Nanocrystal Preparation of Poorly Water-Soluble Drugs with Low Metal Contamination Using Optimized Bead-Milling Technology

Abstract

Nanocrystal preparation using bead milling is an important technology to enhance the solubility of poorly water-soluble drugs. However, there are safety concerns regarding the metal contaminants generated during bead milling. We have previously reported optimized bead-milling parameters that could minimize metal contamination and demonstrated comparable performance to NanoCrystal®, a world-leading contamination-free technology. This study aimed to investigate the applicability of optimized milling parameters for preparing nanocrystals of several poorly water-soluble drugs exhibiting various physicochemical properties. Using our optimized bead-milling parameters, we found that all the tested drugs could be ground into nanosized particles within 360 min. Notably, fenofibrate, which has a low melting point, could be ground into nanosized particles owing to the low level of heat generated during bead milling. Additionally, the concentration of metal contaminants in all the drugs prepared using the optimized milling parameters were approximately ten to twentyfold lower than those prepared without the optimized parameters and were comparable to those prepared using polycarbonate beads, known to minimize metal contamination during bead milling. Our results provide insights into the development of drug nanocrystals with low metal contamination using bead milling.

Keywords

• bead milling
• milling parameters
• drug nanocrystal
• metal contamination
• physicochemical properties