Using in vitro and in silico approaches to investigate ibuprofen particulate and formulation dissolution behaviour under different hydrodynamic conditions.

Abstract

This work investigated the effect of fluid velocity and medium viscosity on the dissolution of ibuprofen powder and ibuprofen immediate release tablets in vitro, in the paddle apparatus and the flow-through apparatus, and in silico, using an in-house dissolution simulation code based on the fluid dynamics theory, SIMDISSOTM. Three levels of viscosity ranging from 0.7 mPa.s to 5.5 mPa.s were investigated using two viscosity enhancing agents, sucrose and hydroxypropyl methylcellulose (HPMC) based on literature reports which show a higher viscosity of the human gastric fluids than that of water. Two agitation speeds were investigated in the paddle apparatus (50 rpm and 100 rpm) and, in the flow-through apparatus, three fluid flow profiles were studied by combining two cell sizes (12 mm and 22.6 mm) and two flow rates (8 ml min-1 and 16 ml min-1). The effects of viscosity on the dissolution of ibuprofen powder and ibuprofen from immediate release tablets depended on the viscosity enhancing agent used, with a lower dissolution rate in sucrose-containing media than in HPMC-containing media in the flow-through apparatus for both ibuprofen powder and ibuprofen immediate release tablets. However, a reduction of the intrinsic dissolution rate of ibuprofen in media containing HPMC was observed, which was similar to the reduction of the intrinsic dissolution rate of ibuprofen in media containing sucrose, for all viscosity levels studied, suggesting impacts of the viscosity enhancing agents on particle motion. SIMDISSOTM simulations served to illustrate the differences in the motion of particles from a particle size distribution within the flow-through cell when media contained either viscosity enhancing agent. SIMDISSOTM was used to investigate the dissolution of ibuprofen active pharmaceutical ingredient under different solubility, fluid velocity and fluid viscosity conditions, in the paddle and the flow-through apparatus. The study highlighted the importance of the definition of an effective particle size for dissolution, more so when agglomeration is suspected, while displaying those scenarios of fast dissolution where a mean particle size input might be sufficiently accurate to predict prespecified dissolution metrics. The definition of particle motion was proven particularly relevant when dissolution occurs in high fluid velocity conditions. The inclusion of a spatial limitation in the vertical direction for particle displacement in the code allowed to simulate the physical boundaries experienced by the drug particles in the in vitro flow-through cell. The flow-through apparatus-generated dissolution profiles for ibuprofen dissolution from immediate release tablets in conditions of increasing viscosity were integrated into a GastroPlus? pharmacokinetic model. The results highlighted the impact of moderate increases of medium viscosity on the predicted pharmacokinetic profile of a weakly acidic drug, suggesting these moderate increases in viscosity could be considered when predicting bioavailability in the fasted state. This study points towards the necessity of a further understanding of the effects of medium viscosity and density on the dissolution and predicted pharmacokinetics of a range of drugs and formulations.