Formula I Crystalline Forms for Stability and Low Water Adsorption
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Solution Overview
Problem
There is a need for improved forms of thyroid hormone receptor β (TRβ) agonists to facilitate pharmaceutical development and address conditions such as adrenoleukodystrophy (ALD) and lipid disorders like hypercholesterolemia and fatty liver diseases.
Innovation Solution
The development of crystalline forms of a compound of Formula I, including solvates and unsolvated Form C, which exhibit specific X-ray powder diffraction peaks and provide improved stability, processability, and low water adsorption, achieved through controlled crystallization methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If amorphous form of compound is used, then ease of manufacture is improved, but stability and water adsorption properties deteriorate
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the compound from amorphous to crystalline form. This phase transition fundamentally alters the molecular arrangement and intermolecular forces, resulting in improved stability and controlled water adsorption properties while maintaining manufacturability through the described crystallization processes.
Solution Approach 2:
The patent directly utilizes phase transitions by converting the amorphous compound into crystalline forms through controlled crystallization. The phase change from disordered amorphous state to ordered crystalline state provides the desired improvement in stability and water vapor adsorption characteristics, resolving the technical contradiction between ease of manufacture and stability.
2Ease of manufacture
If amorphous form of compound is used, then ease of manufacture is improved, but water adsorption properties deteriorate
Solution Approach 1:
The patent applies parameter changes by transforming the physical state of the compound from amorphous to crystalline form. This phase transition fundamentally alters the molecular arrangement and intermolecular forces, resulting in improved stability and controlled water adsorption properties while maintaining manufacturability through the described crystallization processes.
Solution Approach 2:
The patent directly utilizes phase transitions by converting the amorphous compound into crystalline forms through controlled crystallization. The phase change from disordered amorphous state to ordered crystalline state provides the desired improvement in stability and water vapor adsorption characteristics, resolving the technical contradiction between ease of manufacture and stability.
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
The crystalline forms, particularly Form C, offer long-term stability and low water vapor adsorption, enhancing clinical efficacy for treating ALD and lipid disorders.
Implementation Method 1
the crystalline form exhibits an X-ray powder diffraction pattern comprising at least one characteristic peak
Implementation Method 2
X-ray powder diffraction pattern comprising at least one characteristic peak
Implementation Method 3
isolating a crystalline form of a compound of Formula I from the second mixture
Implementation Method 4
isolating a crystalline form of a compound of Formula I from the second mixture
Implementation Method 5
low water adsorption, achieving long-term stability and low water vapor adsorption
Data Source
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AI summary
Disclosed herein are methods of crystallizing the compound of Formula I, as well as crystalline forms thereof. Crystalline forms of Formula I disclosed include the TBME solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, THF solvate crystalline form, EtOAc solvate crystalline form, acetone solvate crystalline form and crystalline Form C.