Towards a better mechanistic comprehension of drug permeation and absorption: Introducing the diffusion-partitioning interplay

The process of passive drug absorption from the gastrointestinal tract is still poorly understood and modelled. Additionally, the rapidly evolving field of pharmaceutics demands efficient, affordable and reliable in vitro tools for predicting in vivo performance. In this work, we combined established methods for quantifying drug diffusivity (localized UV-spectroscopy) and permeability (Permeapad (R) plate) in order to gain a better understanding of the role of unstirred water layers (UWLs) in drug absorption. The effect of diffusion/permeability media composition and viscosity on the apparent permeation resistance (R-app) of model drugs caffeine (CAF) and hydrocortisone (HC) were tested and evaluated by varying the type and concentration of viscosity-enhancing agent - glycerol or a poly(ethylene glycol) (PEG) with different average molecular weights. For all types of media, increased viscosity lead to reduction in diffusivity but could not alone explain the observed effect, which was attributed to intermolecular polymer-drug interactions. Additionally, for both drugs, smaller hydrophilic viscosity-enhancing agents (glycerol and PEG 400) had larger influence than larger ones (PEG 3350 and 6000). The results highlighted the role of UWL as an additive barrier to permeation and indicated that diffusion through UWL is the rate-limiting step to CAF's permeation, whilst HC permeability is a partition-driven process.