Resmetirom Crystalline Forms for Stability and Dissolution
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Solution Overview
Problem
There is a need for additional solid state forms of Resmetirom, including crystalline polymorphs and salts, to improve processing, stability, and bioavailability for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and associated dyslipidemias, as existing efforts have primarily focused on glutaric acid co-crystals with limited success.
Innovation Solution
The development of crystalline polymorphs and salts of Resmetirom, such as Resmetirom:nicotinamide, Resmetirom:caffeine, Resmetirom: 2-picolinic acid, Resmetirom:Urea, Resmetirom N-methyl-morpholine salt, Resmetirom piperazine salt, and Resmetirom benzathine salt, along with their crystalline forms, to enhance properties like chemical stability, solubility, and dissolution profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If extensive efforts are made to prepare co-crystals of Resmetirom with many potential co-formers, then co-crystal formation is attempted, but only the glutaric acid co-crystal has been observed despite extensive efforts
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent types (ethanol, isopropanol, acetonitrile, toluene, dichloromethane), temperature ranges (room temperature to -20°C), and pH levels to successfully obtain multiple new polymorphic forms of Resmetirom that were not accessible through conventional methods
Solution Approach 2:
The patent utilizes phase transitions by employing solvent evaporation, cooling crystallization, and pH-adjustment-induced precipitation to transform Resmetirom from solution phase to solid crystalline phase, enabling the isolation of distinct polymorphic forms with different stability and solubility characteristics
2Reliability
If additional solid state forms are developed to improve processing properties and stability, then more polymorphs and salts are created, but the complexity of characterizing and managing multiple forms increases
Solution Approach 1:
The patent segments the complex task of solid state form development into distinct categories: polymorphic forms (Forms 1-22), salt forms (sodium, potassium, calcium, aluminum salts), and co-crystal forms, each with specific characterization protocols and stability profiles, making the overall development more manageable
Solution Approach 2:
The patent employs X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) thermal profiles, and infrared spectroscopy fingerprints as 'color codes' to quickly identify and differentiate between various polymorphic forms, facilitating efficient characterization and quality control
3Productivity
If new solid state forms are discovered to improve dissolution profile and bioavailability, then formulation options are expanded, but the manufacturing process becomes more complex
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent types (ethanol, isopropanol, acetonitrile, toluene, dichloromethane), temperature ranges (room temperature to -20°C), and pH levels to successfully obtain multiple new polymorphic forms of Resmetirom that were not accessible through conventional methods
Solution Approach 2:
The patent uses specific solvents and co-formers as intermediaries during the crystallization process to mediate the formation of desired polymorphic forms, which then serve as stable intermediates for subsequent formulation and manufacturing processes
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These new solid state forms provide improved processing characteristics, stability, and bioavailability, enabling effective treatment of NASH and NAFLD, with potential benefits in formulation and therapeutic efficacy.
Implementation Method 1
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.
Implementation Method 2
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.
Implementation Method 3
thermal behaviors (e.g., measured by thermogravimetric analysis ("TGA"), or differential scanning calorimetry ("DSC"))
Data Source
AI summary
The present disclosure encompasses solid state forms of Resmetirom, in embodiments crystalline polymorphs of Resmetirom, processes for preparation thereof, and pharmaceutical compositions thereof.