Sub-100nm drug particle suspensions prepared via wet milling with low bead contamination through novel process intensification

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. An intensified wet stirred media milling process was developed here for fast production of sub-100 nm drug particles with low bead contamination and reduced energy consumption. Griseofulvin and indomethacin, two model poorly water-soluble drugs, were wet-milled. Yttrium-stabilized zirconia beads with a nominal size ranging from 50 µm to 800 µm were used in the baseline process, which was subsequently intensified with the optimal bead size by increasing rotor tip speed, bead loading, and suspension flow rate stepwise, as guided by a microhydrodynamic model. Laser diffraction, dynamic light scattering, scanning electron microscopy, and XRD were used to characterize the milled suspensions. Results from the baseline process indicated that sub-100 nm griseofulvin particles were only produced when 50 or 100 µm beads were used in the 360 min milling experiments. Interestingly, using 50 µm beads led to the formation of sub-100 nm griseofulvin particles within 240 min with the lowest bead (zirconium) contamination and specific energy consumption. This could be explained though the microhydrodynamic model, revealing that 50 µm beads led to the highest frequency of drug particle compressions yet generated the lowest bead contact pressure. The processing time was further reduced to as low as 64 min producing griseofulvin particle size of 100 nm through step-wise intensification of the milling process with the 50 µm beads, as quantified by a milling intensity factor. Due to the enhancement of the breakage kinetics, the process intensification enabled shorter milling to attain 100 nm particles, thus resulting in significant energy savings and low bead contamination despite an increase in power consumption. The general applicability of the process intensification method was confirmed through milling of indomethacin, which also led to sub-100 nm particles faster with reduced energy consumption and low contamination.