Controlling particle size of a poorly water-soluble drug using ultrasound and stabilizers in antisolvent precipitation

The objective of this work was to develop a better understanding of a potentially scalable, liquid antisolvent (LAS) precipitation process, for the preparation of stable aqueous suspensions of ultrafine particles of poorly water- soluble active pharmaceutical ingredients (APIs). A novel combination of jets, ultrasound, polymers, and surfactants was used for the precipitation and stabilization of ultrafine particles of griseofulvin (GF). Use of ultrasound and high stream velocities enhances micromixing, whereas addition of polymers/surfactants inhibits/lowers the particle growth. A combination of ultrasound, high jet velocities, and stabilizers decreased the GF particle size to 1.04 μm (±0.46 μm) from 30.8 μm(±14.2 /an), when none of the treatments were used. A rational understanding was developed for predicting process performance and selecting suitable particle growth inhibitors/stabilizers. Favorable process conditions and combinations of polymer and surfactants were also identified experimentally for the precipitation of ultrafine particles of GF with a narrow particle size distribution (PSD).