Solubility vs Dissolution in Physiological Bicarbonate Buffer.

Area of Science:

• Pharmaceutical Science
• Physical Chemistry
• Computational Chemistry

Background:

• Phosphate buffers are common substitutes for physiological bicarbonate buffers in drug dissolution testing.
• Discrepancies in buffer properties complicate the extrapolation of dissolution data from phosphate to in vivo conditions.

Purpose of the Study:

• To characterize solubility and dissolution discrepancies between bicarbonate and phosphate buffers for ionizable compounds.
• To evaluate the predictive accuracy of in silico models for dissolution behavior.

Main Methods:

• In silico simulation of ibuprofen dissolution using reversible non-equilibrium (RNE) and Mooney models.
• In vitro experimental verification of dissolution in bicarbonate and phosphate buffers at varying doses.
• Analysis of surface pH and bulk pH relationships in different buffer systems.

Main Results:

• A significant solubility versus dissolution mismatch was observed between the two buffer systems.
• In-house simulations accurately predicted this mismatch.
• The study identified a large gap between drug surface pH and bulk pH at saturation in bicarbonate, but not in phosphate.

Conclusions:

• The observed discrepancies are attributed to incomplete interfacial reaction equilibrium in bicarbonate buffers.
• Slurry pH measurements are unreliable indicators of surface pH in intestinal bicarbonate buffer.
• Accurate prediction of intestinal drug dissolution requires accounting for H2CO3-CO2 interconversion kinetics.