Mechanistic Analysis of Cocrystal Dissolution, Surface pH, and Dissolution Advantage as a Guide for Rational...

Area of Science:

• Pharmaceutical Sciences
• Physical Chemistry
• Materials Science

Background:

• Ketoconazole, a dibasic drug, exhibits pH-dependent dissolution.
• Cocrystallization is a strategy to modify drug physicochemical properties.
• Understanding dissolution behavior is crucial for drug formulation.

Purpose of the Study:

• To evaluate the pH-dependent dissolution of ketoconazole and its cocrystals.
• To develop mass transport models predicting interfacial pH and drug flux.
• To investigate the impact of acidic coformers on ketoconazole dissolution.

Main Methods:

• Dissolution studies of ketoconazole and its cocrystals with fumaric acid, succinic acid, and adipic acid.
• Application of Fick's law of diffusion and chemical reaction models.
• Development of mass transport models to predict interfacial conditions and flux.

Main Results:

• Cocrystals modulated interfacial pH, reducing ketoconazole's dissolution pH dependence.
• Mass transport models successfully predicted drug flux and interfacial pH.
• A transition pH was identified, above which cocrystal flux surpassed parent drug flux.

Conclusions:

• Cocrystallization with acidic coformers enhances ketoconazole dissolution profiles.
• Mass transport models offer mechanistic insights into dissolution behavior.
• This approach aids in designing cocrystalline solids with improved dissolution.