Experimental investigation and population balance equation modeling of solid lipid nanoparticle aggregation dynamics

Solid lipid nanoparticles (SLNs) have applications in drug delivery and the encapsulation of bioactive, lipophilic compounds. However, SLNs tend to aggregate when stored due to the lipid crystals undergoing a polymorphic transformation from the unstable α form to the stable β form. We developed a population balance equation (PBE) model for prediction of average polymorph content and aggregate size distribution to better understand this undesirable behavior. Experiments with SLNs stored at room temperature showed that polymorphic transformation was the rate determining step for our system, SLNs with smaller initial size distributions aggregated more rapidly, and aggregates contained particles with both α and β crystals. Using parameter values estimated from our data, the PBE model was able to capture the bimodal nature of aggregate size distributions, the α-to-β polymorph ratio, and the faster aggregation dynamics of SLNs with smaller initial size distributions. However, the model was unable to adequately capture the fast disappearance rate of primary particles, the broad size distributions of formed aggregates, and the significant α content of aggregating particles. These discrepancies suggest that a PBE model which accounts for polymorph content as an internal variable along with aggregate size may be required to better reproduce experimental observations.