IDSimF: An Open-Source Framework for the Simulation of Molecular Ion Dynamics in Mass Spectrometry and Ion Mobility Spectrometry.

The development of mass spectrometric and ion mobility devices heavily depends on a comprehensive understanding of the behavior of ions within such systems. Therefore, numerical modeling of ion paths helps to optimize and verify existing devices, and contributes to the development of innovative ion optical systems and multipole geometries. This Article introduces IDSimF (Ion Dynamics Simulation Framework), an open-source simulation tool tailored to the nonrelativistic dynamics of molecular ions in mass and ion mobility spectrometry applications. Addressing limitations in existing software packages, as for example SIMION, OpenFOAM, and COMSOL, IDSimF offers a specialized platform for simulating ion trajectories in electric fields. IDSimF efficiently accounts for space charge effects and considers various ion-neutral collision models while handling chemical kinetics. The framework is highly modular with reduced user input configuration complexity and aims to support simulation efforts in development and optimization of in mass spectrometers.

High-Resolution Electron Ionization Mass Spectrometry of Stannane: Deconvolution of Superimposed Fragmentation Patterns.

In a pulsed laser plasma driven extreme ultraviolet (EUV) light, tin droplets undergo evaporation, eventually depositing on different surfaces. The removal of surface bound tin is commonly achieved with a hydrogen plasma, resulting in the formation of stannane (SnH4). The mechanisms leading to the formation and decomposition of stannane remain incompletely understood. To analyze these mechanisms mass spectrometrically, a reference is crucial, necessitating a high-resolution and thoroughly characterized mass spectrum of stannane. In this paper, a high-resolution 70 eV electron ionization (EI) mass spectrum of stannane is presented. The mass spectrum comprises all ten natural isotopes of the stannane fragments generated through EI. Utilizing the custom analysis program RASP, the relative distribution of fragments is calculated from the isotopically superimposed mass signals, offering crucial insights into the occurring processes. Furthermore, the dependence of fragment formation on ion source pressure and temperature was determined.

Observation of Large, Charged Droplet Signatures within the High-Vacuum Region of a Commercial Electrospray TOF-MS.

Electrospray ionization (ESI) is one of the most prominent atmospheric pressure ionization techniques in modern mass spectrometry. It generates charged droplets from an analyte-containing solution as an initial step in the ionization process. Textbooks and the majority of the articles assume the entire droplet evaporation and release of bare analyte ions within the ionization chamber. However, non-mass-spectrometry-related literature and recent reports demonstrate droplet observation in regions of the vacuum systems of a variety of mass spectrometers. In this work, we report on the observation of large droplet fragments within the orthogonal acceleration stage of a Bruker micrOTOF by connecting an oscilloscope to an auxiliary ion current detector downstream of the acceleration stage. Moreover, we detected fragment debris even with the MCP TOF detector by evaluating individual TOF spectra. Droplet fragments appear as pronounced and intensive pulses of the ion current. This observation is clearly connected to ESI, as other atmospheric pressure ionization methods do not show this behavior. The recorded droplet signatures show clear dependencies on the ion source and transfer stage parameters. The existence of large and highly charged droplets may adversely affect or at least impact the analytical performance of the instrument due to space charge or complex heterogeneous chemical reactions. Furthermore, the penetration of large charged aggregates into the vacuum system explains the reported surface contamination after multipole stages. This contamination of critical components leads to substantially higher maintenance efforts.

Molecular Dynamics-Based Modeling of Ion-Neutral Collisions in an Open Ion Trajectory Simulation Framework.

Ion mobility spectrometry (IMS) and ion mobility mass spectrometry (IMS-MS) methods have become increasingly popular and are important analytical techniques to determine information about the structural parameters of gas-phase analytes. The accurate description of the interaction between molecular ions and neutral background gas particles is an essential part of high-quality simulations of such modern mass- and ion-mobility-spectrometric systems. Established ion-neutral collision models (Hard-sphere collision modeling and statistical diffusion simulations) in common ion-trajectory simulation systems like SIMION use strongly simplified assumptions and are thus limited in their predictive ability. In contrast, collision cross-section (CCS) modeling programs (e.g., MOBCAL, IMoS, and Colloidoscope) allow high-quality ion mobility predictions for low-field equilibrium conditions using explicit scattering processes with a molecular dynamics-based trajectory method but cannot be used for nonequilibrium collision modeling in an ion trajectory simulation. This work presents an extension to the open-source Ion Dynamics Simulation Framework (IDSimF), which allows the simulation of ion dynamics under arbitrary and even nonequilibrium conditions. It was extended by an advanced collision model employing the molecular dynamics trajectory method for a detailed microscopic description of ion-neutral collisions within ion-trajectory simulations. We used drift tube ion mobility spectrometry (DT-IMS) to validate the predictive abilities of the model and to estimate the runtime requirements for productive simulations. Simulated high-field ion mobilities for small ion systems in a drift tube IMS are compared to experimental values from the literature and an implementation of a hard-sphere model in IDSimF for helium and argon as background gas particles. Significant improvements in ion mobility predictions using the molecular dynamics trajectory approach are obtained with deviations of only a few percent from experimental values. Therefore, the established and publicly available MD collision model will serve as foundation for nonequilibrium ion dynamics simulations and the development of improved ion dynamics modeling methods.

Gas chromatography coupled to time-of-flight mass spectrometry using parallel electron and chemical ionization with permeation tube facilitated reagent ion control for material emission analysis.

RATIONALE: Volatile organic compounds (VOCs) emitted by an artificial leather part for car interiors are determined using GC-MS (gas chromatograph coupled to a mass spectrometer) using simultaneous electron and chemical ionization (EI&CI). A device for swift reagent ion switching in CI mode between consecutive runs is presented. METHODS: VOCs emitted from the investigated material were sampled onto Tenax® absorption tubes using micro emission chambers and subsequently injected into the GC through thermal desorption. The detector was a time-of-flight mass spectrometer (TOFMS) simultaneously operating in EI and CI modes during a single chromatographic run. A custom permeation tube setup allowed for swift selection between various reagent ions in CI mode, e.g., [N2 H]+ , [H3 O]+ , [(H2 O)2 H]+ , and [NH4 ]+ . RESULTS: Different reagent ions are swiftly selectable between single GC runs without hardware changes. Differences in precursor ion survival yields and the selectivity of the various reactants were carefully assessed. Several examples for the improved identification of unknown compounds with the available complementary and comprehensive EI&CI data set are demonstrated for a relevant material emission application. CONCLUSION: The presented technique provides additional value to the standard GC-EI/MS procedure commonly used for material emission characterization. It allows for a non-targeted analysis approach with moderate analysis time.

Charging Effects in Inlet Capillaries.

Glass or metal inlet capillaries are commonly used for flow restriction in atmospheric pressure ionization mass spectrometers. They exhibit a high ion transmission rate and stability at most operating conditions. However, transferring unipolar currents of ions through inlet capillaries can lead to sudden signal dropouts or drifts of the signal intensity, particularly when materials of different conductivity are in contact with the capillary duct. Molecular layers of water and other gases such as liquid chromatography solvents always form on the surfaces of inlet capillaries at atmospheric pressure ionization conditions. These surface layers play a major role in ion transmission and the occurrence of charging effects, as ions adsorb on the capillary walls as well, charging the walls to electric potentials of up to kilovolts and eventually leading to a hindrance of ion transport into or through the capillary duct. In this work, surface charging effects are reported in dependence on the capillary material, i.e., borosilicate glass, (reduced) lead silicate, quartz, and metal. Low electrical conductance materials show a more pronounced long-term signal drift (e.g., quartz), while higher electrical conductance materials lead to stable long-term behavior.

Parallel Operation of Electron Ionization and Chemical Ionization for GC-MS Using a Single TOF Mass Analyzer.

This work describes a novel mass spectrometer coupled to gas chromatography (GC-MS) that simultaneously displays the mass spectral information of electron (EI)- and chemical ionization (CI)-generated ion populations for a single chromatographic peak. After GC separation, the eluent is equally split and supplied in parallel to an EI and a novel CI source, both operating continuously. Precise switching of the ion optics provides the exact timing to consecutively extract the respective ion population from both sources and transfer them into a time-of-flight (TOF) mass analyzer. This technique enables the acquisition of complementary information from both ion populations (EI and CI) within a single chromatographic run and with sufficient data points to retain the chromatographic fidelity. The carefully designed GC transfer setup, fast ion optical switching, and synchronized TOF data acquisition system provide an automatic and straightforward spectral alignment of two ion populations. With an eluent split ratio of about 50% between the two ion sources, instrument detection limits of <40 fg on the column (octafluoronaphthalene) for the EI and <2 pg (benzophenone) for the CI source were obtained. The system performance and the additional analytical value for compound identification are demonstrated by means of different common GC standard mixtures and a commercial perfume sample of unknown composition.

Hydrogen Plasma-Based Medium Pressure Chemical Ionization Source for GC-TOFMS.

The construction, critical evaluation, and performance assessment of a medium-pressure (2-13 mbar), high-temperature chemical ionization (CI) source for application in GC-MS is described. The ion source is coupled to a commercial time-of-flight (TOF) mass analyzer. Reagent ions are generated in a two staged process. The first stage uses a filament free, helical resonator plasma (HRP) driven ion source for H3+ generation. Reagent gases, for example, nitrogen, isobutane, and methane are added in a second stage to the H3+ stream, which leads to the formation of final protonation reagents. The GC effluent is added subsequently to the reagent ion gas stream. Designed for the hyphenation with gas chromatography, this GC-CI-TOFMS combination produces GC limited Gaussian peak shapes even for high boiling point compounds. Limits of detection for the compounds investigated are determined as 0.4-1.2 pg on column with nitrogen, 0.6-12.6 pg with isobutane, and 2 pg to >25 pg with methane as reagent gas, respectively. An EPA 8270 LCS mix containing 78 main EPA pollutants is used to evaluate the selectivity of the different reagent ions. Using nitrogen as reagent gas, 74 of 78 compounds are detected. In comparison, 41 of 78 compounds and 62 of 78 compounds are detected with isobutane or methane as CI reagent gas, respectively.

Simulation of Cluster Dynamics of Proton-Bound Water Clusters in a High Kinetic Energy Ion-Mobility Spectrometer.

Ions are separated in ion mobility spectrometry (IMS) by their characteristic motion through a gas-filled drift tube with a static electric field present. Chemical dynamics, such as clustering and declustering of chemically reactive systems, and physical parameters, as, for example, the electric field strength or background gas temperature, impact on the observed ion mobility. In high kinetic energy IMS (HiKE-IMS), the reduced electric field strength is up to 120 Td in both the reaction region and drift region of the instrument. The ion generation in a corona discharge driven chemical ionization source leads generally to formation of proton-bound water clusters. However, the reduced electric field strength and therefore the effective ion temperature has a significant influence on the chemical equilibria of this reaction system. In order to characterize the effects occurring in IMS systems in general, numerical simulations can support and potentially explain experimental observations. The comparison of the simulation of a well characterized chemical reaction system (i.e., the proton-bound water cluster system) with experimental results allows us to validate the numerical model applied in this work. Numerical simulations of the proton-bound water cluster system were performed with the custom particle-based ion dynamics simulation framework (IDSimF). The ion-transport calculation in the model is based on a Verlet integration of the equations of motion and uses a customized Barnes-Hut method to calculate space charge interactions. The chemical kinetics is modeled stochastically with a Monte Carlo method. The experimental and simulated drift spectra are in good qualitative and quantitative agreement, and experimentally observed individual transitions of cluster ions are clearly reproduced and identified by the numerical model.

Observation of charged droplets from electrospray ionization (ESI) plumes in API mass spectrometers.

Electrospray ionization (ESI) generates bare analyte ions from charged droplets, which result from spraying a liquid in a strong electric field. Experimental observations available in the literature suggest that at least a significant fraction of the initially generated droplets remain large, have long lifetimes, and can thus aspirate into the inlet system of an atmospheric pressure ionization mass spectrometer (API-MS). We report on the observation of fragment signatures from charged droplets penetrating deeply the vacuum stages of three commercial mass spectrometer systems with largely different ion source and spray configurations. Charged droplets can pass through the ion source and pressure reduction stages and even into the mass analyzer region. Since droplet signatures were found in all investigated instruments, the incorporation of charged droplets is considered a general phenomenon occurring with common spray conditions in ESI sources.

Field-Dependent Reduced Ion Mobilities of Positive and Negative Ions in Air and Nitrogen in High Kinetic Energy Ion Mobility Spectrometry (HiKE-IMS).

In High Kinetic Energy Ion Mobility Spectrometry (HiKE-IMS), ions are formed in a reaction region and separated in a drift region, which is similar to classical drift tube ion mobility spectrometers (IMS) operated at ambient pressure. However, in contrast to the latter, the HiKE-IMS is operated at a decreased background pressure of 10-40 mbar and achieves high reduced electric field strengths of up to 120 Td in both the reaction and the drift region. Thus, the HiKE-IMS allows insights into the chemical kinetics of ion-bound water cluster systems at effective ion temperatures exceeding 1000 K, although it is operated at the low absolute temperature of 45 °C. In this work, a HiKE-IMS with a high resolving power of RP = 140 is used to study the dependence of reduced ion mobilities on the drift gas humidity and the effective ion temperature for the positive reactant ions H3O+(H2O)n, O2+(H2O)n, NO+(H2O)n, NO2+(H2O)n, and NH4+(H2O)n, as well as the negative reactant ions O2-(H2O)n, O3-(H2O)n, CO3-(H2O)n, HCO3-(H2O)n, and NO2-(H2O)n. By varying the reduced electric field strength in the drift region, cluster transitions are observed in the ion mobility spectra. This is demonstrated for the cluster systems H3O+(H2O)n and NO+(H2O)n.

Negative Reactant Ion Formation in High Kinetic Energy Ion Mobility Spectrometry (HiKE-IMS).

Due to the operation at background pressures between 10-40 mbar and high reduced electric field strengths of up to 120 Td, the ion-molecule reactions in High Kinetic Energy Ion Mobility Spectrometers (HiKE-IMS) differ from those in classical ambient pressure IMS. In the positive ion polarity mode, the reactant ions H+(H2O)n, O2+(H2O)n, and NO+(H2O)n are observed in the HiKE-IMS. The relative abundances of these reactant ion species significantly depend on the reduced electric field strength in the reaction region, the operating pressure, and the water concentration in the reaction region. In this work, the formation of negative reactant ions in HiKE-IMS is investigated in detail. On the basis of kinetic and thermodynamic data from the literature, the processes resulting in the formation of negative reactant ions are kinetically modeled. To verify the model, we present measurements of the negative reactant ion population in the HiKE-IMS and its dependence on the reduced electric field strength as well as the water and carbon dioxide concentrations in the reaction region. The ion species underlying individual peaks in the ion mobility spectrum are identified by coupling the HiKE-IMS to a time-of-flight mass spectrometer (TOF-MS) using a simple gated interface that enables the transfer of selected peaks of the ion mobility spectrum into the TOF-MS. Both the theoretical model as well as the experimental data suggest the predominant generation of the oxygen-based ions O-, OH-, O2-, and O3- in purified air containing 70 ppmv of water and 30 ppmv of carbon dioxide. Additionally, small amounts of NO2- and CO3- are observed. Their relative abundances highly depend on the reduced electric field strength as well as the water and carbon dioxide concentration. An increase of the water concentration in the reaction region results in the generation of OH- ions, whereas increasing the carbon dioxide concentration favors the generation of CO3- ions, as expected.

Non-targeted and targeted analysis of oxylipins in combination with charge-switch derivatization by ion mobility high-resolution mass spectrometry.

Eicosanoids and other oxylipins play an important role in mediating inflammation as well as other biological processes. For the investigation of their biological role(s), comprehensive analytical methods are necessary, which are able to provide reliable identification and quantification of these compounds in biological matrices. Using charge-switch derivatization with AMPP (N-(4-aminomethylphenyl)pyridinium chloride) in combination with liquid chromatography ion mobility quadrupole time-of-flight mass spectrometry (LC-IM-QTOF-MS), we developed a non-target approach to analyze oxylipins in plasma, serum, and cells. The developed workflow makes use of an ion mobility resolved fragmentation to pinpoint derivatized molecules based on the cleavage of AMPP, which yields two specific fragment ions. This allows a reliable identification of known and unknown eicosanoids and other oxylipins. We characterized the workflow using 52 different oxylipins and investigated their fragmentation patterns and ion mobilities. Limits of detection ranged between 0.2 and 10.0 nM (1.0-50 pg on column), which is comparable with other state-of-the-art methods using LC triple quadrupole (QqQ) MS. Moreover, we applied this strategy to analyze oxylipins in different biologically relevant matrices, as cultured cells, human plasma, and serum. Graphical abstract.

Positive Reactant Ion Formation in High Kinetic Energy Ion Mobility Spectrometry (HiKE-IMS).

In contrast to classical Ion Mobility Spectrometers (IMS) operating at ambient pressure, the High Kinetic Energy Ion Mobility Spectrometer (HiKE-IMS) is operated at reduced pressures of between 10 and 40 mbar and higher reduced electric field strengths of up to 120 Td. Thus, the ion-molecule reactions occurring in the HiKE-IMS can significantly differ from those in classical ambient pressure IMS. In order to predict the ionization pathways of specific analyte molecules, profound knowledge of the reactant ion species generated in HiKE-IMS and their dependence on the ionization conditions is essential. In this work, the formation of positive reactant ions in HiKE-IMS is investigated in detail. On the basis of kinetic and thermodynamic data from the literature, the ion-molecule reactions are kinetically modeled. To verify the model, we present measurements of the reactant ion population and its dependence on the reduced electric field strength, the operating pressure, and the water concentration in the sample gas. All of these parameters significantly affect the reactant ion population formed in HiKE-IMS.

Analyzing Positive Reactant Ions in High Kinetic Energy Ion Mobility Spectrometry (HiKE-IMS) by HiKE-IMS-MS.

In contrast to classical ion mobility spectrometers (IMS) operating at ambient pressure, the high kinetic energy ion mobility spectrometer (HiKE-IMS) is operated at reduced pressures between 10-40 mbar. In HiKE-IMS, ions are generated in a reaction region before they are separated in a drift region. Due to the operation at reduced pressure, it is possible to reach high reduced electric field strengths up to 120 Td in both the reaction as well as drift region, resulting in a pronounced decrease in chemical cross sensitivities and a significant enhancement of the dynamic range. Until now though, only limited knowledge about the ionization pathways in HiKE-IMS is available. Typically, proton bound water clusters, H+(H2O)n, are the most abundant positive reactant ion species in classical IMS with atmospheric chemical ionization sources. However, at reduced pressure and increased effective ion temperature, the reactant ion population significantly changes. As the ionization efficiency of analyte molecules in HiKE-IMS strongly depends on the reactant ion population, a detailed knowledge of the reactant ion population generated in HiKE-IMS is essential. Here, we present a coupling stage of the HiKE-IMS to a mass spectrometer enabling the identification of ion species and the investigation of ion molecule reactions prevailing in HiKE-IMS. In the present study, the HiKE-IMS-MS is used to identify positive reactant ion populations in both, purified air and nitrogen, respectively. The experimental data suggest the generation of systems of clustered primary ions (H+(H2O)n, NO+(H2O)m, and O2+(H2O)p), which most probably serve as reactant ions. Their relative abundances highly depend on the reduced electric field strength in the reaction region. Furthermore, their effective mobilities are studied as a function of the reduced electric field strength in the drift region.

Understanding Nontraditional Differential Mobility Behavior: A Case Study of the Tricarbastannatrane Cation, N(CH2CH2CH2)3Sn.

The effect of strong ion-solvent interactions on the differential mobility behavior of the tricarbastannatrane cation, N(CH2CH2CH2)3Sn+, has been investigated. Exotic "type D" dispersion behavior, which is intermediate to the more common types C and A behavior, is observed for gaseous N2 environments that are seeded with acetone and acetonitrile vapor. Quantum chemical calculations and first-principles modeling show that under low-field conditions [N(CH2CH2CH2)3Sn + solvent]+ complexes containing a single solvent molecule survive the entire separation waveform duty cycle and interact weakly with the chemically modified environment. However, at high separation voltages, the ion-solvent bond dissociates and dynamic clustering ensues.

Computational analysis of the proton-bound acetonitrile dimer, (ACN)2 H.

RATIONALE: In atmospheric pressure ionization mass spectrometry the theoretical thermodynamic treatment of proton-bound cluster stabilities helps us to understand the prevailing chemical processes. However, such calculations are rather challenging because low-barrier internal rotations and strong anharmonicity of the hydrogen bonds cause the breakdown of the usually applied harmonic approximation. Even the implemented anharmonic treatment in standard ab initio software failed in the case of (ACN)2 H+ . METHODS: For a case study of the proton-bound acetonitrile dimer, (ACN)2 H+ , we scan the potential energy surface (PES) for the internal rotation and the proton movement in all three spatial directions. We correct the partition functions by treating the internal rotation as a free rotor and by solving the nuclear Schrödinger equation explicitly for the proton movement. An additional PES scan for the dissociation surface further improves the understanding of the cluster behavior. RESULTS: The internal rotation is essentially barrier free (V0 = 2.6 × 10-6 eV) and the proton's movement between the two nitrogen atoms follows a quartic rather than quadratic potential. As a figure of merit we calculate the free dissociation enthalpy of the dimer. Our description significantly improves the standard results from about 118.3 kJ/mol to 99.6 kJ/mol, compared with the experimentally determined value of 92.2 kJ/mol. The dissociation surface reveals strong crosstalk between modes and is essentially responsible for the observed errors. CONCLUSIONS: The presented corrections to the partition functions significantly improve their accuracy and are rather easy to implement. In addition, this work stresses the importance of alternative theoretical methods for proton-bound cluster systems besides the standard harmonic approximations.

Charge Retention/Charge Depletion in ESI-MS: Experimental Evidence.

The effects of liquid and gas phase additives (chemical modifiers) on the ion signal distribution for Substance P (SP), recorded with a nanoelectrospray setup, are evaluated. Depletion of the higher charge state of Substance P ([SP+3H]3+) is observed with polar protic gas phase modifiers. This is attributed to their ability to form larger hydrogen-bonded clusters, whose proton affinity increases with cluster size. These clusters are able to deprotonate the higher charge state. "Supercharging agents" (SCAs) as well as aprotic polar gas phase modifiers, which promote the retention of the higher charge state of Substance P, do not form such large clusters under the given conditions and are therefore not able to deprotonate Substance P. Both SCAs and aprotic modifiers form clusters with the higher charge state, leading to stabilization of the charge. Whereas supercharging agents have low vapor pressures and are therefore enriched in late-stage electrospray droplets, the gas phase modifiers are volatile organic solvents. Collision induced dissociation experiments revealed that the addition of a modifier significantly delays the droplet evaporation and ion release process. This indicates that the droplet takes up the gas phase modifier to a certain extent (accommodation). Depending on the modifier's properties either charge depletion or retention may eventually be promoted.

Charge Retention/Charge Depletion in ESI-MS: Theoretical Rationale.

Gas phase modification in ESI-MS can significantly alter the charge state distribution of small peptides and proteins. The preceding paper presented a systematic experimental study on this topic using Substance P and proposed a charge retention/charge depletion mechanism, explaining different gas- and liquid-phase modifications [Thinius et al. J. Am. Soc. Mass Spec. 2020, 10.1021/jasms.9b00044]. In this work, we aim to support this rational by theoretical investigations on the proton transfer processes from (multiply) charged analytes toward solvent clusters. As model systems we use small (di)amines as analytes and methanol (MeOH) and acetonitrile (ACN) as gas phase modifiers. The calculations are supported by a set of experiments using (di)amines, to bridge the gap between the present model system and Substance P used in the preceding study. Upon calculation of the thermochemical stability as well as the proton transfer pathways, we find that both ACN and MeOH form stable adduct clusters at the protonation site. MeOH can form large clusters through a chain of H-bridges, eventually lowering the barriers for proton transfer to an extent that charge transfer from the analyte to the MeOH cluster becomes feasible. ACN, however, cannot form H-bridged structures due to its aprotic nature. Hence, the charge is retained at the original protonation site, i.e., the analyte. The investigation confirms the proposed charge retention/charge depletion model. Thus, adding aprotic solvent vapors to the gas phase of an ESI source more likely yields higher charge states than using protic compounds.

Ion-Trap Mass Spectrometric Analysis of Bisphenol A Interactions With Titanium Dioxide Nanoparticles and Milk Proteins.

Quantitative analysis of endocrine-disrupting molecules such as bisphenol A (BPA) in freshwater to determine their widespread occurrence in environmental resources has been challenged by various adsorption and desorption processes. In this work, ion trap mass spectrometry (ITMS) analysis of BPA was aimed at studying its molecular interactions with titanium dioxide (TiO2) nanoparticles and milk whey proteins. Addition of sodium formate prevented TiO2 nanoparticles from sedimentation while enhancing the electrospray ionization (ESI) efficiency to produce an abundance of [BPA + Na]+ ions at m/z 251.0. More importantly, the ESI-ITMS instrument could operate properly during a direct infusion of nanoparticles up to 500 µg/mL without clogging the intake capillary. Milk protein adsorption of BPA could decrease the [BPA + Na]+ peak intensity significantly unless the proteins were partially removed by curdling to produce whey, which allowed BPA desorption during ESI for quantitative analysis by ITMS.