Crystalline c-Met Kinase Inhibitor Salts for Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current c-Met kinase inhibitors face challenges in stability and polymorphism, affecting their efficacy and usability in treating disorders related to c-Met kinase functioning, such as cancer and inflammation.
Innovation Solution
The development of crystalline forms of Compound A, specifically hydrochloride salts, including mono-HCl salt anhydrate Form I, mono-HCl salt hydrate, mono-HCl salt anhydrate Form II, 1.6-HCl salt hydrate, 1.6-HCl salt anhydrate, and 1.6-HCl salt DMF solvate, characterized by X-ray diffraction, NMR, DSC, and TG analysis, which provide physical and thermal stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If crystalline forms of c-Met kinase inhibitors are developed, then physical stability is improved, but polymorphism issues arise
Solution Approach 1:
The patent applies parameter changes by systematically varying crystallization conditions including solvent selection (DMF, water, isopropanol, acetone), temperature ranges (room temperature to elevated temperatures), pH levels, and drying conditions to generate and characterize multiple distinct crystalline polymorphic forms of Compound A and its hydrochloride salts, thereby improving physical stability while managing polymorphism through controlled parameter variation
Solution Approach 2:
The patent utilizes phase transitions by inducing and characterizing transitions between different crystalline forms through controlled changes in environmental conditions such as humidity, temperature, and solvent exposure, allowing the identification and stabilization of specific polymorphic forms with desired physical stability properties
2Reliability
If multiple crystalline forms are characterized, then consistency in performance is improved, but analysis complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the comprehensive characterization process into distinct analytical modules including X-ray powder diffraction (XRPD) for crystal structure identification, differential scanning calorimetry (DSC) for thermal properties, thermogravimetric analysis (TGA) for compositional stability, and nuclear magnetic resonance (NMR) for molecular structure confirmation, allowing systematic evaluation of each crystalline form's performance consistency
Solution Approach 2:
The patent utilizes color changes as a visual indicator in the crystallization process, where different polymorphic forms exhibit distinct color characteristics that provide rapid preliminary identification and quality assessment, complementing the more sophisticated instrumental analyses and helping ensure consistent performance across batches
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
These crystalline forms exhibit enhanced physical stability and thermal properties, ensuring consistent performance and effectiveness in treating c-Met kinase-related disorders, with specific forms converting between each other based on humidity and solvent conditions.
Implementation Method 1
characterized by X-ray diffraction, NMR, DSC, and TG analysis
Implementation Method 2
characterized by X-ray diffraction, NMR, DSC, and TG analysis
Implementation Method 3
characterized by X-ray diffraction, NMR, DSC, and TG analysis
Implementation Method 4
characterized by X-ray diffraction, NMR, DSC, and TG analysis
Data Source
AI summary
The instant invention relates to crystalline forms of Compound A, an inhibitor of c-MET kinase. Specifically, the instant invention relates to hydrochloride salts of Compound A.