Crystalline CFTR Modulator Salts for Stability-Solubility Balance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation in the CFTR protein, are inadequate in addressing the reduced anion transport and defective channel gating, leading to severe respiratory and gastrointestinal issues, with a need for compounds that can effectively modulate CFTR activity to reduce disease severity.
Innovation Solution
Development of crystalline forms of the CFTR-modulating compound (14S)-8-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19-hexaene-2,2,4-trione, and its pharmaceutically acceptable salts, which may exhibit higher purity, stability, and lower hygroscopicity compared to amorphous forms, administered alone or in combination with other CFTR modulators to enhance anion transport.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If amorphous forms of CFTR modulators are used, then solubility and bioavailability may be improved, but stability and purity are reduced
Solution Approach 1:
The patent applies parameter changes by transitioning the CFTR modulator from amorphous to crystalline form, fundamentally altering the physical state and molecular arrangement. This phase transition resolves the contradiction by providing a stable, pure crystalline structure that maintains adequate solubility while dramatically improving stability and purity characteristics.
Solution Approach 2:
The invention directly employs phase transitions by discovering and characterizing multiple crystalline polymorphs (Forms A, B, and C) of the CFTR modulator. Each polymorph represents a distinct phase with unique stability and solubility characteristics, allowing optimization of the stability-solubility trade-off through selective crystalline form selection.
2Speed
If amorphous forms of CFTR modulators are used, then dissolution rate may be improved, but manufacturing precision and purity are reduced
Solution Approach 1:
The patent resolves this contradiction by changing the physical state parameter from amorphous to crystalline, achieving well-defined purity standards and manufacturing precision while maintaining clinically effective dissolution rates through polymorph selection and characterization.
3Reliability
If crystalline forms of CFTR modulators are developed, then purity and stability are improved, but device complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the crystalline form characterization into distinct, manageable polymorphs (Forms A, B, and C), each with specific XRPD patterns and characteristics. This segmentation allows systematic identification, characterization, and selection of optimal crystalline forms without overwhelming complexity.
4Reliability
If multiple crystalline polymorphs are characterized, then treatment efficacy can be optimized, but measurement precision requirements increase
Solution Approach 1:
The patent segments the complex task of crystalline form identification into distinct polymorph categories (Forms A, B, and C), each with characteristic XRPD patterns. This segmentation simplifies measurement and identification requirements compared to attempting to characterize all possible crystalline variations as a single complex system.
Data Source
AI summary
Crystalline forms of salts of Compound I are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.