Stereoselective Differences in the Percutaneous Permeation of Ketoprofen Enantiomers and the Underlying Chiral Recognition Mechanisms.

Authors

Zixi Zhou, Kaile Meng, Honghui Wang, Wenxiu Dong, Yinghua Sun, Zhonggui He

Published in

Chirality. Volume 38. Issue 10. Pages e70144.

Abstract

This research aims to investigate the stereoselective permeation differences and molecular recognition mechanisms of ketoprofen enantiomers in the chiral microenvironment of the stratum corneum (SC). This also aims to provide theoretical support for developing highly efficient and precise single-enantiomer transdermal drug delivery systems. The permeation behaviors of dexketoprofen and its racemate through excised full-thickness rat skin in three different solvent systems were studied using Franz diffusion cells. The solubility, apparent partition coefficients, and differential scanning calorimetry were used to assess the physicochemical and thermodynamic properties of both forms. Fourier transform infrared (FTIR), ¹³C NMR, attenuated total reflection-FTIR (ATR-FTIR), and Raman spectroscopic techniques were extensively performed to investigate micro-interactions between drug and core SC (ceramide NP and keratin) components. In addition, in order to affirm the mechanisms, binding energy, cohesive energy density, and the radial distribution function along with mean square displacement were evaluated using molecular docking and molecular dynamics simulations. Based on in vitro permeation results, the cumulative permeated amounts of dexketoprofen in all three solvent systems were significantly higher than those of racemic ketoprofen (approximately 1.2-fold). Characterizations by thermodynamic and physicochemical methods showed that dexketoprofen displayed a relatively low melting point (76.26°C), enthalpy of fusion (26.39 kJ/mol), lattice energy, and higher lipophilicity and solubility, which gave rise to a greater thermodynamic driving force for drug release. Both spectroscopic analyses and molecular simulations confirmed that dexketoprofen formed a stronger intermolecular hydrogen bonding network with ceramide NP (binding energy: -21.63 kcal/mol). This robust spatial affinity remarkably perturbed the tightly ordered arrangement of the SC lipid bilayer, which may induce a decrease in lipid orderliness and substantially increase the fluidity. The transdermal superiority of dexketoprofen within the chiral skin barrier is synergistically attributed to its high thermodynamic activity, driven by a lower lattice energy, and its stronger microscopic stereoselective interactions with SC components. This study systematically elucidates the stereoselective mechanisms underlying the transdermal permeation of chiral drugs, thereby providing a scientific basis for the development of transdermal formulations containing a single enantiomer.

PMID:
42767632
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.

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