FXR Agonist Solid Forms for NASH Stability
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Solution Overview
Problem
There is a need for physically stable, chemically stable, and bioavailable forms of FXR agonists, particularly for the treatment of nonalcoholic steatohepatitis (NASH), as existing forms face challenges with stability, pharmacodynamics variability, drug interactions, pH effects, and oral bioavailability.
Innovation Solution
Development of novel solid forms such as zwitterionic, tromethamine salt, and p-toluenesulfonic acid salt forms of the compound, including crystalline, hydrate, and solvate forms, which exhibit improved physical and chemical stability, bioavailability, and manufacturability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional forms of FXR agonists are used, then the compound can be administered, but physical and chemical stability is poor
Solution Approach 1:
The patent applies parameter changes by converting the compound into different solid forms (crystalline, amorphous, salt forms, solvates, hydrates) which fundamentally alter the physical and chemical parameters of the substance. These parameter changes result in improved stability while maintaining pharmacological activity, directly resolving the contradiction between stability and reliability.
2Stability of the object's composition
If the compound is formulated for improved stability, then stability increases, but aqueous solubility and oral bioavailability decrease
Solution Approach 1:
The patent employs parameter changes by creating various solid forms with different physical properties. The crystalline forms provide stability while the amorphous forms and specific salt forms (like tromethamine salt) enhance solubility and bioavailability, allowing optimization of both stability and ease of operation through selective form selection.
Solution Approach 2:
The patent creates composite material forms by forming salts with tromethamine and other compounds, as well as creating solvates and hydrates. These composite forms combine the active compound with other molecules in specific ratios and structures, achieving both improved stability and maintained or enhanced solubility and bioavailability.
3Ease of manufacture
If stable solid forms are developed, then manufacturing and storage become easier, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the development into distinct solid form categories (crystalline forms, amorphous forms, salt forms, solvates, hydrates). Each category can be independently developed, characterized, and manufactured, simplifying the overall development process despite the multiple forms being explored.
Data Source
AI summary
Disclosed herein are novel solid forms of FXR agonists. The disclosure also relates to pharmaceutical compositions containing one or more of the solid forms disclosed herein, as well as methods of using the solid forms in the treatment of conditions mediated by FXR. The disclosure also relates to methods for obtaining such solid forms.