(667g) 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 such as those required for functional foods. SLNs are commonly obtained by first preparing a lipid emulsion via high pressure homogenization or microfluidization followed by cooling in an ice bath or other low temperature environment such that the lipid emulsion drops crystallize and solid particles are formed. A major obstruction to the industrial use of SLNs is their tendency to aggregate and form large particles and eventually gels when stored at room temperature. The prevailing theory is that aggregation is driven by the lipid crystals undergoing a polymorphic transformation from the thermodynamically unstable a form to stable b form. A large increase in surface area occurs as the spherical a particles are transformed into platelet-like b particles, causing a substantial decrease in surfactant coverage on the hydrophobic surfaces and inducing particle aggregation.

We tested this theory by performing a series of aggregation experiments and by developing a population balance equation (PBE) model for prediction of the aggregation dynamics. Oil-in-water emulsions were prepared by high pressure homogenization with 5 wt% lipid (tristearin) and 1 wt% surfactant (mixture of Tween 60 and Span 60) at 85°C. The lipid emulsions were cooled in an ice bath for 8 hours to obtain SLNs and the resulting solutions were stored at 20°C. Aggregation dynamics were monitored daily by measuring the particle size distributions with light scattering and by examining polymorphic transformation behavior with differential scanning calorimetry. Our experimental results suggest that the polymorphic transformation rather than particle aggregation is the rate determining step of the aggregation process in this system.

The PBE model was formulated to predict the particle volume percent distribution under the assumption that particles collide due to Brownian motion and that only b particles could aggregate. The polymorphic transformation was modeled to be first-order in the concentration of a particles and first-order in the particle surface coverage such that transformation rate was zero if the particle had maximum coverage. An aggregation efficiency was introduced by assuming b particle aggregation was dependent on the surface coverage of each particle, with no aggregation possible when both particles had maximum coverage. The model was able to qualitatively predict our experimental data as well as other SLN aggregation data available in the literature. Our preliminary modeling results further suggest that the polymorphic transformation is the rate determining step of the aggregation process and support the hypothesis that aggregation is driven by the creation of new surface area due to the transformation.