Systematic Investigation of Wet-Milling Kinetics and Colloidal Stability of Pharmaceutical Nanocrystals

Abstract

The size reduction of poorly water-soluble crystalline active pharmaceutical ingredients (APIs) to submicrometer dimensions is an alternative to the formation of amorphous solid dispersions when aiming for dissolution rate and bioavailability enhancement. Pharmaceutical nanosuspensions can be produced by wet-stirred media milling, but there is no established classification for assessing the suitability of a given API for this process. The present work reports a systematic study of milling kinetics and colloidal stability of the resulting nanosuspension for 10 APIs (abiraterone acetate, apixaban, atorvastatin, candesartan cilexetil, deferasirox, hydrochlorothiazide, imiquimod, ivacaftor, tadalafil, and telmisartan) in combination with 6 different stabilizer systems that include SDS, Tween 80, HPMC, Poloxamer 188, DPPC, DPPG, MPEG-2000-DMPE, and their combinations. The combination of steric and electrostatic stabilization resulted in colloidally stable nanosuspensions for a broad spectrum of APIs not only for an already established combination of hydroxypropyl methylcellulose and sodium dodecyl sulfate but also for phospholipid-based stabilizers, which have so far not been widely used in the context of nanomilling. A new classification system of API suitability for nanosuspension formation by wet milling has been proposed on the basis of the texture and morphology of the crude crystals.