A general method to predict and interpret the transfer mechanisms of ionizable compounds at the interface between two immiscible electrolyte solutions (ITIES) is presented. The approach is based on the construction of the ionic partition diagram of the solute. It consists in defining equiconcentration boundaries as a function of the Galvani potential difference and aqueous pH by taking into account the thermodynamic equilibria governing the distribution of the various acid/base forms of the molecules involved. The method defines the domains of predominance of each species either in the aqueous or in the organic phase. The application of ionic partition diagrams to quinidine offers a global and direct visualization of all the species and demonstrates the validity and efficiency of the method in helping to understand the transfer and partition mechanisms of ionizable drugs.

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The electrochemical transfer of quinidine across the H20/ I ,2-dichloroethane interface was investigated by cyclic voltammetry, so as to determine its lipophilicity. The formal transfer potential was measured as a function of the pH of the aqueous phase. Both singly and doubly protonated quinidine cations can transfer across the interface, and their formal Gibbs free energies of transfer were observed to be 7.7 and 31.2 kJ mol-', respectively. Between pH 0 and 3, only the doubly charged quinidine was present in the aqueous phase and was observed to transfer. Between pH 3 and 6, the transfer of both cations occurred. The proportion of doubly charged quinidine decreased progressively in this pH range and disappeared completely above pH 6. The overall process was analyzed using a thermodynamic model. The relationship between the various forms of quinidine in both phases and pH was established and found to he in good agreement with the experimental results. With this model, the acid-base equilibrium constants in the organic phase could be calculated as pK,,, = 9.66 f 0.21 and pK,,, = 14.20 * 0.16 (the subscripts a l o and a20 refer to the first and second dissociation constants). This study illustrates how the partition ofionic species can be taken into account in the determination of lipophilicity and in the description of the passive transfer of organic drugs.