Encapsulation of methyl and ethyl salicylates by β-cyclodextrin: HPLC, UV–vis and molecular modeling studies

Abstract

The complexation of methyl salicylate (MS) and ethyl salicylate (ES), non-steroidal analgesic, anti-inflammatory and antirrheumatic drugs with β-cyclodextrin (βCD) has been studied from thermodynamic and structural points of view. The complexation with βCD has been investigated using reversed-phase liquid chromatography. Retention behavior has been analyzed on a reverse-phase column Luna 18(2) 5 μm. The mobile-phase was methanol:water in different ratios (55:45 to 70:30) in which βCD (1–9 mM) was incorporated as a mobile-phase additive. The decrease in retention times with increasing concentrations of βCD enables the determination of the apparent stability constant of the complexes. Values at 30 °C with 55% methanol were K MS:βCD: 15.84 M −1 and K ES:βCD: 12.73 M −1 for MS and ES, respectively. The apparent stability constants decrease as the polarity of the solvent decreases. The low solubility of MS and ES in aqueous solution has been improved by complexation with βCD (1–9 mM). The stability constants of the complexes obtained from the phase-solubility diagrams using a UV–vis spectrophotometric method were Ḱ MS:βCD: 229 M −1 and Ḱ ES:βCD: 166 M −1. In addition, semi-empirical quantum mechanics calculations using AM1 and PM3 methods in vacuum were performed. The energetically favorable inclusion structures were identified and the most favorable orientation for the inclusion process was found to be the head-down orientation for both complexes. Enthalpy for encapsulation processes was found to be favorable (Δ H° < 0), while entropy (Δ S° < 0) and Gibbs free energy were unfavorable (Δ G° > 0). By means of HPLC and UV–vis measurements and quantum mechanics calculations, it was found that MS and ES form a 1:1 inclusion complex with βCD. The theoretical results are in agreement with the experimental parameters associated with the encapsulation process.