Mechanism of Transfer of a Basic Drug across the Water/1,2‐Dichloroethane Interface: The case of quinidine

Abstract

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.

Ionic partition diagram of tetraphenylporphyrin at the water|1,2-dichloroethane interface

“…Ionic partition diagrams have proved to be a rather useful representation of thermodynamic equilibria involving ionisable species in biphasic liquid systems [21][22][23][24]. The method consists in representing the domains of predominance of the various species as a function of applied potential and aqueous pH.…”

Electrochemistry at liquid/liquid interfaces: methodology and potential applications

“…diffusion controlled) [119,120] transfer of organic ions, which should then be taken into account to model drug disposition. In electrochemical terms, passive transfer simply means partition across an interface, mediated by a potential-driven process [121], which is used here to assess lipophilicity of ions.…”

“…Although this quantity is a constant for neutral solutes (noted then log P N ), the Nernst equation for the ITIES reveals that the partition coefficient of an ion, log P i , depends on the Galvani potential difference across the interface [121]. Thus, log P i can be defined by rewriting Eq.…”

“…As such, they assuredly afford a good representation of the real ion distribution in vivo, but they do not always fit accurately with experimental values. Indeed, when the boundary lines are calculating by solving all the thermodynamic equilibria [121] and hence by taking into account the fact that the partitioning of the neutral species into the organic phase modifies the concentrations of all the forms of a compound in the aqueous phase, the domain of predominance of the neutral species is displaced on the pH scale to an apparent dissociation constant which is shifted by a quantity related to its log P N with respect to the pK w a value obtained in the absence of organic solvent (this is indeed evidenced in Senda's above study [137,138]). Efforts are now paid to refine the theoretical model of ionic partition diagrams, which will have the double advantage of accounting better for the actual distribution of ionisable compounds in experimental conditions and of offering an indirect evaluation of the partition coefficient of the neutral form of a compound.…”

Kinetic Analysis of Distribution of Weak Acid in an Oil-Gelatin Microcapsule/Water System Studied by Microcapillary Injection and Microabsorption Methods

“…[13][14][15] In the model, the dissociated anion (or H + ) transfers from water into oil, and then, H + (or the dissociated anion) is extracted into the oil phase to maintain the electroneutrality in the two phases. Although the model was supported by thermodynamic data of ion transfer in the two-immiscible electrolyte solution systems, no ion species transferring across a liquid/liquid interface during extraction of a weak acid was kinetically detected.…”