Alkali halide‐assisted penetration of neostigmine across excised human skin: A combination of structured water disruption and a donnan‐like effect

The penetration of neostigmine across excised human skin mounted in flow‐through diffusion cells, delivered from a 0.28 M aqueous solution, was below detection limits. The presence of either NaCl or LiCl in the donor solution caused significant fluxes of neostigmine, with permeability coefficients (K_p's) in the range of 10⁻⁶ cm min⁻¹. Paradoxically, low concentrations of NaCl or LiCl (0.25 and 0.5 M) were more effective in this respect than the 1 M solution, which was the least effective concentration in the range of 0.25‐3 M. Thus, the dependence of the experimental K_p values on inorganic ion concentration followed a biphasic course, suggesting the participation of two distinctive mechanisms in the penetration‐enhancement process. The early phase corresponding to 0.25 and 0.5 M NaCl or LiCl is being partly ascribed to a decrease in the viscosity of lamellar water caused by the influx of the respective hydrated ions, hydration of LiCl or NaCl being more extensive at low alkali halide concentration that at higher ones (reference cited). The late phase corresponding to 2 and 3 M LiCl and NaCl is partly ascribed to a Donnan‐like effect whereby the presence of a large excess of poorly diffusible common ion (Na⁺ or Li⁺) enhances the partitioning into the skin of the more diffusible ion, in this case neostigmine cation. The presence of inorganic ions at different concentrations had no effect on the partial molal volume of neostigmine bromide (V_i^∞ = 223.5 cm³ mol⁻¹), which was practically the same for all concentrations of either LiCl and NaCl. Enhancement of the penetration of neostigmine probably by a Donnan‐like effect was far more prominent in the presence of benzalkonium cation, which is less likely to penetrate the skin barrier in comparison to Li⁺ or Na⁺. The K_p's observed were of the order of 10⁻⁵ cm min⁻¹ and showed a clear dependence on benzalkonium chloride molarity in the range of 0.25 to 1 M.