Experimental and Modeling Studies on the Formulation of Stable Lipid Nanoparticle Dispersions

I would like to dedicate my thesis to my beloved grandparents and parents for making me who I am, and friends for all the help and support A special thanks to my family. Words cannot express how grateful I am to my grandparents and my parents for all of the sacrifices that you've made on my behalf. I am also grateful to all my friends in Amherst who make these five years really unforgettable, especially the class of 2009 and all the Chinese graduate students in my department. I would also like to thank all my group members for all the help on my research. Solid lipid nanoparticles (SLNs) have applications in drug delivery and the encapsulation of bioactive, lipophilic compounds such as those required for functional foods. 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. Aggregation is driven by the lipid crystals undergoing a polymorphic transformation from the thermodynamically unstable -form through the '-form to the stable -form. A large increase in surface area occurs as spherical  particles are transformed into platelet-like  particles, causing a substantial decrease in surfactant coverage on the hydrophobic surfaces and inducing particle aggregation. Second generation encapsulation systems have been developed by incorporating a liquid carrier oil into the solid lipid matrix to form so-called nanostructured lipid carriers (NLCs). NLCs have been shown to have improved bioactive compound encapsulation and delivery properties compared to SLNs, but the enhanced stability of NLC dispersions to aggregation is not well understood. This thesis presents both experimental and modeling studies on the formulation of stable lipid nanoparticle dispersions. A population balance equation (PBE) model was developed for prediction of the average polymorph content and aggregate size distribution to better understand the undesirable SLN aggregation behavior. Experimental and modeling studies showed that the polymorphic vii transformation was the rate determining step for my system, SLNs with smaller initial size distributions aggregated more rapidly, and aggregates contained particles with both  and  crystals. Next the effect of different liquid carrier oils on the crystallization and aggregation behavior of tristearin NLC dispersions was investigated. I found that NLC dispersion stability was strongly affected by the type and amount of the oil. The results suggested that oil trapped within the growing crystal matrix accelerated the polymorphic transformation but retarded the large shape …