Monitoring of Partitioning of Poorly Water-Soluble Drugs during In Vitro Lipolysis by Electron Paramagnetic Resonance

Introduction Ingested lipids could offer valuable opportunities for enabling oral drug delivery, as approximately 4070% of all new drug candidates have been estimated to have very poor water solubility and are expected to exhibit low bioavailability when orally dosed. For this class of drug molecules, whose dissolution in water is likely the limiting step of overall oral absorption, the influence of ingested lipids on oral absorption has been associated with complex, poorly characterized interactions between drugs and several colloidal nanostructures, taking place during lipid digestion. In particular, emulsion droplets, micelles and vesicles influence dissolution kinetics and they are able to maintain larger quantities of hydrophobic drugs in solution, increasing the solubilization power of the gastrointestinal (GI) tract contents. Furthermore, the distribution of drugs within oil, aqueous and micellar phases affects their absorption rate. Despite the recognized capability of ingested lipids to impact several processes associated with the overall absorption of hydrophobic drugs, the fate of co-administered drugs remains unclear and unpredictable. In order to investigate the role of lipid-based colloidal particles in the partitioning process of poorly water-soluble drugs during lipid digestion, an updated in vitro lipid digestion model has been designed based on knowledge of gastrointestinal contents. The presence and the size of colloidal species have been evaluated by dynamic light scattering (DLS), while kinetics of drug partitioning between colloidal phases (oil, micellar, aqueous) formed during in vitro digestion has been tracked by electron paramagnetic resonance (EPR). This is a non-invasive technique that has the capability of detecting and quantifying radicals acting as spin probes. Nitroxides are well-known paramagnetic molecule, which can be selected according to their physicochemical properties as models for hydrophobic drugs. Since EPR spectra are highly sensitive to changes in environment micropolarity and microviscosity, the relocation of the selected spin probe within different phases can be monitored in real-time. In addition, EPR spectrum fitting can be used to quantify the amount of paramagnetic species in each phase.