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<p>Apixaban (APX) is an oral anticoagulant that selectively inhibits Factor Xa, effectively preventing and treating thromboembolic disorders. However, its low water solubility and limited oral bioavailability restrict its therapeutic efficacy. Encapsulating APX in a host such as cyclodextrins (CD) might enhance its solubility and subsequently improve its bioavailability. Complexation with methylated βCDs (methyl, dimethyl, trimethyl), as studied via phase solubility diagram (PSDs) indicates a noticeable enhancement in the solubility (~ 3–4fold). The APX–DMβCD (Heptakis(2,6-di-O-methyl)-βCD) complex was prepared with freeze-drying, and its formation was confirmed by differential scanning calorimetry and IR spectroscopy, with the latter indicating the involvement of the amide group of APX in interactions with the host. The <sup>1</sup>H and 2D NMR spectra of APX with DMβCD suggest the formation of an inclusion complex characterized by more than one geometry.&#xa0;Molecular dynamics simulations demonstrate the formation of a stable APX-DMβCD complex in various binding modes. Molecular mechanics Poisson–Boltzmann surface area analysis indicates a preference of the binding mode where the methoxy phenyl is included in the host’s cavity. Furthermore, van der Waals interactions are found to be the predominant forces in stabilizing the complex.</p>

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Exploring Apixaban Interaction with Heptakis(2,6-di-O-methyl)-β-Cyclodextrin: Insights from Phase Solubility Diagrams, 1H NMR and Molecular Dynamics Simulations

  • 期刊论文

  • 发表日期：

    2025年10月5日

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  • Ali I. Ismail,
  • Rania A. Abusa’aleek,
  • Khaled Bodoor,
  • Musa I. El-Barghouthi

摘要

Apixaban (APX) is an oral anticoagulant that selectively inhibits Factor Xa, effectively preventing and treating thromboembolic disorders. However, its low water solubility and limited oral bioavailability restrict its therapeutic efficacy. Encapsulating APX in a host such as cyclodextrins (CD) might enhance its solubility and subsequently improve its bioavailability. Complexation with methylated βCDs (methyl, dimethyl, trimethyl), as studied via phase solubility diagram (PSDs) indicates a noticeable enhancement in the solubility (~ 3–4fold). The APX–DMβCD (Heptakis(2,6-di-O-methyl)-βCD) complex was prepared with freeze-drying, and its formation was confirmed by differential scanning calorimetry and IR spectroscopy, with the latter indicating the involvement of the amide group of APX in interactions with the host. The 1H and 2D NMR spectra of APX with DMβCD suggest the formation of an inclusion complex characterized by more than one geometry. Molecular dynamics simulations demonstrate the formation of a stable APX-DMβCD complex in various binding modes. Molecular mechanics Poisson–Boltzmann surface area analysis indicates a preference of the binding mode where the methoxy phenyl is included in the host’s cavity. Furthermore, van der Waals interactions are found to be the predominant forces in stabilizing the complex.