The purpose of this study is to increase oral absorption of the highly charged drug alendronate using an ion pair strategy. Ion pairing is a formulation approach in drug delivery that is performed to improve the lipophilicity of ionized drugs. Cationic counter ions, such as arginine, phenazopyridine, hyoscine and pyridostigmine, were selected to enhance the lipophilicity and permeability of alendronate. Data obtained from quasi-equilibrium analysis were used to calculate the binding constant and intrinsic partition coefficient of ion pairs in an octanol/water system. The results of the partitioning study in an octanol/water system were confirmed using in vitro transport models with PAMPA and Caco-2 monolayer assays. Two counter ions, phenazopyridine and arginine, substantially increased the partition coefficient of alendronate by up to 1.15 and 0.73 units, respectively, in the octanol/water system. Binding constants of 117 M−1 for alendronate-arginine and 90 M−1 for alendronate-phenazopyridine ion pairs were obtained using quasi equilibrium analysis. Arginine and phenazopyridine enhanced the apparent permeability of alendronate by 14- and 26-fold in the PAMPA model and 6.5- and 4.4-fold across caco-2 cell monolayers, respectively. Based on this study, the lipophilicity and permeability of alendronate across lipophilic membranes was increased by suitable counter ions and could be used to establish a new formulation to increase the oral absorption of alendronate.