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Direct ambient ionization techniques have been developed with the aim to reduce the complexity of mass spectrometry analysis by minimizing sample preparation and chromatographic separation. In this context, paper spray-MS (PS-MS) is an innovative approach that provides faster and cheaper analysis of biofluids by the addition of the sample directly to a paper. In forensic toxicology, the analytical workflow for the detection and quantification of drugs of abuse is onerous, including sample treatment, extraction and clean up, especially regarding complex biological matrices. PS-MS allows the detection of analytes of toxicological interest in blood, plasma and urine using low sample volume. This review aims to discuss the potential use, advances and challenges of PS-MS in forensic toxicology.

Cannabinoids present a unique set of analytical challenges. An increasing number of states have voted to decriminalize recreational marijuana use, creating a need for new kinds of rapid testing. At the same time, synthetic compounds with activity similar to THC, termed synthetic cannabinoids, have become more prevalent and pose significant health risks. A rapid method capable of detecting both natural and synthetic cannabinoids would be useful in cases of driving under the influence of drugs, where it might not be obvious whether the suspect consumed marijuana, a synthetic cannabinoid, or both. Paper spray mass spectrometry is an ambient ionization technique which allows for the direct ionization of analyte from a biofluid spot on a piece of paper. Natural cannabinoids like THC, however, are labile and rapidly disappear from dried sample spots, making it difficult to detect them at clinically relevant levels. Presented here is a method to concentrate and preserve THC and synthetic cannabinoids in urine and oral fluid on paper for analysis by paper spray mass spectrometry. Sesame seed oil was investigated both as a means of preserving THC and as part of a technique, termed paper strip extraction, wherein urine or oral fluid is flowed through an oil spot on a strip of paper to preconcentrate cannabinoids. This technique preserved THC in dried biofluid samples for at least 27 days at room temperature; paper spray MS/MS analysis of these preserved dried spots was capable of detecting THC and synthetic cannabinoids at low ng/mL concentrations, making it suitable as a rapid screening technique. The technique was adapted to be used with a commercially available autosampler.

Paper spray ionization (PSI) is an extractive ambient ionization technique for mass spectrometry (MS), whereby a triangular paper tip serves as the sampling base and the electrospray tip. During PSI, analytes are extracted and transported to the edge of the paper tip by the applied spraying solvent. Analytes can be purified from a sample matrix and separated from each other by this transportation process. In this study, we investigated and utilized the analyte transportation process of PSI for the in situ separation and analysis of lipid mixtures. We found that differential transport of phosphatidylcholine (PC) and triacylglycerol (TAG), the two most abundant lipid classes in animals, occurred during PSI. We also found that the order in which these lipids moved strongly depended on how the spraying solvent was applied to the paper base. The more polar PC moved faster than the less polar TAG during PSI, when a polar solvent was slowly fed into a paper tip, whereas TAG was transported faster than PC when excess solvent was applied to the tip at once. In addition, we achieved a complete separation and detection of PC and TAG by slowly supplying a nonpolar solvent to a PSI tip.

RATIONALE Paper spray (PS) has been developed as a method of choice for point-of-care analysis in many real cases, where its applications can be further expanded with delicate high-throughput design. To achieve this goal, we developed a new PS regime, with the assembly of an induced high voltage into the ion source. Compared with regular DC high voltage, the newly developed setup is capable of high-throughput, simple configuration and rapid switching between individual papers without complicated electric/mechanic design. METHODS A device of high-throughput induced PS (IPS) was designed by using a two-dimensional (2D) rotating platform equipped with a circular glass plate. The paper substrate was placed on the circular glass plate and separated from the electrode. The method avoids physical contact between the electrode and the sample. Charged droplets were generated at the paper tip once an induced high voltage was applied to a wet paper. RESULTS A relatively rapid analytical speed of 2.6 s per sample was achieved via IPS-MS. Rapid quantification of amitriptyline (AMT) in complicated matrices was obtained within 1 min using an isotope internal standard method. Limits of detection for AMt in urine, FBS and blood were calculated to be 1.04, 0.84 and 1.33 ng/mL, respectively. In addition, high-throughput IPS-MS can be used for chemical reaction monitoring. CONCLUSIONS We have demonstrated the versatility of high-throughput IPS-MS in ambient ionization, which successfully simplified the experimental installation and facilitated the experimental operation. Therefore, we believe that high-throughput IPS-MS analysis will be widely used for discovering drugs and screening reactions, and the present design has the potential for applications in paper chip-MS analysis.

RATIONALE Accurate measurement of trace compounds in blood samples is important in clinical diagnosis and life science. Ambient ionization mass spectrometry, however, suffers from the matrix effect when dealing with complex samples such as blood. Therefore, it is important to reduce the matrix effects in blood samples. METHODS A low-cost and disposable Teflon tube was used as a platform to precipitate the protein in blood. The analytes are extracted into organic solvent, and the precipitated protein can be adsorbed by the chromatography paper inserted. Therefore, the Teflon tube after precipitation can be directly subjected to paper spray ionization mass spectrometry, achieving one-step analysis of blood. RESULTS High sensitivity and satisfactory stability were achieved for pharmaceuticals, acids, and endogenic metabolites in blood. The absolute signal intensities of characteristic product ions of the tested analytes were 8-20 times higher after protein precipitation than those obtained using paper spray. Detection limits and quantitative performance were evaluated for three drugs: carbamazepine, metformin, and tioconazole. In addition, the limits of detection and quantitation were improved 9-14- and 8-12-fold, respectively. CONCLUSIONS Protein precipitation coupled to paper spray with a tube and then to mass spectrometry was successfully achieved and applied in the one-step analysis of trace compounds in blood samples. The experimental results showed that this method was sensitive, stable, convenient, and economic for the direct analysis of blood.

Rapid, on-site analysis was achieved through significantly simplified operation procedures for a wide variety of toy samples (crayon, temporary tattoo sticker, finger paint, modeling clay, and bubble solution) using a miniature mass spectrometry system with ambient ionization capability. The labor-intensive analytical protocols involving sample workup and chemical separation, traditionally required for MS-based analysis, were replaced by direct sampling analysis using ambient ionization methods. A Mini β ion trap miniature mass spectrometer was coupled with versatile ambient ionization methods, e.g. paper spray, extraction spray and slug-flow microextraction nanoESI for direct identification of prohibited colorants, carcinogenic primary aromatic amines, allergenic fragrances, preservatives and plasticizers from raw toy samples. The use of paper substrates coated with Co3O4 nanoparticles allowed a great increase in sensitivity for paper spray. Limits of detection as low as 5μgkg-1 were obtained for target analytes. The methods being developed based on the integration of ambient ionization with miniature mass spectrometer represent alternatives to current in-lab MS analysis operation, and would enable fast, outside-the-lab screening of toy products to ensure children's safety and health.

Rationale Paper spray ionization (PSI) is an attractive ambient ionization source for mass spectrometry (MS) since it allows the combination of surface sampling and ionization. The minimal sample preparation inherent in this approach greatly reduces the time needed for analysis. However, the ions generated from interfering compounds in the sample and the paper substrate may interfere with the analyte ions. Therefore, the integration of PSI with high-field asymmetric ion mobility spectrometry (FAIMS) is of significant interest since it should reduce the background ions entering the mass analyzer without complicating the analysis or increasing analysis time. Here we demonstrate the integration of PSI with FAIMS/MS and its potential for analysis of samples of forensic interest. Methods In this work, the parameters that can influence the integration, including sampling and ionization by paper spray, the FAIMS separation of analytes from each other and background interferences, and the length of time that a usable signal can be observed for explosives on paper, were evaluated with the integrated system. Results In the negative ion analysis of 2,4,6-trinitrotoluene (TNT), pentaerythritol tetranitrate (PETN), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), and 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), amounts as low as 1 ng on paper were readily observed. The successful positive ion separation of a set of illicit drugs including heroin, methamphetamine, and cocaine was also achieved. In addition, the positive ion analysis of the chemical warfare agent simulants dimethyl methylphosphonate (DMMP) and diisopropyl methylphosphonate (DIMP) was evaluated. Conclusions The integration of PSI-FAIMS/MS was demonstrated for the analyses of explosives in negative ion mode and for illicit drugs and CW simulants in positive mode. Paper background ions that could interfere with these analyses were separated by FAIMS. The compensation voltage of an ion obtained by FAIMS provided an additional identification parameter to be combined with the mass spectrum for each analyte.

The increasing number of new psychoactive substances (NPS) and their quick worldwide spreading, often only slightly modified in the form of new derivatives and analogues, have brought the need for fast, wide-ranging, and unequivocal identification methods in clinical and forensic investigations. Because it usually provides secure results, gas chromatography coupled to mass spectrometry (GC-MS) has been routinely employed as the standard technique for the detection of NPS in blotter papers. For 25I-NBOH (N-(2-hydroxybenzyl)-2-(4-iodo-2,5-dimethoxyphenyl)ethan-1-aminium), however, GC-MS analysis of an blotter paper extract leads to incorrect results. In this work, we investigated whether easy ambient sonic-spray mass spectrometry imaging (EASI-IMS), and ambient ionization MS method can be applied directly to the surface of the sample requiring therefore no extraction or sample preparations, would serve as an efficient, sensitive, and secure alternative for 25I-NBOH screening.

A new kind of ambient ionization method named superhydrophobic preconcentration paper spray ionization mass spectrometry (SHPPSI MS) is introduced, where superhydrophobicity and paper spray mass spectrometry (PS MS) are coupled. The SHPPSI MS requires only microliter amounts of analyte solutions, allows easy sampling procedure, and provides high sensitivity for a diverse array of analytes. It can be used to detect food adulteration at extremely low concentrations. The experimental methodology involves modifying one of the surfaces of a triangularly cut filter paper to make it acquire low surface energy by drop casting a green and ecofriendly superhydrophobic coating material over it followed by drying. A micrometer scale defect was made at close proximity to one of the tips of the paper using a pin. Preconcentration of the sample was accomplished by allowing a 10 μL droplet of an aqueous solution of the analyte to stand at the defect followed by drying naturally. The dried paper was used as the substrate for paper spray mass spectrometry by eluting the analyte with a suitable solvent. This novel technique was used to detect melamine in adulterated milk, whose detection at the ppt level in milk normally needs sophisticated instruments, a larger amount of sample, and a complex sampling procedure, including further purification and separation. The SHPPSI MS detects melamine directly from milk at the sub-ppb level by simply putting a microdroplet of adulterated milk at the substrate and eluting the sample with methanol. This paper-based technique can be a promising tool for direct sensing of analytes such as drugs in body fluids, pesticides in water and soil, etc.

The Jatropha curcas plant (Jatropha) has been proposed as a source of biodiesel fuel, as it yields crude glycerol as an abundant by-product. Its by-products could serve as a starting material in making glycerol for FDA-regulated products. Jatropha is not regarded as a source of edible vegetable oil since it contains phorbol esters (PEs). PEs, even at very low exposure concentrations, demonstrate various toxicities in humans and animals, but may not be detected by routine impurity analyses. Here, we demonstrate the development of a rapid and simplified method for the detection and quantification of Jatropha-derived PE toxins using ambient ionization mass spectrometry. To do this, we successfully coupled a paper spray ambient ionization source with an ion trap portable mass spectrometer. The paper spray source was assembled using chromatography papers, and analyte ions were generated by applying a high voltage to a wetted paper triangle loaded with PE standards. For method development, we used commercially available PE standards on an ion trap portable mass spectrometer. Standard solutions were prepared using ethanol with PE concentrations ranging from 1.0 to 0.0001 mg mL−1. Spike and recovery experiments were performed using USP grade and commercially available glycerol. To discern chemical differences between samples, we applied multivariate data analysis. Based on the results obtained, paper spray coupled with a portable mass spectrometric method can be successfully adopted for the analysis of toxic contaminants present in glycerol-based consumer products with LOD and LOQ of 0.175 μg mL−1 and 0.3 μg mL−1 respectively. This direct, simple design, and low-cost sampling and ionization method enables fast screening with high sensitivity in non-laboratory settings.

Paper spray high-resolution accurate mass spectrometry is a fast and versatile analysis method. This ambient ionization technique enables the quantitation of xenobiotics in complex biological matrices without chromatography or conventional sample extraction. The simplicity, rapidity, and affordability of the paper spray mass spectrometry (PS-MS) method make the technique especially attractive for clinical investigations where fast and affordable sample analysis is crucial. A new PS-MS method for the quantitation of voriconazole in equine tears was developed and validated. For a concentration range of 10 to 1000 ng/mL, good linearity (R2 > 0.99), inter- and intra-run precision (coefficient of variation (CV) max. 11.9%), accuracy (bias of the nominal concentration ± 13.9%), and selectivity (signal areas of the double blanks represent 0.13 ± 0.05% of the lower limit of quantitation (LLOQ) signal in equine tears) were observed. The quantitation of voriconazole was based on three product ions and calculated relative to the isotope-labeled internal standard, voriconazole-d3, which had a final concentration of 250 ng/mL in the standards and samples. The matrix effect of the method showed an ionization suppression by reduction of the voriconazole response to 63.6%, 70.2%, and 81.9% for 30 ng/mL, 450 ng/mL, and 900 ng/mL in equine tears compared with voriconazole in solvent (methanol:water, 50:50, v:v). The method was used to analyze 126 study samples collected for a pharmacokinetic study investigating a novel approach for treatment of fungal keratitis in horses. Therefore, the integrity of the sample dilution (n = 6, CV 6.90%, and bias of nominal concentration + 8.40%) and the carryover effect (increase from 0.33 ± 0.21% to 1.33 ± 0.89% of the signal of the LLOQ) was further investigated. To our knowledge, this method is the first application of PS-MS for quantitation of drug concentrations in tears from any species.

Proteinaceous toxins are harmful proteins derived from plants, bacteria, and other natural sources. They pose a risk to human health due to infection and also as possible biological warfare agents. Paper spray mass spectrometry (PS-MS) with wipe sampling was used to detect proteins from surfaces as a potential tool for identifying the presence of these toxins. Proteins ranging in mass between 12.4 and 66.5 kDa were tested, including a biological toxin simulant/vaccine for Staphylococcal enterotoxin B (SEBv). Various substrates were tested for these representative proteins, including a laboratory bench, a notebook cover, steel, glass, plant leaf and vinyl flooring. Carbon sputtered porous polyethylene (CSPP) was found to outperform typical chromatography paper used for paper spray, as well as carbon nanotube (CNT)-coated paper and polyethylene (PE), which have been previously shown to be well-suited for protein analysis. Low microgram quantities of the protein toxin simulant and other test proteins were successfully detected with good signal-to-noise from surfaces using a porous wipe. These applications demonstrate that PS-MS can potentially be used for rapid, sample preparation-free detection of proteins and biological warfare agents, which would be beneficial to first responders and warfighters.

Paper spray mass spectrometry is a method for the direct analysis of biofluid samples in which extraction of analytes from dried biofluid spots and electrospray ionization occur from the paper on which the dried sample is stored. We examined matrix effects in the analysis of small molecule drugs from urine, plasma, and whole blood. The general method was to spike stable isotope labeled analogs of each analyte into the spray solvent, while the analyte itself was in the dried biofluid. Intensity of the labeled analog is proportional to ionization efficiency, whereas the ratio of the analyte intensity to the labeled analog in the spray solvent is proportional to recovery. Ion suppression and recovery were found to be compound- and matrix-dependent. Highest levels of ion suppression were obtained for poor ionizers (e.g., analytes lacking basic aliphatic amine groups) in urine and approached -90%. Ion suppression was much lower or even absent for good ionizers (analytes with aliphatic amines) in dried blood spots. Recovery was generally highest in urine and lowest in blood. We also examined the effect of two experimental parameters on ion suppression and recovery: the spray solvent and the sample position (how far away from the paper tip the dried sample was spotted). Finally, the change in ion suppression and analyte elution as a function of time was examined by carrying out a paper spray analysis of dried plasma spots for 5 min by continually replenishing the spray solvent. Graphical Abstract ᅟ.

Paper spray has been developed as an ambient ionization method for direct analysis of biological samples using mass spectrometry. While distinct advantages of paper spray have been demonstrated, especially for quantitative analysis and design of disposable sample cartridges, the need for improvement has also been recognized, especially for the use with miniature mass spectrometers. In this study, we made an improvement to the sampling and ionization by adding a capillary emitter to the paper substrate to produce a paper-capillary spray, which has been shown to have significant, positive impact on the sensitivity and reproducibility for direct mass spectrometry analysis. The paper-capillary devices were fabricated and the effects of the geometry, the treatment of the capillary emitters, as well as the sample disposition methods were characterized. The method's analytical performance was also characterized for analysis of therapeutic drugs in blood samples. Quantitation of cotinine in blood using a commercial triple quadrupole and sitagliptin (Januvia®) in blood using a desktop Mini 12 ion trap mass spectrometer was also demonstrated.

Paper spray ionization (PSI) is a direct, fast, and low-cost ambient ionization technique which may have clinical utility for qualitative and quantitative analysis of therapeutic drugs and metabolites from patient specimens. We developed and validated a PSI-mass spectrometry (PSI-MS/MS) method according to the US-FDA guidelines for bioanalytical studies to measure the prostate cancer drug abiraterone directly from patient plasma. The established linearity range was 3.1-156.8 ng/mL with a precision (%CV) and an accuracy (%) range of 0.5-10.7 and 93.5-103.2, respectively. The mean internal standard normalized matrix factor for abiraterone was just below 1 with highest %CV of 10.2 at the low-level quality control. In benchmarking the performance of this assay against a published LC-MS/MS assay, we showed they were mostly equivalent, with the exception of accuracy with clinical samples. We found the quantitative values observed for abiraterone measured directly from patient plasma using PSI-MS/MS showed positive bias. Upon investigation, we concluded the increased values were due to summed quantitation of isomeric abiraterone conjugates and metabolites which are separable by LC-MS/MS, but not with the current PSI-MS/MS configuration. Despite demonstrating the utility of PSI-MS/MS for rapid bioanalysis, this study also highlighted a limitation encountered with the direct analysis of abiraterone in clinical samples.

A new ambient ionization method allowing the direct chemical analysis of living human body by mass spectrometry (MS) was developed. This MS method, namely Megavolt Electrostatic Ionization Mass Spectrometry, is based on electrostatic charging of a living individual to megavolt (MV) potential, illicit drugs, and explosives on skin/glove, flammable solvent on cloth/tissue paper, and volatile food substances in breath were readily ionized and detected by a mass spectrometer.

Paper spray (PS) ionization, an ambient ionization method, has previously been explored as a direct and fast method for mass spectrometric analysis of complex mixtures. It has been applied to the analysis of a wide variety of compounds, mostly small molecules. The work reported here extends the application of PS ionization to noncovalent protein complexes on an ion mobility tandem mass spectrometer. Similar mass spectra for protein complexes were obtained by PS ionization and nanoflow electrospray ionization (nESI), indicating that intact protein complexes can be preserved in PS ionization. In addition, collisional cross sections measured by ion mobility provide evidence that the protein assemblies may remain compact by PS ionization. With PS, it is possible to detect hemoglobin tetramer from a blood sample with minimal sample preparation. This is the first report to show that PS ionization is a promising ionization method for nonconvalent protein complexes.

Paper spray (PS) is an ambient ionization technique applicable to ionizing analytes from untreated dried biofluid samples. In-field sample analysis could benefit from the capability to use a finger prick of blood to measure drugs in whole blood at low cost and in a short time. Some studies may require specialized blood collection devices that can be used in remote areas. In this study, four different dried blood spot (DBS) devices are used with PS sources and tested for rapid quantification of imatinib and N-desmethyl-imatinib. A triple quadrupole mass spectrometer allows analyte detection with high sensitivity. Analytical figures of merit for the four devices are compared, and it is concluded that several of the novel devices successfully deploy DBS with PS and yield similar results to traditional manual PS methods. Clinical samples collected in a remote location were analyzed as a proof of concept for in-field blood collection and subsequent rapid laboratory analysis. Graphical abstract Dried blood spot analyis by paper spray ionization MS/MS for in field sample collection.

Paper spray MS is part of a cohort of ambient ionization or direct analysis methods that seek to analyze complex samples without prior sample preparation. Extraction and electrospray ionization occur directly from the paper substrate upon which a dried matrix spot is stored. Paper spray MS is capable of detecting drugs directly from dried blood, plasma and urine spots at the low ng/ml to pg/ml levels without sample preparation. No front end separation is performed, so MS/MS or high-resolution MS is required. Here, we discuss paper spray methodology, give a comprehensive literature review of the use of paper spray MS for bioanalysis, discuss technological advancements and variations on this technique and discuss some of its limitations.

New psychoactive substances (NPS) have been associated with fatalities and severe injuries in a number of cases in the United States and have led investigators to rethink traditional drug monitoring protocols. Of particular interest are the variable phenethylamine chemical structures known as 'NBOMes', which pose an emerging threat to public health with incidence steadily growing over the past decade. In this study, direct sample analysis (DSA)-time of flight mass spectrometry was employed to leverage rapid and sensitive ambient ionization mass spectrometry without chromatographic separation as verified with an authentic case sample. Samples for method development were prepared at Boston University School of Medicine's Biomedical Forensic Sciences program (Boston, MA) and analyzed at the State of Maine Health and Environmental Testing Laboratory's Forensic Chemistry Section (Augusta, ME). Preliminary method development work was performed at the University of Central Florida (Orlando, FL). DSA without any extraction step in addition to the evaluation of methanol, dichloromethane and hexane extractions were conducted. Methanol was found to not be a suitable extraction solvent for DSA analysis of these compounds. For the screening of NBOMe designer drug variables on blotter paper, DSA-TOFMS was successful at reducing analysis time to ∼15s per sample, for qualitative identification for the selected analytes of interest. The analysis of an authentic forensic case sample by DSA-TOFMS using the method development parameters demonstrates its utility in forensic laboratories. 25C-NBOMe was identified with an exact mass accuracy of 0.60ppm.

One limitation in the growing field of ambient or direct analysis methods is reduced selectivity caused by the elimination of chromatographic separations prior to mass spectrometric analysis. We explored the use of high-field asymmetric waveform ion mobility spectrometry (FAIMS), an ambient pressure ion mobility technique, to separate the closely related opiate isomers of morphine, hydromorphone, and norcodeine. These isomers cannot be distinguished by tandem mass spectrometry. Separation prior to MS analysis is, therefore, required to distinguish these compounds, which are important in clinical chemistry and toxicology. FAIMS was coupled to a triple quadrupole mass spectrometer, and ionization was performed using either a pneumatically assisted heated electrospray ionization source (H-ESI) or paper spray, a direct analysis method that has been applied to the direct analysis of dried blood spots and other complex samples. We found that FAIMS was capable of separating the three opiate structural isomers using both H-ESI and paper spray as the ionization source.

Paper spray mass spectrometry ambient ionization is utilized for rapid discrimination of bacteria without sample preparation. Bacterial colonies were smeared onto filter paper precut to a sharp point, then wetted with solvent and held at a high potential. Charged droplets released by field emission were sucked into the mass spectrometer inlet and mass spectra were recorded. Sixteen different species representing eight different genera from Gram-positive and Gram-negative bacteria were investigated. Phospholipids were the predominant species observed in the mass spectra in both the negative and positive ion modes. Multivariate data analysis based on principal component analysis, followed by linear discriminant analysis, allowed bacterial discrimination. The lipid information in the negative ion mass spectra proved useful for species level differentiation of the investigated Gram-positive bacteria. Gram-negative bacteria were differentiated at the species level by using a numerical data fusion strategy of positive and negative ion mass spectra.

Rapid qualitative and quantitative analysis of 4-methylimidazole (4-MEI) in caramel and beverage samples is demonstrated using the paper spray form of ambient ionization mass spectrometry. The minimum level of pure 4-MEI detectable using multiple reaction monitoring (MRM) in a triple quadrupole instrument was 3 pg μL−1 in neat solvent and 5 pg μL−1 in a matrix containing caramel. This method was used to analyze 11 caramel samples for 4-MEI. After implementing effective quality control protocols, average relative standard deviations for paper spray triple quadrupole MS were less than 15% and the linear dynamic range was three orders of magnitude. Results obtained on three different days by two different analyst groups agreed closely. An ion trap tandem MS method of approximate quantitative analysis is also described and it gave similar precision to the triple quadrupole experiment when fluctuations in ion currents were cancelled by simultaneously isolating the analyte and internal standard and fragmenting both in an ion trap simultaneous MRM experiment. As another alternative, a rapid qualitative screening method based on the use of high-resolution measurements instead of tandem mass spectrometry using an Orbitrap was also tested and found to give a detection limit of 100 pg μL−1.

A simple and efficient ambient ionization method based on paper spray combined with tandem mass spectrometry allows rapid detection and quantitation of various contaminants (clenbuterol, melamine, plasticizer and sudan red) in various foodstuffs (e.g., meat, milk, sports drinks and chili powder).

Paper spray is a newly developed ambient ionization method that has been applied for direct qualitative and quantitative analysis of biological samples. The properties of the paper substrate and spray solution have a significant impact on the release of chemical compounds from complex sample matrices, the diffusion of the analytes through the substrate, and the formation of ions for mass spectrometry analysis. In this study, a commercially available silica-coated paper was explored in an attempt to improve the analysis of therapeutic drugs in dried blood spots (DBS). The dichloromethane/isopropanol solvent has been identified as an optimal spray solvent for the analysis. The comparison was made with paper spray using chromatography paper as substrate with methanol/water as solvent for the analysis of verapamil, citalopram, amitriptyline, lidocaine, and sunitinib in dried blood spots. It has been demonstrated that the efficiency of recovery of the analytes was notably improved with the silica coated paper and the limit of quantitation (LOQ) for the drug analysis was 0.1 ng mL(-1) using a commercial triple quadrupole mass spectrometer. The use of silica paper substrate also resulted in a sensitivity improvement of 5-50-fold in comparison with chromatography papers, including the Whatman ET31 paper used for blood cards. Analysis using a hand-held miniature mass spectrometer Mini 11 gave LOQs of 10-20 ng mL(-1) for the tested drugs, which is sufficient to cover the therapeutic ranges of these drugs.

Non-polar solvents like hexane allow ionization of insoluble drugs, peptides, nucleotides and phospholipids as solids from paper. Ambient ionization is achieved simply by application of a high voltage to the wet paper. Transport and ionization mechanisms are discussed, including the possibility of field desorption from dendritic structures formed on the paper.

Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (1 ng μL(-1)) and over a dynamic range of ∼5 pg μL(-1) to 500 pg μL(-1) (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng μL(-1).