The present work employs an experimental design methodology to optimize the spray-drying production of micron-size hollow aggregates of biocompatible silica nanoparticles that are aimed to serve as drug delivery vehicles in inhaled photodynamic therapy. To effectively deliver the nanoparticles to the lung, the aerodynamic size (d(A)) of the nano-aggregates, which is a function of the geometric size (d(G)) and the degree of hollowness, must fall within a narrow range between 2 and 4 mu m. The results indicate that (1) the feed concentration, (2) the feed pH, and (3) the ratio of the gas atomizing flow rate to the feed rate are the three most significant parameters governing the nano-aggregate morphology. Spray drying at a low pH (<7) and at a low feed concentration (<1%, w/w) generally results in nano-aggregates having small geometric and aerodynamic sizes (d(A) = d(G) approximate to 3 mu m) with a relatively monodisperse size distribution. Spray drying at a higher feed concentration produces nano-aggregates having a larger d(G) but with a multimodal particle size distribution. A trade-off therefore exists between having large d(G) to improve the aerosolization efficiency and obtaining a uniform particle size distribution to improve the dose uniformity. (C) 2009 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.