Bead milled drug nanocrystal suspensions fine enough to pass through 0.22 ​μm sterilization filters

Abstract

Nanocrystal suspensions have been introduced to overcome the low bioavailability of poorly water-soluble drug compounds by increasing the dissolution rates. For both injection- and inhalation-based administrations it is important that the suspensions are sterile to eliminate any adverse events from potential microbial infections, but it has proven very challenging to sterilize nanocrystal suspensions without aggregation or degradation. Here we describe bead milling methodology to generate ultrafine nanocrystal suspensions of several poorly water-soluble drug compounds that can be passed through 0.22 ​μm sterilization filters. The most important factors for successful milling to ultrafine nanocrystal suspensions are the stabilizer excipients combined with fine milling-beads. The sodium dodecyl sulphate (SDS) or docusate sodium/aerosol OT (AOT) combined with Polyvinylpyrrolidone K30 (PVP) stabilizer systems and 1,2-Dipalmitoryl-sn-Glycero-3-Phosphoethanolamine conjugated methoxy Polyethylene Glycol (DPPE) and 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine conjugated methoxy Polyethylene Glycol (DSPE) surfactants were among the best stabilizer excipients studied.