||An optimization strategy based on a factorial design is presented for the separation of samples containing acidic solutes by ion-pair liquid chromatography. The pH of the mobile phase and the concentration of the ion-pair reagent, tetrabutylammonium nitrate, are varied systematically in nine separate systems. Capacity factor plots of the sample components allow for selection of the optimum mobile phase. The design is applied to the chromatographic optimization of one mixture of benzoic acid derivatives and another of Sulindac and related compounds. A model for mass overload in preparative liquid chromatography is presented. A program for computer simulations of overload is used to develop a data base. The simulations assume that counter-current extraction is a valid approximation of chromatographic behavior and that solutes follow a Langmuir isotherm. Correlations are presented between an increase in injected sample mass and the decrease in capacity factor, the decrease in efficiency and the increase in asymmetry. These correlations are used to simulate chromatograms. Comparisons to experimental chromatograms are made for nine reversed phase systems. The results of isotherm measurements are presented. A discussion is included of saturation weights as determined by such measurements and as determined by curve fitting to experimentally derived master curves.