Crystalline Solvate Forms of CFTR Potentiator Compound
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the CFTR protein, face challenges in stabilizing and delivering effective pharmaceutical compositions that can address the defective trafficking and function of mutant CFTR proteins like ΔF508, leading to inadequate ion and fluid transport in patients.
Innovation Solution
Development of crystalline solvate forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, including Forms D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, W, and Hydrate B, which are characterized by specific XRPD patterns and thermogravimetric traces, to enhance bioavailability and therapeutic efficacy as CFTR potentiators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If crystalline solvate forms are developed to improve stability and bioavailability, then therapeutic efficacy is improved, but the complexity of the pharmaceutical composition increases
Solution Approach 1:
The patent applies parameter changes by developing multiple crystalline solvate forms (Forms D through T and Hydrate B) with different solvent molecules and crystalline structures. Each form represents a different physical state parameter of the same chemical compound, allowing optimization of stability and bioavailability without changing the core molecular structure. This resolves the contradiction by providing stable formulations through physical form variation rather than chemical modification.
Solution Approach 2:
The patent employs composite materials by creating crystalline solvates where the active pharmaceutical ingredient forms a composite crystal structure with various solvent molecules (acetonitrile, methylethyl ketone, isopropyl acetate, water). These composite crystalline structures combine the drug molecule with solvent molecules in specific ratios and arrangements, achieving enhanced stability and bioavailability while maintaining a defined compositional framework that manages complexity.
2Reliability
If crystalline solvate forms are developed to improve bioavailability, then therapeutic efficacy is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-characterizing multiple crystalline solvate forms with their specific XRPD patterns, thermogravimetric traces, and stability profiles before clinical use. By establishing the characteristics of Forms D through T and Hydrate B in advance, the patent enables selection of the most manufacturable form based on predetermined data, reducing the need for extensive development work during production and simplifying the manufacturing process.
3Reliability
If multiple crystalline forms are developed to address defective CFTR trafficking, then therapeutic efficacy is improved, but the time required for development and characterization increases
Solution Approach 1:
The patent applies phase transitions by utilizing different crystalline phases (Forms D through T and Hydrate B) of the same compound. Each crystalline form represents a different solid phase with distinct properties. By systematically characterizing these phase transitions and their corresponding XRPD patterns and thermogravimetric behaviors, the patent accelerates the identification of optimal therapeutic forms, reducing development time through structured phase analysis rather than trial-and-error approaches.
Data Source
AI summary
The present invention relates to crystalline solvate forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and methods for their preparation. The present invention further relates to pharmaceutical compositions comprising the crystalline solvate forms, as well as methods of treatment therewith.