Akademik Veri Yönetim Sistemi
Journal of Molecular Structure, cilt.1373, 2026 (SCI-Expanded, Scopus)
This study presents an integrated experimental and computational investigation of the pH-dependent inclusion complexation of ketoprofen (KP) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Phase-solubility studies showed linear AL-type profiles at pH 3.0, 6.0, and 7.4, indicating soluble 1:1 inclusion complex formation. The apparent stability constants (Ks) decreased markedly with increasing pH, demonstrating that KP ionization progressively weakens host-guest complexation due to increased aqueous solubility and hydration. However, measurable Ks at pH 7.4 indicated that complexation was weakened but not completely suppressed under predominantly ionized conditions. HP-β-CD exhibited higher Ks and complexation efficiency than β-CD at all pH values. Temperature-dependent phase-solubility analysis at pH 3.0 and 6.0 demonstrated that complexation with both CDs was spontaneous, exothermic, and predominantly enthalpy-driven, as indicated by negative ΔG°, ΔH°, and ΔS° values. Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) analyses supported inclusion complex formation and revealed structural and morphological changes. Density functional theory (DFT) calculations performed for unionized KP and ionized KP⁻ showed that the phenyl-inserted Cor1 orientation was generally favored, while ionization increased localized polar interactions involving the carboxylate group. ESP, NBO, and NCI analyses indicated that stabilization was mainly governed by dispersion-driven cavity interactions complemented by hydrogen bonding. Overall, these findings provide molecular-level insight into ionization-dependent KP-CD complexation and support the rational design of CD-based delivery systems for poorly water-soluble ionizable drugs.