Impact of Media Material and Process Parameters on Breakage Kinetics-Energy Consumption During Wet Media Milling of Drugs

While crosslinked polystyrene (CPS) beads and yttrium-stabilized zirconia (YSZ) beads have been commonly used as media for wet milling of poorly soluble drugs and their dissolution enhancement, no first-principle rationale exists for selecting the bead material. The aim of this study is to investigate the impact of stirrer speed (2000-4000 rpm) and CPS bead loading (similar to 20-60%) on the breakage kinetics-energy consumption during milling of griseofulvin, a model poorly soluble drug, and compare the performance of CPS vs. YSZ at the highest bead loading. Laser diffraction, SEM, rheological analysis, and XRPD were used for characterization. The milling was most effective at the highest bead loading-stirrer speed. A microhydrodynamic model suggests that an increase in stirrer speed led to faster breakage due to more frequent and forceful CPS bead-bead collisions. Despite causing slight decrease in maximum contact pressure, an increase in CPS bead loading caused a dramatic increase in average frequency of drug particle compressions, which dominated the faster breakage observed. While YSZ generally required higher specific energy consumption than CPS, it achieved the same product fineness faster than CPS. The microhydrodynamic model rationalized the favorable use of YSZ over CPS beads within the experimental domain studied.