Stability of irinotecan loaded halloysite nanotubes under different pH conditions: Experimental data and molecular simulations

Halloysite is widely used for the development of nanocomposites for drug delivery applications. Μany active pharmaceutical substances exist in multiple protonation states depending on the surrounding pH environment. Irinotecan is such a compound, occurring in cationic, neutral, or anionic forms. Understanding halloysite's interactions with all of its protonation states is critical for the design and development of pharmaceutical carriers, evaluation of its behavior following oral administration, and treatment of environmental receptors of the active substance (i.e., water and soil). This study combines experimental and computational approaches to investigate the stability of irinotecan-halloysite nanotube complexes. Drug-loaded halloysite samples were incubated under acidic and neutral conditions simulating the stomach and intestinal environments and characterized using X-ray diffraction, transmission electron microscopy, and dynamic light scattering. Density functional theory and classical molecular simulations were also employed to examine the interactions between each protonation state of irinotecan and the halloysite surfaces. Both experimental and computational findings demonstrate that adsorption energies, drug orientation, water interactions, electrostatic forces, and H-bonding depend strongly on the drug's protonation state and the halloysite surface involved. The cationic form of irinotecan exhibits the highest stability (average total energy −1,568,227 ± 311 kJ/mol from FF calculations and adsorption energy −616 kJ/mol from DFT calculations), supported by the formation of a weak to strong H-bonding network. These findings highlight the potential of halloysite for long-term drug storage in pharmaceutical applications and the molecular simulations results suggest its potential as a sorbent for irinotecan removal from soil and wastewater.