Many topically applied drugs are ionized molecules that exhibit poor penetration across the lipid domains of the stratum corneum. Reduction of the charge on the molecule would be expected to enhance skin penetration. The objective of this study was to investigate the interaction of the non-steroidal anti-inflammatory drug benzydamine hydrochloride with suitable counter-ions including ibuprofen sodium. The influence of pH of the donor solution and hence degree of ionization on partitioning between n-octanol:buffer and the flux of benzydamine hydrochloride across polydimethyl siloxane (PDMS) membrane and human epidermis was determined. The maximum flux was determined at pH 7.6 when the fraction unionized was 2.51%, rather than at pH 9 when the fraction unionized was 38.7%. This suggests that at higher pH, although the permeability coefficient is increased, the decrease in solubility and therefore concentration of dissolved benzydamine in the medium results in a decrease in flux across the PDMS membrane. Ion-pair formation or interaction with each of the counter-ions was confirmed by NMR spectroscopy. Significant increases in logP and flux across PDMS membrane were determined for the ion-pairs (0.087, 12.54, 11.31, 0.121 microg cm(-2)h(-1) for benzydamine hydrochloride and ion-pairs with ibuprofen sodium, sodium benzoate and sodium octane sulfonate respectively). This study shows that it is possible to significantly enhance the flux of salts across a lipophilic membrane in the presence of counter-ions, resulting from intermolecular interaction and/or ion-pair formation.