A Model-Guided Process Intensification Strategy for the Preparation of Sub-100 nm Drug Nanoparticles via Wet Stirred Media Milling

There is sustained interest in sub-100 nm particles of poorly water-soluble drugs as such small particles offer improved permeation through various biological barriers and result in rapid onset of therapeutic action. For fast production of sub-100 nm drug particles, yttrium-stabilized zirconia beads with a nominal size ranging from 50 µm to 800 µm were used in a baseline wet stirred media milling (WSMM) process, which was subsequently intensified with the optimal bead size by increasing rotor tip speed, bead loading, and suspension flow rate step-wise, as guided by a microhydrodynamic model. This study has demonstrated, for the first time, the use of small beads in an intensified WSMM process for faster production of sub-100 nm particles of two BCS Class II drugs while achieving reduced energy consumption and keeping metal (Zr) contamination low.