The poor aqueous solubility of niclosamide (Nic), a drug with broad therapeutic potential beyond its original antiparasitic use, presents a major challenge for formulation development. Here, the molecular basis of Nic solubilization by 2-hydroxypropyl-β-cyclodextrin (HPβCD) is elucidated through combined experimental and computational approaches.
¹HNMR spectroscopy indicated the coexistence of inclusion and non-inclusion complexes in HPβCD/Nic systems. Non-biased molecular dynamics (MD) simulations further showed that both protonated and deprotonated forms of Nic can spontaneously enter the HPβCD cavity—preferentially through the nitrophenyl moiety—in agreement with NMR observations. Additional MD simulations involving multiple Nic molecules revealed strong, concentration-dependent self-association driven by π–π stacking and cation–π interactions, consistent with radial distribution function profiles. HPβCD also self-associated, forming aggregates that disrupted Nic–Nic interactions. Nic–Nic hydrogen bonds decreased by more than half upon HPβCD addition, while Nic–HPβCD hydrogen bonds increased, accompanied by a rise in the solvent-accessible surface area of HPβCD/Nic assemblies. Dynamic light scattering experiments supported this mechanism. Pure Nic formed large clusters of ∼700 nm, whereas HPβCD alone displayed mainly small species near 2 nm and a minor population around 300 nm. In the presence of HPβCD, the ∼700 nm Nic clusters disappeared, giving rise to mixed aggregates of roughly 300–400 nm across multiple stoichiometries. Although inclusion complexation is thermodynamically feasible, Nic predominantly associated with HPβCD aggregates rather than forming classical host–guest complexes.
Together, these findings establish a complementary solubilization mechanism—Cyclodextrin-Driven Drug Deaggregation (CD-DA)—in which HPβCD enhances solubility by preventing or reversing drug self-association through peripheral non-covalent interactions and occasional inclusion events. This work advances the molecular understanding of HPβCD/Nic systems and highlights CD-DA as a relevant mechanism for improving the solubility of self-association–prone drugs.
Hector Luis Valdés-Negrín, Natalia Rincón-Londoño, Susana Figueroa-Gerstenmaier, Patricia Guadarrama, Alberto S. Luviano, Yareli Rojas-Aguirre (2026) Beyond inclusion: Mechanistic insights into niclosamide dual solubilization by 2-hydroxypropyl-β-cyclodextrin through experimental and theoretical approaches. Journal of Molecular Structure 1355, 144980. https://doi.org/10.1016/j.molstruc.2025.144980
