Chirality quantification

Al-Dirbashi O, Wada M, Kuroda N, Takahashi M, Nakashima K. 2000. Achiral and chiral quantification of methamphet-amine and amphetamine in human urine by semi-micro column high-performance liquid chromatography and fluorescence detection. J Forensic Sci 45(3) 708-714. 

L. Wu et al., Chiral quantification of D-, L-, and meso-tartaric acid mixtures using a three-point calibration kinetic method. Chem. Commun. 137, 136—137 (2003)... 

The chirality quantification technique proposed by Harary and Mezey [54,55] is motivated by the Resolution Based Similarity Measure (RBSM) approach used in more general molecular similarity analysis [243]. This method does not rely on a single reference object. Instead, it characterizes shape on any desired finite level of resolution by considering various A(J,n) parts of square lattices, called lattice animals or P(G,n) parts of cubic lattices called polycubes which can be inscribed within the two- or three-dimensional objects J or G, respectively. In the above... 

Sources (1) Liau, A. S., et al. "Optimization of a simple method for the chiral separation of methamphetamine and related compounds in clandestine tablets and urine samples by beta-cyclodextrine modified capillary electrophoresis a complementary method to GC-MS." Forensic Science International, 134 2003,17-24. (2) Cheng, W.-C., et al. "Enantiomeric Separation of Methamphetamine and Related Analogs by Capillary Zone Electrophoresis Intelligence Study in Routine Methamphetamine Seizures." Journal of Forensic Sciences, 47 2002,1248-1252. (3) Al-Dirbashi, O., et al. "Achiral and Chiral Quantification of Methamphetamine and Amphetamine in Urine by Semi-micro Column High Performance Liquid Chromatography and Fluorescence Detection." Journal of Forensic Sciences, 45 2000,708-714. 

Integration of the peaks for the two diastereomers accurately quantifies the relative amounts of each enantiomer within the mixture. Such diastereometic derivatives may also be analy2ed by more accurate methods such as gc or hplc. One drawback to diastereometic detivatization is that it requites at least 15 mg of material, which is likely to be material painstakingly synthesized, isolated, and purified. The use of analytical chiral chromatographic methods allows for the direct quantification of enantiomeric purity, is highly accurate to above 99.8% ee, and requites less than one milligram of material. 

One of the most useful applications of chiral derivatization chromatography is the quantification of free amino acid enantiomers. Using this indirect method, it is possible to quantify very small amounts of enantiomeric amino acids in parallel and in highly complex natural matrices. While direct determination of free amino acids is in itself not trivial, direct methods often fail completely when the enantiomeric ratio of amino acid from protein hydrolysis must be monitored in complex matrices. 

Nikolai LN, McClure EL, MacLeod SL, Wong CS (2006) Stereoisomer quantification of the Beta-blocker drugs atenolol, metoprolol, and propranolol in wastewaters by chiral high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr A 1131 103-109... 

Achiral-chiral LC-LC is most often used to separate the desired analyte from interfering components, such as matrix components, metabolites, excess derivatiza-tion reagent, or other impurities. Separating such interferents from the analyte allows for better analyte quantification or enantiomeric ratio determination. Also, achiral columns are seen as a way to protect the more expensive chiral columns from matrix components that might become irreversibly retained and deteriorate column performance. Short achiral columns (trap columns) are sometimes used to reconcentrate the chiral analyte after a previous separation (either chiral or achiral) as a type of online enrichment. Configurations that combine an achiral column for increased selectivity and trap column(s) for online enrichment are relatively common, though this type of configuration requires more columns and increases complexity. 

The chlorides 73a and 73b on reacting with dimethylamine in benzene afforded the amidates 92 and 93 respectively with complete diastereoselectivity. [58] The diastero-meric amides 94-96 were prepared in a similar manner by reacting 73a with chiral primary amines (optically active or racemic) and the isolated amides were applied for quantification of enantiomeric excesses of the amines of interest (Scheme 27) [55], A similar reaction with 1,2-diaminoethane gave bisphosphoramide 98 [59],... 

The condensation of 101a with chiral alcohols or amines afforded the corresponding diastereomeric derivatives 102a,b-105a,b which are suitable for quantification of enantiomeric excesses of alcohols or amines of interest (Scheme 30) [55],... 

Bakhtiar, R., Ramos, L., and Tse, F.L.S., Quantification of methylphenidate (Ritalin ) in rabbit fetal tissue using a chiral liquid chromatography/tandem mass spectrometry assay, Rapid. Commun. Mass Spectrom., 16, 81, 2002. 

Examples of specific methods important to neurochemists include separation and quantification of R- and S-fluoxetine and R- and S-norfluoxetine in brain tissue and body fluids using derivatization with (—)-(S)-N-(trifluoracetyl)prolyl chloride, a chiral derivatizing agent (Torok-Both et al., 1992 Aspeslet et al., 1994). A similar method has been used to separate the enantiomers of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) (Hegadoren et al., 1993). Eluoxetine and norfluoxetine enantiomers have also been separated on a chiral column in series with a nonchiral column with NPD detections (Ulrich, 2003). Reviews of the analysis of enantiomers of several drugs of abuse are available (Jirovsky et al., 1998 Tao and Zeng, 2002 Liu and Liu, 2002). 

From a practical point of view, and related to method development for impurity testing, it can be recommended that a method be developed in such a way that the impurity elutes before the main component. It will be easier to obtain a baseline separation and one that reduces quantification problems that might occur when the impurity elutes in the tail of the main peak. Moreover, the peak obtained for the main compound might be rather broad and tailing in chiral chromatography (as will be shown further in this chapter) which favors even more the development of methods with the impurity eluting first. 

Newly used chiral surfactants often have a low critical micellar concentration, are highly soluble and can be synthesized both in L- and D-forms. This last feature makes it possible to easily change the migration order of the optical isomers, which is very interesting for the determination of the optical pnrity of drugs, where for quantification purposes it is favorable that the chiral impurity migrates before the main component. 

CE has been touted as a replacement for HPLC in the pharmaceutical industry. This was a shame, since the techniques are so different. For many measurements, it is an orthogonal technique to HPLC. Whereas HPLC separates based on interaction with the stationary phase, CE separates based on the ratio of charge to mass. There are numerous examples of where CE exceeds the resolving power of HPLC (e.g., ion analysis, chiral analysis, DNA quantification, separation, large molecule analysis, etc.). 

Figure 25-8 Baseline separation of enantiomers of the drug Ritalin by HPLC with a chiral stationary phase. One enantiomer is pharmacologically active for treating attention deficit disorder and narcolepsy. The other enantiomer has little activity but could contribute to undesired side effects. Pharmaceutical companies are moving toward providing enantiomerically pure drugs, which could be safer than mixtures of optical isomers. [From R. Bakhtiar, L Ramos, and F. L. S. Tse, "Quantification of Methylphenidate in Plasma Using Chiral Uquid-Chromatography/Tandem Mass Spectrometry Application to Taxicokinetic Studies," Anal. Chim. Acta 2002, 469.261.]...

G. P. Blanch, A. Glausch, V. Schurig, R. Serrano and M. J. Gonzalez, Quantification and determination of enantiomeric ratios of chiral PCB 95, PCB 132 and PCB 149 in shark liver samples (C. coelolepis) from the Atlantic ocean , J. High Resolut. Chromatogr. 19 392-396 (1996). 

Orlando and Bonato [73] presented a practical and selective HPLC method for the separation and quantification of omeprazole enantiomers in human plasma. Ci8 solid-phase extraction cartridges were used to extract the enantiomers from plasma samples and the chiral separation was carried out on a Chiralpak AD column protected with a CN guard column, using ethanol-hexane (70 30) as the mobile phase, at a flow-rate of 0.5 ml/min. The detection was carried out at 302 nm. The method is linear in the range of 10-1000 ng/ml for each enantiomer, with a quantification limit of 5 ng/ml. Precision and accuracy, demonstrated by within-day and between-day assays, were lower than 10%. 

Martens-Lobenhoffer et al. [119] used chiral HPLC-atmospheric pressure photoionization tandem mass-spectrometric method for the enantio-selective quantification of omeprazole and its main metabolites in human serum. The method features solid-phase separation, normal phase chiral HPLC separation, and atmospheric pressure photoionization tandem mass spectrometry. The internal standards serve stable isotope labeled omeprazole and 5-hydroxy omeprazole. The HPLC part consists of Agilent 1100 system comprising a binary pump, an autosampler, a thermo-stated column component, and a diode array UV-VIS detector. The enantioselective chromatographic separation took place on a ReproSil Chiral-CA 5 ym 25 cm x 2 mm column, protected by a security guard system, equipped with a 4 mm x 2-mm silica filter insert. The analytes were detected by a Thermo Scientific TSQ Discovery Max triple quadrupole mass spectrometer, equipped with an APPI ion source with a... 

Franco et al. [45] described an HPLC method for simultaneous determination of the R-( ) and (S)-(+)-enantiomers of vigabatrin in human serum after precolumn derivatization with 2,4,6-trinitrobenzene sulfonic acid (TNBSA) and detection at 340 nm. Separation was achieved on a reversed phase chiral column (Chiralcel-ODR, 25 cm x 4.6 mm) using 0.05 M potassium hexafluorophosphate (pH4.5) acetonitrile ethanol (50 40 10) as a mobile phase at a flow rate of 0.9 ml/min. The calibration graphs for each enantiomer were linear over the concentration range of 0.5-40 fig/ml with a limit of quantification of 0.5 fig/ml. No interferences were found from commonly coadministered antiepileptic drugs. 

The third approach for quantification of hyoscyamine enantiomers was carried out as a non-chiral RP-LC-ESIMS/MS procedure combined with an enantioselective sample preparation step [47,49], As illustrated in Fig. 4 atropine-containing plasma samples were mixed either with human serum (procedure A) or with rabbit serum (procedure B). The latter one contains atropinesterase (AtrE) whereas human serum... 

Subsequent attempts by Singleton and Vo supported these results [36]. Also in this case, a clear random distribution of the R and S enantiomers in a number of the 54 experiments was observed, indicating that a systematic effect coming from chiral impurities may be excluded. Each experimental rim afforded a clearly detectable prevalence of either the R or the S enantiomer, giving rise to a total of 27 events in which the R enantiomer dominated and 27 events in which the S enantiomer was found in excess (no quantification of the particular ee was given). 

P.W. Fowler, Quantification of chirality Attempting the impossible. Symmetry Cult. Sci. 16, 321-334 (2003)... 

W.A. Tao et al., Copper(II)-assisted enantiomeric analysis of D, L-amino acids using the kinetic method Chiral recognition and quantification in the gas phase. J. Am. Chem. Soc. 122, 10598-10609 (2000)... 

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