Cocrystal solubility product analysis - Dual concentration-pH mass action model not dependent on explicit solubility...

Area of Science:

• Pharmaceutical Sciences
• Computational Chemistry
• Physical Chemistry

Background:

• Cocrystal (CC) solubility product (Ksp) determination is crucial for drug development.
• Existing methods may not fully capture complex pH-dependent behaviors of CCs.
• Understanding CC solubility is key to predicting drug performance and bioavailability.

Purpose of the Study:

• To introduce a novel general computational approach for CC Ksp determination.
• To develop and validate a program (pDISOL-X) for analyzing CC systems.
• To investigate pH-dependent solubility and potential complexation in various drug-cocrystal systems.

Main Methods:

• Development and validation of the pDISOL-X computational program.
• Utilized published dual concentration-pH data for active pharmaceutical ingredients (APIs) and coformers.
• Applied Stokes-Robinson hydration theory to adjust equilibrium constants for activity effects based on calculated ionic strength.

Main Results:

• Validated pDISOL-X with multiple API-CC systems (carbamazepine, indomethacin, nevirapine, gabapentin).
• Observed pH-dependent solubility elevation in carbamazepine-cinnamic acid CC, suggesting complex formation.
• Identified distinct solid suspension zones for the gabapentin:3-hydroxybenzoic acid CC system across different pH ranges.

Conclusions:

• The pDISOL-X program offers a versatile computational tool for CC Ksp determination.
• The approach successfully models complex equilibria, including drug-coformer complexation.
• Insights into pH-sensitive dissolution effects can inform bioavailability predictions.