RORγt Modulator Solid Forms and Synthesis
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Solution Overview
Problem
Current methods for developing commercial drug candidates, such as the compound (S)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl) acetamide, face challenges in finding cost-effective synthetic methods for large-scale manufacturing and suitable pharmaceutically acceptable salt forms that offer improved handling, physicochemical, and pharmacokinetic properties.
Innovation Solution
The development of novel solid state forms, including crystalline and amorphous forms, of the compound, along with an improved process for large-scale synthesis that provides high yield and purity, suitable for pharmaceutical compositions and therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthetic methods are used for large-scale manufacturing, then the compound can be produced, but the cost-effectiveness and efficiency are insufficient
Solution Approach 1:
The patent modifies reaction parameters including using cesium carbonate as a superior base, conducting reactions at optimized temperatures, and adjusting solvent systems to achieve higher yields and purity, thereby improving both productivity and cost-effectiveness of large-scale manufacturing
Solution Approach 2:
The patent replaces conventional mechanical filtration methods with filtration through celite bed, and substitutes traditional workup procedures with more efficient purification methods that reduce time and resource consumption in large-scale production
2Reliability
If the compound is developed for pharmaceutical use, then therapeutic efficacy is achieved, but suitable pharmaceutically acceptable salt forms with improved handling properties are difficult to obtain
Solution Approach 1:
The patent prepares multiple salt forms including hydrochloride, sulfate, and mesylate salts by reacting the free base with different acids, thereby optimizing handling properties such as solubility, stability, and crystallinity while maintaining therapeutic efficacy
Solution Approach 2:
The patent creates composite pharmaceutical compositions by combining the RORγt modulator with pharmaceutically acceptable excipients, carriers, and formulation agents to improve handling, stability, and delivery while preserving the core therapeutic activity
3Manufacturing precision
If pure crystalline forms are produced, then purity and stability are improved, but the manufacturing process complexity increases
Solution Approach 1:
The patent incorporates preliminary filtration through celite during the reaction process to remove impurities early, and uses pre-optimized crystallization conditions to directly obtain pure crystalline product, thereby achieving high purity without requiring multiple complex purification steps
Solution Approach 2:
The patent uses celite as an intermediary filtration medium to simplify purification, and employs specific solvents as intermediaries to facilitate crystallization of pure product, reducing overall process complexity while maintaining high manufacturing precision
Data Source
AI summary
The present invention is directed to solid state forms of a compound which has retinoid-related orphan receptor gamma (RORy) modulator activity. Particularly the present invention relates to solid state forms of the compound (S)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl) acetamide, processes for their preparation, pharmaceutical compositions containing the same and their use in therapy. More, particularly the present invention relates to crystalline form of the compound (S)-2-(4-(1,1-difluoro-2-hydroxypropyl)phenyl)-N-(4-(3-(2-ethylphenyl)pyrazin-2-yl)phenyl)acetamide, processes for their preparation, pharmaceutical compositions containing the same and their use in therapy.