Synthesis And Application Of A New β-cyclodextrin Bonded Silica Gel As Chiral Stationary Phase For The Resolution Of (±)-naproxen

Naproxen,6-methoxy-α-methyl-2-naphthalene acetic acid, is a non-steroidalanti-inflammatory drug and widely used as mild to moderate pain relief and in thetreatment of rheumatic and fever. Naproxen has a pair of enantiomers named asR-naproxen and S-naproxen because its chemical structure possesses an asymmetricα-carbon atom. Clinical studies showed that the pharmaceutic potency of S-naproxenis30times more active than that of R-naproxen, and only the S-isomer is used as adrug for humans. However, the chemical synthesis of naproxen often producesracemic mixture. Direct uptake of the racemate will no doubt increase the burden ofmetabolism, and lead to reduce the drug efficacy. In order to reduce the drugconsumption, decrease the side effects, improve the drug efficacy, naproxen wasrequired to sale in its pure enantiomer form. Thus, new methods with good sensitivity,accuracy, and high efficiency for the separation and determination of (±)-naproxenmixture have gained more and more attention. The aim of this study is to establishnew methods for the resolution and determination racemic naproxen, which includesthe thin layer chromatography (TLC) method and the high performance liquidchromatography method.(1) A new method has been developed to separate naproxen racemate byapplying TLC. In the proposed method, a new kind of β-CD/SiO2chiral stationaryphase was prepared by bonding β-CD onto the surface of silica gel and characterizedby X-ray photoelectron spectroscopy (XPS) and Fourier Transform Infra-Red (FTIR)spectroscopy to prove the successful immobilization of β-CD derivatives bondedsilica gel. The thermal behavior of the CSP was studied by differential scanningcalorimetry (DSC). It was used as chiral stationary phase of thin-layer chromatography to separate naproxen racemate. Several factors affecting theseparation efficiency of naproxen enantiomers were investigated systematically,including the mobile phase, temperature, colour development reagents. The followingparameters were selected: ethyl acetate-chloroform (1:4, v/v) was selected as themobile phase, the temperature was15℃, and iodine fuming method was used ascolour development. Under optimal conditions, the results showed that this methodhas a favourable separate capability and the separate faction of (±)-naproxen wasreached to1.45.(2) A novel and simple HPLC method is developed based on derivativedβ-cyclodextrin (β-CD) bonded silica gel (β-CD/SiO2) as chiral stationary phase (CSP)to chiral separation of racemic naproxen. Several important parameters controlling theinfluence of the separation efficiency of naproxen enantiomers were investigated andoptimized. The optimal conditions were shown as follows: methanol-0.01mol/Lphosphate buffer solution (85:15, v/v) with pH3.5was selected as the mobile phase,the flow rate was1.0mL/min, and the column temperature was35℃. Under optimalconditions, the racemic naproxen was successfully separated by HPLC withβ-CD/SiO2CSP. This method was successfully employed for determining the contentof S-naproxen in commercial naproxen sustained release tablets. Additionally, theenantioseparation mechanism was also discussed.