Complexation of Ketoconazole by Native and Modified Cyclodextrins

Complexation of ketoconazole (KET), a broad-spectrum antifungal drug, with beta - and gamma -cyclodextrins (CDs), heptakis (2,6-di-O-methyl)- beta -CD (2,6-DM- beta -CD), heptakis (2,3,6-tri-O-methyl)- beta -CD (TM- beta -CD), 2-hydroxypropyl- beta -CD (2HP- beta -CD) and carboxymethyl- beta -CD (CM- beta -CD) was studied. The stability constants were determined by the solubility method at pH = 6 and for 2,6-DM- beta -CD and CM- beta -CD at pH = 5. At pH = 6, the stability constants increased in the order: TM- beta -D < gamma -CD < 2HP- beta -CD < beta -CD < CM- beta -CD < 2,6-DM- beta -CD. At pH = 5, due to the increased ionization of KET, the stability constant with CM- beta -CD increased and with 2,6-DM- beta -CD decreased. For complexes of KET with 2HP- beta -CD and 2,6-DM- beta -CD, the thermodynamic parameters of complexation were determined from the temperature dependence of the corresponding stability constants. For beta - gamma and TM- beta -CD complexes, calculations using HyperChem 6 software by the Amber force field were carried out to gain some insight into the host-guest geometry.