(416f) A Drug-Sparing Approach to the Preparation of Drug Nanosuspensions: High-Intensity Vibratory Milling

Almost 40% of the new chemical entities in drug pipeline of pharmaceutical companies have low aqueous solubility, which leads to poor bioavailability in vitro and in vivo. Reduction of drug particle size down to nano-scale has been an effective way of increasing the dissolution rate of poorly water-soluble drugs. In this study, we aim to elucidate the impact of the process parameters on the breakage kinetics and particle size during the preparation of drug nanosuspensions via high-intensity vibratory milling, which can be used as a drug-sparing approach in early development. Griseofulvin (GF) particles were wet-milled in the presence of two stabilizers, hydroxypropyl cellulose (HPC) and sodium dodecyl sulfate (SDS), to prepare stable GF suspensions under various processing conditions. Laser diffraction (LD), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD) were used to characterize the suspensions. Several milling experiments were performed to determine the optimal bead size at low power density. Then, the process was intensified with the optimal bead size and operated at a much higher power density by increasing the vibration intensity and bead loading step-wise with the objective of increasing the breakage rate. After examining the breakage kinetics upon intensification, additional experiments were performed with various bead sizes to explore if and how the optimal bead size depends on the power density. Finally, a comparative assessment of the performance of vibratory milling vs. wet stirred media milling has been carried out in view of the power density, resultant breakage kinetics, and final drug particle size attained. This study provides a systematic process intensification approach as well as guidance for bead size selection and suggests process/design improvement strategies for fast preparation of drug nanosuspensions via vibratory milling.