Development of Novel Bead Milling Technology with Less Metal Contamination by pH Optimization of the Suspension Medium.

To develop novel contamination-less bead milling technology without impairing grinding efficiency, we investigated the effect of the formulation properties on the grinding efficiency and the metal contamination generated during the grinding process. Among the various formulations tested, the combination of polyvinylpyrrolidone and sodium dodecyl sulfate was found to be suitable for efficiently pulverizing phenytoin. However, this stabilization system included a relatively strong acid, which raised the concern of possible corrosion of the zirconia beads. An evaluation of the process clearly demonstrated that acidic pH promoted bead dissolution, suggesting that this could be suppressed by controlling the pH of the suspension. Among the various pH values tested, the metal contamination generated during the grinding process could be significantly reduced in the optimized pH range without significant differences in the particle size of the phenytoin suspension after pulverization. In addition, the contamination reduction by pH optimization in the presence of physical contact among the beads was approximately 10-times larger than that without bead contact, suggesting that pH optimization could suppress not only bead dissolution but also the wear caused by bead collisions during the grinding process. These findings show that pH optimization is a simple but effective approach to reducing metal contamination during the grinding process.