Ionic liquids (ILs), as separation media, have made significant contributions in the past decades in advancing research in gas chromatography (GC), liquid chromatography (LC), and capillary electrophoresis (CE). This review, covering reports published from the mid 1980s to early 2007, shows how ILs have been used so far in separation science, originally primarily as GC stationary phases and later as mobile phase additives (both millimolar and major percent levels) for LC and CE. Representative GC and LC chromatograms as well as CE electropherograms are shown. In addition, the very recent findings on the development of ionic liquids with surfactant properties and its applications for chiral and achiral analysis are discussed.
Two amino acid derived (leucinol and N-methyl pyrrolidinol) chiral ionic liquids are synthesized and characterized both in monomeric and polymeric forms. Leucinol based chiral cationic surfactant is room a temperature ionic liquid (RTIL), and pyrrolidinol based chiral cationic surfactant melts at 30-35 °C to form ionic liquid (IL). The monomeric and polymeric ILs are thoroughly characterized to determine critical micelle concentration, aggregation number, polarity, optical rotation and partial specific volume. Here in, we present the first enantioseparation using chiral IL as pseudostationary phase in capillary electrophoresis. Chiral separation of two acidic analytes, (±)-alpha-bromophenylacetic acid (±)-(α-BP-AA) and (±)-2-(2-chlorophenoxy)propanoic acid(±)-(2-PPA) can be achieved with both monomers and polymers of undecenoxy carbonyl-L-pryrrolidinol bromide (L-UCPB) and undecenoxy carbonyl-L-leucinol bromide (L-UCLB) at 25 mM surfactant concentration using phosphate buffer at pH 7.50. The chiral recognition seems to be facilitated by the extent of interaction of the acidic analytes with the cationic head group of chiral selectors. Polysodium Nundecenoxy carbonyl-L-leucine sulfate (poly-L-SUCLS) and polysodium N-undecenoxy carbonyl-L-leucinate (poly-L-SUCL) were compared at high and low pH for the enantioseparation of (±)-(2-PPA). At pH 7.5, poly-L-SUCLS, poly-L-SUCL and ±-2-PPA are negatively charged resulting in no enantioseparation. However, chiral separation was observed for (±)-(2-PPA) using poly-L-SUCLS at low pH (pH 2.00) at which analyte is neutral. The comparison of chiral separation of anionic and cationic surfactants demonstrates that the electrostatic interaction between the acidic analyte and cationic micelle plays a profound role in enantioseparation.The separation of chiral compounds is currently the center of great interest. 1 This interest can be attributed largely to a heightened awareness that enantiomers of a racemic drug usually display markedly different pharmacological activities. 2,3 The human body metabolizes individual enantiomers by separate pathways to produce different pharmacological effects. Presently, a majority of commercially available drugs are synthetic and chiral. Most of these chiral drugs are obtained as a mixture of two enantiomers during synthesis. 4 In order to avoid the possible undesirable effects of enantiomeric impurity in chiral drug, it is inevitable that only therapeutically active form be marketed. Hence there is a continuous need to develop technologies that have the ability to separate enantiomers. In this study, we report the synthesis, characterization and application of novel IL type surfactants and their polymers for chiral separation of acidic analytes in MEKC. Acidic analytes due to inherent negative charge poorly interact with most commonly employed chiral anionic surfactants at basic pH. As a result, still a large number of acidic analytes could not be resolved by MEKC. The cationic surfactant, undecenoxy carbonyl-L-leucinol bromide (L-UCLB) i...
The coupling of chiral micellar electrokinetic chromatography (CMEKC) to mass spectrometry (MS) using conventional surfactant [above the critical micelle concentration (cmc)] is very challenging. Preliminary investigation in this laboratory indicates that the use of a chiral polymeric surfactant provides one possible solution to this difficult coupling. This is because of many positive attributes of micelle polymers which include zero cmc, lower surface activity, low volatility, high electrophoretic mobility, and function as a suitable separation medium even at lower concentrations of pseudophases. In this work, the feasibility of using poly(sodium N-undecanoyl-L-valinate (poly-L-SUV) in CMEKC-MS is demonstrated. After CMEKC separation, enantiomers of 1,1'-binaphthol (BOH) were detected using electrospray ionization mass spectrometry (ESI-MS) by selected ion monitoring (SIM) in the negative ion mode. Although in the SIM mode ESI-MS parameters (nebulizer pressure, drying gas flow rate, drying gas temperature, and sheath liquid flow rate) affected only the signal-to-noise ratio of (+/-)BOH, two of the ESI-MS parameters (nebulizer pressure, sheath flow rate) were found to have a significant impact on chiral resolution of (+/-)BOH. At the optimum ESI-MS conditions, the enantioseparation of (+/-)BOH was successfully accomplished by varying the buffer pH, concentration of the volatile background electrolyte, and poly-L-SUV.
The feasibility of using a new and more versatile polymeric chiral surfactant, i.e., poly(sodium N-undecenoxy carbonyl-L-leucinate (poly-L-SUCL) is investigated for simultaneous enantioseparation and detection of eight structurally similar beta-blockers with tandem UV and MS detection. Three optimization approaches, i.e., direct infusion-MS, capillary zone electrophoresis-MS, and chiral micellar electrokinetic chromatography-mass spectrometry (CMEKC-MS), were investigated to optimize sheath liquid parameters, spray chamber parameters, and CMEKC separation parameters for maximum sensitivity and chiral resolution. Compared to unpolymerized micelle of L-SUCL, the use of micelle polymer (i.e., poly-L-SUCL) provided significantly higher separation efficiency, lower separation current, and higher detection sensitivity for CMEKC-ESI-MS of beta-blockers. It was also observed that, unlike monomeric L-SUCL, polymeric L-SUCL provided enantioseparation of all beta-blockers even at the lowest surfactant concentration (i.e., 5 mM poly-L-SUCL). Under optimum CMEKC and ESI-MS conditions (15 mM poly-L-SUCL, 25 mM each of NH4OAc and TEA (pH 8.0); 80% (v/v) methanol sheath liquid containing 40 mM NH4OAc (pH 8.0); sheath liquid flow rate, 5.0 microL/min; drying gas flow rate, 5 L/min; drying gas temperature, 200 degrees C; nebulizing pressure, 6 psi (0.414 bar); capillary voltage, +2.5 kV; fragmentor voltage, 85 V), baseline enantioseparation of eight beta-blockers was achieved by tandem UV (in approximately 30 min) and MS (in approximately 60 min) detection. Calibration curves for all beta-blockers were linear in the range of 0.01-0.6 mM for both CMEKC-UV and CMEKC-MS methods, but the later method provided better concentration limit of detection with similar RSD for migration time and peak areas. The CMEKC-ESI-MS method appears suitable for use as a routine procedure for high-throughput separation of beta-blockers with high sensitivity.
The hyphenation of chiral capillary electrochromatography (CEC) with electrospray ionization mass spectrometry (ESI-MS) is very challenging but promising due to the fact that it combines sensitivity with high specificity and selectivity. In this work, CEC capillaries packed with (3R,4S)-Whelk-O1 chiral stationary phase were used for simultaneous enantioseparation of (+/-)-warfarin and its internal standard, (+/-)-coumachlor. Furthermore, both the chiral CEC separation and MS detection parameters were examined in detail. First, the influence of different column fabrication was investigated. Second, enantioseparation was optimized by varying CEC parameters, including acetonitrile concentration, buffer pH, and ionic strength. Under the optimum chiral CEC conditions, ESI-MS parameters such as sheath liquid pH and composition, sheath liquid flow rate, drying gas flow rate, drying gas temperature, nebulizer pressure, and fragmentor voltage were investigated to achieve maximum MS signals of the separated enantiomers. Finally, using solid-phase extraction as sample preparation method, (+/-)-warfarin spiked in 100-microL human plasma samples were analyzed. The calibration curves showed good linearity for both (R)-warfarin (R = 0.9979) and (S)-warfarin (R = 0.9978) enantiomers. The experimental limit of detection was approximately 25 ng/mL for both enantiomers. Even though the data are still preliminary, we can state with confidence that chiral CEC-ESI-MS has the potential to establish itself as a very powerful technique for the determination of enantiomeric ratios in human body fluid.
We describe here the state-of-the-art development of on-line capillary electrophoresis-mass spectrometry (CE-MS) over the last two years. Technological developments included are novel designs of new interfaces and ionization sources, new capillary coatings, buffers, and micelles as well as application of various modes of CE-MS published in the recent literature. The areas of CE-MS application in analysis of small achiral and chiral solutes are covered in sections that highlight the recent advances and possibilities of each mode of CE-MS. Application areas reviewed in this paper include achiral and chiral pharmaceuticals, agrochemicals, carbohydrates, and small peptides. The separation of enantiomers using micellar electrokinetic chromatography (MEKC)-MS with molecular micelles and capillary electrochromatography (CEC)-MS using pack tapered columns appears to provide good tolerance to electrospray stability for routine on-line CE-MS. These two modes seem to be very suitable for sensitive detection of chiral pharmaceuticals in biological samples, but their use will probably increase in the near future. Overall, it seems that one mode of CE-MS, in particular capillary zone electrophoresis (CZE)-MS, is now recognized as established technique for analysis of small charged solutes, but other modes, such as MEKC-MS and CEC-MS, are still within a period of development in terms of both MS-compatible pseudostationary phases and columns as well as applications.
Electrokinetic chromatography (EKC) with poly(sodium undecylenic sulfate) (poly-SUS) is utilized to separate environmental pollutants such as 2−6-ring polycyclic aromatic hydrocarbons (PAHs). Parameters such as pH, concentration of polymeric surfactants, and the use of organic modifiers were investigated to follow the retention trends of PAHs. A baseline separation of all 16 PAHs in about 30 min, using 0.50% (w/v) of poly-SUS/12.5 mM sodium phosphate−borate buffer (pH 9.2) with 40% (v/v) acetonitrile, was possible for the first time in EKC by a single-surfactant system.
In this work, three amino acids derived (L-leucinol, L-isoleucinol and L-valinol) sulfated chiral surfactants are synthesized and polymerized. These chiral sulfated surfactants are thoroughly characterized to determine critical micelle concentration, aggregation number, polarity, optical rotation and partial specific volume. For the first time the morphological behavior of polymeric sulfated surfactants is revealed using cryogenic high-resolution electron microscopy (cryo-HRSEM). The polysodium N-undecenoyl-L-leucine sulfate (poly-L-SUCLS) shows distinct tubular structure, while polysodium N-undecenoyl-L-valine sulfate (poly-L-SUCVS) also shows tubular morphology but without any distinct order of the tubes. On the other hand, polysodium N-undecenoyl-Lisoleucine sulfate (poly-L-SUCILS) displays random distribution of coiled/curved filaments with heavy association of tightly and loosely bound water. All three polymeric sulfated surfactants are compared for enantio-separation of broad range of structurally diverse racemic compounds at very acidic, neutral and basic pH conditions in micellar electrokinetic chromatography (MEKC). A small combinatorial library of 10 structurally related phenylethylamines (PEAs) is investigated for chiral separation under acidic and moderately acidic to neutral pH conditions using an experimental design. In contrast to neutral pH conditions, at acidic pH, significantly enhanced chiral resolution is obtained for class I and class II PEAs due to the compact structure of polymeric sulfated surfactants. It is observed that the presence of hydroxy group on the benzene ring of PEAs resulted in deterioration of enantioseparation. A sensitive MEKC-mass spectrometry (MS) method is developed for one of the PEA (e.g., (±)-pseudoephedrine) in human urine. Very low limit of detection (LOD) is obtained at pH 2.0 (LOD 325 ng/mL), which is ca 16 times better compared to pH 8.0 (LOD 5.2 µg/mL). Other broad range of chiral analytes (β-blockers, phenoxypropionic acid, benzoin derivatives, PTHamino acids, and benzodiazepinones) studied also provided improved chiral separation at low pH compared to high pH conditions. Among the three polymeric sulfated surfactants, poly-L-SUCILS with two chiral centers on the polymer head group provided overall higher enantioresolution for the investigated acidic, basic and neutral compounds. This work clearly demonstrates for the first time the superiority of chiral separation and sensitive MS detection at low pH over conventional high pH chiral separation and detection employing anionic chiral polymeric surfactants in MEKC and MEKC-MS. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOver the last 20 years, the number of materials and products developed as pure enantiomers (eutomer) has continued to increase. With evidence of problems related to stereoselectivity in drug action, enantioselective analysis by separation are of particular importance for production, therapeutic monitoring or pharmacokinetic studies, and/or to validate the opt...
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