Buffer gas additives (modifiers/shift reagents) in ion mobility spectrometry: Applications,predictions of mobility shifts,and influence of interaction energy and structure

Ion mobility spectrometry (IMS) is an analytical technique used for fast and sensitive detection of illegal substances in customs and airports, diagnosis of diseases through detection of metabolites in breath, fundamental studies in physics and chemistry, space exploration, and many more applications. Ion mobility spectrometry separates ions in the gas‐phase drifting under an electric field according to their size to charge ratio. Ion mobility spectrometry disadvantages are false positives that delay transportation, compromise patient's health and other negative issues when IMS is used for detection. To prevent false positives, IMS measures the ion mobilities in 2 different conditions, in pure buffer gas or when shift reagents (SRs) are introduced in this gas, providing 2 different characteristic properties of the ion and increasing the chances of right identification. Mobility shifts with the introduction of SRs in the buffer gas are due to clustering of analyte ions with SRs. Effective SRs are polar volatile compounds with free electron pairs with a tendency to form clusters with the analyte ion. Formation of clusters is favored by formation of stable analyte ion‐SR hydrogen bonds, high analytes' proton affinity, and low steric hindrance in the ion charge while stabilization of ion charge by resonance may disfavor it. Inductive effects and the number of adduction sites also affect cluster formation. The prediction of IMS separations of overlapping peaks is important because it simplifies a trial and error procedure. Doping experiments to simplify IMS spectra by changing the ion‐analyte reactions forming the so‐called alternative reactant ions are not considered in this review and techniques other than drift tube IMS are marginally covered.     

An Ion Mobility/Ion Trap/Photodissociation Instrument for Characterization of Ion Structure

A new instrument that combines ion mobility spectrometry (IMS) separations with tandem mass spectrometry (MS(n)) is described. Ion fragmentation is achieved with vacuum ultraviolet photodissociation (VUV PD) and/or collision-induced dissociation (CID). The instrument is comprised of an approximately 1 m long drift tube connected to a linear trap that has been interfaced to a pulsed F(2) laser (157 nm). Ion gates positioned in the front and the back of the primary drift region allow for mobility selection of specific ions prior to their storage in the ion trap, mass analysis, and fragmentation. The ion characterization advantages of the new instrument are demonstrated with the analysis of the isomeric trisaccharides, melezitose and raffinose. Mobility separation of precursor ions provides a means of separating the isomers and subsequent VUV PD generates unique fragments allowing them to be distinguished.     

Chemical standards for ion mobility spectrometry: a review

Ion mobility spectrometry (IMS), using stand-alone instrumentation and hyphenated with mass spectrometry (IM-MS), has recently undergone significant expansion in the numbers of users and applications, particularly in sectors outside its established user base; predominantly military and security applications. Although several IMS reference standards have been proposed, there are no currently universally recognised reference standards for the calibration and evaluation of mobility spectrometers. This review describes current practices and the literature on chemical standards for validating IMS systems in positive and negative ion modes. The key qualities and requirements an ‘ideal’ reference standard must possess are defined, together with the instrumental and environmental factors such as temperature, electric field, humidity and drift gas composition that may need to be considered. Important challenges that have yet to be resolved are also identified and proposals for future development presented.     

A Mass-Selective Variable-Temperature Drift Tube Ion Mobility-Mass Spectrometer for Temperature Dependent Ion Mobility Studies

A hybrid ion mobility-mass spectrometer (IM-MS) incorporating a variable-temperature (80–400 K) drift tube is presented. The instrument utilizes an electron ionization (EI) source for fundamental small molecule studies. Ions are transferred to the IM-MS analyzer stages through a quadrupole, which can operate in either broad transmission or mass-selective mode. Ion beam modulation for the ion mobility experiment is accomplished by an electronic shutter gate. The variable-temperature ion mobility spectrometer consists of a 30.2 cm uniform field drift tube enclosed within a thermal envelope. Subambient temperatures down to 80 K are achievable through cryogenic cooling with liquid nitrogen, while elevated temperatures can be accessed through resistive heating of the envelope. Mobility separated ions are mass analyzed by an orthogonal time-of-flight (TOF) mass spectrometer. This report describes the technological considerations for operating the instrument at variable temperature, and preliminary results are presented for IM-MS analysis of several small mass ions. Specifically, mobility separations of benzene fragment ions generated by EI are used to illustrate significantly improved (greater than 50%) ion mobility resolution at low temperatures resulting from decreased diffusional broadening. Preliminary results on the separation of long-lived electronic states of Ti⁺ formed by EI of TiCl₄ and hydration reactions of Ti⁺ with residual water are presented.     

The use of shift reagents in ion mobility-mass spectrometry: Studies on the complexation of an active pharmaceutical ingredient with polyethylene glycol excipients

Gas-phase ion mobility studies of mixtures containing polyethylene glycols (PEG) and an active pharmaceutical ingredient (API), lamivudine, have been carried out using electrospray ionization-ion mobility spectrometry-quadrupole-time-of-flight mass spectrometry (ESI-IMS-Q-TOF). In addition to protonated and cationized PEG oligomers, a series of high molecular weight ions were observed and identified as noncovalent complexes formed between lamivudine and PEG oligomers. The noncovalent complex ions were dissociated using collision induced dissociation (CID) after separation in the ion mobility drift tube to recover the protonated lamivudine free from interfering matrix ions and with a drift time associated with the precursor complex. The potential of PEG excipients to act as “shift reagents,” which enhance selectivity by moving the mass/mobility locus to an area of the spectrum away from interferences, is demonstrated for the analysis of lamivudine in a Combivir formulation containing PEG and lamivudine.     

Monte Carlo simulation of ion transport in ion mobility spectrometry

A program for simulation of ion trajectories in ion mobility spectrometry (IMS) instruments has been developed and incorporated into SIMION 7.0 [Int. J. Mass Spectrom. 200 (2000) 3–25]. Simulations were based on elastic collisions between ions and gas particles and conducted for an IMS drift tube. The program was validated by comparing the reduced mobility of helium ions derived from the simulation with the experimental data for helium ions in neon drift gas in low electric fields. Typical IMS parameters, including pressure, temperature, and flow rate of the drift gas were taken into account in the simulations. The program demonstrates capabilities of generating IMS spectra and predicting ion transport efficiency and separating ions. For the IMS drift tube studied, a correlation between imperfection of the electric field distribution and low resolution has been observed.     

A study of focusing effect in the variable DC electric fields Ion mobility spectrometry

Drift tube Ion Mobility Spectrometry (IMS) is an atmospheric analysis technology which was developed in the 1970s. It has been widely used in the detection of drugs, explosives and environmental monitoring. IMS has characteristics of high sensitivity, portability and quick detection. In addition, it has a focusing effect for the ions passed by. In the work reported in this paper, a variable DC electric fields Ion Mobility Spectrometry was constructed, and the characteristic of focusing was studied by simulation and experiments. The results showed that the focusing effect had a strong correlation with the field distribution. With the increasing of the additional voltage δv, the focusing effect enhanced. The peak intensity of the IMS increases, and the drift time increases firstly and then decreases. The good agreements between simulation and experiment show that the simulation has predictive power for ion motion in IMS. This study can serve as visual aids for intuitively understanding the factors that determine ion transport.     

Electrospray ionization-voltage sweep-Ion mobility spectrometry for biomolecules and complex samples

Voltage Sweep Ion Mobility Spectrometry (VSIMS) has been applied to complex samples using electrospray ionization (ESI). The usable range of VSIMS has been extended from that obtained in previous studies where only volatile compounds were investigated. Using ESI, VSIMS was evaluated with compounds with reduced mobility values as low as 0.3 V²cm^?1 s^?1. The primary advantage of VSIMS is to enable a drift time ion mobility spectrometer (DTIMS) to detect both fast and slow moving ions at optimal resolving power, thus improving the peak capacity. In this work ESI-VSIMS was applied to a series of small peptides and drugs spanning a large range of reduced mobility values in order to demonstrate ESI-VSIMS to separation. To demonstrate improved peak capacity of IMS with voltage scan operation, oligomers of silicone oil provided a series of evenly-spaced peaks, ranging in reduced mobility values from 0.85 to 0.3 V²cm^?1 s^?1. The peak capacity of 61 for a standard IMS was improved to 102 when voltage sweep operation was employed. In addition, VSIMS increased the average resolving power of the DTIMS from 66 to 106 for silicone oil.     

Evaluation of micro- versus nano-electrospray ionization for ambient pressure ion mobility spectrometry

The comparison of nanospray and microspray ionizations for detecting mixtures of compounds by ion mobility spectrometry has been investigated for sensitivity, ion transmission through a drift tube, and ion suppression effects when used as an ionization source for ambient pressure ion mobility spectrometry (IMS). Several articles have demonstrated that nano-electrospray ionization mass spectrometry (n-ESI-MS) has improved sensitivity, provides less background noise, and lower limits of detection than micro-electrospray ionization (μ-ESI) for IMS. Most importantly, data from n-ESI-MS is concentration-sensitive. Our laboratory previously published an article that observed a striking result when μ-ESI-IMS was investigated for a single compound in the positive ion mode. The data reported was mass-sensitive. In this new investigation, we have investigated mixtures, and experiments were designed to evaluate the effect of sensitivity, ion transmission and ion suppressions in μ-ESI-IMS and n-ESI-IMS. At an electrospray flow rate in the μL min⁻¹ range, compounds with higher proton affinities responded best while at the nanospray flow rates of nL min⁻¹, relative responses were more equal. This study observed that a decreased ESI flow rate resulted in a decreased ion signal. These trends demonstrated less sensitivity for ESI-IMS at reduced flow rates but suggest better quantification. At higher flow rates, relative ionization efficiencies were still uniform for all the components studied individually and in mixtures and sensitivity improved by about 78%. Concentration studies showed that at high concentrations, ion detection efficiencies were uniform at about 33% for all compounds studied individually and in mixtures. At low concentrations, the detection efficiency varied from 31% to 86%, depending on the proton affinity of the component in the mixture. Ion transmission through the IMS tube measured with a segmented Faraday detector that was incorporated into the IMS design indicated that most of the ion current for mixtures was transported through the IMS tube with a radius of less than 18 mm for both positive and negative ion modes.     

Mobility spectrometry of amino acids and peptides with matrix assisted laser desorption and ionization in air at ambient pressure

Gas phase ions for valine, glutamate, phenylalanine, angiotensin, bradykinin, LH-RH, and bombesin were formed through matrix assisted laser desorption-ionization (MALDI) in air at ambient pressure and were characterized by ion mobility spectrometry (IMS). The IMS drift tube was operated at 100 °C with air as the drift gas and without an ion shutter. Responses were obtained using α-cyano-4-hydroxycinnamic acid as the matrix and a Nd-YAG laser at 355 nm with an unfocused beam at 6 mJ per pulse and 7 mm² cross section. Matrix and analyte were applied to a borosilicate glass target and microgram amounts of sample provided responses lasting 10 to 15 s with the laser operated at 11 Hz. Detection limits for the peptides were estimated to be 10 to 100 pmol per laser shot. The mobility spectra for individual amino acids and peptides exhibited multiple peaks with spectral distortions and raised baselines. These features and calculated values for reduced mobilities were consistent with the existence of clusters between analyte ions and matrix neutrals and the dissociation of these clusters in the drift region of the analyzer. Mobility spectra with distinctive peaks were not obtained for MALDI-IMS of peptides larger than 5700 amu, though ion formation was suggested from the depletion of matrix signal.     

Overtone mobility spectrometry: Part 2. Theoretical considerations of resolving power

The transport of ions through multiple drift regions is modeled to develop an equation that is useful for an understanding of the resolving power of an overtone mobility spectrometry (OMS) technique. It is found that resolving power is influenced by a number of experimental variables, including those that define ion mobility spectrometry (IMS) resolving power: drift field (E), drift region length (L), and buffer gas temperature (T). However, unlike IMS, the resolving power of OMS is also influenced by the number of drift regions (n), harmonic frequency value (m), and the phase number (Φ) of the applied drift field. The OMS resolving power dependence upon the new OMS variables (n, m, and Φ) scales differently than the square root dependence of the E, L, and T variables in IMS. The results provide insight about optimal instrumental design and operation.     

Ion mobility spectrometry in scientific literature and in the International Journal for Ion Mobility Spectrometry (1998–2007)

Starting in 1998 the International Society for Ion Mobility Spectrometry, organising the annual conferences on ion mobility spectrometry, began to issue the International Journal for Ion Mobility Spectrometry. Now, in the 11th year the journal will be the first year together with SPRINGER. Therefore, the article focusses on the history of IMS providing an up to date account based on a systemetic search using the Web-of-Science and SciFinder search engines.     

Simultaneous fragmentation of multiple ions using IMS drift time dependent collision energies

Ion mobility spectrometry coupled with mass spectrometry (IMS-MS) was utilized to evaluate an ion collision energy ramping technique that simultaneously fragments a variety of species. To evaluate this technique, the fragmentation patterns of a mixture of ions ranging in mass, charge state, and drift time were analyzed to determine their optimal fragmentation conditions. The precursor ions were pulsed into the IMS-MS instrument and separated in the IMS drift cell based on mobility differences. Two differentially pumped short quadrupoles were used to focus the ions exiting the drift cell, and fragmentation was induced by collision induced dissociation (CID) between the conductance limiting orifice behind the second short quadrupole and before the first octopole in the mass spectrometer. To explore the fragmentation spectrum of each precursor ion, the bias voltages for the short quadrupoles and conductance limiting orifices were increased from 0 to 50 V above nonfragmentation voltage settings. An approximately linear correlation was observed between the optimal fragmentation voltage for each ion and its specific drift time, so a linear voltage gradient was employed to supply less collision energy to high mobility ions (e.g., small conformations or higher charge state ions) and more to low mobility ions. Fragmentation efficiencies were found to be similar for different ions when the fragmentation voltage was linearly ramped with drift time, but varied drastically when only a single voltage was used.     

Paper spray ionization with ion mobility spectrometry at ambient pressure

A paper spray ion source was combined with a drift tube operating at ambient pressure for mobility measurements of ions derived from pharmaceutical solutions. Paper spray ionization with solvent alone resulted in a mixture of ions convolved to a single peak with a reduced mobility of 2.19 cm²/Vs in the mobility spectrum. These were mass-identified principally as m/z 157, (MeOH)₂(HCOOH)₂H⁺ and m/z 129, (MeOH)₄(H₂O)H⁺ while pharmaceuticals with nitrogen bases formed MH⁺ product ions. The duration of response was governed by the volume of liquid added to the paper source and was limited by evaporation of solvent in gas at 58 °C venting the drift tube. Quantitative variation was attributed in part to morphologic changes in the tip of the paper spray source. This was associated with mass flow in the electrical discharge and not due alone to cycles of wetting and drying of the paper. Mobility spectra of chlorpromazine in urine, exhibited a single product ion peak and linear response was 30 to 500 ng with an estimated limit of detection of 1.5 ng. Ion flux could be prolonged by continuous addition of liquid and findings portend a combination of paper spray ionization IMS with paper chromatography.     

Decomposition of overlapping plasmagram peaks by spectral subtraction

Low field atmospheric pressure Ion Mobility Spectroscopy (IMS) involves the careful analysis of plasmagrams with multiple peaks which can mask one another when they are closely spaced in drift time or corresponding reduced mobility. A typical signal processing approach to decomposing overlapped peaks would be to use an orthogonal decomposition technique, but unfortunately Gaussian-like functions are not orthogonal, so no unique decomposition can be guaranteed. However, each ion species in the drift tube will arrive at the Faraday plate with a known statistical distribution determined by the IMS instrument’s drift tube design, electric field strength, reagent gas flow and other instrument-specific factors such as the ion gate function. This paper presents a straightforward algorithm for decomposing plasmagrams into distinct peaks using a subtractive technique that independently estimates the statistical parameters of each peak, rejecting spurious peaks and electrical noise. The results show that for relatively short gate times, the plasmagram peaks are nearly Gaussian-shaped, but slightly fatter and asymmetric. We show that including of the gate rise and fall times is also significant in matching the plasmagram peak shape. We also show that the diffusion effects on resolution can be attributed to combinations of non-uniform ion distributions in the reaction chamber as well as detritus effects in the drift tube. Given the known peaks statistical parameters, one can then separate overlapping peaks using a straightforward spectral subtractive technique.     

A critical review of ion mobility spectrometry for the detection of explosives and explosive related compounds

Ion mobility spectrometry has become the most successful and widely used technology for the detection of trace levels of nitro-organic explosives on handbags and carry on-luggage in airports throughout the US. The low detection limits are provided by the efficient ionization process, namely, atmospheric pressure chemical ionization (APCI) reactions in negative polarity. An additional level of confidence in a measurement is imparted by characterization of ions for mobilities in weak electric fields of a drift tube at ambient pressure. Findings from over 30 years of investigations into IMS response to these explosives have been collected and assessed to allow a comprehensive view of the APCI reactions characteristic of nitro-organic explosives. Also, the drift tube conditions needed to obtain particular mobility spectra have been summarized. During the past decade, improvements have occurred in IMS on the understanding of reagent gas chemistries, the influence of temperature on ion stability, and sampling methods. In addition, commercial instruments have been refined to provide fast and reliable measurements for on-site detection of explosives. The gas phase ion chemistry of most explosives is mediated by the fragile CONO(2) bonds or the acidity of protons. Thus, M(-) or M.Cl(-) species are found with only a few explosives and loss of NO(2), NO(3) and proton abstraction reactions are common and complicating pathways. However, once ions are formed, they appear to have stabilities on time scales equal to or longer than ion drift times from 5-20 ms. As such, peak shapes in IMS are suitable for high selectivity and sensitivity.     

Micro-plasma: a novel ionisation source for ion mobility spectrometry

Ion mobility spectrometry is an analytical method for identification and quantification of gas-phase analytes in the ppb_v-ppt_v range. Traditional ionisation methods suffer from low sensitivity (UV light), lack of long-term stability (partial discharge), or legal restrictions when radioactive sources are used. A miniaturised helium plasma was applied as ionisation source in an ion mobility spectrometer (IMS). Experiments were carried out to compare plasma IMS with β-radiation IMS. It could be demonstrated that the plasma IMS is characterised by higher sensitivity and selectivity than β-radiation ionisation. Plasma IMS is approximately 100 times more sensitive than the β-radiation IMS. Furthermore, variable sensitivity can be achieved by variation of the helium flow and the electric field of the plasma, and variable selectivity can be achieved by changing the electric field of the IMS. The experimental arrangement, optimisation of relevant conditions, and a typical application are presented in detail. Figure Micro-plasma used in ion mobility spectrometry     

Ion mobility spectrometry as flow-injection detector and continuous flow monitor for aniline in hexane and water

Ion mobility spectrometry (IMS) was used as a flow-injection detector to quantitatively examine the ionization chemistry of aniline in hexane. A 5-microl sample was vaporized at 15-90-sec intervals in a flowing air stream and analyzed with an IMS equipped with acetone reactant ion chemistry, ambient temperature drift tube and membrane-based inlet. Precision was 3-11% relative standard deviation for 1-100 ppm aniline in hexane with 90-sec injection intervals and detection limits were ca. 0.5 ppm with 5-microl injections. Matrix effects with amine and organic solvent mixtures were observed and corrected for low and medium proton affinity interferences with standard addition methods. Pronounced fouling of the IMS occurred when a continuous water flow was introduced for aqueous flow injection-IMS. Continuous water monitoring without degraded IMS performance was possible by sampling air flow through a Silastic tube immersed in an aqueous sample.     

Evaluation of micro-electrospray ionization with ion mobility spectrometry/mass spectrometry

In recent years, the resolving power of ion mobility instruments has been increased significantly, enabling ion mobility spectrometry (IMS) to be utilized as an analytical separation technique for complex mixtures. In theory, decreasing the drift tube temperature results in increased resolution due to decreased ion diffusion. However, the heat requirements for complete ion desolvation with electrospray ionization (ESI) have limited the reduction of temperatures in atmospheric pressure ion mobility instruments. Micro-electrospray conditions were investigated in this study to enable more efficient droplet formation and ionization with the objective of reducing drift tube temperatures and increasing IMS resolution. For small molecules (peptides), the drift tube temperature was reduced to ambient temperature with good resolution by employing reduced capillary diameters and flow rates. By employing micro-spray conditions, experimental resolution values approaching theoretically predicted resolution were achieved over a wide temperature range (30 to 250 °C). The historical heat requirements of atmospheric pressure IMS due to ESI desolvation were eliminated due to the use of micro-spray conditions and the high-resolution IMS spectra of GLY-HIS-LYS was obtained at ambient temperature. The desolvation of proteins (cytochrome c) was found to achieve optimal resolution at temperatures greater than 125 °C. This is significantly improved from earlier IMS studies that required drift tube temperatures of 250°C for protein desolvation.