In vitro and in silico methods to investigate the effect of moderately increasing medium viscosity and density on...

Medium viscosity can affect drug dissolution rate, however, it is not usually considered in routine dissolution testing or less complex biorelevant media. The effects of moderately increasing medium viscosity on the in vitro and in silico dissolution of ibuprofen were investigated with two viscosity enhancing agents (VEA) (hydroxypropyl methylcellulose (HPMC) and sucrose), three viscosity levels (range 0.7-5.5 mPa.s), two solubilities and two fluid velocities in the paddle, flow-through and intrinsic dissolution apparatuses. A factorial design analysis highlighted which factors significantly affected key dissolution metrics. Experimental results in the flow-through apparatus (FTA) were compared with in silico dissolution profiles generated by an in-house simulation code (SIMDISSO^TM). Increasing viscosity reduced the intrinsic dissolution rate of ibuprofen for both VEAs. The dissolution rate reduction was also observed in the FTA with sucrose, but less so with HPMC, suggesting particle wetting, motion and surface area effects. Particle motion simulations suggested reduced particle lifting times as viscosity increased, indicating an effect of viscosity on particle dispersal. The viscosity- and fluid density-mediated reduction in the dissolution rate observed with sucrose was accurately simulated by SIMDISSO^TM, in particular at higher velocities. Velocity had a significant impact on dissolution rates in the paddle apparatus, with a significant viscosity-related reduction in dissolution observed in the low solubility-low velocity scenario. Even small increases in medium viscosity can reduce the dissolution rate of a BCS class II drug, and in silico particle motion and dissolution data can assist interpretation of particulate dissolution behaviour.