Quercetin/beta-cyclodextrin solid complexes prepared in aqueous solution followed by spray-drying or by physical mixture

Abstract

The present study was designed to investigate the influence of operating conditions (temperature, stirring time, and excess amount of quercetin) on the complexation of quercetin with beta-cyclodextrin using a 2(3) factorial design. The highest aqueous solubility of quercetin was reached under the conditions 37 degrees C/24 h/6 mM of quercetin. The stoichiometric ratio (1:1) and the apparent stability constant (Ks = 230 M(-1)) of the quercetin/beta-cyclodextrin complex were determined using phase-solubility diagrams. The semi-industrial production of a 1:1 quercetin/beta-cyclodextrin solid complex was carried out in aqueous solution followed by spray-drying. Although the yield of the spray-drying process was adequate (77%), the solid complex presented low concentration of quercetin (0.14%, w/w) and, thus, low complexation efficiency. The enhancement of aqueous solubility of quercetin using this method was limited to 4.6-fold in the presence of 15 mM of beta-cyclodextrin. Subsequently, an inclusion complex was prepared via physical mixture of quercetin with beta-cyclodextrin (molar ratio of 1:1 and quercetin concentration of 23% (w/w)) and characterized using infrared spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy, and scanning electron microscopy analyses. The enhancement of aqueous solubility of quercetin using this method was 2.2-fold, similar to that found in the complex prepared in aqueous solution before the spray-drying process (2.5-fold at a molar ratio of 1:1, i.e., 6 mM of quercetin and 6 mM of beta-cyclodextrin).

Fig. 1

Quercetin: chemical structure

Fig. 2

Phase-solubility diagrams of quercetin/β-cyclodextrin complexes obtained using a 2³ factorial design (n = 2). Stirring time of 24 or 48 h, temperature of 25°C or 37°C and excess amount of quercetin of 3 or 6 mM

Fig. 3

Phase-solubility diagram of quercetin/β-cyclodextrin complex (n = 3). Stirring time of 24 h, temperature of 37°C, and excess amount of quercetin of 6 mM

Fig. 4

Differential scanning calorimetry curves of β-cyclodextrin a; quercetin b; physical mixture of quercetin with β-cyclodextrin c; quercetin/β-cyclodextrin solid complex d

Fig. 5

¹HNMR spectra of quercetin a; stored physical mixture of quercetin with β-cyclodextrin b; fresh physical mixture of quercetin with β-cyclodextrin c

Fig. 6

2D-ROESY spectrum of stored physical mixture of quercetin with β-cyclodextrin

Fig. 7

Photomicrographs obtained by scanning electron microscopy of β-cyclodextrin a; quercetin b; physical mixture of quercetin with β-cyclodextrin c; quercetin/β-cyclodextrin solid complex d