Computational Modeling to Guide the Design of Mesalazine Nanoparticles Tailored for the Incorporation of Chitosan

The main objective of treatment with MSZ is to ensure that the drug reaches the colon, where it exerts its therapeutic effect. However, due to pH variation throughout the gastrointestinal tract and the risk of degradation or premature absorption, a considerable portion of the drug may not reach the colon in adequate concentrations. In this study, computational modeling was combined with experimental approaches for the design of MSZ nanoparticles (MSZ-NPs) suitable for chitosan (CS) incorporation. Quantum chemical calculations and molecular modeling revealed the importance of pH as a nucleation determinant and in the growth of the MSZ complexes. At pH~1.0, cationic clusters predominated, characterized by higher interaction energies and larger volumes/surface areas. At pH~4.0, zwitterionic clusters were stabilized, whereas at pH~6.0, anionic clusters formed the most compact assemblies, with the smallest calculated volume (4817 ų) and surface area (2458 Ų). Consistent with the computational predictions, experimental approaches showed a progressive reduction in particle size with increasing pH. Nanoparticles prepared at pH 1.5 (F1.5), 4.0 (F4.0), and 6.0 (F6.0) showed mean diameters of 937, 556, and 146 nm, respectively, with corresponding zeta potentials (ZPs) of +8.5, -22.3, and -31.6 mV. Drug precipitation efficiency was as follows: 51.6% to F1.5, 95.1% to F4.0, and 75.5% to F6.0. F4.0 and F6.0 were selected to evaluate the effect of CS incorporation. The CS incorporation resulted in a reversal in the zeta potential in formulations prepared at pH 4.0 and 6.0. When 5% CS was added during nanoparticle formation (F4.0-5 and F6.0-5), the particles were smaller in diameter and had a lower positive ZP. F6.0-5 achieved the most favorable properties and strong mucoadhesion, evidenced by the ZP shift from +26.8 mV to -1.9 mV at a pH of 6.8. The modeling and experimental approaches guided the rational design of MSZ-NPs for CS incorporation, yielding mucoadhesive nanoparticles for colon-targeted drug delivery.