Cryo-milling with spherical crystalline cellulose beads: A contamination-free and safety conscious technology

Crystalline cellulose is a common inactive pharmaceutical additive. If this material can also be used to construct beads for the wet milling of pharmaceutical compounds, it could possibly address issues related to wear and contamination associated with zirconia and polyethylene beads. In this study, the model drug phenytoin was milled with spherical crystalline cellulose (SCC) in liquid nitrogen. The particle size of the milled product was found to be comparable to that obtained using zirconia beads, verifying the feasibility of using SCC beads for this purpose. Using a design of experiment approach, the bead amount, agitation speed, and milling time were all determined to have a significant effect on the milled particle size, giving a D50 value as low as 0.3 μm. No breakage of the SCC beads was observed during the milling process in durability tests under conditions that will degrade spherical D-mannitol beads, showing that this material exhibits sufficient durability. In addition, the variation in elastic modulus between beads was minimal. Because SCC is commercially available and easy to handle, the present wet milling technique is considered to have potential applications to the manufacture of pharmaceuticals on an industrial scale, as it shows sufficient milling capability and durability.