Continuous synthesis of nano-drug particles by antisolvent crystallization using a porous hollow-fiber membrane module

Abstract

The synthesis of nano-size drug particles by antisolvent crystallization using a porous hollow fiber membrane provides promising benefits such as the capability of continuous operation, low energy input, and ease of scale-up for a variety of industrial processes. Porous hollow fiber membranes have also been shown to produce more efficient mixing than conventional mixing equipment mostly because in mixing binary fluids, they provide sufficient mixing time, retention time, and a large contact interface for the drug solution and the antisolvent, allowing for the precise control of nucleation and crystal growth necessary to form nano-size particles.This study reports an experimental and numerical approach to obtain a further understanding of the fundamental principles of antisolvent crystallization using a porous hollow fiber membrane. This includes producing a particle size-controlled drug nanosuspension experimentally using a commercial microfiltration (MF) pencil scale module, and a numerical analysis of mixing behavior using a computational fluid dynamics (CFD) simulation. From the results obtained, a nanosuspension of a model drug, Indomethacin, with particles of average diameter 0.320 µm was prepared. Furthermore, this nanosuspension has higher stability and a much lower tendency to agglomerate as compared to simple mixing of the anti-solvent and drug solution. Results from the numerical simulation showed that micromixing is possible using the porous hollow fiber membrane even under the most compromising conditions.