Vapor detection and vapor pressure measurements of fentanyl and fentanyl hydrochloride salt at ambient temperatures.

There is a need for non-contact, real-time vapor detection of drugs to combat illicit transportation and help curb the opioid epidemic. The low volatility of drugs, like fentanyl, makes room temperature vapor detection of illicit drugs challenging, but feasible by atmospheric flow tube-mass spectrometry (AFT-MS). AFT-MS is a non-contact vapor detection approach capable of ultra-trace detection of drugs, including fentanyl and its analogs at low parts-per-quadrillion (ppqv) levels. The determination of vapor pressure values of fentanyl is necessary to understand potential vapor concentrations that may be available for detection. In this paper, vapor pressures of fentanyl free base and fentanyl hydrochloride salt (a common form of the illicit drug) were measured as a function of temperature at or near ambient conditions using the transpiration (gas saturation) method and AFT-MS. Based on our measurements, the vapor pressure of fentanyl at 25 °C is 9.0 × 10-14 atm (90 ppqv), and the vapor pressure of fentanyl hydrochloride at 25 °C is 1.8 × 10-17 atm (0.018 ppqv). We also demonstrate non-contact, real-time vapor detection of fentanyl. Preconcentration of vapors can further extend the detection capabilities. The collection, desorption, and detection of fentanyl vapors at ambient conditions was demonstrated for sampling times of seconds to an hour resulting in increased signal. AFT-MS is a viable detection method of fentanyl and other drugs for screening of packages and cargo.

Proton Affinity Values of Fentanyl and Fentanyl Analogues Pertinent to Ambient Ionization and Detection.

Proton affinity is a major factor in the atmospheric pressure chemical ionization of illicit drugs. The detection of illicit drugs by mass spectrometry and ion mobility spectrometry relies on the analytes having greater proton affinities than background species. Evaluating proton affinities for fentanyl and its analogues is informative for predicting the likelihood of ionization in different environments and for optimizing the compounds' ionization and detection, such as through the addition of dopant chemicals. Herein, density functional theory was used to computationally determine the proton affinity and gas-phase basicity of 15 fentanyl compounds and several relevant molecules as a reference point. The range of proton affinities for the fentanyl compounds was from 1018 to 1078 kJ/mol. Fentanyl compounds with the higher proton affinity values appeared to form a bridge between the oxygen on the amide and the protonated nitrogen on the piperidine ring based on models and calculated bond distances. Experiments with fragmentation of proton-bound clusters using atmospheric flow tube-mass spectrometry (AFT-MS) provided estimates of relative proton affinities and showed proton affinity values of fentanyl compounds >1000 kJ/mol, which were consistent with the computational results. The high proton affinities of fentanyl compounds facilitate their detection by ambient ionization techniques in complex environments. The detection limits of the fentanyl compounds with AFT-MS are in the low femtogram range, which demonstrates the feasibility of trace vapor drug detection.

Non-contact detection of thiodiglycol vapors and associated degradation products using atmospheric flow tube mass spectrometry.

Thiodiglycol (TDG) is a synthetic precursor and an environmental degradation product of sulfur mustard (HD). Consequently, its presence can be indicative of illicit preparation or historical presence of chemical weapons, but its lower toxicity lends itself to use as an HD simulant for testing and method development. Detection of TDG vapor often proves elusive with existing techniques exhibiting undesirably high detection limits in the gas phase (>ppm). Moreover, traditional approaches to detecting TDG vapor rely upon non-specific approaches that do not provide the certainty afforded by mass spectrometry. Using atmospheric flow tube mass spectrometry (AFT-MS), which has previously demonstrated the capacity to detect parts-per-quadrillion levels of vapor, we evaluate the capacity of this approach for non-contact residue analysis based upon TDG vapor sampling and nitrate clustering chemistry. Furthermore, we discuss challenges with ambient vapor detection using the AFT-MS system and associated observations related to TDG degradation into 2,2'-sulfonyldiglycol from exposure to ambient conditions with vapor detection being possible even after 7-weeks of sample aging.

Ion Mobility Spectrometry Characterization of the Intermediate Hydrogen-Containing Gold Cluster Au7(PPh3)7H52.

We employ ion mobility spectrometry and density functional theory to determine the structure of Au7(PPh3)7H52+ (PPh3 = triphenylphosphine), which was recently identified by high mass resolution mass spectrometry. Experimental ion-neutral collision cross sections represent the momentum transfer between the ionic clusters and gas molecules averaged over the relative thermal velocities of the colliding pair, thereby providing structural insights. Theoretical calculations indicate the geometry of Au7(PPh3)7H52+ is similar to Au7(PPh3)7+, with three hydrogen atoms bridging two gold atoms and two hydrogen atoms forming single Au-H bonds. Collision-induced dissociation products observed during IMS experiments reveal that smaller hydrogen-containing clusters may be produced through fragmentation of Au7(PPh3)7H52+. Our findings indicate that hydrogen-containing species like Au7(PPh3)7H52+ act as intermediates in the formation of larger phosphine ligated gold clusters. These results advance the understanding and ability to control the mechanisms of size-selective cluster formation, which is necessary for scalable synthesis of clusters with tailored properties.

Trace explosive residue detection of HMX and RDX in post-detonation dust from an open-air environment.

Explosives are often used in industry, geology, mining, and other applications, but it is not always clear what remains after a detonation or the fate and transport of any residual material. The goal of this study was to determine to what extent intact molecules of high explosive (HE) compounds are detectable and quantifiable from post-detonation dust and particulates in a field experiment with varied topography. We focused on HMX (1,3,5,7-Tetranitro-1,3,5,7-tetrazocane), which is less studied in field detonation literature, as the primary explosive material and RDX (1,3,5-Trinitroperhydro-1,3,5-triazine) as the secondary material. The experiment was conducted at Site 300, Lawrence Livermore National Laboratory's Experimental Test Site, in California, USA. Two 20.4 kg and one 40.8 kg above ground explosions (primarily comprised of LX-14, an HMX-based polymer-bonded high explosive) were detonated on an open-air firing area on separate days. The complex terrain of the firing area (e.g., buildings, berm, low-height obstacles) was advantageous to study HE deposition in relation to plume dynamics. Three types of samples were collected up to 100 m away from each shot: surface swipes of aluminum plates, surface swipes of fixed objects, and filters from air samples. We used atmospheric flow tube-mass spectrometry (AFT-MS) to quantify picogram levels of molecular residue of HE material in the post-detonation dust. An aliquot of sample extract in methanol (e.g., 1 µL of 0.5 mL) was placed onto a resistive material and then thermally desorbed into the AFT-MS. We successfully detected and quantified both HMX and RDX in many of the samples. Based on mass (pg) detected and solution dilution, we back-calculated the mass collected on the swipe or filter (ng per sample). The aerial distribution of molecular residue was consistent with the path of the plume, which was strongly determined by wind speed and direction at the time of each shot. The quantity of material detected appeared to correlate more with distance from the shot and the wind conditions than with shot size. This study demonstrates that the picogram detection levels of AFT-MS are well-suited for quantification of analytes (e.g., HMX and RDX) in environmental samples.

Vapor Pressures of RDX and HMX Explosives Measured at and Near Room Temperature: 1,3,5-Trinitro-1,3,5-triazinane and 1,3,5,7-Tetranitro-1,3,5,7-tetrazocane.

Knowing accurate saturated vapor pressures of explosives at ambient conditions is imperative to provide realistic boundaries on available vapor for ultra-trace detection. In quantifying vapor content emanating from low-volatility explosives, we observed discrepancies between the quantity of explosive expected based on literature vapor pressure values and the amount detected near ambient temperatures. Most vapor pressure measurements for low-volatility explosives, such as RDX (1,3,5-trinitro-1,3,5-triazinane) and HMX (1,3,5,7-tetranitro-1,3,5,7-tetrazocane), have been made at temperatures far exceeding 25 °C and linear extrapolation of these higher temperature trends appears to underestimate vapor pressures near room temperature. Our goal was to measure vapor pressures as a function of temperature closer to ambient conditions. We used saturated RDX and HMX vapor sources at controlled temperatures to produce vapors that were then collected and analyzed via atmospheric flow tube-mass spectrometry (AFT-MS). The parts-per-quadrillion (ppqv) sensitivity of AFT-MS enabled measurement of RDX vapor pressures at temperatures as low as 7 °C and HMX vapor pressures at temperatures as low as 40 °C for the first time. Furthermore, these vapor pressures were corroborated with analysis of vapor generated by nebulizing low concentration solutions of RDX and HMX. We report updated vapor pressure values for both RDX and HMX. Based on our measurements, the vapor pressure of RDX at 25 °C is 3 ± 1 × 10-11 atm (i.e., 30 parts per trillion by volume, pptv), the vapor pressure of HMX is 1.0 ± 0.6 × 10-14 atm (10 ppqv) at 40 °C and, with extrapolation, HMX has a vapor pressure of 1.0 ± 0.6 × 10-15 atm (1.0 ppqv) at 25 °C.

Non-contact vapor detection of illicit drugs via atmospheric flow tube-mass spectrometry.

Real-time, non-contact detection of illicit drugs is a desirable goal for the interdiction of these controlled substances, but the relatively low vapor pressures of such species present a challenge for trace vapor detection technologies. The introduction of atmospheric flow tube-mass spectrometry (AFT-MS), which has previously been demonstrated to detect gas-phase analytes at low parts-per-quadrillion levels for explosives and organophosphorus compounds, also enables the potential for non-contact drug detection. With AFT-MS, direct vapor detection of cocaine and methamphetamine from ∼5 µg residues at room temperature is demonstrated herein. Furthermore, thermal desorption of low- to sub-picogram levels of cocaine, methamphetamine, fentanyl, and heroin is observed via AFT-MS using a carrier flow rate of several L min-1 of air. These low levels can permit non-contact sampling through collection of vapor, effectively preconcentrating the analyte before desorption and analysis. Quantitative evaluation of the thermal desorption approach has yielded limits of detection (LODs) on the order of 10 fg for cocaine and fentanyl, 100 fg for methamphetamine, and 1.6 pg for heroin. The LOD for heroin was lowered to 300 fg by using tributyl phosphate as a dopant to form a proton-bound heterodimer with heroin. When used with AFT-MS, the intentional formation of specific drug-dopant adducts has the potential to enhance detection limits and selectivity of additional drug species. Species that are prone to form adducts present a challenge to analysis, but that difficulty can be overcome by the intentional addition of a dopant. Molecules unlikely to form adducts will remain essentially unimpacted, but the adduct-forming species will interact with the dopant to compress the analyte signal into a single peak. This approach would be valuable in the application of non-contact screening for illicit substances via vapor collection followed by thermal desorption for analysis.

Interrogating Proton Affinities of Organophosphonate Species Via Atmospheric Flow Tube Mass Spectrometry and Computational Methods.

Within trace vapor analysis in environmental monitoring, defense, and industry, atmospheric flow tube mass spectrometry (AFT-MS) can fill a role that incorporates non-contact vapor analysis with the selectivity and low detection limits of mass spectrometry. AFT-MS has been applied to quantitating certain explosives by selective clustering with nitrate and more recently applied to detecting tributyl phosphate and dimethyl methylphosphonate as protonated species. Developing AFT-MS methods for organophosphorus species is appealing, given that this class of compounds includes a range of pollutants, chemical warfare agent (CWA) simulants, and CWA degradation products. A key aspect of targeting organophosphorus analytes has included the use of dopant ion chemistry to form adducts that impart additional analytical selectivity. The assessment of potential dopant molecules suited to enhance detection of these compounds is hindered by few published ion thermochemical properties for organophosphorus species, such as proton affinity, which can be used for approximating proton-bound dimer bond strength. As a preliminary investigation for the progression of sensing methods involving AFT-MS, we have applied both the extended kinetic method and computational approaches to eight organophosphorus CWA simulants to determine their respective gas-phase proton affinities. Notable observed trends, supported by computational efforts, include an increase in proton affinity as the alkyl chain lengths on the phosphonates increased. Graphical Abstract .

Ambient vapor sampling and selective cluster formation for the trace detection of tributyl phosphate via atmospheric flow tube mass spectrometry.

In addition to serving as an f-element ligand and rare-earth method complexing agent, tributyl phosphate is a compound containing core functional groups that mimic those routinely found in degradation products from industrial processes. Because detection of trace quantities of tributyl phosphate can provide insight into the routes of contamination and degradation in the environment, there is a need to develop methods capable of detecting trace quantities of tributyl phosphate. Vapor detection at atmospheric pressure is one approach that is both sensitive and rapid. We present here the use of atmospheric flow tube mass spectrometry for the ambient vapor sampling of tributyl phosphate from headspace of ppb-level solutions in methanol. Gas phase clustering reactions were to enhance detection levels via the addition of small quantities of the dopants diethylamine, triethylamine, and pinacolyl methylphosphonate in the vapor stream. Detection of the tributyl phosphate vapor emanating from these solutions demonstrated a linear range for the protonated tributyl phosphate species of 1-1000 ppb from solution. The clusters of tributyl phosphate with diethylamine, triethylamine, and pinacolyl phosphonate each yielded linear ranges of 1-250 ppb for tributyl phosphate in solution. Despite smaller linear ranges, the addition of these dopant species added a layer of analytical selectivity and reduced variability in signals from quality control samples. These data were obtained using an atmospheric flow tube source coupled to a linear ion trap mass spectrometer, which demonstrates the applicability of trapping systems to the atmospheric flow tube ionization technique while monitoring positive ions.

Optimized Reconstruction Techniques for Multiplexed Dual-Gate Ion Mobility Mass Spectrometry Experiments.

When coupling drift-tube gas-phase ion mobility separations with ion trapping mass analyzers an integrative, stepped approach to spectral reconstruction is a logical, yet highly inefficient means to determine gas-phase mobility coefficients. This experimental mode is largely predicated on the respective time scales of the two techniques each requiring tens of milliseconds to complete under routine conditions. Multiplexing techniques, such as Fourier and Hadamard based techniques, are a potential solution but still require extended experimental times that are not fully compatible with modern front-end separation schemes. Using a basis pursuit denoising (BPDN) approach to deconvolute Fourier transform ion mobility mass spectrometry (FT-IMMS) drift time spectra, we demonstrate significant time savings while maintaining a high degree of spectral resolution and signal-to-noise ratio. Under ideal conditions, the FT-IMMS operates with increased ion transmission (up to 25%); however, the linear chirp that spans into the kHz range often leads to significant levels of ion gate depletion, which limit both resolving power and ion transmission. The method proposed in this manuscript demonstrates the potential to reduce IMS acquisition time while simultaneously maximizing spectral resolution at longer effective gate pulse widths compared to the traditional set of multiplexing and signal averaging experiments.

Assessment of Dimeric Metal-Glycan Adducts via Isotopic Labeling and Ion Mobility-Mass Spectrometry.

Adduction of multivalent metal ions to glycans has been shown in recent years to produce altered tandem mass spectra with collision-induced dissociation, electron transfer techniques, and photon-based fragmentation approaches. However, these approaches assume the presence of a well-characterized precursor ion population and do not fully account for the possibility of multimeric species for select glycan-metal complexes. With the use of ion mobility separations prior to mass analysis, doubly charged dimers are not necessarily problematic for tandem MS experiments given that monomer and dimer drift times are sufficiently different. However, multistage mass spectrometric experiments performed on glycans adducted to multivalent metals without mobility separation can yield chimeric fragmentation spectra that are essentially a superposition of the fragments from both the monomeric and dimeric adducts. For homodimeric adducts, where the dimer contains two of the same glycan species, this is less of a concern but if heterodimers can form, there exists the potential for erroneous and misleading fragment ions to appear if a heterodimer containing two different isomers is fragmented along with a targeted monomer. We present an assessment of heterodimer formation between a series of six tetrasaccharides, of which three are isomers, adducted with cobalt(II) and a monodeuterated tetrasaccharide. Using ion mobility separations prior to single-stage and tandem mass analysis, the data shown demonstrate that heterodimeric species can indeed form, and that ion mobility separations are highly necessary prior to using tandem techniques on metal-glycan adducts. Graphical Abstract ᅟ.

Characterization of alkylphosphonic acid vapors using atmospheric flow tube-ion trap mass spectrometry.

RATIONALE: A key aspect of detecting hazardous compounds at ultra-trace levels for processing, compliance, and clean-up purposes involves developing methods that are not only sensitive, but also highly selective with minimal sampling effort. Atmospheric flow tube mass spectrometry (AFT-MS) using dielectric barrier discharge ionization has emerged as a technique that combines such features for vapor detection. AFT-MS is thus appealing for application to ambient screening for chemical warfare agents (CWAs) and their degradation products. Initial characterization of AFT-MS for CWA detection necessitates examining less harmful simulant species. A predominant hydrolysis product of most organophosphorus CWAs is methylphosphonic acid and most other hydrolysis products consist of some form of an alkylphosphonic acid. METHODS: An application of AFT-MS is presented wherein a homologous series of four alkylphosphonic acids (methyl-, ethyl-, propyl-, and t-butylphosphonic acid) were first qualitatively evaluated as anionic clusters with nitrate. These anionic adducts were subsequently quantified from non-equilibrium headspace vapor sampled over alkylphosphonic acid solutions in methanol. RESULTS: The series of phosphonic acids demonstrated consistent relative ion abundances thought to be related at least in part to the relative vapor pressures depending on their alkyl chains. For quantitation, the resulting linear ranges were found to be 2 to 50 ppmsoln for methylphosphonic acid, 5 to 50 ppmsoln for ethylphosphonic acid, and 2 to 25 ppmsoln for propylphosphonic acid and t-butylphosphonic acid; quality controls of 15 ppmsoln were used to assess the quantitation accuracy. CONCLUSIONS: Although measured over a limited dynamic range, the real-time analysis afforded by this method suggests the feasibility of using thermodynamically stable anionic adducts to monitor organophosphorus compounds via AFT-MS. In addition, this is proof-of-concept for the use of this ambient sensing technique to detect phosphonic acids. Furthermore, a discussion is included regarding gaps in clustering thermodynamics literature that would assist in uncovering physical or chemical explanations for observed trends.

Contemporary glycomic approaches using ion mobility-mass spectrometry.

Characterization of complex oligosaccharides has historically required extensive sample handling and separations before analysis using nuclear magnetic resonance spectroscopy and electron impact mass spectra following hydrolysis, derivatization, and gas chromatographic separation. Advances in liquid chromatography separations and tandem mass spectrometry have expanded the range of intact glycan analysis, but carbohydrate structure and conformation-integral chemical characteristics-are often difficult to assess with minimal amounts of sample in a rapid fashion. Because ion mobility spectrometry (IMS) separates analytes based upon an effective 'size-to-charge' ratio, IMS is, by extension, highly applicable to glycomics. Furthermore, the speed of IMS, its growing levels of separation efficiency, and direct compatibility with all forms of mass spectrometry, illustrates is core role in the future of glycomics efforts. This review assesses the current state of ion mobility-mass spectrometry applied to glycan, glycoprotein, and glycoconjugate analysis. Currently, assessing optimal ion polarity and adduct type for a glycan class along with the appropriate tandem mass spectrometry technique underpin many of the current glycan analysis efforts using ion mobility-mass spectrometry (IMMS). Once determined, these parameters have enabled a growing and impressive range of glycomics campaigns employing this technique. Additionally, the combination of IMS with tandem mass spectrometry, and even spectroscopic methods, further expands the dimensionality of hybrid instrumentation to provide a more comprehensive assessment of glycan structure across a wide dynamic range. Continued computational efforts to complement experimental and instrumental advancements also serve as a core component of IMMS workflows applied to glycomics and promise to maximize the information gained from mobility separations.

Differential Fragmentation of Mobility-Selected Glycans via Ultraviolet Photodissociation and Ion Mobility-Mass Spectrometry.

The alternative dissociation pathways initiated by ultraviolet photodissociation (UVPD) compared with collision-induced dissociation (CID) may provide useful diagnostic fragments for biomolecule identification, including glycans. However, underivatized glycans do not commonly demonstrate strong UV absorbance, resulting in low fragmentation yields for UVPD spectra. In contrast to UVPD experiments that leverage covalent modification of glycans, we detail the capacity of metal adduction to yield comparatively rich UVPD fragmentation patterns and enhance separation factors for an isomeric glycan set in a drift tube ion mobility system. Ion mobility and UVPD-MS spectra for two N-acetyl glycan isomers were examined, each adducted with sodium or cobalt cations, with the latter providing fragment yield gains of an order of magnitude versus sodium adducts. Furthermore, our glycan analysis incorporated front-end ion mobility separation such that the structural glycan isomers could still be identified even as a mixture and not simply composite spectra of isomeric standards. Cobalt adduction proved influential in the glycan separation by yielding an isomer resolution of 0.78 when analyzed simultaneously versus no discernable separation obtained with the sodium adducts. It is the combined enhancement of both isomeric drift time separation and isomer distinction with improved UVPD fragment ion yields that further bolster multivalent metal adduction for advancing glycan IM-MS experiments. Graphical Abstract ᅟ.

Enhanced Mixture Separations of Metal Adducted Tetrasaccharides Using Frequency Encoded Ion Mobility Separations and Tandem Mass Spectrometry.

Using five isomeric tetrasaccharides in combination with seven multivalent metals, the impact on mobility separations and resulting CID spectra were examined using a hybrid ion mobility atmospheric pressure drift tube system coupled with a linear ion trap. By enhancing the duty cycle of the drift tube system using a linearly chirped frequency, the collision-induced dissociation spectra were encoded in the mobility domain according to the drift times of each glycan isomer precursor. Differential fragmentation patterns correlated with precursor drift times ensured direct assignment of fragments with precursor structure whether as individual standards or in a mixture of isomers. In addition to certain metal ions providing higher degrees of separation than others, in select cases more than one arrival time distribution was observed for a single pure carbohydrate isomer. These observations suggest the existence of alternative coordination sites within a single monomeric species, but more interesting was the observation of different fragmentation ion yields for carbohydrate dimers formed through metal adduction. Positive-ion data were also compared with negative-ion species, where dimer formation did not occur and single peaks were observed for each isomeric tetrasaccharide-alditol. This enhanced analytical power has implications not only for carbohydrate molecules but also for a wide variety of complex mixtures of molecules where dissociation spectra may potentially be derived from combinations of monomeric, homodimeric, and heterodimeric species having identical nominal m/z values. Graphical Abstract ᅟ.

Augmenting Ion Trap Mass Spectrometers Using a Frequency Modulated Drift Tube Ion Mobility Spectrometer.

Historically, high pressure ion mobility drift tubes have suffered from low ion duty cycles and this problem is magnified when such instrumentation is coupled with ion trap mass spectrometers. To significantly alleviate these issues, we outline the result from coupling an atmospheric pressure, dual-gate drift tube ion mobility spectrometer (IMS) to a linear ion trap mass spectrometer (LIT-MS) via modulation of the ion beam with a linear frequency chirp. The time-domain ion current, once Fourier transformed, reveals a standard ion mobility drift spectrum that corresponds to the standard mode of mobility analysis. By multiplexing the ion beam, it is possible to successfully obtain drift time spectra for an assortment of simple peptide and protein mixtures using an LIT-MS while showing improved signal intensity versus the more common signal averaging technique. Explored here are the effects of maximum injection time, solution concentration, total experiment time, and frequency swept on signal-to-noise ratios (SNRs) and resolving power. Increased inject time, concentration, and experiment time all generally led to an improvement in SNR, while a greater frequency swept increases the resolving power at the expense of SNR. Overall, chirp multiplexing of a dual-gate IMS system coupled to an LIT-MS improves ion transmission, lowers analyte detection limits, and improves spectral quality.