Wet stirred media milling (WSMM) of poorly water-soluble drugs (BCS Class II) increases surface area of drug crystals significantly, thus enhancing their dissolution rate and bioavailability (Li et al., 2016). Although WSMM has proven to be a robust process for producing nanoparticle suspensions of a wide range of materials, selection of media (bead) size has been largely empirical, lacking fundamental rationale (Bilgili et al, 2016). This study aims to establish such rationale by investigating the impact of bead size at various stirrer speeds on the breakage kinetics of a BCS Class II drug. In previous studies (Bilgili and Afolabi, 2012; Afolabi et al., 2014), we used a variation of the microhydrodynamic model proposed by Eskin et al. (2005), where the impact of various formulation and process parameters on the breakage kinetics of BCS Class II drugs was investigated. In this study, we used this model to gain insight into the impact of bead size at various energetic conditions. To this end, stable suspensions of griseofulvin, a model BCS Class II drug, were prepared using hydroxypropyl cellulose and sodium dodecyl sulfate. The suspensions were milled at four different stirrer speeds using various sizes of yttrium-stabilized zirconia beads. Laser diffraction, SEM, and XRPD were used for characterization. Our experimental and modeling results suggest that there is an optimal bead size that achieves fastest breakage at each stirrer speed and that it shifts to a smaller size at higher speed. Calculated microhydrodynamic parameters reveal two counteracting effects of bead size: more bead–bead collisions with less energy/force upon a decrease in bead size. The optimal bead size exhibits a negative power-law correlation with either specific energy consumption or the microhydrodynamic parameters. Overall, this study has rationalized the use of smaller beads for more energetic wet media milling and provided an overarching explanation as to the use of smaller beads in wet stirred media mills than in low-energy mills such as ball mills including centrifugal or planetary ball mills. This study is expected to guide the design and optimization of wet media milling processes in terms of proper choice of bead size for optimal performance.
References:
Afolabi, A., Akinlabi, O., Bilgili, E., 2014. Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: A microhydrodynamic view. Eur. J. Pharm. Sci. 51, 75‒86.
Bilgili, E., Afolabi, A., 2012. A combined microhydrodynamics–polymer adsorption analysis for elucidation of the roles of stabilizers in wet stirred media milling. Int. J. Pharm. 439, 193‒206.
Bilgili, E., Capece, M., Afolabi, A., 2016. Modeling of Milling Processes via DEM, PBM, and Microhydrodynamics, in: Pandey, P., Bharadwaj, R. (Eds.), Predictive Modeling of Pharmaceutical Unit Operations. Elsevier, Amsterdam, Netherlands, pp. 159–203.
Eskin, D., Zhupanska, O., Hamey, R., Moudgil, B., Scarlett, B., 2005. Microhydrodynamic analysis of nanogrinding in stirred media mills. AlChE J. 51, 1346–1358.
Li, M., Azad, M., Davé, R., Bilgili, E., 2016. Nanomilling of drugs for bioavailability enhancement: A holistic formulation–process perspective. Pharmaceutics 8, 17.
