Resmetirom: caffeine according to claim 11 , wherein the crystalline form is an anhydrous form.
  16. 16 . The crystalline Resmetirom: caffeine according to claim 11 , which contains no more than about 20% of any other crystalline forms of Resmetirom:caffeine or crystalline Resmetirom: caffeine salt.
  17. 17 . The crystalline Resmetirom: caffeine according to claim 11 , which contains no more than about 20% of amorphous Resmetirom: caffeine or Resmetirom:caffeine salt.
  18. 18 . A pharmaceutical composition comprising a crystalline product according to claim 1 , and at least one pharmaceutically acceptable excipient.
  19. 19 . A process for preparing a pharmaceutical composition comprising combining the crystalline Resmetirom: caffeine according to claim 1 with at least one pharmaceutically acceptable excipient.
  20. 20 . A medicament comprising the crystalline Resmetirom: caffeine according to claim 1 .

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a National Stage of, and claims priority to and the benefit of, International Patent Application No. PCT/US2021/055507, filed Oct. 19, 2021, which, in turn, claims the benefit of and priority to, U.S. Provisional Application No. 63/093,396, filed on Oct. 19, 2020; U.S. Provisional Application No. 63/125,425, filed on Dec. 15, 2020; U.S. Provisional Application No. 63/146,776, filed on Feb. 8, 2021; U.S. Provisional Application No. 63/158,540, filed on Mar. 9, 2021; and U.S. Provisional Application No. 63/208,032, filed on Jun. 8, 2021, the entire disclosures of each of which are incorporated by reference herein. FIELD OF THE DISCLOSURE The present disclosure encompasses solid state forms of Resmetirom, in embodiments crystalline polymorphs of Resmetirom, processes for preparation thereof, and pharmaceutical compositions thereof. BACKGROUND OF THE DISCLOSURE Resmetirom, 2-[3,5-dichloro-4-[(6-oxo-5-propan-2-yl-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile, has the following chemical structure: Resmetirom is a thyroid hormone receptor (THR) β-selective agonist, and it is developed for the treatment of for non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias. The compound is described in International Publication No. WO 2007/009913. International Publication Nos. WO 2014/043706, WO 2018/075650, WO 2020/010068, WO 2021/063367 and WO 2021/129465 relate to crystalline forms and salts of Resmetirom. International Publication No. WO 2020/010068 discloses difficulties in preparing co-crystal of Resmetirom with many potential co-formers, and only the glutaric acid co-crystal has been observed, despite extensive efforts. Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient. Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Resmetirom. SUMMARY OF THE DISCLOSURE The present disclosure provides crystalline polymorphs of Resmetirom and salts thereof. The present disclosure further provides crystalline Resmetirom:nicotinamide, Resmetirom:caffeine, Resmetirom: 2-picolinic acid and/or Resmetirom:Urea and solid state forms thereof. The present disclosure further provides Resmetirom N-methyl-morpholine salt, Resmetirom piperazine salt, Resmetirom benzathine salt, Resmetirom:L-proline, and crystalline forms thereof. The present disclosure also provides processes for preparation thereof, and pharmaceutical compositions thereof. The crystalline forms of Resmetirom as well as R