Limited extent of stereochemical conversion of chiral non-steroidal anti-inflammatory drugs induced by derivatization methods employing ethyl chloroformate.
A potential problem with chiral derivatization is the possibility of stereochemical conversion during the derivatization reaction. This possibility has been examined using the non-steroidal anti-inflammatory drugs ibuprofen, ketoprofen, etodolac and flurbiprofen. To avoid possible interference from stereochemical impurities, male Sprague-Dawley rats were dosed intraperitoneally with the S enantiomer (100 mg/kg) of each drug and the R enantiomer of etodolac. Blood samples were taken 4 h afterwards. The plasma samples were analyzed using published stereospecific methods involving chiral derivatization with ethyl chloroformate followed by either R-(+)-alpha-phenylethylamine or L-leucinamide. For all the drugs examined, the percentage of formation of the antipode was between 1.0 and 5.8%. In vitro studies of the R and S enantiomers demonstrate that the apparent extent of conversion is inversely related to the concentration of ethyl chloroformate present during the derivatization reaction for ibuprofen, ketoprofen and flurbiprofen but not for etodolac. However, both the R and S enantiomers appear to be inverted to the same extent in the presence of ethyl chloroformate. These results suggest that the degree of stereochemical conversion induced by these assay procedures is small and would not contribute significantly to analytical error in the absence of a large difference in concentrations of the enantiomers.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
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Wright
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Jamali
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000737:chemistry* / Q000302:isolation & purification; D002851:Chromatography, High Pressure Liquid; D005563:Formic Acid Esters / Q000737:chemistry; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005563:Formic Acid Esters; C007658:ethyl chloroformate