Miniature Ion Trap Research Articles

Photothermal Desorption and Reagent-Assisted Low-Temperature Plasma Ionization Miniature IT-MS/MS for On-Site Analysis of Illicit Drugs in Saliva and Urine.

Globally, drug-impaired driving fatalities now exceed those from drunk driving, urging the need for on-site and roadside detection methods. In this study, a photothermal desorption and reagent-assisted low-temperature plasma ionization miniature ion trap mass spectrometer (PDRA-LTP-ITMS) was developed for on-site detection of drug-impaired driving. The pseudomultiple reaction monitoring (MRM) in PDRA-LTP-ITMS enables continuous ion selection during ion introduction and improved sensitivity to nearly 3-fold compared with the conventional full scan mode. The PDRA-LTP integrated the ionization source and photothermal desorption region into the LTP tube with a volume of 0.05 mL. Photoionization and Penning ionization from LTP discharging facilitate proton transfer reactions with the dopant and produce characteristic [M + H]+ for drugs. Dopants of butanol and acetone were separately employed to enhance the thermal desorption and ionization efficiency, resulting in a 2.6-fold sensitivity increase. Saliva and urine samples were collected with a medical swab, and only 10 μL of sample is required for each analysis. The sample is rapidly heated to 250 °C using a halogen lamp and analyzed within 5 s. With these designs, a 4-fold and 10-fold increase in sensitivity was achieved compared to APPI and nano-ESI, respectively. The limits of detection (S/N = 3) of illicit drugs, including MDMA, MDA, methamphetamine, amphetamine, ketamine, and cocaine, in saliva ranged from 4.5 pg μL -1 to 20 pg μL-1 and met the threshold values of GA1333-2017. The performance of the PDRA-LTP-ITMS was even comparable to that of LTQ-Orbitrap Velos Pro ETD MS, providing a novel method of rapid on-site drug-impaired driving analysis.

TDDA: A Targeted Data-Dependent Acquisition Mode for Rapid Screening of Targets in Complex Matrices.

Miniaturized mass spectrometers offer significant potential for in situ analysis due to their high specificity and portability. In traditional data-dependent acquisition (DDA) mode, precursor ions for tandem analysis are selected based on the full-scan mass spectrum. However, in situ applications often require the direct analysis of complex samples without extensive sample pretreatment, making them susceptible to chemical noise that can result in false negatives. To address this challenge, we propose a targeted data-dependent acquisition (tDDA) mode that substantially improves the accurate detection of target compounds in complex matrices. Unlike conventional DDA, the tDDA method eliminates reliance on the full-scan mass spectrum, where signals of interest are often obscured by matrix effects. This approach leverages sine amplitude modulation of sinusoidal frequency modulated (SAM-SFM) waveforms technology, which enables the real-time generation of isolated waveforms, allowing tDDA to achieve parallel, high-speed screening. Additionally, targeted automatic gain control (AGC) technology enhances the detection of low-concentration analytes, further reducing the false-negative rate. The tDDA mode was successfully integrated and validated on a modified "Brick" miniaturized ion trap mass spectrometer. Experimental results demonstrated its capability to detect low concentrations of illicit drugs spiked in blood and saliva samples, highlighting its potential for effective in situ screening.

Coupling Trapped Ions to a Nanomechanical Oscillator.

Cold ions in traps are well-established, highly controllable systems with a wide variety of applications in quantum science, precision spectroscopy, clocks, and chemistry. Nanomechanical oscillators are used in advanced sensing applications and for exploring the border between classical and quantum physics. Here, we report on the implementation of a hybrid system combining a metallic nanowire with laser-cooled ions in a miniaturized ion trap. Operating the experiment in the classical regime, we demonstrate resonant and off-resonant coupling of the two systems and the coherent motional excitation of the ion by the mechanical drive of the nanowire. The present results prove the feasibility of mechanically coupling ions to nanooscillators and open up avenues for mechanically manipulating the motion of trapped ions as well as for the development of ion-mechanical hybrid quantum systems.

A simplified coaxial ion trap mass analyzer: Characterization of the simplified toroidal ion trap with a rectilinear ion guide

A new miniature coaxial ion trap mass analyzer with a rectilinear ion guide has been constructed using a combination of planar and cylindrical electrodes. The results reported here focus on characterizing the performance of the rectilinear ion guide and simplified toroidal ion trap components. The simplified toroidal ion trap was found to have an ion capacity in excess of 105 ions and mass spectral resolution of 0.5–0.6 when used as a mass analyzer. The ion storage efficiency within the toroidal trapping region was evaluated and found the stored ion population decreased exponentially with storage time. Ion losses depended slightly on the stored βz condition. Ion losses within the toroidal region are attributed primarily to field instabilities at the intersection point of the two components while charge exchange reactions were observed but considered a minor loss mechanism. The ability to mass selectively ejection ions of a specific mass from the toroidal trapping region was characterized and found to approach 100 % efficiency under appropriate ejection conditions.

Fourier Transform Ion Trap Mass Analysis by Deciphering Ion Ejection Signals in the Frequency Domain.

Mass analysis in an ion trap is conventionally realized through time domain analysis of the ejected ion current collected from an electron multiplier (EM), in which the ion ejection time is found to have a correlation with the mass-to-charge (m/z) ratio of the ion. In this study, we investigated a new method for mass analysis by examining ion ejection signals in the frequency domain. Theoretical analysis and ion trajectory simulations show that ions of the same m/z ratio are ejected from an ion trap at regular intervals, producing a periodic pulsed signal on the EM. The period of this pulsed ejection signal is directly linked to the m/z values of the ions. To realize this method experimentally, a broadband preamplifier was built and integrated on a miniature ion trap mass spectrometer (the "Brick" series from Nier Inc.) to capture this pulsed ion ejection signal collected from the EM. Experimental results were in good agreement with theoretical and simulation analyses. This method has the potential to improve the mass resolution of an ion trap mass analyzer. As a proof-of-concept demonstration, a peak width of 0.1 Da at a m/z value of 281 was achieved in experiments.

A simple numerical simulation model can elucidate the key factors for designing a miniaturized ion trap mass spectrometer

BackgroundMiniature ion trap mass spectrometer enables mass-to-charge ratio analysis of ions via quadrupole field in a low vacuum environment. It plays an important role in on-site detection due to its portability and specificity. In order to gain a deeper understanding of the analysis mechanism of miniature ion trap mass spectrometers, a quadrupole MS ion trajectory numerical simulation model (QITNS) is established in this paper for ions trajectory calculation under the action of quadrupole field, exciting field and neutral gas molecule collision. Compared with the existing methods, the model in this paper is simpler and more direct, which effectively explored the effects of dipole excitation and quadrupole excitation on ion manipulation under high background pressure. ResultsThe simulation results demonstrate that high RF amplitude, low auxiliary AC amplitude and quadrupole excitation can effectively improve the isolation resolution. Besides, it clarified the difference between the analysis mechanism of ion trap mass spectrometers under high background pressure (above 13.332 Pa) and absolute vacuum conditions. The relevant results are consistent with the conclusions of previous experiments and other theories, proving the applicability and accuracy of the proposed calculation model and solution method. SignificanceThis research bears the guiding significance for further understanding the mechanism of quadrupole mass spectrometry as well as designing and developing miniature mass spectrometers.

Research on double resonant excitation in a triangular electrode ion trap with asymmetric geometry.

The triangular electrode linear ion trap with asymmetric geometry has been reported to possess a high ion unidirectional ejection efficiency and a reasonable mass resolution. To further improve its performance, a double resonant excitation method involving a dipolar and a quadrupolar resonant excitation was applied here. The dipolar excitation method was carried out by applying a supplementary alternating voltage out of phase to one pair of the electrodes, whereas the quadrupolar excitation (QE) method was carried out by adding a supplementary alternating voltage in phase to another pair of electrodes. Numerical simulations were performed to explore the impact of the frequency difference between the alternating current (AC) and the QE voltage (∆ω), the frequency of the AC voltage (ωAC), and the QE voltage amplitude (VQE). The mass resolution could be improved to ~4700 , which was approximately twice compared to that with only dipolar resonant excitation, and the ion unidirectional ejection efficiency could be improved to 97%. Even with a high scan rate of 6000 Da/s, there was minimal loss of mass resolution caused by increased scan rate in double resonant excitation mode. By employing the double resonant excitation method, the mass resolution could be further increased while maintaining a considerably high ion unidirectional ejection efficiency, which might be a simple and practical approach for developing a high-performance miniature ion trap mass analyzer.

Accurate Detection of G-Series Agent Simulants by Pseudo-Multiple Reaction Monitoring on Miniature LIT-MS.

Rapid and accurate on-site detection of chemical warfare agents (CWAs) could defend military and civilian populations against current and emerging chemical weapons. With the development of ambient ionization and linear ion trap technology, the rapid and accurate quantitative determination method of CWAs based on direct ionization and multistage mass spectrometry has attracted widespread attention. In this study, a microliter electrospray ionization-miniature linear ion trap mass spectrometry (LIT-MS) instrument was designed and constructed, and the effects of quadrupole enhanced dipole resonance excitation on the resolution and sensitivity were investigated; consequently, the parameters of CWAs detection were optimized. Based on the broad time-frequency ion excitation technology, accurate multiple reaction monitoring (MRM) quantitative analysis of DMMP (G-series agent simulants, m/z 125 → m/z 93) was obtained. The linear correlation coefficient in the concentration range of 1 to 20 μg/mL could reach 99.02%, and the relative standard deviations (RSD) of continuous repeatability, interday repeatability, and intraday repeatability were all less than 10%. The results showed that the accurate pseudo-MRM detection method based on miniature linear ion trap mass spectrometry for CWAs detection was feasible.

Differentiating enantiomers by directional rotation of ions in a mass spectrometer

Conventional mass spectrometry does not distinguish between enantiomers, or mirror-image isomers. Here we report a technique to break the chiral symmetry and to differentiate enantiomers by inducing directional rotation of chiral gas-phase ions. Dual alternating current excitations were applied to manipulate the motions of trapped ions, including the rotation around the center of mass and macro movement around the center of the trap. Differences in collision cross section were induced, which could be measured by ion cloud profiling at high resolutions above 10,000. High-field ion mobility and tandem mass spectrometry analyses of the enantiomers were combined and implemented by using a miniature ion trap mass spectrometer. The effectiveness of the developed method was demonstrated with a variety of organic compounds including amino acids, sugars, and several drug molecules, as well as a proof-of-principle ligand optimization study for asymmetric hydrogenation.

SAM-SFM: High-Efficiency and High-Resolution Tandem Mass Spectrometry Enabled by Sinusoidal Amplitude Modulation of Multiple Sinusoidal Frequency-Modulated Waveforms.

In miniature ion trap mass spectrometry, achieving a balance between isolation resolution and efficiency is a formidable challenge. The presence of absorption curves causes target ions to inadvertently absorb energy from AC signal components near their resonant frequencies. To mitigate this issue, SAM-SFM waveforms introduce a parameter known as the decreasing factor. Unlike SWIFT waveforms, SAM-SFM's spectral profile intentionally departs from a rectangular window, adopting an arch-shaped excitation window to minimize the impact on target ions and improve ion isolation efficiency. SAM-SFM waveforms have the advantage of low computational complexity, enabling real-time computation using an embedded FPGA technology. Regardless of any parameter changes, the FPGA can consistently guarantee waveform output within 1 μs. This not only enhances throughput but also eliminates the need for a PC in miniature mass spectrometry devices. The performance of SAM-SFM has been validated on an improved "Brick" miniature ion trap mass spectrometer. Comparative experiments with SWIFT waveforms confirm the lossless unit-mass isolation capabilities of SAM-SFM. This waveform has the capability to simultaneously isolate multiple target ions, even allowing for the lossless isolation of ions with lower abundance within isotopic clusters, albeit at the cost of requiring extended isolation durations.

SR-Unet: A Super-Resolution Algorithm for Ion Trap Mass Spectrometers Based on the Deep Neural Network.

The mass spectrometer is an important tool for modern chemical analysis and detection. Especially, the emergence of miniature mass spectrometers has provided new tools for field analysis and detection. The resolution of a mass spectrometer reflects the ability of the instrument to discriminate between adjacent mass-to-charge ratio ions, and the higher the resolution, the better the discrimination of complex mixtures. Quadrupole ion traps are generally considered as a low-resolution mass spectrometry method, but they have gained wide attention and development in recent years because of their suitability for miniaturization and high qualitative capability. For an ion trap mass spectrometer, the mass sensitivity and resolution can be mutually constrained and need to be balanced by setting an appropriate scanning speed. In this study, a super-resolution U-net algorithm (SR-Unet) is proposed for ion trap mass spectrometry, which can estimate the possible ions from the overlapping ion peaks of low-resolution spectra and improve the equivalent resolution while ensuring sufficient sensitivity and analysis speed of the instrument. By determining the mass spectra of a linear ion trap mass spectrometer (LTQ XL) in Turbo and Normal scan modes, the same unit mass resolution as that at a scan speed of 16,667 Da/s was successfully obtained at 125,000 Da/s. Also, the experiments demonstrated that the algorithm is capable of the mass-to-charge ratio and instrument migration. SR-Unet can be migrated and applied to a miniature mass spectrometer for cruise detection of volatile organic compounds (VOCs), and the identification of VOC species in Photochemical Assessment Monitoring Stations (PAMS) was improved from 31 to 50 species with the same monitoring and analysis speed requirement. Further, super-unit mass resolution peptide detection was achieved on a miniature mass spectrometer with the help of the SR-Unet algorithm, which reduced the full width at half-maxima (FWHM) of bradykinin divalent ions (m/z 531) from 0.35 to 0.15 Da at a scan speed of 375 Da/s and improved the equivalent resolution to 3540. The proposed method provides a new idea to enhance the field mixture detection capability of miniature ion trap mass spectrometers.

Radial Electric Field Driven Collision-Induced Dissociation in a Miniature Continuous Atmospheric Pressure Interfaced Ion Trap Mass Spectrometer.

Miniature ion trap mass spectrometry with the unique ability of tandem-in-time analysis is extensively used in public security and environmental pollution detection. In this study, a novel radial electric field driven collision-induced dissociation (REFD-CID) is presented with high fragmentation efficiency for different species by adjusting the float DC, the initial kinetic energy of ions, and the pressure in a miniature continuous atmospheric pressure interfaced ion trap mass spectrometer (CAPI-ITMS). It is noteworthy that multiple fragment ions ([M+H-nC2H4]+, where n = 1, 2, 3) of triethyl phosphate were observed with a single injection of ions. The underlying mechanism of the REFD-CID revealed that the enhanced radial electric field by modulation of the float DC drove ions toward regions of intense RF field where broadband heating and dissociation of ions took place through theoretical simulations. Finally, the REFD-CID was utilized to improve the instrument performances. The existence of reagent ions led to a severe space charge effect as the ion injection duration of the CAPI-ITMS was extended to enhance the sensitivity of aniline. Through selective fragmentation of reagent ions, peak broadening and mass shift were eliminated, and meanwhile, a 28-fold improvement of aniline in a signal-to-noise ratio was achieved with the ion injection duration varying from 50 to 2500 ms. Moreover, isomeric illicit drugs (JWH-018 and acetylcodeine) were distinguished by generating multiple characteristic fragment ions, demonstrating potential applications in the identification of synthetic illicit drugs.

Rapid on-site detection of persistent organic pollutants using multiwalled carbon nanotube-modified paper spray ionization and a miniature mass spectrometer.

Rapid on-site detection of persistent organic pollutants (POP) is highly desirable for environmental protection. Herein, a rapid on-site analytical workflow was developed for the investigation of polycyclic aromatic hydrocarbons and perfluorinated compounds using multiwalled carbon nanotube-modified paper spray ionization (PSI) coupled with a miniature ion trap mass spectrometer. Critical parameters regarding PSI and miniature mass spectrometry analysis were optimized. The analytical performance of the developed method was evaluated under optimized conditions, obtaining a short analysis duration of less than 1min, sufficient linearity with correlation coefficients greater than 0.99, acceptable recovery rates of 93.1%-105.8% with relative standard deviations of between 3.5% and 10.3%, and reasonable sensitivity with limits of detection and quantitation of 2-200 and 5-500 μg/L, respectively. Considering these aspects, it was concluded that the present approach demonstrated a promising solution for rapid on-site detection of emerging POPs.

Hexapole-Assisted Continuous Atmospheric Pressure Interface for a High-Pressure Photoionization Miniature Ion Trap Mass Spectrometer.

Miniature mass spectrometers are powerful tools for on-site chemical analysis in the fields of homeland security, personal healthcare, and environmental monitoring. This study presents a novel hexapole-assisted continuous atmospheric pressure interface for a high-pressure photoionization miniature ion trap mass spectrometer (HA-HPPI-IT). Efficient ion transmission was achieved by combining radial focusing by an RF electric field and axial driving by gas flow, which was demonstrated by SIMION simulation and experimental verification. The pressure in the ionization-transmission chamber and the inner diameter of the skimmer were optimized, which helped in determining the number density of product ions and affected the ion transmission in the hexapole, respectively. After systematic optimizations, about 16-fold increase in signal intensity was achieved as the RF amplitude was varied from 140 to 400 Vpp, and a limit of detection of 1 ppbv was obtained. In addition, the HA-HPPI-IT exhibited high stability and the relative standard deviation was as low as 5.47%. Finally, the apparatus was applied for discovering the simulated spot for illicit drug synthesis by detecting toluene and propiophenone released to air and monitoring the evolutions of perchloroethylene residues from dry-cleaned clothes.

Development and application of a miniature mass spectrometer with continuous sub-atmospheric pressure interface and integrated ionization source

For the miniature mass spectrometer (MS) with a continuous atmospheric pressure interface (CAPI), the gas in the multi-stage chambers directly affects the performance of the instrument. In this study, a sealed ionization chamber is designed to couple with a conventional mini CAPI-MS. In this configuration, the gas environment in the first ionization chamber can be flexibly changed to regulate the gas conditions throughout the entire instrument. By studying the effect of gas pressure on the performance of the instrument, we found that the instrument shows some unique advantages when the first ionization chamber is under sub-atmospheric pressure (SAP) conditions, such as reducing the load of the vacuum pump by 40%, achieving pump-free injection for gas and liquid samples, and improving the resolution by a factor of 2 without loss of detection sensitivity. Therefore, we propose a new integrated interface called continuous sub-atmospheric pressure interface (CSAPI) for building a miniature ion trap mass spectrometer. The CSAPI specially integrates sample introduction, gas/ions interface, and ionizations, including electrospray ionization (ESI) and secondary electrospray ionization (SESI), making this system more convenient for non-professional handlers to rapidly identify or monitor target analytes in gaseous- and solution-phase samples. We also use this system to study gas composition to further improve performance, being able to achieve a 5-fold sensitivity and 2-fold resolution improvement. At last, some custom applications of the current CSAPI-MS platform are explored and demonstrated, including real-time monitoring of chemical reactions in solution and long-distance sampling and analysis of dried Chinese herbs. In conclusion, this study provides a new approach to constructing a complete, versatile and practical miniature MS instrument.

A compact liquid chromatography-mass spectrometry instrument for the quantitation of immunosuppressants

Liquid chromatography tandem mass spectrometry (LC-MS/MS) plays an important role in clinical diagnostics. Although LC-MS/MS is superior in terms of accurately quantifying molecules in complex matrices, instrument footprint, operation and maintenance complexity also hinder its expansion as the analytical technique of choice. In this study, a compact LC-MS instrument was developed, in which an assembled liquid chromatograph was coupled with a miniature ion trap mass spectrometer. The overall instrument has a footprint of 69 cm × 31 cm × 31 cm, and it requires no gas supply as well as minimum maintenance. Furthermore, the use of LC-MS is in accord with conventional clinical diagnostic protocols, and the choice of ion trap offers tandem MS performance. The results showed that the use of LC could improve both mixture analysis capability and detection sensitivity of the miniature mass spectrometer. After optimization, feasibility of this instrument in clinical practice was demonstrated by the quantitation of four widely used immunosuppressants in blood samples. Relatively good linearities were obtained, which spanned the reference ranges of effective therapeutic concentrations of each immunosuppressant. Intra-day and inter-day accuracy and precision of analytical method were also assessed. This work showed that a compact LC-MS instrument could be used in clinical diagnosis, either to replace conventional lab-scale instruments or to be used in POCT applications.

High-Throughput Screening Using a Synchronized Pulsed Self-aspiration Vacuum Electrospray Ionization Miniature Mass Spectrometer.

With the advantages of rapid analysis, high sensitivity, and multicomponent identification, mass spectrometry (MS) is recognized as an appealing choice for high-throughput screening (HTS) analysis. Aiming at the small size, simple operation, and adequate performance, the development of miniature mass spectrometers has made great progress over the last 2 decades. Besides the essential analytical performance, simple operation and HTS capability are two other crucial features desired in miniature MS instruments. In this paper, an induced self-aspiration vacuum electrospray ionization source (ISA-VESI) was developed and coupled to a miniature ion trap mass spectrometer. A special timing sequence was designed to synchronize all the operation steps in each measurement, including dual-pulse sample injection, multipulse gas injection, MS analysis, and the movement of the homemade HTS platform used as the sampler. Then, the automatic high-throughput analysis of multiple samples can be accomplished with close coordination among the sample delivery, the sample introduction and ionization, and the ion trap operation. The measurement time of each ISA-VESI-MS analysis was about 7 s, with a sample consumption of less than 100 nL.

Rapid screening of illegally added drugs in functional food using a miniature ion trap mass spectrometer

With the expansion of the functional food market, the qualification assessment of these products has become a major challenge, and efficient analytical tools are urgently needed. Here, a miniature mass spectrometer (MS) with self-aspiration capillary electrospray ionization (SACESI) source and ion trap analyzer was developed for rapid screening of various illegally added drugs in functional foods. No chromatographic separation was required, but a simplified two-step pretreatment method was developed to reduce the operational procedures and time consumption of the entire analysis. SACESI source uses capillary action to drive solution injection, which utilizes a simple structure and convenient operation to constitute a kind of disposable MS detection solution. To achieve accurate and automatic identification, an intelligent recognition algorithm with steps of spectrum preprocessing, characteristic peak matching, and support vector machine learning was constructed. The relative accuracy of rapid screening of 31 suspicious drugs in various samples is up to 99.78%. It achieves 100% correct identification for the 55 batches of actual samples captured by on-site inspection, which demonstrates the feasibility of the proposed analytical system and strategy in food safety applications.

Triboionization in Discontinuous Atmospheric Pressure Inlet for a Miniature Ion Trap Mass Spectrometer.

Discontinuous atmospheric pressure interface (DAPI) consisting of a pinch valve, a silicone tube, and two metal capillaries has been widely used in miniature mass spectrometry. It is interesting that clear ion signals could be observed even when the extra ionization source was turned off. In-depth analysis suggested that this new ionization phenomenon known as triboionization is based on the surface friction on the inner surface of the silicone tube during the on/off of the pinch valve. In this study, triboionization in the DAPI of a miniature ion trap mass spectrometer was investigated. It was discovered that the signal intensity depended greatly on the material and the roughness of the silicone tube used in the DAPI. By rubbing the inner surface of the silicone tube, for example, the signal intensity can increase by nearly 20 times. Two connected pinch valves were developed to study the effects of the discharge pressure, the number, and the frequency of on/off of the pinch valve on triboionization, which were verified to have a large impact on the product ions. In addition, the humidity of the inner surface of the silicone tube impacted the signal intensity of product ions and the mass spectrum patterns, where the product ions were typically protonated ions. As the humidity increases, the signal intensity of analytes with high proton affinity increases accordingly. This triboionization source, which does not require heat, light, radiation, auxiliary gas, or solution, has been preliminarily proved to have potential for surface detection after continuous enrichment.

Novel Ion Trap Scan Modes to Develop Criteria for On-Site Detection of Sulfonamide Antibiotics.

Advances in ambient ionization techniques have facilitated the direct analysis of complex mixtures without sample preparation. Significant attention has been given to innovating ionization methods so that multiple options are now available, allowing for ready selection of the best methods for particular analyte classes. These ambient techniques are commonly implemented on benchtop systems, but their potential application with miniature mass spectrometers for in situ measurements is even more powerful. These applications require that attention be paid to tailoring the mass spectrometric methodology for the on-site operation. In this study, combinations of scan modes are employed to efficiently determine what tandem mass spectrometry (MS/MS) operations are most useful for detecting sulfonamides using a miniature ion trap after ionization. First, mixtures of representative sulfonamide antibiotics were interrogated using a 2D MS/MS scan on a benchtop ion trap in order to determine which class-specific fragments (ionic or neutral) are shared between the sulfonamides and thus have diagnostic value. Then, three less-used combination scans were recorded: (i) a simultaneous precursor ion scan was used to detect both analytes and an internal standard in a single ion injection event to optimize quantitative performance; (ii) a simultaneous precursor/neutral loss scan was used to improve detection limits; and finally, (iii) the simultaneous precursor/neutral loss scan was implemented in a miniature mass spectrometer and representative sulfonamides were detected at concentrations as low as 100 ng/mL by nano-electrospray and 0.5 ng absolute by paper spray ionization, although improvements in the stability of the home-built instrumentation are needed to further optimize performance.