The purpose of the present work was to provide theoretical and experimental support in generating an optimal pH (pH(max)) for a representative weak base compound (propranolol), that can lead to enhanced sublingual absorption. Initially equations for pH-solubility and pH-permeability profiles were derived and compared to the profiles obtained experimentally. Excellent correlation (R(2)=0.999) of solubility profiles was obtained using non-linear regression, and the permeability profiles further predicted that at certain pH (pH(max)), optimal mucosal permeation could be achieved. Subsequently, in a pharmacokinetics study, a buffered sublingual propranolol tablet, designed to achieve its pH(max) (when dissolved in saliva), were compared to that from a marketed product (Inderal) which could not achieve pH(max)) in 8 healthy subjects. Each subject received the products sublingually for 15 min followed by swallowing the remaining drug-saliva. The plasma propranolol concentrations of AUC during first 30 min from the buffered tablet were significantly higher than that from the Inderal tablet (p<0.05), and no significant differences in the remaining AUC were observed. These in vitro and in vivo results on propranolol provided experimental confirmation of the pH(max) concept as well as its utility in sublingual drug delivery. Such an approach may be applicable to other similar compounds to improve sublingual drug delivery.