Use of Bead Mixtures as a Novel Process Optimization Approach to Nanomilling of Drug Suspensions.

We aimed to evaluate the feasibility of cross-linked polystyrene (CPS)–yttrium-stabilized zirconia (YSZ) bead mixtures as a novel optimization approach for fast, effective production of drug nanosuspensions during wet stirred media milling (WSMM). Aqueous suspensions of 10% fenofibrate (FNB, drug), 7.5% HPC-L, and 0.05% SDS were wet-milled at 3000–4000 rpm and 35%–50% volumetric loading of CPS:YSZ bead mixtures (CPS:YSZ 0:1–1:0 v:v). Laser diffraction, SEM, viscometry, DSC, and XRPD were used for characterization. An nth-order model described the breakage kinetics, while a microhydrodynamic model allowed us to gain insights into the impact of bead materials. CPS beads achieved the lowest specific power consumption, whereas YSZ beads led to the fastest breakage. Breakage followed second-order kinetics. Optimum conditions were identified as 3000 rpm and 50% loading of 0.5:0.5 v/v CPS:YSZ mixture from energy–cycle time–heat dissipation perspectives. The microhydrodynamic model suggests that YSZ beads experienced more energetic/forceful collisions with smaller contact area as compared with CPS beads owing to the higher density–elastic modulus of the former. We demonstrated the feasibility of CPS–YSZ bead mixtures and rationalized its optimal use in WSMM through their modulation of breakage kinetics, energy utilization, and heat dissipation.