The Kinetic Rationale of Two- and Three-Phase Transfer Cells as Drug Absorption Models

Abstract

Two- and three-phase stirred transfer cells have been investigated as drug absorption models. The kinetics of interfacial transfer of a homologous series of model solutes were investigated as functions of stirring speed and solute partition coefficient (KD). The theoretical dependence of these transfer kinetics upon solute diffusion coefficients, boundary layer thicknesses, phase volumes, interfacial areas and kD was derived. Agreement between experiment and theory showed the predictability of conventional kinetic rate constants from these mass transfer descriptors. It proved possible in symmetrically stirred transfer cells to predict phase concentrations versus time profiles as functions of KD. The theory predicts that the dependence of transfer kinetics upon KD differs dramatically between cells employing different solvents or different stirring arrangements. A theoretical rationale is proposed to enable logical transfer cell design according to in vivo drug absorption versus time profiles. It was theoretically possible to predict the absorption profile for a new compound in a homologous series provided KD in chosen solvent systems, and its intrinsic pharmacokinetics were known. A bacterial suspension was developed and evaluated in order to test these theories. Chloramphenicol (CAP) and chloramphenicol succinate (CAP-succ) concentrations were monitored as functions of time subsequent to their introduction into the aqueous phase of the suspensions. Accordingly, a sensitive GLC assay for CAP and a differential assay for CAP and CAP-succ based upon this GLC technique was developed. Due to CAP induced perturbations in the bacteria at drug concentrations necessitated by assay sensitivity, it proved impossible to test the mass transfer theories developed earlier. Attempts to correlate CAP uptake and protein synthetic inhibition in whole cells, as opposed to the cell free system reported in the literature, showed that there were most likely antibiotic effects additional to those only requiring inhibition of protein synthesis.