A Biopredictive Fed-State Dissolution Method Incorporating High-Viscosity Media and Hydrodynamic Stress

Background: Postprandial gastric conditions such as changed motility and increased viscosity of gastric content can interact with an ingested dosage form, such as a tablet. This can affect the mechanisms of disintegration and dissolution and result in the altered performance of the tablet. Hereby, the individual characteristics of the tablet play a crucial role, since they determine the interaction potential with hydrodynamic and physico-chemical properties of the gastric environment. Excipient properties such as solubility, swellability, or gelling tendency can have an influence. Further, tablet characteristics such as porosity or pore size can affect its breakdown by regulating water uptake or determining its physical stability. Methods: Four midodrine hydrochloride generic products with known in vivo bioequivalence, but different formulations, were used as references to improve the simulated fed-state disintegration and dissolution testing methods involving highly viscous media. The tablet samples were evaluated towards the aforementioned characteristics, estimating which parameters of the testing method influence their dissolution performance under highly viscous conditions. Hereby, different hydrodynamic and mechanical stresses were simulated by a previously presented computed numerical controlled apparatus, as well as a novel flow-through cell for viscous media. By a mechanistic biopharmaceutics modeling approach, the convoluted dissolution data were compared to in vivo plasma profiles. Results: A sequential motion method yielded similar dissolution profiles as assessed by the similarity factor (f2). Convoluted plasma profiles showed good approximation with the in vivo profiles. Conclusions: The sequential dissolution method was established as a biopredictive tool for simulating the fed state by incorporating physiologically increased postprandial chyme viscosity and hydrodynamic stress.