Simultaneous Determination of the Ionization Constant and the Solubility of Sparingly Soluble Drug Substances. A Physical Chemistry Experiment

We examine the use of the inverse titration method for determining the ionization constant of weak organic bases when the basic form of the substance is highly insoluble in aqueous solutions. The inverse titration involves progressive dissolution of the precipitate of the insoluble basic form through addition of a strong acid, and determination of the total solubility at each step with a suitable analytical technique. Analysis of the experimental data allows the simultaneous determination of the ionization constant and the solubility of the basic form. We use dibucaine, a local anaesthetic, and analyze its total solubility after each acid addition using UV spectrophotometry. This simple experiment allows the accurate determination of the pKa of the compound at various temperatures, but provides only a rough estimate of the solubility of the basic form.