(227k) On the Dissolution Stability of Ionically Crosslinked Chitosan Nanoparticles

Ionically crosslinked chitosan nanoparticles are widely explored as drug delivery vehicles. They are biocompatible, mucoadhesive, facilitate transport across epithelial membranes, and can be formed through simple mixing of chitosan solutions with multivalent anions, such as tripolyphosphate (TPP) and pyrophosphate (PPi). To ensure that these particles release their payloads at target rates, it is essential to control their dissolution stability. Yet, literature on this subject remains confounded by opposing reports (with some indicating such particles to remain stable at physiological pH and ionic strength, while others reporting them to dissolve). To address this, we used isothermal titration calorimetry (ITC), dynamic light scattering (DLS) and UV-Vis spectroscopy to investigate the effect of chitosan degree of deacetylation (DD) on chitosan/TPP nanoparticle stability. This revealed the stability of chitosan/TPP particles to be very sensitive to chitosan DD (which is often not reported, and may underlie some of the conflicting findings). Particles formed using high DD-values remained intact, while those formed using lower DD-values dissolved at physiological ionic strengths (where the dissolution likely reflected the weaker chitosan/TPP binding). These experiments also showed that cumulant analysis of DLS data (which is often used for chitosan/TPP nanoparticle characterization without supporting techniques) can lead to misleading conclusions on their stability, and might be another source of conflicting results. Finally, to advance the understanding of chitosan nanoparticle dissolution, we investigated the reversibility of their ionic crosslinking (using chitosan/PPi nanoparticles as the model system). This indicated the crosslinking to be irreversible, where the particles remained partly intact even when the PPi concentration was reduced below that required for their formation. This irreversibility was attributed to the cooperativity of chitosan/PPi binding and modeled using the Bragg-Williams theory.