Various contributions have been reported concerning the inclusion of flavonoids in cyclodextrins (CDs). The association constant ( \({K}_{ass}\) ) is one fundamental aspect for characterizing inclusion compounds. Distinct association constants were obtained depending on the experimental technique or the pH for flavonoids included in CD. In the present study, we applied two recently developed theoretical methodologies based on a multi-equilibrium approach to estimate the \({K}_{ass}\) for the inclusion of the neutral flavonoids morin (MOR), quercetin (QUE), luteolin (LUT), and kaempferol (KAE) into β-cyclodextrin (β-CD). The analysis of the experimental data for an appropriate pH range, in conjunction with the theoretical response from quantum GFN2-xTB and classical molecular dynamics, addressed the following stability order: LUT@β-CD > QUE@β-CD ~ KAE@β-CD. The combined theoretical and experimental data suggest as more representative experimental Kass for neutral systems, the following values (in M−1): 462 (2020) – 545 (2013) for LUT@β-CD, 398 (2008) for QUE@β-CD, and 375 (2007) for KAE@β-CD. The theoretical information did not align with the experimental data previously published for MOR@β-CD at low pH, indicating the need for further studies.
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