The objective of this work was to delineate the contribution of thermodynamic activities of ionized and unionized species on buccal drug permeation. The flux and permeability of a model acidic (nimesulide) and basic (bupivacaine) drug were determined across porcine buccal mucosa at different pH conditions. Thermodynamic activities of ionized and unionized drug species were expressed as degree of saturation (DS) and also calculated using a modified Debye-HΓΌckel equation. Flux of model drugs across buccal mucosa depended on pH and donor chamber concentration. For saturated solution, the DS or the relative activity of the unionized species remained constant (DS(unionized) = 1) under different pH conditions. The DS of ionized species (DS(ionized)), however, increased (nimesulide) or decreased (bupivacaine) with an increase in pH, resulting in either an increased (nimesulide) or decreased (bupivacaine) flux. On the contrary, at subsaturated drug concentrations in the donor chamber, a decrease in nimesulide flux was observed with an increase in pH due to a decrease in DS(unionized). In case of a subsaturated bupivacaine solution, DS(unionized) increased with pH, thereby increasing the flux. In conclusion, thermodynamic activities of both ionized and unionized species of a drug contribute to flux across the buccal mucosa. The ionized and unionized species contributed equally to total flux when 90% of the drug was ionized.