Kinase Inhibitor Polymorphs for Stable Cancer Drug Formulation
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Solution Overview
Problem
Existing kinase inhibitors lack stable polymorphic forms that maintain their physical and pharmacokinetic properties, affecting drug quality, safety, and efficacy, and there is a need for specific compounds that inhibit tyrosine and serine/threonine kinases to regulate abnormal cell proliferation.
Innovation Solution
Development of crystalline forms of a compound of Formula I, characterized by specific X-ray powder diffraction patterns and thermal properties, including polymorphs Form I and Form VI, which are stable under various storage conditions and maintain their integrity over time.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If kinase inhibitors are developed to inhibit tyrosine and serine/threonine kinases for treating cancer, then therapeutic efficacy is improved, but physical stability and pharmacokinetic consistency deteriorate due to polymorphism
Solution Approach 1:
The patent applies parameter changes by identifying and characterizing specific polymorphic forms (Form I and Form VI) with distinct crystal structures and physical properties. By controlling polymorphic form selection and characterization through X-ray powder diffraction patterns and thermal properties, the invention achieves both therapeutic efficacy and physical stability. The different polymorphic forms offer varying solubility, dissolution rate, and stability parameters that can be optimized for specific therapeutic applications.
Solution Approach 2:
The patent employs composite material principles by creating pharmaceutical compositions that incorporate specific polymorphic forms of kinase inhibitors with defined physical characteristics. The composition includes the crystalline form combined with excipients and manufacturing processes that maintain polymorphic integrity, ensuring consistent pharmacokinetic profiles and therapeutic reliability while addressing physical stability concerns.
2Ease of manufacture
If polymorphic forms are used to optimize drug properties, then manufacturing flexibility is improved, but product consistency and quality control deteriorate
Solution Approach 1:
The patent resolves this contradiction by establishing precise parameter specifications for each polymorphic form through characterization of X-ray powder diffraction patterns, thermal properties, and physical constants. This enables manufacturers to select appropriate polymorphic forms based on desired properties while maintaining strict quality control through defined acceptance criteria, thus achieving both manufacturing flexibility and product consistency.
Solution Approach 2:
The patent replaces physical inspection methods with X-ray powder diffraction analysis and thermal characterization techniques for polymorphic form identification and quality control. This substitution of analytical methods enables precise, objective measurement of crystal structure parameters, ensuring consistent product quality while allowing flexibility in manufacturing different polymorphic forms as needed.
3Duration of action of stationary object
If storage conditions are optimized to maintain drug stability, then shelf life is improved, but physical form transformation and degradation worsen under varying environmental conditions
Solution Approach 1:
The patent applies preliminary anti-action by pre-characterizing the stability profiles of different polymorphic forms under various environmental conditions (temperature, humidity, light). This advance knowledge enables the establishment of appropriate storage conditions and packaging requirements before market release, preventing polymorphic transformation and degradation. The invention identifies which polymorphic forms are inherently more stable under specific conditions, allowing proactive selection and protection strategies.
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 of Formula I provide stability and consistency in drug properties, enabling effective treatment of cancers mediated by EGFR mutations, with potential for prolonged storage and reduced degradation.
Implementation Method 1
the polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 21.4 ±0.2 degrees, 18.3 ±0.2 degrees and 22.7 ±0.2 degrees two theta
Implementation Method 2
characterized by an X-ray powder diffraction pattern comprising peaks
Implementation Method 3
the composition can be stored at about 40 °C, 75% relative humidity, for a time period of about 30 days or more without significant degradation or change in the crystalline form
Implementation Method 4
The identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial. Moreover, differences in these properties can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug
Data Source
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AI summary
Chemical entities that are kinase inhibitors, their polymorphs, pharmaceutical compositions and methods of treatment of cancer are described herein.