Crystalline Kinase Inhibitor Salts for Stability and Bioavailability
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Solution Overview
Problem
There is a need for compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer to treat various cancers, as their overexpression leads to tumor growth and metastasis.
Innovation Solution
Development of crystalline forms and salts of the kinase inhibitor Compound 1, including specific crystalline solids and crystalline salts, which offer increased stability, solubility, and bioavailability, thereby effectively inhibiting protein kinases like Axl, Mer, c-Met, and KDR.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline forms of Compound 1 are developed, then stability and solubility are improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline forms (polymorphs) of Compound 1, each with distinct crystal structures and properties. Different crystalline forms exhibit varying degrees of stability, solubility, and bioavailability, allowing optimization of these parameters through selective crystal structure engineering rather than modifying the chemical structure itself.
Solution Approach 2:
The patent employs composite material strategies by creating crystalline salts of Compound 1 with various counterions. These salt forms combine the active pharmaceutical ingredient with different ions to achieve enhanced stability and solubility profiles, effectively creating composite crystalline materials with tailored properties for improved therapeutic performance.
2Ease of operation
If crystalline forms of Compound 1 are developed, then solubility and bioavailability are improved, but manufacturing complexity increases
Solution Approach 1:
The patent utilizes parameter changes by establishing structure-property relationships between different crystalline forms and their bioavailability characteristics. By controlling crystal packing arrangements, intermolecular interactions, and lattice energies, the patent optimizes dissolution rates and bioavailability without altering the molecular structure of Compound 1.
Solution Approach 2:
The patent applies phase transition principles by developing multiple solid-state phases (polymorphs) of Compound 1. Each polymorph represents a distinct phase with unique thermodynamic and kinetic properties that directly influence solubility and bioavailability. The selection of appropriate polymorphic forms enables control over dissolution behavior and therapeutic efficacy.
3Reliability
If multiple crystalline forms and salts are developed, then therapeutic efficacy is improved, but product complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically varying crystalline form parameters (polymorphs, salt forms, hydrates) to optimize therapeutic efficacy. Each crystalline modification allows fine-tuning of pharmacokinetic properties such as dissolution rate, stability, and bioavailability, enabling enhanced therapeutic outcomes through solid-state engineering.
Solution Approach 2:
The patent employs segmentation by dividing the single compound into multiple distinct crystalline entities (different polymorphs and salt forms). This segmentation allows each form to be independently characterized, manufactured, and selected for specific therapeutic indications or delivery requirements, facilitating targeted optimization of therapeutic efficacy for different clinical scenarios.
Data Source
AI summary
The present invention relates to crystalline free base of the tyrosine kinase inhibitor, Compound 1. The invention also relates to crystalline salts of Compound 1. The invention also relates to pharmaceutical compositions comprising the solid polymorphs of the free base and salts of Compound 1. The invention further relates to methods of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase.