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

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.