Exploring bulk volume, particle size and particle motion definitions to increase the predictive ability of in vitro...

The definition of the local dissolution environment is central to accurate particle dissolution simulation, and is determined by the apparatus and conditions used. In the flow-through apparatus dissolution occurs in the cell, often in a low velocity environment, with the reservoir considered the relevant volume for dissolution kinetics. Dissolution simulations were conducted using a reduced-order model based on the Ranz-Marshall correlation for mass transfer from spherical particles. Using ibuprofen as a model drug, the effect of defining a local volume to simulate dynamic bulk concentration conditions in the flow-through and paddle apparatus was assessed by comparing use of a near particle volume (NPV), extending a distance of one radius from the particle surface, with a flow-through apparatus cell volume or paddle apparatus vessel volume as the relevant instantaneous volume for dissolution. The instantaneous inlet concentration to NPV or cell volume is the reservoir/vessel concentration at that simulation time point, reflecting the continuous input to the cell of more dilute solution from the reservoir (closed system). Additionally, inputting particle size distribution (PSD) instead of a median particle size (MPS) and enabling or disabling particle motion were investigated, in two media (resulting in low and high solubility) and with two fluid velocity conditions in each apparatus. The NPV predicted effects of fluid velocity differences on dissolution in the high solubility medium in the flow-through apparatus, but had no effect on predictive ability in the paddle apparatus. In both apparatuses, simulations were reasonable for the high solubility environment but underpredicted dissolution in the low solubility environment. The PSD option and disabling particle motion increased the predictive ability of the simulations in low solubility media in the flow-through apparatus. The results highlight the necessity to incorporate the local dynamic dissolution conditions in the flow-through apparatus for accurate dissolution simulation, and the challenges of defining an effective particle size for dissolution simulation and of reflecting hydrodynamic complexity in simulating dissolution in the paddle apparatus.