Mechanisms Underlying the Rheological Changes of Drug Nanosuspensions in Wet Media Milling

This study investigated the rheological behavior of nanosuspensions prepared by a wet media milling technique using various model drugs and hydroxypropyl methylcellulose (HPMC) as a dispersing agent. These nanosuspensions were classified into two groups based on their apparent fluidity: the first included fenofibrate, glimepiride, and phenytoin nanosuspensions, which maintained high fluidity and exhibited Newtonian-like behavior (yield stress <0.09 Pa in the Herschel-Bulkley model); and the second comprised griseofulvin, ketoconazole, and nevirapine nanosuspensions, which showed markedly reduced fluidity and non-Newtonian characteristics (yield stress >1.7 Pa in the Herschel-Bulkley model). Quantitative analysis of HPMC adsorption showed a tendency for drugs with high HPMC adsorption (11.2-12.4 wt%) to demonstrate high fluidity, while drugs with low HPMC adsorption (8.14-8.86 wt%) generally showed reduced fluidity. Notably, fenofibrate remained flowable despite relatively low HPMC adsorption, underscoring that the adsorption amount alone is not sufficient to explain fluidity and that adsorption mode and coverage may also contribute. Rheological analysis under heating conditions revealed that all nanosuspensions exhibited a temperature-dependent rheological transition at temperatures lower than those typically reported for pure HPMC solutions. A reduction in fluidity was observed when this transition occurred below room temperature. Together, these results indicate that drug-dependent fluidity loss in wet-milled nanosuspensions is associated with differences in interfacial HPMC association and temperature-dependent structuring, involving both hydrophobic nanoparticle network formation and HPMC molecular assembly.