Impact of molecular rearrangement of amphiphilic stabilizers on physical stability of itraconazole nanoparticles prepared by flash nanoprecipitation.

Flash nanoprecipitation (FNP) is a controlled antisolvent precipitation process that has proven effective for consistent production of drug nanoparticles with a defined mean particle size and narrow particle size distribution. However, physical instability of the generated nanoparticles remains a major challenge in the application of this technology in pharmaceutical formulation. Aimed at resolving this problem, the present study has investigated the FNP process and associated stabilization mechanism of itraconazole (ITZ) nanoparticles through in-depth nanoparticle characterization. Results showed that ITZ nanoparticles could be reproducibly produced with a mean particle size <100 nm and a polydispersity index <0.2 in the presence of amphiphilic stabilizers (ASs). Surface analysis of freshly formed nanoparticles by X-ray photoelectron spectroscopy (XPS) revealed initially a disordered packing structure and subsequently a time-dependent molecular rearrangement of incorporated AS towards a micelle-like structure. The faster the molecular rearrangement of AS, the more stable the nanoparticles, as monitored by the change in particle size with time. These findings may have important implications for the selection of effective ASs for formulating stable drug nanoparticles. The present study is the first of its kind to demonstrate the utility of XPS to track the molecular transport of stabilizers in rapidly generated nanoparticles.