Solubilization and Stabilization of Sodium Dicloxacillin by Cyclodextrin Inclusion

Maria   Magdalena   Echezarreta-Lopez; Iria      Otero-Mazoy; Hector   Luis   Ramirez; Reynaldo      Villalonga; Juan   Jose   Torres-Labandeira

doi:10.2174/157016308784746328

Abstract

The aim of this work is to analyze the effect of cyclodextrin (CD) complexation on the solubilization and stabilization of sodium dicloxacillin in acid aqueous solutions. The effect of four cyclodextrins α-, β-,γ- and hydroxypropyl-β-CD was studied. Phase solubility diagrams obtained are AL or BS type, depending on the cyclodextrin used and on the pH of the solution. The highest stability constants of the inclusion complexes are obtained with γ-CD at pH 1 and 2 and HPβ-CD at pH 3. The structure of the inclusion complex in solution is characterized by nuclear magnetic resonance (1H-NMR). This study suggests that the 7-oxo-4-thia-1-azabicyclo group is located in the CD cavity. Nevertheless, molecular modelling calculations predict two different orientations of dicloxacillin in the γ-CD cavity in vacuum and in aqueous solution. In vacuum, the results predict the inclusion of the dichlorophenyl ring of dicloxacillin instead of 7-oxo-4-thia-1-azabicyclo group into the γ-CD cavity. However, the results are different in aqueous solution and this conformation is confirmed by the NMR study. The effect of γ-CD and HPβ-CD in the stability of the drug in solution was studied. The degradation of sodium dicloxacillin in solution follows a pseudo-first-order kinetics and the cyclodextrin do not change this fact. Both cyclodextrins increase the stability of the drug but the efficacy is higher with γ-CD.

Keywords: Benzylpenicillin, cyclodextrin, solubility, drug stability, molecular modeling