Preparation of quercetin-nicotinamide cocrystals and their evaluation under in vivo and in vitro conditions

Abstract

Quercetin is a flavonoid abundant in the plant kingdom. Various types of bioactivities of quercetin have been demonstrated in vitro. Although quercetin has been proposed to exhibit numerous pharmacological benefits, it suffers from low bioavailability on account of its obviously poor solubility in water. Cocrystals have generated interest recently as a way of enhancing the dissolution in vitro and creating relative bioavailability of insoluble medicine. In this study, quercetin-nicotinamide cocrystals were obtained via a solvent evaporation technique. Furthermore, quercetin-nicotinamide cocrystals were characterized via Fourier transform infrared (FI-IR) spectroscopy, X-ray powder diffraction (PXRD), and differential scanning calorimetry (DSC) techniques. Quercetin-nicotinamide cocrystals are a new phase material, and the established intermolecular forces such as hydrogen bonds between quercetin and nicotinamide existed in the quercetin-nicotinamide cocrystals, as confirmed from the solid-state analysis. The dissolution of quercetin-nicotinamide cocrystals was found to be significantly higher than that of quercetin crystals. The pharmacokinetic data from the in vivo experiments suggested that quercetin-nicotinamide cocrystals could significantly increase the oral absorption of quercetin by nearly 4-fold. These results demonstrate that the developed quercetin-nicotinamide cocrystals are a promising oral formulation toward improvement in the dissolution and bioavailability of quercetin.

Fig. 1. PXRD patterns of nicotinamide, quercetin–nicotinamide cocrystals (1 : 1 and 1 : 2), physical mixture (1 : 1) and quercetin (up to bottom); (a) nicotinamide, (b) quercetin–nicotinamide cocrystal (1 : 1), (c) quercetin–nicotinamide cocrystal (1 : 2), (d) physical mixture (1 : 1), (e) quercetin.

Fig. 2. DSC thermograms for nicotinamide, quercetin–nicotinamide cocrystals (1 : 1 and 1 : 2), physical mixture (1 : 1) and quercetin, (a) physical mixture (1 : 1), (b) quercetin–nicotinamide cocrystal (1 : 2), (c) quercetin–nicotinamide cocrystal (1 : 1), (d) nicotinamide, (e) quercetin.

Fig. 3. FT-IR spectra showing the region from 4000 cm⁻¹ to 400 cm⁻¹ of quercetin, nicotinamide, physical mixture (1 : 1) and quercetin–nicotinamide cocrystals (1 : 1 and 1 : 2), (a) physical mixture (1 : 1); (b) nicotinamide; (c) quercetin–nicotinamide cocrystal (1 : 2), (d) quercetin–nicotinamide cocrystal (1 : 1); (e) quercetin.

Fig. 4. Dissolution profiles of quercetin, physical mixture (1 : 1) and quercetin–nicotinamide cocrystals (1 : 1 and 1 : 2) in water.

Fig. 5. HPLC chromatograms of blank rat plasma (a), rat plasma spiked with quercetin plus genistein (b) and rat plasma sample after the oral administration (10 mg kg⁻¹) of quercetin or quercetin–nicotinamide cocrystals (1 : 1) (c). (1), quercetin; (2), genistein.

Fig. 6. Plasma concentration–time curves of quercetin in rats after the oral administration (10 mg kg⁻¹) of quercetin or quercetin–nicotinamide cocrystals (1 : 1) (n = 5).