On the Stability of Nano-formulations Prepared by Direct Synthesis: Simulated Ostwald Ripening of a Typical Nanocrystal Distribution Post-nucleation

Compared to more traditional top-down processing, the less common route to preparing drug nanocrystals through direct synthesis, e.g., starting with the nucleation of dissolved drug molecules (bottom-up processing), can offer both speed and cost advantages that makes it worthy of investigation. The current, theoretical work puts forth a technical basis and simulated results that could provide additional impetus for conducting further experimental work in this area. Specifically, an asymmetrical particle size distribution generated through the nucleation of a typical small-molecule drug, mirrored after carbamazepine hydrate based on a recent work [Skrdla PJ. J Phys Chem C 116:214-25, 2012], is subject to growth over time by a particle-coarsening mechanism using simulations of Ostwald ripening. Compared to a symmetrical, Gaussian distribution under the same conditions (fixed, relatively low concentration of free drug molecules in solution), it is found that, at longer times, the asymmetrical distribution formed through nucleation broadens more slowly. This finding could represent an additional benefit of synthetic strategies for the preparation of nano-formulations, previously unreported.