INVESTIGADORES
LONGHI Marcela Raquel
artículos
Título:
Characterization of the Hydrochlorothiazide: β‑Cyclodextrin Inclusion Complex. Experimental and Theoretical Methods
Autor/es:
R. ONNAINTY; E. SCHENFELD; M. QUEVEDO; M. FERNANDEZ; M. LONGHI; G. GRANERO
Revista:
JOURNAL OF PHYSICAL CHEMISTRY B - (Print)
Editorial:
AMER CHEMICAL SOC
Referencias:
Lugar: Washington; Año: 2013 vol. 117 p. 206 - 217
ISSN:
1520-6106
Resumen:
Hydrochlorothiazide (HCT) is one of the most
commonly prescribed antihypertensive drugs. In an attempt to
gain an insight into the physicochemical and molecular aspects
controlling the complex architecture of native β-cyclodextrin
(β-CD) with HCT, we performed multiple-temperature−pH
isothermal titration calorimetric measurements of the HCT:
β-CD system, together with proton nuclear magnetic resonance
spectroscopy (1H NMR), phase solubility analysis, and molecular
modeling methods. The AL-type diagrams, obtained at different
pH values and temperatures, suggested the formation of
soluble 1:1 inclusion complexes of β-CD with HCT. The corresponding
stability constants (K1:1) were determined by phase
solubility studies and compared with those obtained by ITC,
with good agreement between these two techniques being found. The three-dimensional array of the complex was studied by 1H
NMR and molecular modeling methods. Both techniques confirmed the formation of the inclusion complex, with good agreement
between the experimental and theoretical techniques regarding the HCT binding mode to β-CD. Also, the forces involved in the
association process were determined, both from the thermodynamic parameters obtained by ITC (association enthalpy, binding
constant, Gibbs free energy, and entropy) and from energetic decomposition analyses derived from computational methods. We
concluded that the formation of the HCT:β-CD complex was enthalpy driven, with the inclusion mode of HCT being highly
dependent on its ionization state. In all cases, sustained hydrogen bond interactions with hydroxyl groups of β-CD were identified,
with the solvation energy limiting the affinity. Regarding the pH and temperature dependence, lower affinity constants were found at
higher HCT ionization states and temperatures.