Journal of Pharmaceutical and Biomedical Analysis 35 (2004) 379–387 Improvement in solubility and dissolution rate of flavonoids by complexation with -cyclodextrin Silvana Tommasini, Daniela Raneri, Rita Ficarra, Maria Luisa Calabrò ∗ , Rosanna Stancanelli, Paola Ficarra Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy Received 29 June 2003; received in revised form 25 September 2003; accepted 29 September 2003 Abstract The inclusion into the -cyclodextrin is used to improve pharmacokinetic characteristics of hesperetin and naringenin. Solu- bility of hesperetin and naringenin with increasing concentrations of -cyclodextrin grows as long as the temperature increased. Stability constants were determined by the solubility method by Higuchi and Connors at different temperatures, and the thermo- dynamic parameters were calculated for inclusion complex formation in aqueous solution. The solid complexes were obtained in a molar ratio of 1:1 and their dissolution behavior at different pH was examined. © 2003 Elsevier B.V. All rights reserved. Keywords: Hesperetin; Naringenin; -Cyclodextrin; Phase solubility studies; Dissolution 1. Introduction In the pharmaceutical field, cyclodextrins have been recognized as potent candidates to overcome the undesirable properties of drug molecules through the formation of inclusion complexes, in which each guest molecule is surrounded by the hydrophobic environment of the CD cavity. This can lead to the alteration of physicochemical properties of guest molecules. The flavanones hesperetin and naringenin (Fig. 1) are widely spread in nature and easily extracted from a lot of different plants. Their protective effect against lipid peroxidation of membranes, involved in several ∗ Corresponding author. Tel.: +39-090-6766409; fax: +39-090-355613. E-mail address: mlcalabro@pharma.unime.it (M.L. Calabr` o). physiological and pathological disorders, as aging, in- flammation, atherosclerosis, ischemia, toxicity of oxy- gen and chemical substances has been largely studied [1–7]. Since a limiting factor of the use of flavonoids is their low water solubility, the aim of this study was to increase the solubility and dissolution rate of hes- peretin and naringenin by inclusion complex forma- tion with -cyclodextrin (-CD). Inclusion with cyclodextrins is a convenient alter- native to solve the problems encountered in the ad- ministration of hydrophobic drugs. Cyclodextrins are cyclic oligosaccharides able to include entirely or, at least partially, into their hydrophobic cavity, a lot of molecules with different structures. This inclusion pro- cess leads to changes in the physicochemical proper- ties of the guest, such as solubility, dissolution rate and bioavailability [8–16]. 0731-7085/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0731-7085(03)00647-2