Charge and Delocalisation Effects on the Lipophilicity of Protonable Drugs

Abstract

The transfer mechanisms of ionisable compounds of pharmaceutical interest were studied by cyclic voltammetry at the water/1,2-dichloroethane interface. The partition coefficients of the various ions were deduced from the voltammograms which were monitored as a function of aqueous pH. The dissociation constants and the partition coefficients of the neutral species were determined by a pH-metric titration technique, and the results obtained are displayed in the form of ionic partition diagrams which define the predomi-nance domains of each species in both phases. These diagrams afford an easy interpretation of the mechanisms governing ion transfer and show how neutral species can facilitate the passage of protons from water into an organic phase and thus how ionisable compounds can modulate the pH. The change in lipophilicity between charged and neutral forms of a given compound is discussed in terms of an intramolecular stabilisation of the charge. The nature of the substituents surrounding the charged atom as well as the degree of delocalisation of the charge are shown to contribute markedly to the stabilisation of ionic species in the organic phase. Borns solvation model is also used to illustrate qualitatively the effect of the molecular radius on the lipophilicity and to show that ions retain more water molecules when they transfer into octanol than into 1,2-dichloroethane.

Biphasic Electrospray Ionization for the Study of Interfacial Complexes

“…5,6,15,16 The electrochemical methodology can be used to determine the stoichiometry of the organic complexes, as well as their lipophilicity. [17][18][19] To gain more information on the interfacial reaction mechanisms, different spectroscopic techniques such as voltabsorptometry or voltfluorimetry have been developed.…”

Improved Thin-layer Electrolysis Cell for Ion Transfer at the Liquid|Liquid Interface Using a Conducting Polymer-coated Electrode

“…The electrolysis cell has a simple laminate structure, which enables sample volumes to be as low as 1 μL. While TEA + was chosen as the target ion in this work, other comparatively hydrophobic ions, such as ClO4 -22,25 or ionic drugs, [46][47][48][49][50] could be determined using the present system. If the facilitated transfer of a hydrophilic ion with a neutral ionophore was achieved in the present thin-layer cell, the variety of target ions would be enlarged.…”

Use of voltammetry for in vitro equilibrium and transport studies of ionisable drugs

“…However, the partition coefficients of ionised fractions of drugs were usually ignored. The increasing interest in partitioning of fully or partially ionised drugs prompted the search for new methodologies to determine partition coefficients [10][11][12].…”