Effect of cyclodextrin additives on azithromycin in aqueous solution and insight into the stabilization mechanism by sulfobutyl ether-β-cyclodextrin

Abstract

The stability of azithromycin in buffered aqueous solution at pH 6.7 was investigated in the presence of different cyclodextrin (CD) additives by HPLC monitoring of the drug concentration over time. In the presence of γ-CDs, either in native or derivatized form, the long-term stability of azithromycin was sensibly decreased with respect to the reference sample without any additives, whereas the opposite effect was observed with all the three tested β-CDs. The most effective stabilization of the drug was obtained by using sulfobutyl ether-β-cyclodextrin, which allowed a concentration of azithromycin in solution at 99% up to 6 months at room temperature. The positive action of sulfobutyl ether-β-cyclodextrin was mainly exerted through the suppression of a degradation pathway leading to the opening of lactone ring of azithromycin. The formation of dynamic inclusion complexes in solution was ruled out by NMR data and stabilization of azithromycin by the amphiphilic sulfobutyl ether-β-cyclodextrin through surfactant-like effects was proposed on the basis of the strict similarity, either in the degradation profiles and in the NMR data, with a solution of the drug in the presence of sodium hexylsulphonate as surfactant.