Study of drug supersaturation for rational early formulation screening of surfactant/co-solvent drug delivery systems

Abstract

To advance in vitro screening of surfactant/co-solvent formulations in early development by considering drug supersaturation and the mechanism of solubilization upon aqueous dilution. Two surfactant/co-solvent model systems were studied at practically relevant aqueous dilution ratios. Precipitation of the model drug fenofibrate was characterized by focused beam reflectance measurement, X-ray diffraction, and Raman spectroscopy. We calculated drug supersaturation in diluted systems and introduced a theoretical model to study the role of excipient interaction in the process of drug solubilization. Finally, vehicle phase changes upon dilution were examined using dynamic light scattering and ultrasound analysis. Phase changes occurred at low dilution levels, while more extensive dilution barely led to further structural changes. In undiluted formulations, ethanol-surfactant domains were responsible for fenofibrate solubilization. In dispersed formulations, however, the co-solvent partitioned out of the surfactant microstructure, leading to drug solubilization by independent micellization and co-solvency. This loss of excipient interaction caused formulation-specific supersaturation, which was indicative for the risk of drug precipitation. Experimental protocols of in vitro formulation screening should include both low and high dilution levels of physiological relevance. The study of excipient interaction and estimation of supersaturation allows the identification of formulations that are prone to drug precipitation.