Resolution of the enantiomers of ibuprofen; comparison study of diastereomeric method and chiral stationary phase method

doi:10.1016/0378-4347(93)E0425-P

Journal of Chromatography B: Biomedical Sciences and Applications

Volume 653, Issue 2, 4 March 1994, Pages 163-169

https://doi.org/10.1016/0378-4347(93)E0425-P Get rights and content

Abstract

In this study, an indirect diastereomeric method and a direct method utilizing a chiral stationary phase (CSP) were investigated for the resolution of ibuprofen enantiomers. In the indirect method, ethylchloroformate (ECF) and 2-ethoxy-1-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) were utilized as first-step derivatizing reagents in acetonitrile or toluene. In the direct CSP method, ibuprofen enantiomers were derivatized to p-nitrobenzyl ureides and then resolved on an (R)-(−)-(1-naphthyl)ethylurea CSP column. The derivatization procedure took place in 10 min with an overall inversion efficiency of 90.3%. Racemization was not observed under the derivatization conditions used. The HPLC-CSP method was utilized to study the pharmacokinetics of ibuprofen enantiomers in dog plasma after a single oral administration of 200 mg of ibuprofen racemate.

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Of the three branches of the simultaneous determination of enantiomers based on separation methods (indirect methods based on precolumn covalent, diastereomeric derivatization with homochiral derivatizing agents and separation on achiral stationary phases, and direct separation on chiral stationary phases or on achiral stationary phases using chiral additives in the mobile phase), the first is the subject of this chapter. Advantages and disadvantages of this approach are discussed. It is concluded that the commercial availability of a great variety of homochiral derivatizing agents and several publications up to the present time indicate that this approach cannot be considered outdated even in the era of direct methods. The main methods for the derivatization of amines, amino acids, alcohols, and carboxylic acids are presented and illustrated by several examples published mainly in the last decade. Derivatization with achiral reagents aiming at enhancing the possibilities of direct methods is also discussed.
Enantioselective analysis of ibuprofen, ketoprofen and naproxen in wastewater and environmental water samples
2011, Journal of Chromatography A
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These MDLs were determined to be in the range of 0.2–1.4 ng L−1 for (S)-ibuprofen, 0.3–1.2 ng L−1 for (S)-naproxen and 1.3–3.3 ng L−1 for ketoprofen. Alteration of EF has previously been shown to occur during activation/amidation of profens [22,25,33]. The causes of such alterations could theoretically include enantiomeric inversion, thermodynamic differences in the equilibrium of the derivatization reactions for (R)- and (S)-enantiomers, or kinetic differences in the rate of formation of the diastereomers by the (R)- and (S)-enantiomers.
A highly sensitive and reliable method for the enantioselective analysis of ibuprofen, ketoprofen and naproxen in wastewater and environmental water samples has been developed. These three pharmaceuticals are chiral molecules and the variable presence of their individual (R)- and (S)-enantiomers is of increasing interest for environmental analysis. An indirect method for enantioseparation was achieved by the derivatization of the (R)- and (S)-enantiomers to amide diastereomers using (R)-1-phenylethylamine ((R)-1-PEA). After initial solid phase extraction from aqueous samples, derivatization was undertaken at room temperature in less than 5 min. Optimum recovery and clean-up of the amide diastereomers from the derivatization solution was achieved by a second solid phase extraction step. Separation and detection of the individual diastereomers was undertaken by gas chromatography–tandem mass spectrometry (GC–MS/MS). Excellent analyte separation and peak shapes were achieved for the derivatized (R)- and (S)-enantiomers for all three pharmaceuticals with peak resolution, R_s is in the range of 2.87–4.02 for all diastereomer pairs. Furthermore, the calibration curves developed for the (S)-enantiomers revealed excellent linearity (r² ≥ 0.99) for all three compounds. Method detection limits were shown to be within the range of 0.2–3.3 ng L⁻¹ for individual enantiomers in ultrapure water, drinking water, surface water and a synthetic wastewater. Finally, the method was shown to perform well on a real tertiary treated wastewater sample, revealing measurable concentrations of both (R)- and (S)-enantiomers of ibuprofen, naproxen and ketoprofen. Isotope dilution using racemic D₃-ibuprofen, racemic D₃-ketoprofen and racemic D₃-naproxen was shown to be an essential aspect of this method for accurate quantification and enantiomeric fraction (EF) determination. This approach produced excellent reproducibility for EF determination of triplicate tertiary treated wastewater samples.
Second order standard addition method and fluorescence spectroscopy in the quantification of ibuprofen enantiomers in biological fluids
2011, Chemometrics and Intelligent Laboratory Systems
Citation Excerpt :
These methods involve toxic and expensive solvents and they are tedious and time consuming. Moreover, many times indirect analysis is used based on diasteroisomeric formation [6–23]. In these cases, the imprecision in results can be higher due to impurities in reagents for derivatization or racemization used in the procedure [7].
The second order standard addition method and spectrofluorimetry were used for determination of ibuprofen enantiomers in human plasma and urine. The methodology was based on chiral recognition of ibuprofen by formation of an inclusion complex with a chiral auxiliary, β-cyclodextrin, in the presence of 1-butanol. The strategy combines the use of PARAFAC, for extraction of the pure analyte signal, with the standard addition method, for determinations in presence of a matrix effect. A specific PARAFAC model was built for each sample and the scores were related to (S)-ibuprofen concentration using a linear regression in the standard addition method. Feasible results were obtained for determinations in the molar fraction range from 50 to 80% of (S)-ibuprofen, providing absolute errors lowers than 4.0% for plasma and urine.
Chiral discrimination of multiple profens as diastereomeric (R)-(+)-1-phenylethylamides by achiral dual-column gas chromatography
2004, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Profens were converted into diastereomeric (R)-(+)-1-phenylethylamides using ethyl chloroformate and triethylamine in dichloromethane. Gas chromatographic analysis on dual-columns with different polarities provided complete enantioresolution of eight profens, facilitating chiral discrimination based on matching with retention index sets characteristic of each enantiomer. The present method was linear (r≥0.9992) with good precision (0.8–6.0%) and accuracy (−9.3 to 0.003%), allowing detection of trace (R)-profens in optical purity test on four (S)-profen mixture in a single run. And the method allowed simultaneous enantiomeric screening for ibuprofen enantiomers and their chiral metabolites excreted in urine following administration of racemic ibuprofen.
Stereospecific high-performance liquid chromatographic analysis of ibuprofen in rat serum
2003, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
A simple, rapid and sensitive high-performance liquid chromatographic method was developed for determination of ibuprofen, (±)-(R, S)-2-(4-isobutylphenyl)-propionic acid, enantiomers in rat serum. Serum (0.1 ml) was extracted with 2,2,4-trimethylpentane/isopropanol (95:5, v/v) after addition of the internal standard, (S)-naproxen, and acidification with H₂SO₄. Enantiomeric resolution of ibuprofen was achieved on ChiralPak AD-RH column with ultraviolet (UV) detection at 220 nm without interference from endogenous co-extracted solutes. The calibration curve demonstrated excellent linearity between 0.1 and 50 μg/ml for each enantiomer. The mean extraction efficiency was >92%. Precision of the assay was within 11% (relative standard deviation (R.S.D.)) and bias of the assay was lower than 15% at the limit of quantitation (0.1 μg/ml). The assay was applied successfully to an oral pharmacokinetic study of ibuprofen in rats.
Supercritical fluid extraction with in situ chiral derivatization for the enantiospecific determination of ibuprofen in urine samples
2001, Analytica Chimica Acta
Citation Excerpt :
Ibuprofen is marketed as a racemate in most countries, and its enantioselective pharmacokinetics in healthy humans is a subject of much interest. A number of chromatographic methods for the determination of the enantiomeric composition of ibuprofen in plasma and urine samples, based on direct and indirect approaches to the enantioseparation, have been reported [8–16]. Most methods involve several steps namely: hydrolysis, extraction, drying, derivatization, redissolution and injection into the chromatographic system.
In situ chiral derivatization was used to obtain diastereomeric amides of ibuprofen for their subsequent extraction with supercritical carbon dioxide. For this purpose, ibuprofen [racemic 2-(4-isobutylphenyl)propionic acids] was previously extracted on a C-18 SPE device and quantitatively transferred into the supercritical fluid extraction (SFE) vessel for derivatization and extraction with (R)-1-(naphthen-1-yl)ethylamine as chiral derivatizing base, and a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole as reagents, in order to obtain and extract the corresponding diastereoisomeric amides, which were subsequently determined by liquid chromatography. The influence of different extraction and derivatization variables (pressure, temperature, extraction time in the static and dynamic extraction modes, and amount of chiral base) on the extraction efficiency was studied. Spiked and native urine samples containing ibuprofen were used to demonstrate the application of this method. The absolute recovery, selectivity, precision and accuracy of the combined solid-phase extraction (SPE)/SFE approach were compared to those provided by conventional liquid–liquid extraction. The results indicated that SFE seems to be an effective choice for in situ derivatization since analysis times and solvent consumption were dramatically reduced.

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Resolution of the enantiomers of ibuprofen; comparison study of diastereomeric method and chiral stationary phase method

Abstract

J. Chromatogr.

J. Pharm. Sci.

J. Pharm. Sci.

J. Chromatogr.

J. Pharm. Biomed. Anal.

Clin. Chem.