(158c) Salt-Assisted Analysis of Chitosan/Tripolyphosphate Micro- and Nanogel Formation

Biobased micro- and nanogels ranging from tens of nanometers to microns in diameter can be prepared by ionically crosslinking chitosan with tripolyphosphate (TPP). These soft materials attract widespread interest as potential drug and gene carriers. To this end, much empirical work has been done to characterize the effect of process and formulation parameters on their size distribution, swelling and stability. Despite these efforts, however, the mechanism of their formation remains poorly understood. This lack of understanding stems (at least in part) from the very rapid kinetics of chitosan/TPP gelation, which make the micro- and nanogel formation process very difficult to study. To address this, we used stopped-flow and dynamic light scattering (DLS), isothermal titration calorimetry (ITC) and transmission electron microscopy (TEM) to dissect the mechanism of ionotropic chitosan/TPP gelation in the presence of monovalent salt (NaCl). This revealed that the micro- and nanogel formation rates are extremely sensitive to TPP and NaCl concentrations, and scale approximately with [TPP]⁵ and [NaCl]^-5. By slowing down their formation using high NaCl and low TPP concentrations, the temporal evolution in micro- and nanogel structure could be probed by DLS and TEM. The ionotropic gelation was shown to occur in two stages: first, the formation of small primary nanoparticles (average diameter ~ 30 nm); then, their secondary aggregation into larger micro- and nanogels. Furthermore, by slowing down the ionotropic gelation process, we were able to dramatically enhance the colloidal stability during chitosan/TPP mixing, and produce particles with more-uniform size distributions.