PI3K Inhibitor Crystalline Forms for Stability and Bioavailability
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Solution Overview
Problem
Existing PI3K inhibitors face challenges in developing forms with desirable properties for drug development, including stability, reproducibility, and bioavailability, which are crucial for effective treatment of diseases such as cancer.
Innovation Solution
Development of salts and crystalline forms of PI3K inhibitors, characterized by unique lattice configurations, to enhance stability and bioavailability, including anhydrous and solvated forms, identified by XRPD, DSC, and TGA, which can be prepared through specific solvent and temperature-controlled processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional forms of PI3K inhibitors are used, then the drug can be administered, but the stability and shelf-life are insufficient
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of the PI3K inhibitor with different lattice configurations. These polymorphic forms exhibit varying degrees of stability and solubility, allowing optimization of both shelf-life and bioavailability. The specific crystalline forms are characterized by unique XRPD patterns, DSC profiles, and TGA data, representing different physical states of the same compound that can be selected based on desired stability and release properties.
2Duration of action of stationary object
If the drug form is optimized for stability, then shelf-life is prolonged, but bioavailability may be reduced
Solution Approach 1:
The patent resolves this contradiction by providing multiple crystalline forms with different physical properties. Less stable polymorphs with lower melting points and higher solubility are selected when bioavailability is the priority, while more stable polymorphs are chosen when shelf-life is critical. This allows flexible selection of the optimal crystalline form based on the specific formulation requirements and intended use.
3Reliability
If amorphous form is used, then bioavailability is improved, but stability and reproducibility deteriorate
Solution Approach 1:
The patent addresses this by characterizing and controlling the crystalline state of the inhibitor. By establishing specific polymorphic forms with defined lattice structures and physical properties, the patent achieves both reproducibility in manufacturing and adequate bioavailability. The crystalline forms provide structural regularity that enhances manufacturing consistency while maintaining sufficient solubility for drug delivery.
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 provide improved stability and bioavailability, prolonging shelf-life and increasing drug efficacy in treating diseases with abnormal PI3K activity.
Implementation Method 1
Development of salts and crystalline forms of PI3K inhibitors, characterized by unique lattice configurations, to enhance stability and bioavailability, including anhydrous and solvated forms, identified by XRPD, DSC, and TGA, which can be prepared through specific solvent and temperature-controlled processes.
Data Source
AI summary
The present invention relates to salts and crystalline forms of 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, crystalline forms of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, and crystalline forms of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d3)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, which are PI3K inhibitors useful in the treatment of cancer and other diseases.