Charge and delocalisation effects on the lipophilicity of protonable drugs

The transfer mechanisms of ionisable compounds of pharmaceutical interest w ere studied by cyclic voltammetry at the water/1,2-dichloroethane interface . The partition coefficients of the various ions were deduced from the volt ammograms which were monitored as a function of aqueous pH. The dissociatio n constants and the partition coefficients of the neutral species were dete rmined by a pH-metric titration technique, and the results obtained are dis played in the form of ionic partition diagrams which define the predominanc e domains of each species in both phases. These diagrams afford an easy int erpretation of the mechanisms governing ion transfer and show how neutral s pecies can facilitate the passage of protons from water into an organic pha se and thus how ionisable compounds can modulate the pH. The change in lipo philicity between charged and neutral forms of a given compound is discusse d in terms of an intramolecular stabilisation of the charge. The nature of the substituents surrounding the charged atom as well as the degree of delo calisation of the charge are shown to contribute markedly to the stabilisat ion of ionic species in the organic phase. Born's solvation model is also u sed to illustrate qualitatively the effect of the molecular radius on the l ipophilicity and to show that ions retain more water molecules when they tr ansfer into octanol than into 2,2-dichloroethane.