Markus Juza

Minimum alveolar anesthetic concentration values for the enantiomers of isoflurane differ minimally

Results of in vivo and in vitro studies of the anesthetic potencies of the enantiomers (optical isomers) of isoflurane provide various results ranging from no difference to differences of nearly two fold.A finding of a difference in anesthetic requirement in the whole animal has particular relevance to theories of anesthetic mechanisms of action because it suggests that anesthesia may result from a specific anesthetic-receptor interaction. This led to our decision to redetermine the minimum alveolar anesthetic concentration (MAC) of (+)-S and (-)-R enantiomers of isoflurane in 12 Sprague-Dawley rats (six per group). The (+)-S enantiomer gave a MAC of 0.0144 +/- 0.0012 atm (i.e., 1.44% +/- 0.12% at 1 atm pressure; mean +/- SD) and the (-)-R enantiomer gave a MAC of 0.0169 +/- 0.0020 atm. Although the 17% greater value for the (-)-R enantiomer is qualitatively consistent with previous results the difference is not significant (P = 0.06), and the absolute difference is smaller than that found by a previous study. However, given the small sample size, our power to define a small significant difference is limited. Regardless of statistical significance, our results do not confirm the conclusion that interaction with a specific receptor is important to the mechanism of action of inhaled anesthetics. (Anesth Analg 1997;85:188-92)

Approach to the thermodynamics of enantionmer separation by gas chromatography Enantioselectivity between the chiral inhalation anesthetics enflurane, isoflurane and desflurane and a diluted γ-cyclodextrin derivative

Abstract The thermodynamics of enantioselectivity, −ΔD,L(ΔG), −ΔD,L(ΔH), ΔD,L(ΔS) and Tiso, have been determined by gas chromatography employing the concept of the retention increment R′ for the inhalation anesthetics enflurane (1), isoflurane (2) and desflurane (3) and the selector octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-γ-cyclodextrin (4) in the polysiloxane SE-54. It is shown that the separation factor α is concentration dependent. Therefore, the separation factor α should not be employed as a criterion for enantioselectivity in diluted systems. The −ΔD,L(ΔG) data for 1 and 4 are corroborated by 1H NMR spectroscopic measurements.

Analysis of charged cyclomalto-oligosaccharides (cyclodextrin) derivatives by ion-spray, matrix-assisted laser-desorption/ionization time-of-flight and fast-atom bombardment mass spectrometry, and by capillary electrophoresis

The use of electrospray-ionization mass spectrometry (ESIMS), matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDITOFMS), and fast-atom bombardment mass spectrometry (FABMS) for the rapid determination of molecular weight, degree of substitution (ds), and purity is demonstrated for charged derivatives of cyclomalto-heptaose (beta CD) and -octaose (gamma CD). The access to anionic sulfoalkyl ethers (alkyl: ethyl, n-propyl, and n-butyl) and to beta CD-2-hydroxy-3-trimethylammoniumpropyl ether chlorides (HTAP-beta CD) leads only to mixtures of products, the compositions of which can be determined directly from ESI and MALDITOF mass spectra. All charged derivatives consist of a mixture of unreacted and higher substituted compounds. The substitution patterns obtained by MS are in good agreement with the results of experiments on the separation of beta CD-sulfoalkyl ethers by capillary electrophoresis (CE).

Batch and simulated moving bed chromatographic resolution of a pharmaceutical racemate.

The preparative chromatographic resolution of racemates has become over the past few years a standard approach for the generation of enantiomers in pharmaceutical research and development. This paper will discuss the chromatographic resolution of a racemic pharmaceutical intermediate. Initial analytical method development to determine the best preparative conditions will be presented. Batch resolution of kg quantities of racemate followed by the simulated moving bed resolution of tens and hundreds of kg of racemate will also be discussed. Finally the different approaches used for the separation will be compared.

Preparative enantiomer separation of the inhalation anesthetics enflurane, isoflurane and desflurane by gas chromatography on a derivatized γ-cyclodextrin stationary phase

The preparative enantiomeric separation of the inhalation anesthetics enflurane (1) and isoflurane (2) in very high chemical (> 99.5%) and enantiomeric excess (ee > 99%) by gas chromatography (GC) on octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-gamma-cyclodextrin (4), dissolved in the apolar polysiloxane SE-54 and coated on Chromosorb P AW DMCS, is described. Up to 1 g of each enantiomer of 1-2 can been obtained per diem. The enantiomers of the highly volatile desflurane (3) can also be separated, albeit with diminished ee. The enantiomeric excess of 1-3 was checked by analytical GC on 4 and the absolute configuration of 2 and 3 has been determined via anomalous X-ray diffraction.

Macrocycle conformation and self-inclusion phenomena in octakis(3-O-butanoyl-2,6-di-O-pentyl)-γ-cyclodextrin (Lipodex E) by NMR spectroscopy and molecular dynamics

Octakis(3-O-butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex E) is a lipophilic chiral selector successfully used for the enantioselective gas chromatographic separation of a multitude of racemic analytes. NMR data (13C chemical shifts, 3J(HH), rotating frame NOEs (ROEs)) and molecular dynamics (MD) simulations point out that the macrocycle is distorted with respect to the canonical truncated-cone shape of native cyclodextrins, although C(8) symmetry is retained on the NMR timescale. ROE data and MD trajectories provide evidence for self-inclusion of one 6-O-pentyl pendant chain within the cavity of Lipodex E. The interpretation of long-range and low-intensity ROEs is supported by the calculation of average internuclear distances by using the radial distribution function (RDF) calculated from MD trajectories. MD simulations are eventually used to compare the flexibility of the macrocycle of Lipodex E with that of native gammaCD.

The Analytical Separation of Enantiomers by Gas Chromatography on Chiral Stationary Phases

Enantioselective GC is of widespread use in the enantiomeric analysis of volatile natural products such as pheromones, flavors, fragrances, and essential oils as well as synthetic products obtained from asymmetric syntheses and kinetic resolutions. Whereas enantioseparation of derivatized α-amino acids is performed on chiral stationary phases (CSPs) based on α-amino acid derivatives, alkylated/acylated cyclodextrins are employed as versatile CSPs for a multitude of volatile derivatized and nonderivatized enantiomers. Three main types of CSPs are reviewed and the miniaturization of enantioselective GC, the quantification of enantiomers, and validation issues are described. A list of commercially available fused silica capillary columns coated with various CSPs is compiled.