Nanoparticle stability: Processing pathways for solvent removal

Processing of hydrophobic organic compounds into nanoparticle form by rapid precipitation requires the use of organic solvents in which the compounds are initially dissolved. Mixing with an antisolvent induces supersaturation, nucleation and particle growth. In most cases the nanoparticle is to be dispersed in an aqueous phase and so the antisolvent is water and the organic solvent is a water-miscible organic. Ultimately the organic solvent must be removed because its presence either has toxicological consequences or it reduces particle stability against Ostwald ripening. Dialysis is commonly used to remove organics; however, the process is slow and costly. We present an efficient and scalable process of solvent removal based on flash evaporation. The non-ideality of the water:tetrahydrofuran (THF) activity coefficient makes the process especially effective. The results are compared against phase equilibria calculations and two flash stages are shown to reduce THF concentrations by over 95%, and bring the residual solvent concentration within acceptable limits for drug applications.