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<p>Chlorzoxazone (CLZ) is a centrally acting muscle relaxant used to relieve muscle spasms and associated pain, but it carries a risk of liver toxicity. Encapsulation of drug molecules within suitable hosts can modify their physical properties and potentially reduce side effects. This study investigates the complexation of CLZ by natural cyclodextrins (CDs) using experimental methods (phase solubility diagrams and <sup>1</sup>H NMR spectroscopy) and molecular dynamics (MD) simulations. Phase solubility diagrams indicated A<sub>L</sub>-type for α- and βCDs and A<sub>N</sub>-type for γCD, with binding constants in the order: βCD &gt; γCD &gt; αCD. Analysis of the <sup>1</sup>H NMR spectra for free and bound CLZ revealed partial inclusion within αCD and full inclusion within the larger CDs. <sup>1</sup>H NMR analysis was extended to assess complexation with 2-amino-4-chlorophenol (ACP), a regulated toxic precursor in CLZ synthesis (USP limit: ≤ 0.5% in the final product). The results demonstrated stable complexes with αCD and, to a lesser extent, with βCD, but not with γCD. MD simulations revealed that αCD and βCD form stable 1:1 complexes with both CLZ and ACP, while γCD forms 1:1 and 2:1 complexes with CLZ only. Furthermore, the binding free energies of the complexes were estimated with the MM-PBSA method, which showed similar affinities of αCD for ACP and CLZ, whereas βCD exhibited a higher affinity for CLZ (ΔΔ<i>G</i> ~ 8.4&#xa0;kJ·mol<sup>− 1</sup>).</p> Graphical Abstract <p></p>

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Cyclodextrin complexation of chlorzoxazone and its toxic impurity: insights from experiment and simulation

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Aya W. Bani Melhem,
  • Musa I. El-Barghouthi,
  • Ali I. Ismail,
  • Khaled Bodoor

摘要

Chlorzoxazone (CLZ) is a centrally acting muscle relaxant used to relieve muscle spasms and associated pain, but it carries a risk of liver toxicity. Encapsulation of drug molecules within suitable hosts can modify their physical properties and potentially reduce side effects. This study investigates the complexation of CLZ by natural cyclodextrins (CDs) using experimental methods (phase solubility diagrams and 1H NMR spectroscopy) and molecular dynamics (MD) simulations. Phase solubility diagrams indicated AL-type for α- and βCDs and AN-type for γCD, with binding constants in the order: βCD > γCD > αCD. Analysis of the 1H NMR spectra for free and bound CLZ revealed partial inclusion within αCD and full inclusion within the larger CDs. 1H NMR analysis was extended to assess complexation with 2-amino-4-chlorophenol (ACP), a regulated toxic precursor in CLZ synthesis (USP limit: ≤ 0.5% in the final product). The results demonstrated stable complexes with αCD and, to a lesser extent, with βCD, but not with γCD. MD simulations revealed that αCD and βCD form stable 1:1 complexes with both CLZ and ACP, while γCD forms 1:1 and 2:1 complexes with CLZ only. Furthermore, the binding free energies of the complexes were estimated with the MM-PBSA method, which showed similar affinities of αCD for ACP and CLZ, whereas βCD exhibited a higher affinity for CLZ (ΔΔG ~ 8.4 kJ·mol− 1).

Graphical Abstract