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Ferrocene and its derivatives and nickelocene undergo facile ionization when exposed directly to the ionizing plasma of a helium-plasma ionization (HePI) source. Mass spectra recorded from such samples under ambient positive-ion-generating conditions show intense peaks for the respective molecular ions [M+•] and protonated species [(M + H)+]. The protonation process occurs most efficiently when traces of water are present in the heated nitrogen used as the "heating gas." In fact, the relative population of the two categories of ions generated in this way can be manipulated by regulating the heating-gas flow. Moreover, rapid and highly efficient gas-phase hydrogen-deuterium exchange (HDX) reactions can be performed in the ion source by passing the heating gas through a vial with D2O before it reaches the HePI source. Moreover, the ionized species generated in this way can be subjected to in-source CID fragmentation in the QDa-HePI source very efficiently by varying the sampling-cone voltage. By this procedure, ions generated from ferrocene and nickelocene could be stripped so far as to ultimately generate the bare-metal cation. Other typical fragment-ions produced from protonated metallocenes included the M(cp)1+ ions (M = Fe or Ni), by elimination of a cyclopentadiene molecule, or the molecular cation, by loss of a H• radical. Moreover, H/D exchanges and subsequent tandem mass spectrometric analysis indicated that the central metal core participates in the initial protonation process of ferrocene under HePI conditions. However, in compounds such as ferrocene carboxaldehyde and ferrocene boronic acid, the protonation takes place at the peripheral functional group.

Understanding ion transport mechanisms in the flow expansion section of the first vacuum region of a mass spectrometer (MS) with an atmospheric pressure ionization source is essential for optimizing the MS sampling interface design. In this study, numerical simulations of three types of ions in two different MS interface designs have been carried out. In contrast to previously reported numerical studies, nonequilibrium gas dynamics due to rarefied gas effects has been considered in modeling the flow expansion and a realistic space charge effect has been considered in a continuous ion injection mode. Numerical simulations reveal that a flat plate interface has a higher peak buffer gas velocity but a narrower zone of silence compared to the conical interface. Shock wave structures are clearly captured, and the Knudsen number distribution is displayed. Simulation results show that in the axial direction the buffer gas effect is much stronger than the electric force effect in the current configuration. The conical interface leads to both a strong ion acceleration in the zone of silence and a strong ion deceleration downstream. In the radial direction, both the electric force and buffer gas drag force play an important role. The conical interface introduces a relatively stronger ion focusing effect from the radial buffer gas effect and a stronger ion dispersion from the radial electric force than the flat plate interface. The net effect for the current configuration is an increase in ion losses for the conical interface. Nanoelectrospray ionization experiments were carried out to validate the ion transmission efficiency.

The emergence of ambient ionization techniques and their combination with smaller, cheaper mass spectrometers is beginning to make real the possibility of mass spectrometry measurements being made routinely outside of traditional laboratory settings. Here, we describe the development of an atmospheric solids analysis probe (ASAP) source for a commercially available miniaturized, single-quadrupole mass spectrometer and subsequent modification of the instrument to allow it to run as a deployable system; we further go on to describe the application of this instrument to the identification of the contents of drug seizures. For the drug seizure analysis, a small quantity of the material (powder, tablet, resin, etc.) was dissolved in ethanol and shaken to extract the analytes, the resulting solutions were then sampled by dipping a sealed glass capillary into the solution prior to analysis by ASAP-MS. Identification of the contents of the seizures was carried out using a NIST searching approach utilizing a bespoke spectral library containing 46 compounds representative of those most commonly encountered in UK forensic laboratories. In order to increase confidence in identification the library sample and subsequent analyses were carried out using a four-channel acquisition method; each channel in this method used a different cone voltage (15, 30, 50, and 70 V) inducing differing levels of in-source fragmentation in each channel; the match score across each channel was then used for identification. Using this developed method, a set of 50 real-life drug samples was analyzed with each of these being identified correctly using the library searching method.

Five different classes of explosives were analysed by ambient ionisation mass spectrometry testing selectivity, sensitivity, and repeatability. We compare the effectiveness of two techniques (ASAP and SESI) for the trace detection of five explosives representative of the most common classes of high explosive: HMTD, RDX, PETN, Tetryl and TNT. Experiments also compared the effectiveness of sample loading via a glass fibre swab or glass rod. All analyses were carried out with a Waters Acquity QDa mass spectrometer, a small format mass spectrometer which can be operated in a transportable mode (using ambient air and a small diaphragm pump). Both ambient ionisation techniques, ASAP and SESI, successfully detected the five different explosives which could make them suitable for a screening method. By directly comparing a calibration range of 0.8–10 ng on both swabs and rods for each explosive, it appears that SESI produces less variability per repeat, particularly at the higher end of the range when compared to ASAP which typically has a lower limit of detection and better linearity.

Previous investigations have evaluated the efficacy of anions such as NO3−, Cl−, Br−, CH3COO−, and CF3COO− as additives to generate or enhance mass spectrometric signals from explosives under plasma ionization conditions. The results of this study demonstrate that for detecting nitramine-class explosives, such as 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) and 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane (HMX), 1,4-benzoquinone (BQ) is a highly effective and efficient dopant. When used in conjunction with ambient-pressure negative-ion helium-plasma ionization (HePI), 1,4-benzoquinone readily captures an electron, forming an abundant molecular anion (m/z 108), which upon exposure to vapors of RDX and HMX generates adduct ions of m/z 330 and 404, respectively. The signal level recorded for RDX upon adduction to the radical anion of 1,4-benzoquinone under our experimental conditions was significantly higher than that realized by chloride adduction using dichloromethane (DCM) as the dopant.

Eicosanoids, including prostaglandins and thromboxanes are lipid mediators synthetized from polyunsaturated fatty acids. They play an important role in cell signaling and are often reported as inflammatory markers. LC-MS/MS is the technique of choice for the analysis of these compounds, often in combination with advanced sample preparation techniques. Here we report a head to head comparison between an electrospray ionization source (ESI) and a new atmospheric pressure ionization source (UniSpray). The performance of both interfaces was evaluated in various matrices such as human plasma, pig colon and mouse colon. The UniSpray source shows an increase in method sensitivity up to a factor 5. Equivalent to better linearity and repeatability on various matrices as well as an increase in signal intensity were observed in comparison to ESI. publisher: Elsevier articletitle: Enhanced performance for the analysis of prostaglandins and thromboxanes by liquid chromatography-tandem mass spectrometry using a new atmospheric pressure ionization source journaltitle: Journal of Chromatography A articlelink: http://dx.doi.org/10.1016/j.chroma.2016.02.055 content_type: article copyright: Copyright © 2016 Elsevier B.V. All rights reserved. ispartof: Journal of Chromatography A vol:1440 pages:260-5 ispartof: location:Netherlands status: published

The MS hyphenation performance of UniSpray®, a new design of atmospheric pressure ionization source was evaluated in both SFC and RPLC modes. Sensitivity, stability, versatility and matrix effects offered by the UniSpray were assessed in positive and negative ionization modes and systematically compared to an electrospray source (ESI) using 120 natural compounds covering an extended chemical space. In a first instance, a multivariate approach was used to screen and optimize the UniSpray source settings to maximize detection sensitivity. The position of the source capillary against the fixed charged rod was highlighted as the major parameter affecting the detection sensitivity. The sensitivity improvement in Unispray vs. ESI strongly depends on the compounds chemical class and the chromatographic mode. For a few compounds (i.e. anabasine, theanine, caproic acid, fumaric acid and protopanaxatriol), up to a 10-fold increase in sensitivity was noticed with UniSpray. The signal stability over multiple injections was also found to be equivalent between both sources with RSD values on peak intensity lower than 14% on >100 injections, in both chromatographic modes. On complex plant extract, the matrix effects occurring from the secondary metabolites were also found to be comparable between ESI and UniSpray, at least in the positive ionization mode. However, a systematic decrease of MS signal intensity was observed in SFC mode when compounds were ionized using UniSpray in the negative ion mode.

Understanding ion transport properties from the ion source to the mass spectrometer (MS) is essential for optimizing device performance. Numerical simulation helps in understanding of ion transport properties and, furthermore, facilitates instrument design. In contrast to previously reported numerical studies, ion transport simulations in a continuous injection mode whilst considering realistic space-charge effects have been carried out. The flow field was solved using Reynolds-averaged Navier-Stokes (RANS) equations, and a particle-in-cell (PIC) method was applied to solve a time-dependent electric field with local charge density. A series of ion transport simulations were carried out at different cone gas flow rates, ion source currents, and capillary voltages. A force evaluation analysis reveals that the electric force, the drag force, and the Brownian force are the three dominant forces acting on the ions. Both the experimental and simulation results indicate that cone gas flow rates of ≤250 slph (standard liter per hour) are important for high ion transmission efficiency, as higher cone gas flow rates reduce the ion signal significantly. The simulation results also show that the ion transmission efficiency reduces exponentially with an increased ion source current. Additionally, the ion loss due to space-charge effects has been found to be predominant at a higher ion source current, a lower capillary voltage, and a stronger cone gas counterflow. The interaction of the ion driving force, ion opposing force, and ion dispersion is discussed to illustrate ion transport mechanism in the ion source at atmospheric pressure. Graphical Abstract.

A new atmospheric pressure ionization (API) source, viz. UniSpray, was evaluated for mass spectrometry (MS) analysis of pharmaceutical compounds by head-to-head comparison with electrospray ionization (ESI) on the same high-resolution MS system. The atmospheric pressure ionization source is composed of a grounded nebulizer spraying onto a high voltage, cylindrical stainless steel target. Molecules are ionized in a similar fashion to electrospray ionization, predominantly producing protonated or deprotonated species. Adduct formation (e.g., proton and sodium adducts) and in-source fragmentation is shown to be almost identical between the two sources. The performance of the new API source was compared with electrospray by infusion of a mix of 22 pharmaceutical compounds with a wide variety of functional groups and physico-chemical properties (molecular weight, logP, and pKa) in more than 100 different conditions (mobile phase strength, solvents, pH, and flow rate). The new API source shows an intensity gain of a factor 2.2 compared with ESI considering all conditions on all compounds tested. Finally, some hypotheses on the ionization mechanism, similarities, and differences with ESI, are discussed. Graphical Abstract ᅟ.

Methylphenidate (MP, Ritalin®) is a psychotropic drug widely prescribed to children for treating the symptoms of attention deficit disorder with and without hyperactivity. Because little information exists about the effects of chronic MP administration on cognitive function in children, measures of behavior changes in non-human primates are important surrogates. An essential component of such studies is the determination of MP plasma levels under chronic and acute dosing conditions. An analytical method was developed that provided sufficient sensitivity to measure low levels of the active parent drug (lower limit of quantitation = 0.25 ng/mL) and the inactive metabolite, ritalinic acid (RA), in monkey plasma as well as the ability to conveniently analyze large numbers of samples. The method uses a polymeric reversed-phase sorbent for solid phase extraction, an efficient reverse-phase high performance liquid chromatography (HPLC) separation, deuterated internal standards for isotope dilution quantification of MP and RA, and detection by sensitive electrospray ionization mass spectrometry (ES-MS) with a single quadrupole instrument. The method responses are linear over the range of plasma concentrations of MP and RA observed in monkeys, gives respective analyte recoveries of 75 and 60% with reasonable precision and accuracy, and demonstrates robust MS performance for rapid determination of MP/RA plasma levels. The average peak MP concentration (ca. 16 ng/mL) and half-lives for MP and RA elimination in monkeys (1.79 and 2.31 h, respectively) were not significantly different under acute vs. chronic dosing conditions and were comparable to values previously reported from human studies. Copyright © 2000 John Wiley & Sons, Ltd.

A critical limitation of electrospray ionization (ESI) liquid chromatography/mass spectrometry (LC/MS) sources is the susceptibility to blockage of interface orifices due to the deposition of involatile components from the sample and/or mobile phase. These components, including salts, buffers, and ion-pairing agents, can be essential to the performance of the chosen analytical method. We report here the performance enhancements provided by a novel atmospheric pressure ionization (API) source in the analysis of erythromycin A (ERY) using mobile phases that contain involatile components. The enhanced robustness of the new source is derived from the use of a continuous flow of aqueous solvent at the sampling cone orifice that maintains unobstructed ion transmission. The ESI mass spectral responses measured for ERY, using an LC separation that incorporates 10 mM sodium phosphate with and without 10 mM octane sulfonate, were monitored by repeated injections over 13-15 h total analysis time. Minimal effects on ESI mass spectral responses (integrated peak area) or chromatographic performance (peak shape, retention time) were observed during these studies. In the absence of the aqueous cleaning flow, complete loss of mass spectral responses and total blocking of the sampling cone was observed in less than 30 min. Responses for ERY spiked into chicken and beef liver, and catfish muscle at or below the regulatory level of interest (100 ppb), were quantified by internal standard calibration using this procedure. These results demonstrate the ability of a novel API-MS ion source to perform analyses that require the use of involatile mobile phase additives.

Gentian violet (GV) is a triphenylmethane dye antiseptic with potential for illegal use in livestock production, especially aquaculture where the related malachite green has been widely used. This potential misuse has regulatory importance because of the observed rodent carcinogenicity of GV. This report describes the use of online LC-APCI/MS for confirmation of incurred GV residues, and those of its principal metabolite, LGV, in catfish muscle following treatment of live catfish with GV under putative use conditions. LC with APCI/MS detection provided sensitive analysis of GV and LGV with estimated detection limits of < 1 pg observed for both compounds. Fragmentation of GV and LGV via in-source CID was effected by varying the sampling cone-skimmer voltage. Ion intensity data were collected using a rapid cone voltage switching procedure that permits selected ion acquisition under optimal conditions for the parent molecule and several selected fragment ions. For GV, four ions including the ionized molecule were used and for LGV, six ions including the protonated molecule were used. The levels of GV and LGV in muscle from fish dosed with 10 micrograms/l in aquarium water were determined by LC/VIS to be 0.5 and 44 ppb, respectively. Analysis of these samples yielded ion intensity ratios that agreed precisely between injections (< 5%) and accurately with those generated by a comparable amount of authentic GV and LGV (< 10% deviation). These results show the utility of on-line LC-APCI/MS to do both sensitive confirmatory analyses of incurred drug residues for use in monitoring the food supply.

Liquid chromatography coupled to atmospheric-pressure chemical ionization mass spectrometry and tandem mass spectrometry (MS/MS) methods for the determination and quantification of four quinolone antibiotics were adapted from a published procedure for liquid-liquid extraction from catfish muscle and high-performance liquid chromatographic analysis. In-source collision-induced dissociation was used to optimize fragmentation to produce mass spectra consisting of the protonated molecule and two characteristic fragment ions of nearly equal intensity. Selected ion monitoring of three ions per quinolone yielded sensitive detection in catfish muscle extracts (estimated instrumental detection limits 0.8-1.7 ppb). The intensity ratios were used to confirm the presence of three of the quinolones based on the accurate agreement (< or equal to 10% deviation) between ratios derived from fortified catfish extracts and those from standard quinolones. MS/MS was used to increase the specificity and sensitivity of analysis. Scans using constant neural loss (CNL) of 18 mass units gave a sensitive response for the quinolones suggesting that CNL scans may be applicable to multiresidue screening for unknown quinolones. MS/MS with multiple reaction monitoring of the [MH - 18]+ transition for each quinolone yielded the highest sensitivity analysis in catfish extracts (estimated instrumental detection limits 0.08-0.16 ppb).

Fumonisin (FB) mycotoxins are produced by Fusarium monoliforme, which grows primarily on yellow corn. Ingestion of FB1-contaminated food causes leukoencephalomalacia in horses, pulmonary edema in pigs, and is suspected in the etiology of human esophageal cancer. Chromatographic separation and detection of underivatized fumonisins has been hampered because these compounds are nonvolatile, thermally labile, and devoid of chromophoric functional groups. We report here a simple liquid chromatography/mass spectrometry method employing chromatographic separation on a polymer-based column coupled with sensitive detection using positive-ion electrospray mass spectrometry for the quantification of fumonisins B1, B2 and B3 in extracts of commercial corn meal.

Seventeen pesticides in five chemical classes (triazines, phenylureas, carbamates, organophosphates, miscellaneous) from the US Environmental Protection Agency's National Pesticide Survey of groundwater contaminants were selected for analysis by atmospheric pressure chemical ionization (APCI-MS). The spectra obtained from most compounds consisted solely of [M + H]+ in positive-ion mode. One example, p-nitrophenol produced only the [M − H]− ion in negative-ion mode. Increasing the potential on the sampling cone effected voltage-dependent fragmentation of all carbamates ad alachlor to form diagnostic daughter ions. Detection limits (Limit of detection (LOD), signal-o-noise ratio=3) in full-scan or selected-ion monitoring mode varied from 0.8–10 ng of 0.01-1 ng, respectively, and calibration curves were highly linear from the LOD to 100 ng. Mobile phase composition (50–100% acetonitrile in water) and flow rate (0.24 and 1.25 mL/min) had small effects on sensitivity of response. These reslts suggest that the sensitivity of APCI-MS is affected less than that for thermospray and particle beam LC/MS by chemical differences in analyte structure for the pesticide classes tested. The low detection limits, high degree of linearity, the ability t produce diagnostic fragment ions using cone voltage fragmentation and the inter-class versatlity suggest that APCI is a valuable technique for multiresidue confrmations of pesticides in groundwater.

The use of a particle beam (PB) interface for quantitation by isotope dilution LC/MS was investigated. Coelution of single-labeled internal standards (IS) with native compounds caused enhancement of the IS signal. The magnitude of enhancement for [3- 13 C 1 ]caffeine was affected by several experimental parameters, but no differences were observed in the 12 C/ 13 C response ratios under these conditions or upon analyte introduction via a gas chromatographt (GC) interface

The U.S. Environmental Protection Agency (US EPA) lists 126 polar, water-soluble compounds in the National Pesticide Survey (NPS) because of their potential for contaminating ground water. From this list, approximately 100 compounds were analyzed by particle beam liquid chromatography/mass spectrometry (PB/LC/MS). The fragmentation patterns of the electron impact (EI) spectra were generally comparable to reference EI spectra and were useful for analyte confirmations. A study of four different commercial nebulizers was performed to assess the effect on chromatographic integrity. In addition to the use of PB/LC/MS as a qualitative confirmation tool, its use as a selective LC detector was evaluated. Forty three of the NPS analytes showed sufficient sensitivity for detection of and spectrum generation from 100 ng or less. Using published concentration and cleanup methods, this sensitivity is sufficient for confirming the presence of these analytes in ground water at the 0.1 ppb level.

Beta-adrenergic receptor agonists are growth-promoting drugs with the potential for illegal use in livestock, and human toxicity has resulted from consumption of contaminated meat. On-line liquid chromatography with atmospheric pressure chemical ionization mass spectrometry (LC/APCI-MS) was used for sensitive detection of several beta-agonists in retina, a tissue reported to concentrate and retain such residues for extended periods. Multiresidue extraction, separation, detection, and confirmation procedures were developed for retinal tissue and applied to eyes from cattle treated with clenbuterol (69-201 ppb) and to control eyes spiked with salbutamol (100 ppb) and terbutaline (25-100 ppb). Rapid switching of the potential difference between sampling cone and skimmer in the transport region of the API source was used to optimize acquisition of the protonated molecules and characteristic fragment ions obtained by collision-induced dissociation reactions. The respective selected ions were simultaneously acquired using a single quadrupole mass spectrometer. The accurate and precise agreement observed for diagnostic ion intensity ratios between beta-agonists in retinal samples and authentic standards suggests that LC/APCI-MS can be used for confirmation of analyte structure at trace levels and does not require the use of a triple-stage quadrupole mass analyzer.

Clenbuterol is a β-agonist drug used illegally as a growth stimulant in meat-producing animals and human athletes. The analysis of clenbuterol in spiked human plasma was performed using on-line liquid chromatography/atmospheric-pressure chemical-ionization mass spectrometry (LC/APCI-MS) using a conventional bore LC column (flow rate = 1.0 mL/min). At low sampling cone voltages, the mass spectrum was predominantly the [M + H]+ ion but diagnostic fragment ions were formed upon incremental increases in sampling cone voltage. The detection limit (signal-to-noise ratio of 3) using selected-ion monitoring of the [M + H]+ ion was 0.1 ng on-column (l0 ppb). This is a 50-fold better sensitivity of detection than that previously reported for an on-line thermospray LC/MS method. The extraction procedures were not optimized for maximum sensitivity and the lack of interferences suggests that much lower detection limits for clenbuterol in plasma are attainable.