Parent and Derivative Cyclodextrin Complexes: A Systematic and Critical Analysis of Quercetin and Rutin

Introduction: This systematic review and meta-analysis aimed to compare parent Cy-clodextrins (CDs) and their derivatives in terms of stability constants and solubility of flavonoid-CD inclusion complexes. Methods: The meta-analysis was performed on quercetin and rutin cyclodextrin complexes. A to-tal of 98 studies out of 3,193 published between January 1, 2005, and December 31, 2023, were qualified for full-text screening. Studies that did not meet the review's inclusion criteria were eliminated, leaving 38 papers in the final analysis. Results: Most of the selected research focused on the stability constants of the inclusion com-plexes and improvement in the solubility of flavonoids when complexed with various cyclodex-trin derivatives, such as hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD). These findings were compared to those obtained with parent cyclodex-trins, primarily β-cyclodextrin (β-CD). The meta-analysis revealed that derivative CDs signifi-cantly enhanced the stability constants of flavonoid complexes compared to parent CDs. For quercetin, a pooled mean stability constant of 8.26 (95% CI: 4.77–11.74; p < 0.00001) was ob-served, while for rutin, the pooled mean stability constant was 11.29 (95% CI: 2.79-19.78; p-value of 0.009). Discussion: These findings demonstrate the superior complexation efficiency of cyclodextrin de-rivatives in stabilizing and solubilizing flavonoids. Enhanced stability constants imply stronger host–guest interactions, which may translate to better in vivo bioavailability. Compared to parent CDs, derivatives possess modified physicochemical properties that improve their interaction with hydrophobic drugs. Conclusion: Cyclodextrin derivatives significantly enhance the solubility and stability of flavo-noid complexes, making them valuable carriers in pharmaceutical and nutraceutical applications. Further in vivo studies are necessary to explore their broader potential.