Enhanced Solution Concentration of Quercetin in Amorphous Solid Dispersions

Abstract

The flavonol quercetin is present in foods such as apples and onions and has potential beneficial bioactivities against cardiovascular disease, obesity, and oxidative stress. However, the benefits of quercetin are limited by poor bioavailability, primarily attributed to its crystallinity (resulting in low aqueous solubility) and extensive Phase‐II/III metabolism. Increasing solution concentrations of quercetin in the intestinal lumen has the potential to increase its diffusion across the unstirred water layer, thus improving absorption. Improving the bioavailability of quercetin is critical for enhancing its efficacy in vivo. Various strategies have been employed to improve quercetin dissolution in the intestinal lumen. One promising approach is to incorporate quercetin into amorphous solid dispersions (ASD). Cellulosic polymers with carboxylic acid functionality disperse quercetin, eliminating crystallinity, and selectively release quercetin at intestinal pH due to electrostatic repulsion of deprotonated acid groups. We assessed the utility of commercially available and novel cellulose derivatives for improving in vitro dissolution properties of quercetin, measured by the area under the concentration/time curve (AUC). Quercetin was dispersed via spray drying with novel cellulose derivatives [cellulose acetate suberate (CASub) and cellulose acetate adipate propionate (CAAdP)], and commercially available derivatives [hydroxypropylmethyl cellulose (HPMCAS) and carboxycellulose acetate butyrate (CCAB)]. Amorphous structure was confirmed by X‐ray diffraction. In vitro dissolution was performed at gastric and small intestinal pH (1.2 and 6.8, respectively). Crystalline quercetin showed poor solubility at both gastric and intestinal pH. At pH 1.2, amorphous quercetin in all cellulose derivatives showed poor dissolution, as expected. At pH 6.8, 10% (w/w) amorphous quercetin in CCAB provided significantly enhanced quercetin solution concentrations compared to crystalline quercetin and 25% and 50% amorphous quercetin; thus, 10% quercetin was employed for the other polymers. Amorphous quercetin (10%) in HPMCAS provided enhanced dissolution profile for quercetin at intestinal pH, substantially increasing its AUC compared to quercetin dispersed in CCAB. These results provide promising, novel opportunities for increasing the bioavailability of quercetin in vivo, and support the use of HPMCAS to achieve this. Furthermore, in vivo bioactivity studies are warranted to assess the ability of ASD to improve upon the bioactivity of crystalline quercetin.Support or Funding InformationFunding provided by the Institute for Critical Technologies and Applied Science at Virginia Tech.