Entropy–Enthalpy Switching and Protonation-Gated Fluorescence in Olanzapine–Cyclodextrin Inclusion Complexes

Olanzapine (OLP), a poorly water-soluble antipsychotic, forms host–guest inclusion complexes with cyclodextrins (CDs) that can improve aqueous solubility and photostability. Here, we quantify OLP binding to α-, β-, γ-, and hydroxypropyl-β-cyclodextrin (HP-β-CD) using pH-resolved UV–visible and steady-state fluorescence spectroscopy, supported by density-functional theory (DFT). Benesi–Hildebrand (1:1) analysis yields association constants (K ₁₁ ) of 6–110 M⁻¹ at 25°C with pronounced pH dependence. Temperature-dependent measurements (25–45°C) enable extraction of standard thermodynamic parameters, showing that inclusion is spontaneous (ΔG° = −RT lnK < 0) over the studied range, with small-to-large positive enthalpy changes (ΔH° > 0) compensated by favorable entropy gains (ΔS° > 0). Accordingly, the standard free energies fall within the expected range ( ≈ − 5 to − 12 kJ·mol⁻¹ at 298 K). DFT calculations predict stabilizing electronic interaction energies that mirror the experimental affinity trends (e.g., ΔE _stab  = − 31.8 kJ·mol⁻¹ for β-CD and − 27.4 kJ·mol⁻¹ for HP-β-CD). Ground- and excited-state acidity constants (pK _a ≈ 8.8; pK _a * ≈ 7.7) indicate protonation-gated inclusion that modulates fluorescence intensity and spectral shifts. Overall, the study establishes a quantitative, pH-resolved connection between photophysics and thermodynamics in OLP–CD complexes and provides mechanistic guidance for the rational design of CD-based delivery systems for aromatic psychotropics.