Quantitative analysis of small pharmaceutical drugs using a high repetition rate laser matrix-assisted laser/desorption ionization source

In this work, a high repetition rate laser matrix-assisted laser desorption/ionization (MALDI) source is studied on a quadrupole-time-of-flight (QqTOF) and a triple quadrupole (QqQ) mass spectrometer for rapid quantification of small pharmaceutical drugs. The high repetition rate laser allows an up to 100-fold higher pulse frequency as compared with regular MALDI lasers, resulting in much larger sample throughput and number of accumulated spectra. This increases the reproducibility of signal intensities considerably, with average values being around 5% relative standard deviation after taking into account the area ratio of the analyte to an internal standard. Experiments were conducted in MS/MS mode to circumvent the large chemical background due to MALDI matrix ions in the low mass range. The dynamic range of calibration curves on the QqTOF mass spectrometer extended over at least two orders of magnitude, whereas on the QqQ it extended over at least three orders of magnitude. Detection limits ranged from 60-400 pg/microL on the QqTOF and from 6-70 pg/microL on the QqQ for a series of benzodiazepines. The benzodiazepine content of commercial pill formulations was quantified, and less than 5% error was obtained between the present method and the manufacturer's certified values. Furthermore, a high sample throughput was achieved with this method, so that a single MALDI spot could be quantitatively scanned in as little as 15 s, and an entire 96-well MALDI plate in 24 min.     

Synthese und Kristallstruktur von [(Me3Si)2BiCu(PMe3)3], dem ersten Komplex mit einer Bismut—Kupfer‐Bindung

Synthesis and Crystal Structure of [(Me₃Si)₂BiCu(PMe₃)₃] — the First Complex with a Bismuth—Copper Bond The reaction of CuO^t Bu with PMe₃ and Bi(SiMe₃)₃ in hexane yields the phosphine‐stabilized complex [(Me₃Si)₂Bi‐Cu( PMe₃)₃]. This synthesis gave rise to the first binuclear Bi—Cu compound to be structurally characterized by X‐ray crystallography.     

Effects of the bead-bead potential on the restricted rotational diffusion of nonrigid macromolecules

The influence of the bead-bead interaction on the rotational dynamics of macromolecules which are immersed into a solution has been investigated by starting from the microscopic theory of the macromolecular motion, i.e., from a Fokker-Planck equation for the phase-space distribution function. From this equation, we then derived an explicit expression for the configuration-space distribution function of a nonrigid molecule which is immobilized on a surface. This function contains all the information about the interaction among the beads as well as the effects from the surrounding solvent particles and from the surface. For the restricted rotational motion, the dynamics of the macromolecules can now be characterized in terms of a rotational diffusion coefficient as well as a radial distribution functions. Detailed computations for the rotational diffusion coefficient and the distribution functions have been carried out for HOOKEAN, finitely extensible nonlinear elastic, and a DNA type bead-bead interaction.     

Regio- and Enantioselective Substitution of Acyclic Allylic Sulfoximines with Butylcopper in the Presence of Lithium Iodide and Boron Trifluoride

Enantiomerically pure N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(phenyl)cinnamylsulfoximines as well as the corresponding crotylsulfoximines have been prepared from N-methyl-, N-benzyl-, and N-(methoxyethyl)-S-(lithiomethyl)sulfoximines and carbonyl compounds by an addition-elimination-isomerization reaction sequence. Under basic conditions, complete isomerization of the vinylic sulfoximines, obtained as intermediates, to the corresponding allylic sulfoximines takes place. Chromatographically separable mixtures of (E) and (Z) allylic sulfoximines were isolated in the case of beta,gamma-disubstituted allylic sulfoximines. The (E/Z) ratio depends on the nature of the substituents in the beta- and gamma-positions, and the equilibrium amount of the (Z) isomer varies from 68% to nil. The allylic N-methylsulfoximines do not racemize thermally, and their rearrangement to the corresponding allylic sulfinamides is negligible. Upon prolonged treatment with boron trifluoride at low temperatures allylic N-methylsulfoximines are recovered unchanged. The crystal structure of S-(3,4-dihydronaphthalen-2-ylmethyl)-N-methyl-S-phenylsulfoximine was determined. Reaction of the allylic sulfoximines with butylcopper in the presence of lithium iodide and boron trifluoride leads with very high gamma-selectivities and moderate to high enantioselectivities to the corresponding chiral alkenes. Their configuration was determined by chemical correlation through ozonolysis to the corresponding carbonyl compounds. The asymmetric induction exerted by the chiral N-methyl-S-phenylsulfoximine group strongly depends on the double bond configuration and the substituents in the beta- and gamma-positions. The (E) allylic sulfoximines are substituted with low to moderate enantioselectivities (2-66%), whereas the (Z) allylic sulfoximines react with much higher enantioselectivities (69-92%). Interestingly, substitution of the beta-methyl-gamma-phenyl-substituted (Z) allylic sulfoximine and its beta-phenyl-gamma-methyl isomer proceeded with almost the same degree of asymmetric induction but with the opposite sense. Replacement of the N-methyl group by a benzyl or a methoxyethyl group has no significant influence on the regio- and enantioselectivity of the substitution.     

Studies on azaspiracid biotoxins. I. Ultrafast high-resolution liquid chromatography/mass spectrometry separations using monolithic columns

In this study, the performance of monolithic columns was evaluated for ultrafast liquid chromatography/mass spectrometry (LC/MS) analyses and for high-resolution separations of several azaspiracid biotoxin analogs. Because of their high permeability, monolithic columns offer a number of advantages over conventional packed columns; viz., very low backpressures and relatively flat van Deemter curves at high flow rates. That is, very high flow rates can be used for ultrafast analyses or, by using longer than normal columns, high-resolution separations are possible. In a series of experiments, we varied the mobile phase flow rates between 1 and 8 mL/min, and studied their impact on chromatographic parameters such as retention time, resolution, number of plates and pressure. The chromatographic run times could be reduced to ca. 30 s without a significant change in the separation efficiency. A signal intensity comparison revealed interesting differences between atmospheric-pressure chemical ionization (APCI) and electrospray ionization (ESI) in their flow-rate dependency. An explanation with respect to the behavior as of a mass-flow or a concentration-dependent device is given in the paper. Additionally, the column length was varied between 10 and 70 cm. As a result, the number of theoretical plates increased substantially. In the example shown in the report, an increase from 13 000 plates for a 10-cm column to 80 000 for a 70-cm column is demonstrated. In addition, the potential of the monolithic columns for high-resolution LC/MS separations is shown for a complex biotoxin mixture, which was separated on a 40-cm-long column.     

Bimetallic complexes from amphoteric group 13/15 ligands: syntheses and X-ray crystal structures

Bimetallic, pentel-bridged complexes of the type [(dmap)Me2M-E(SiMe3)2-M'(CO)n] (M=Al, Ga; E=P, As, Sb; M'=Cr, Fe, Ni; DMAP=4-(dimethylamino)pyridine) are formed by reactions of DMAP-coordinated monomeric Group 13/15 compounds [(dmap)Me2M-E(SiMe3)2] with the transition metal complexes [(Me3N)Cr(CO)5], [Fe3(CO)12], and [Ni(CO)4]. For the first time, this reaction offers a general pathway to compounds containing a Group 13 metal and a transition metal bridged by a pentel atom. Complexes prepared in this way were characterized by IR and multinuclear NMR spectroscopy and by single-crystal X-ray structure analysis. Their electronic and structural properties are discussed in detail. The Group 13/15 ligands are very weak acceptors, which is likely to be due to the electropositive Group 13 metal, and the complexes feature comparatively long pentel-transition metal bonds. In addition, the synthesis and structural characterization of the parent DMAP-coordinated gallanes [(dmap)Me2Ga-E(SiMe3)2] (E=P, As) are reported.     

Determination of carbonyl compounds in exhaust gas by using a modified DNPH-method

The determination of carbonyl compounds in gaseous samples is usually accomplished by enrichment methods, in which 2,4-dinitrophenyl-hydrazine (DNPH) as a derivatization reagent has become established to a large extent. However, the conventional methods of DNPH-impingers and of DNPH-cartridges are applicable to emission measurements in a limited way only, depending on the NO₂-concentration in the exhaust gas. It could be proved that DNPH-derivatives, as well as DNPH, are also decomposed by NO₂ at a different speed, in which the hydrazones of unsaturated carbonyl compounds are probably more sensitive than those of the saturated carbonyl compounds. In view of this fact, the collecting methods had to be modified to avoid losses with the enrichment. The analysis of the compounds is carried out by HPLC with an effective gradient-system which is able to separate and detect the carbonyl compounds in exhaust gas within 16 min. Furthermore, a simple working-up procedure is presented which facilitates a parallel analysis by GC.