# 2-Hydroxypropyl-β-Cyclodextrin-Based Complexes Improve Polyphenol Solubility and Bioaccessibility: Evaluation by Validated HPLC–DAD Method

## TL;DR

This study shows that using 2-hydroxypropyl-β-cyclodextrin improves the solubility and digestive stability of propolis polyphenols, though their intestinal absorption remains limited.

## Contribution

A validated HPLC–DAD method and a green complexation approach for enhancing propolis polyphenol solubility and bioaccessibility are introduced.

## Key findings

- HP-β-CD complexation significantly improved the solubility and gastrointestinal stability of propolis polyphenols.
- Intestinal bioaccessibility of polyphenols ranged from 77.2% to 124.9%, but dialyzable polyphenols were reduced, with CA being undetectable.
- PC and CAPE were more stable during digestion compared to GN, CR, and CA, which showed significant degradation.

## Abstract

Propolis is a rich natural source of biologically active polyphenols; however, their therapeutic potential is often limited by poor oral bioaccessibility and bioavailability. This study reports the development and validation of a high-performance liquid chromatography–diode array detector (HPLC–DAD) method optimized for the quantification of major propolis polyphenols—caffeic acid (CA), pinocembrin (PC), chrysin (CR), caffeic acid phenethyl ester (CAPE), and galangin (GN) in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD)-based complexes. A green complexation approach based on HP-β-CD and lyophilization was applied to continental propolis, yielding a water-soluble formulation suitable for oral administration. The isocratic HPLC–DAD method demonstrated linearity, sensitivity, and precision, suitable for reliable analysis of polyphneols in cyclodextrin-based matrices. Gastrointestinal behavior was evaluated using a simulated oral, gastric, and intestinal digestion model. PC and CAPE remained stable throughout digestion, whereas GN, CR, and CA showed higher sensitivity, with decreases of 43.1–71.6% compared to undigested samples. HP-β-CD complexation enhanced polyphenol solubility and improved gastrointestinal stability. Intestinal bioaccessibility, assessed by a centrifugation model, ranged from 77.2% (CR) to 124.9% (CA). However, the complexes did not permeate the artificial intestinal membrane, resulting in reduced dialyzable polyphenols, with CA being undetectable. These findings provide a validated analytical platform and mechanistic insight into the gastrointestinal behavior of cyclodextrin-complexed propolis polyphenols, supporting their application in oral functional formulations.