Kinase Inhibitor Polymorphs via Controlled Crystallization
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Solution Overview
Problem
There is a need for polymorphs and salt forms of inhibitors targeting PI3Ks, mTor, and Akt, as existing kinase inhibitors face challenges due to variations in chemical and physical properties affecting manufacturing, quality, safety, and efficacy.
Innovation Solution
A method involving suspending or dissolving a compound in an organic solvent system, adding an acid, subjecting the mixture to heating and cooling cycles, and isolating the resulting polymorph or salt, specifically using nitromethane, THF, or acetonitrile as solvents and hydrochloric or hydrobromic acid as acids to produce pharmaceutically acceptable crystalline salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing kinase inhibitors are used, then therapeutic activity is achieved, but variations in chemical and physical properties affect manufacturing consistency and drug quality
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent type (nitromethane, THF, acetonitrile), acid selection (hydrochloric or hydrobromic acid), temperature cycles, and pH levels to generate distinct polymorphic forms. Each polymorph exhibits consistent and unique chemical and physical properties, thereby resolving the issue of property variations while maintaining manufacturing reliability
Solution Approach 2:
The invention utilizes phase transitions through controlled heating and cooling cycles during crystallization to produce different polymorphic forms. By manipulating temperature phases and solvent evaporation rates, the patent generates stable crystalline structures with consistent properties, eliminating the variability problem while ensuring reliable manufacturing outcomes
2Manufacturing precision
If polymorphic forms are developed to improve manufacturing consistency, then production complexity increases
Solution Approach 1:
The patent employs parameter changes by establishing specific, optimized crystallization conditions for each polymorph. By defining precise parameters such as solvent composition, acid concentration, temperature ranges, and pH levels, the process achieves high manufacturing precision while maintaining operational simplicity through standardized protocols
Solution Approach 2:
The crystallization process utilizes self-service principles by allowing the system to naturally progress through heating and cooling cycles that drive spontaneous crystal formation. The selected solvents and acids facilitate automatic phase separation and crystal precipitation, reducing the need for complex external interventions while ensuring consistent drug product quality
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
This method produces stable and effective polymorphs and salts of kinase inhibitors with consistent chemical and physical properties, enhancing manufacturing processes and pharmacokinetic profiles, thereby improving the quality and safety of drug products.
Implementation Method 1
suspending or dissolving the compound of Formula I in an organic solvent system
Implementation Method 2
subjecting the mixture to at least one heating and cooling cycle
Implementation Method 3
isolating the polymorph
Data Source
AI summary
Polymorphs of chemical compounds that modulate kinase activity, including PI3K activity, and chemical compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3K activity, are described herein.