KRAS G12C Inhibitor Polymorphs for Solubility and Stability
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Solution Overview
Problem
Existing polymorphic forms of Compound 1, a selective KRAS G12C inhibitor, do not meet regulatory approval standards for solubility, stability, and bioavailability, which are crucial for effective cancer treatment formulations.
Innovation Solution
Development of new crystalline, anhydrous, hydrate, and solvate forms of Compound 1, along with pharmaceutical compositions, to enhance solubility, stability, and bioavailability, addressing regulatory requirements for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing polymorphic forms of Compound 1 are used, then the compound can be manufactured, but the solubility, stability, and bioavailability do not meet regulatory approval standards
Solution Approach 1:
The patent applies parameter changes by discovering and characterizing multiple polymorphic forms (Forms I-V) of Compound 1, each with distinct crystal structures and physical properties. By changing the polymorphic form parameter, the invention achieves different solubility, stability, and bioavailability profiles, allowing selection of forms that meet regulatory standards while maintaining manufacturability
Solution Approach 2:
The patent employs composite material strategies by creating pharmaceutical compositions that combine Compound 1 in specific polymorphic forms with excipients and formulation components. These composite formulations optimize the therapeutic performance and regulatory compliance of the drug product
2Reliability
If new polymorphic forms are developed to improve solubility and bioavailability, then regulatory approval prospects improve, but formulation and manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by thoroughly characterizing and establishing the stability profiles of multiple polymorphic forms before formulation development. By pre-identifying the most suitable polymorphic forms and their optimal formulation conditions, the invention reduces downstream manufacturing complexity and facilitates regulatory approval
Solution Approach 2:
The patent employs simplified characterization methods and readily available analytical techniques to assess polymorphic forms, avoiding the need for complex, expensive, or specialized equipment. This approach reduces manufacturing complexity while maintaining rigorous quality standards
3Ease of operation
If polymorphic forms with different physical properties are selected, then solubility and bioavailability can be optimized, but manufacturing and storage stability becomes more challenging
Solution Approach 1:
The patent applies local quality by optimizing formulation conditions specifically tailored to each polymorphic form's unique physical properties. By adjusting local formulation parameters (such as pH, excipients, and processing conditions) to match the characteristics of selected polymorphic forms, the invention achieves both high solubility/bioavailability and manufacturing/storage stability
Solution Approach 2:
The patent employs beforehand cushioning by incorporating stability-enhancing excipients and protective formulation strategies that prevent polymorphic transitions during manufacturing and storage. By pre-mitigating potential stability issues through careful formulation design, the invention maintains both high solubility performance and long-term stability
Data Source
AI summary
The present disclosure provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, including several anhydrous, hydrate and solvate forms, and solid state forms thereof, pharmaceutical compositions, and methods of treating a disease mediated by KRAS G12C inhibition.