Exploration of bead mixtures containing yttrium-stabilized zirconium and cross-linked polystyrene beads for the preparation of nano- and microsuspensions

During wet bead media milling, adjusting different process parameters can be key for defining the final formulation characteristics such as the particle size profiles of nano- and microsuspensions. Yttrium-stabilized zirconium (YSZ) and cross-linked polystyrene (CPS) beads are the most commonly used milling media for pharmaceutical applications which vary in bead characteristics (i.e., differences in bulk density). In the current work, it was investigated if combing these two bead types could make a more effective milling process due to the higher grinding area generated when a soft and a hard bead interact. Milling using only CPS beads led to a lower degree of particle size reduction compared to YSZ beads accompanied by a lower rise in sample temperature as the impact between CPS beads during milling was less intense than YSZ beads. The smallest sizes of drug particles were achieved using 0.2 mm YSZ beads while comparable particle size profiles were obtained using bead mixtures containing both YSZ and CPS beads. Overall, however, bead mixtures did not result in an increased size reduction of different model compounds that were investigated with different brittleness. Powder X-ray diffraction (XRPD) and Raman spectra confirmed no apparent changes in the solid-state of any of the prepared suspensions, yet indomethacin suspensions differed visually in color depending on bead type used indicating induction of amorphization below the level of quantification by XRPD and Raman. The physical stability assessment of cinnarizine suspensions milled with the different bead types, sizes, and bead mixtures showed consistent particle growth for all suspensions prepared and no distinct correlations to the bead mixtures used during mulling.