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<p>Honokiol (HNK), a bioactive neolignan derived from <i>Magnolia officinalis</i>, exhibits a wide range of pharmacological activities; however, its pharmacological applicability is limited by extremely poor aqueous solubility. In this study, solvent-free mechanochemical inclusion complexes of HNK with β-cyclodextrin (βCD) or γ-cyclodextrin (γCD) were prepared using a three-dimensional (3D) ball-milling technique, and their physicochemical properties, dissolution behavior, and biofunctional performance were systematically evaluated. Phase-solubility analyses revealed the formation of 1/1 inclusion complexes for both systems, with a significantly higher stability constant for HNK/βCD than for HNK/γCD. Solid-state characterization through PXRD, DSC, TG, NIR spectroscopy, and SEM revealed amorphization, particle size reduction, and humidity-induced recrystallization into CD-specific polymorphs, confirming successful formation of inclusion complexes. Dissolution studies showed significant enhancement of HNK early-stage dissolution from the ground mixtures, particularly for HNK/βCD, which exhibited a significantly higher 5-min dissolution rate than HNK/γCD. NOESY and DOSY NMR analyses revealed distinct inclusion orientations for HNK within the βCD and γCD cavities, providing molecular-level insight into the observed differences in stability and dissolution behavior. Of note, DPPH radical-scavenging and antifungal assays demonstrated that the antioxidant and antifungal activities of HNK were fully preserved after complexation. Molecular modeling results supported the experimentally observed inclusion modes and stability trends. Collectively, these results demonstrate that mechanochemical cyclodextrin inclusion is an effective green formulation strategy for significantly improving honokiol solubility while maintaining its intrinsic bioactivity, offering a practical approach for developing functional pharmaceutical and nutraceutical formulations for hydrophobic natural compounds.</p> Graphical Abstract <p></p>

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Green mechanochemical inclusion of honokiol in cyclodextrins for enhanced solubility and preserved bioactivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Kaede Yoshino,
  • Shun-ichi Mitomo,
  • Nao Kodama,
  • Hikari Yoshida,
  • Takami Yokogawa,
  • Masashi Kitamura,
  • Hitoshi Kamauchi,
  • Hiroshi Saito,
  • Yutaka Inoue

摘要

Honokiol (HNK), a bioactive neolignan derived from Magnolia officinalis, exhibits a wide range of pharmacological activities; however, its pharmacological applicability is limited by extremely poor aqueous solubility. In this study, solvent-free mechanochemical inclusion complexes of HNK with β-cyclodextrin (βCD) or γ-cyclodextrin (γCD) were prepared using a three-dimensional (3D) ball-milling technique, and their physicochemical properties, dissolution behavior, and biofunctional performance were systematically evaluated. Phase-solubility analyses revealed the formation of 1/1 inclusion complexes for both systems, with a significantly higher stability constant for HNK/βCD than for HNK/γCD. Solid-state characterization through PXRD, DSC, TG, NIR spectroscopy, and SEM revealed amorphization, particle size reduction, and humidity-induced recrystallization into CD-specific polymorphs, confirming successful formation of inclusion complexes. Dissolution studies showed significant enhancement of HNK early-stage dissolution from the ground mixtures, particularly for HNK/βCD, which exhibited a significantly higher 5-min dissolution rate than HNK/γCD. NOESY and DOSY NMR analyses revealed distinct inclusion orientations for HNK within the βCD and γCD cavities, providing molecular-level insight into the observed differences in stability and dissolution behavior. Of note, DPPH radical-scavenging and antifungal assays demonstrated that the antioxidant and antifungal activities of HNK were fully preserved after complexation. Molecular modeling results supported the experimentally observed inclusion modes and stability trends. Collectively, these results demonstrate that mechanochemical cyclodextrin inclusion is an effective green formulation strategy for significantly improving honokiol solubility while maintaining its intrinsic bioactivity, offering a practical approach for developing functional pharmaceutical and nutraceutical formulations for hydrophobic natural compounds.

Graphical Abstract