Mass Transport Analysis of Bicarbonate Buffer: Effect of the CO₂–H₂CO₃ Hydration–Dehydration Kinetics in the Fluid Boundary Layer and the Apparent Effective pKa Controlling Dissolution of Acids and Bases

The main buffering system influencing ionizable drug dissolution in the human intestinal fluid is bicarbonate-based; however, it is rarely used in routine pharmaceutical practice due to the volatility of dissolved CO₂. The typical pharmaceutical buffers used fail to capture the unique aspects of the hydration-dehydration kinetics of the bicarbonate-CO₂ system. In particular, CO₂ is involved in a reversible interconversion with carbonic acid (H₂CO₃), which is the actual conjugate acid of the system, as follows CO₂ + H₂O ⇌ H₂CO₃. In contrast to ionization reactions, this interconversion does not equilibrate very rapidly compared to the diffusional processes through a typical fluid diffusion boundary layer at a solid-liquid interface. In this report, a mathematical mass transport analysis was developed for ionizable drug dissolution in bicarbonate using the rules of conservation of mass and electric charge in addition to accounting for the diffusional times and reaction rate constants of the CO₂-H₂CO₃ interconversion. This model, which includes both the hydration reaction rate and dehydration reaction rate, we called the "reversible non-equilibrium" (RNE) model. The predictions made by this RNE approach for ionizable drug dissolution rates were compared to the experimental data generated by an intrinsic dissolution method for three ionizable drugs, indomethacin, ibuprofen, and haloperidol. The results demonstrate the superiority of predictions for the RNE approach compared to the predictions of a model assuming equilibrium between CO₂ and H₂CO₃, as well as models ignoring reactions. The analysis also shows that bicarbonate buffer can be viewed as having an effective p Ka in the boundary layer that is different from that in bulk and is hydrodynamics-dependent.