Enteric coatings have shown in vivo dissolution rates that are poorly predicted by traditional in vitro tests, with the in vivo dissolution being considerably slower than in vitro. To provide a more mechanistic understanding of this, the dependence of the release properties of various enteric-coated (EC) products on bulk pH and bicarbonate molarity was investigated. It was found that, at presumably in vivo-relevant values, the bicarbonate molarity is a more significant determinant of the dissolution profile than the bulk pH. The findings also indicate that this steep relationship between the dissolution of enteric coatings and bicarbonate molarity limits those coatings’ performance in vivo. This is attributed to the relatively low bicarbonate molarities in human intestinal fluids. Further, the hydration and dehydrations kinetics of carbonic acid and carbon dioxide are not sufficiently rapid to reach equilibrium in the diffusion layer surrounding a dissolving ionizable solid. This results in the effective pKa of bicarbonate in the diffusion layer being lower than that determined potentiometrically at equilibrium in the bulk surrounding fluid. These results demonstrate the importance of thoroughly investigating the intestinal bicarbonate concentrations and using bicarbonate buffers or properly designed surrogates (if possible) when evaluating enteric drug products during product development and quality control.