Multimodal Vacuum-Assisted Plasma Ion (VaPI) Source with Transmission Mode and Laser Ablation Sampling Capabilities

Article abstract of DOI:10.1007/s13361-016-1354-8

We have developed a multimodal ion source design that can be configured on the fly for various analysis modes, designed for more efficient and reproducible sampling at the mass spectrometer atmospheric pressure (AP) interface in a number of different applications. This vacuum-assisted plasma ionization (VaPI) source features interchangeable transmission mode and laser ablation sampling geometries. Operating in both AC and DC power regimes with similar results, the ion source was optimized for parameters including helium flow rate and gas temperature using transmission mode to analyze volatile standards and drug tablets. Using laser ablation, matrix effects were studied, and the source was used to monitor the products of model prebiotic synthetic reactions. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13361-016-1354-8

B American Society for Mass Spectrometry, 2016
J. Am. Soc. Mass Spectrom. (2016) 27:897Y907
DOI: 10.1007/s13361-016-1354-8
RESEARCH ARTICLE
Multimodal Vacuum-Assisted Plasma Ion (VaPI) Source
with Transmission Mode and Laser Ablation Sampling
Capabilities
Joel D. Keelor,1 Paul B. Farnsworth,2 Arthur L. Weber,3 Heather Abbott-Lyon,4
Facundo M. Fernández1
1School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
2Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA
3SETI Institute, Mountain View, CA 94043, USA
4Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA 30144, USA
Abstract. We have developed a multimodal ion source design that can be configured
on the fly for various analysis modes, designed for more efficient and reproducible
sampling at the mass spectrometer atmospheric pressure (AP) interface in a number
of different applications. This vacuum-assisted plasma ionization (VaPI) source
features interchangeable transmission mode and laser ablation sampling geome-
tries. Operating in both AC and DC power regimes with similar results, the ion source
was optimized for parameters including helium flow rate and gas temperature using
transmission mode to analyze volatile standards and drug tablets. Using laser abla-
tion, matrix effects were studied, and the source was used to monitor the products of
model prebiotic synthetic reactions.
Keywords: Ambient plasma ionization, Mass spectrometry, Transmission mode, Laser ablation, Prebiotic
chemistry
Received: 18 September 2015/Revised: 22 January 2016/Accepted: 25 January 2016/Published Online: 16 February 2016
[9, 12] and drug quality analysis [13–15], and more recently in
metabolic fingerprinting for diagnostic applications [16, 17].
Introduction
mbient plasma-discharge ionization continues to be a
burgeoning field in mass spectrometry. Since direct anal-
Performance has been shown to be comparable between dif-
ferent source constructs, with unique plasma characteristics
principally dictated by device dimensions, power regime (AC
or DC), and discharge gases used [18, 19]. The currently
understood glow discharge ionization mechanisms and physi-
ochemical variables influencing ionization efficiency have
been summarized elsewhere in detail [20, 21].
Ambient fluid dynamics at the spectrometer inlet signifi-
cantly impact ion transmission and can be difficult to control.
Reproducible sampling and quantitation with plasma discharge
sources have proven to be complicated, necessitating the use of
internal standards [22, 23] and automated sampling approaches
[24]. Much effort has been dedicated to improving the sensi-
tivity and sampling efficiency of these ionization techniques
with the aid of simulations that model gas flow patterns [25, 26]
and real-time visualization of source gas flow profiles using the
Schlieren technique [27–29]. The most successful attempts at
enhancing the quantitative capability of ambient plasma-based
analysis have been realized with DART-MS systems
A
ysis in real time (DART) was reported in 2005 by Cody et al.
[1], a variety of different plasma ionization technologies have
been developed, most notable examples including low temper-
ature plasma (LTP) [2], plasma-assisted desorption ionization
(PADI) [3, 4], and flowing atmospheric pressure afterglow
(FAPA) [5, 6]. Plasma ion sources have garnered wide accep-
tance and demonstrated utility for routine detection of small
molecules in homeland security and forensic applications [7,
8], environmental [9, 10] and reaction monitoring [11], food
Electronic supplementary material The online version of this article (doi:10.
1007/s13361-016-1354-8) contains supplementary material, which is available
to authorized users.
Correspondence to: Facundo M. Fernández;
e-mail: facundo.fernandez@chemistry.gatech.edu

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J. D. Keelor et al.: VaPI Source
incorporating a Vapur interface, rail-mounted sampling probes,
and auxiliary pumping, all of which help entrain divergent gas
flows toward the mass spectrometer inlet and reduce variability
[30]. More recently, continuous quantitative surface scanning
sample complexity. The best sample delivery practices to en-
sure sampling reproducibility are also discussed.
with DART has been accomplished using planar substrates in Experimental
place of capillary holders [31].
Materials and Sample Preparation
Spatial resolution for plasma ion sources, affected by sam-
ple size and shape, is typically limited by dispersive gas-flow
dynamics. One successful strategy used to improve spatial
resolution has been coupling of plasma ionization with laser
ablation, wherein high-energy laser pulses desorb neutral ma-
terial with micron spatial resolution. For example, laser abla-
tion has been paired successfully with dielectric-barrier-
discharges (DBD) [32] to examine nonvolatile explosives,
and used with DART [33] and FAPA [34] for imaging mass
spectrometry of biological tissues, dyes, and drugs. In these
approaches, the substrate radiation absorption efficiency and
ablation plume expansion remain the limiting factors determin-
ing the abundance of aerosolized sample available for ioniza-
tion, while the plasma ion current and source gas-flow fidelity
dictate the ion generation and transmission efficiencies,
respectively.
The increasingly more accessible mass spectrometer AP
interfaces continue to enable new sample introduction modes
that alleviate ion losses related to mass transport. For example,
vacuum-assisted sampling has been coupled with rf plasma
discharges within or directly connected to the inlet transfer
capillary [35–37]. Such sampling approaches function as aero-
dynamic remote sampling stages similar to the remote analyte
sampling, transport, and ionization (RASTIR) [38] idea imple-
mented with extractive electrospray ionization (EESI).
Drawing inspiration from these AP sampling techniques
and several methodologies established in the same vein, in-
cluding electrothermal vaporization (ETV)-DART [39] or
Drop-on-Demand FAPA [40], we present a multimodal plasma
ion source named vacuum-assisted plasma ionization (VaPI)
that integrates laser ablation and transmission mode sampling
with AC/DC plasma ionization mass spectrometry. The core
component of this new ion source architecture is a central cross
union bridging a plasma discharge cell to the mass spectrom-
eter transfer capillary in a coaxial orientation. Open cross
bridge joints are interchangeably adapted with either a mesh
sample screen for transmission mode analysis (TM-VaPI) or
sealed with a sapphire window permitting focused laser
throughput for ablation experiments (LA-VaPI). The suction
of the mass spectrometer is partially maintained within the
cross union when using helium discharge gas, thereby allowing
material to be drawn into the source, improving sampling
consistency. With increasing plasma power and concomitant
rising cell temperature, the union serves as an incubated vessel
facilitating analyte desolvation and mixing, as well as efficient
ionization and transmission. Optimal settings for co-dependent
variables affecting ionization efficiency and transmission,
namely helium gas flow rate, cell temperature, and plasma
power, have been determined. Effects of matrix composition
were also investigated, showcasing VaPI’s robust tolerance to
Reagent grade dimethyl methylphosphonate [DMMP] and 2,4-
lutidine were purchased from Sigma-Aldrich (St. Louis, MO,
USA) and prepared as aqueous solutions by serial dilution in
concentrations of 6.25, 12.5, 25, 50, 100, and 200 μM from a
1 mM stock solution. An analytical grade standard mixture of
amino acids was also procured from Sigma-Aldrich and used
without further preparation. The mixture concentration was
2.5 μmol mL–1 in 0.1 N HCl for all components unless otherwise
specified, and consisted of L-alanine, ammonium chloride, L-
asparagine, L-aspartic acid, L-cystine (1.25 μmol mL–1), L-
glutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-
lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-
threonine, L-tyrosine, and L-valine. Triaminopyrimidine [TAP]
(Acros Organics, part of Thermo Fisher Scientific Inc., NJ,
USA) was made into 2.5 mM aqueous solutions mixed with
potassium chloride (J.T. Baker brand from Avantor Performance
Materials, Center Valley, PA, USA) using salt concentrations of
5, 10, 20, and 40 mM KCl. Poly(ethylene) glycol [Mn 395, Mw
430] from American Polymer Standards Corporation (Mentor,
OH, USA) was dissolved into ~4 mg mL–1 aqueous solutions
with solvent compositions of 0%, 20%, 50%, and 90% volume
methanol (LC-MS grade, Sigma-Aldrich).
Drug tablet samples included acetaminophen [500 mg] sold
by Target, Inc. (Minneapolis, MN, USA), Doralgine [25/
500 mg caffeine/noramidopyrine] made by Medical Supply
Company, Ltd. (Phnom Penh, Cambodia), and Coartem [20/
120 mg artemether/lumefantrine] from Novartis AG Pharma-
ceutical Company (Suffern, NY, USA).
Synthetic nucleobase mixtures were produced from two sep-
arate model prebiotic reactions. Purine and pyrimidine com-
pounds were synthesized in the formamide reaction. A ~5 mL
volume of formamide (reagent grade, Sigma-Aldrich) was heat-
ed in an oven at 160 °C for up to 120 h in a 20-mL scintillation
vial covered with foil. Fractions of the reaction mixture were
collected at 72 and 120 h time points and stored at 8 °C for 24 h
before workup. Reacted formamide mixture aliquots of 100 μL
or ~120 mg were dissolved in 10 mL of deionized water and
filtered through a 0.45 μm PTFE membrane before analysis.
Pyrazine derivatives were synthesized from a one-pot reaction,
in which 1,3-dihydroxyacetone, glycolaldehyde, and 2-
aminoacetamidine-dihydrobromide (0.10 M 1:1:1 ratio) were
mixed in aqueous solution with sodium phosphate (0.25 M) at
pH 7.4 by addition of NaOH, then heated to 85 °C for 24 h. In a
2-mL microvial, reaction contents were de-aerated and purged
with nitrogen before being sealed under vacuum. A 1.0 mL
aliquot of the product mixture was diluted with 8 mL of water,
and a 5 mL portion was then desalted on a 20 mL Discovery
DSC-18 column (Supelco, Bellefonte, PA, USA). Material was
eluted with 36 mL water and 44 mL 50% methanol/water,

J. D. Keelor et al.: VaPI Source
899
collected in 20 separate fractions. Salt-free fractions #10-20
(from 37-80 mL eluent) were combined and concentrated to
0.5 mL syrup using a CentriVap centrifuge. After storage at –
20 °C, the mixture was suspended in 200 μL water, and 50 μL
aliquots were further diluted in 300 μL water for adequate
ampoule sampling volume.
within the cross union was estimated with a DM8320 digital
manometer (General Tools, Secaucus, NJ, USA) fastened on
one open joint while keeping the others sealed.
Instrumentation and Sampling Methods
Deionized water was generated with a Barnstead Nanopure
Diamond laboratory water system (Thermo Fisher Scientific,
Inc.) and ultrapure (99.999%) helium source gas was supplied
by Airgas (Atlanta, GA, USA).
For transmission mode geometry sampling, a 40 × 40
stainless steel mesh screen (diameter = 9.35 mm) was
fastened in the top cross union opening of the VaPI
ion source and the lower union opening was kept sealed.
During ion source characterization, volatile compounds
were sampled from a strictly aqueous matrix to reduce
spectral complexity. The droplet water introduced during
sampling would only contribute to the (H2O)nH+ reactant
ion population, thereby preventing the possibility of ion
competition with an organic solvent. Solutions were spot-
ted onto the mesh in 3 μL aliquots using a micropipette.
For solids analysis, drug tablet fragments were placed
atop the mesh with tweezers for approximately 1 min,
and then removed. If needed, methanol solvent or water
was spotted in aliquots of 10–100 μL to rinse the mesh.
When sampling by laser ablation, the bottom union inlet
was left open and a sapphire window (h = 1 mm,
diameter=9.35 mm) was fastened in the top joint. Laser abla-
tion was performed using an IR Opolette OPO laser model
2731 (Opotek, Inc., Carlsbad, CA, USA). Laser wavelength
and frequency were tuned to 2940 nm and 10 Hz, respectively.
Laser energy was tuned to 88.1%, equating to an output energy
of ~1.55 mJ measured with an ES111C pyroelectric sensor
(Thorlabs, Inc., Newton, NJ, USA), focused by a MgF2
plano-convex lens (f.l. 5 cm) through the Swagelok cross
union. Ablation of sample solution was conducted from
10 μL droplets deposited on an Omni slide glass substrate with
Teflon-coated spot arrays (Prosolia, Indianapolis, IN, USA), or
from a 200 μL reservoir of solution contained in a quarter-inch
quartz ampoule. Unless otherwise specified, all ablation was
performed from aqueous solutions. Laser ablation was also
performed using an open AP interface arrangement during a
comparison study. In place of the cross union bridge unit, the
discharge source was capped with a quarter-inch Swagelok end
fitting as the grounded counter electrode and positioned
~0.5 cm away from the spectrometer capillary inlet. The planar
Omni slide substrate was mounted on a guide arm extending
from a xyz stage, and centered below the spectrometer inlet in
the interface flush underneath the plasma endcap electrode.
All experiments were conducted on a JEOL JMS-T100LC
AccuTOF mass spectrometer (JEOL USA, Inc., Peabody, MA,
USA) using the following positive mode tune parameters opti-
mized for the low mass range — orifice #1: 25 V, orifice #2:
5 V, ring lens: 10 V, orifice temperature: 100 °C; ion guide rf
voltage: 100–400 V, sweep time: 80%; guide bias voltage:
29 V, pusher bias voltage: –0.28 V, MCP detector: 2650 V.
In most cases, nominal masses are reported for known com-
pound peaks, but for unknown species, assigned ion formulas
were deduced from the accurate masses provided in the text.
VaPI Plasma Ion Source Design and Operation
The custom plasma discharge source was fashioned from a
quarter-inch PFA Swagelok (Solon, OH, USA) T-junction se-
curing a quartz tube (l=50 mm, o.d. =6.25 mm, i.d. =3.95 mm)
that enclosed a tungsten needle electrode (l = 120 mm,
diameter=1 mm) at one joint opening. The point electrode
was center-mounted in a perforated ceramic piece
(dia.meter = 3.95 mm) inserted at the base of the quartz tube,
and the electrode rod extended within the T-junction body
through a Teflon plug capping the opposite joint. A gas feed
line was fitted in the top opening. The quartz tube terminated at
an eighth-inch metal ferrule (grounded counter-electrode) in a
stainless steel quarter-inch Swagelok cross union, which was
connected on-axis with the mass spectrometer via a truncated
glass transfer capillary (l = 40 mm, o.d. = 6.35 mm,
i.d. = 500 μm) from Bruker (Billerica, MA, USA). The
Swagelok cross union body was wrapped in 1 ft. high-
temperature heating cord (22 W) with a J-type thermocouple,
allowing temperature to be regulated using an SDC digital
temperature controller (Briskheat, Columbus, OH, USA).
High-temperature quarter-inch 60%/40% vespel/graphite fer-
rules (Restek, Bellefonte, PA, USA) were used at all Swagelok
joint connections. Thermal images of the plasma source and
cross unit were collected with a FLIR T300 IR camera (FLIR
Systems AB, Danderyd, Sweden).
The electric discharge was operated at powers of ~20 1 W
in both AC and DC regimes using helium source gas. In DC
mode, a negative potential bias of ~2500 V was applied to the
tungsten needle in series with 50 kΩ ballast resistor using a
Bertan Associates 205A-50R HV power supply (Bertan Asso-
ciates Inc., Hicksville, NY, USA). The effective DC electrode
potential and current measured with a HV probe were ~1850 V
and ~11 mA, respectively. For AC mode, power was applied to
the tungsten needle from a T&C Power Conversion AG-0201A
rf power supply (T&C Power Conversion Inc., Rochester, NY,
USA). Plasma power was estimated from the difference be-
tween effective load powers (PLoad =PForward – PReverse) with
the discharge on and off. AC electrode potentials of ~1240–
1460 Vrms were measured on an oscilloscope (Tektronix, Bea-
verton, OR, USA), with Irms estimated between 13 and 16 mA
for a 20 W AC discharge. Helium flow rates were controlled
between 1.0 and 2.0 LPM using an analog rotameter (Aalborg,
Orangeburg, NY, USA) in-line with an M series digital flow
meter (Alicat Scientific, Tuscon, AZ, USA). Vacuum pressure

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J. D. Keelor et al.: VaPI Source
of extracted ion chronograms for the DMMP protonated mono-
mer and dimer detected from a 50 μM solution. Differences in
desorption profile shapes were observed based on analyte
volatility. For instance, the desorption profile for DMMP sug-
gested a lower volatility from the droplet surface, indicated by
the gradual rise to a maximum and subsequently sharp decrease
to baseline upon depletion of the droplet, compared with the
more volatile 2,4-lutidine, the peak profile of which showed an
inverse trend. Furthermore, as it is apparent in Supplementary
Figure S2b, the DMMP dimer peak emerged later than the
monomer, appearing only after concentration by the shrinking
droplet. These observations were compatible with DMMP’s
slightly higher enthalpy of vaporization and boiling point.
Meanwhile, no dimer ion was observed for the more rapidly
volatilized 2,4-lutdine even at 1 mM solution concentrations.
However, a minor ion suspected to form through a pyridine N-
oxide intermediate did appear at higher 2,4-lutidine concentra-
tions, with the formula [C7H8NO]+ assigned by accurate mass
(m/z=122.0628). The origin of this and other product ions is
discussed in following sections.
The cross union pressure and vacuum draw were largely
influenced by the plasma helium flow rate and cell union
temperature, which in turn impacted sampling reproducibility
and sensitivity for TM-VaPI. Figure 2a shows the signal inten-
sity as a function of helium flow rate for aliquots of DMMP and
2,4-lutidine spotted on the mesh. When the glow discharge was
active, the cross union vacuum pressure measured between –
116 mmHg at 1.0 LPM helium to –13 mmHg at 1.8 LPM
helium. A plot of relative cross union pressure (normalized to a
percentage) as a function of flow rate and temperature can be
found in Supplementary Figure S3. Signal was seen to increase
for each analyte with helium flow rates up to ~1.6 LPM (cell
pressure: –40 mmHg) due to a higher flux of plasma species
into the VaPI cross joint available to sustain ionization
Results and Discussion
TM-VaPI Characterization
A schematic illustration of the VaPI source assembly is
depicted in Figure 1, with corresponding pictures presented in
Supplementary Figure S1a, b (in supporting information). The
source configuration in Figure 1a, intended for transmission
mode analysis, features a mesh sample screen on the top cross
union joint. A steady draw of air flows into the cross union
through the sample mesh, driven by the suction from the
spectrometer inlet and modulated by helium flow rate and cell
temperature. This source design mitigates the unfavorable fluid
dynamics of open format (ambient) plasma ion sources, with
the focused vacuum draw through the mesh improving sensi-
tivity by affording more complete entrainment of volatilized
sample into the plasma gas. With this setup, an elevated plasma
gas temperature was necessary not only to initiate analyte
thermal desorption but also to enhance analyte cluster
desolvation and minimize condensation on the interior cell
surface. Accordingly, glow discharges were operated at target
powers of ~20 W, where helium gas temperatures measured
with a thermocouple reached 200 °C in the cross union without
the addition of extra heating elements.
Aqueous solutions of 2,4-lutidine and DMMP were sam-
pled first to determine general performance and dynamic range
while optimizing for helium gas flow rate and cell temperature.
When microliter aliquots of solution were spotted onto the
screen, the droplet was slowly aspirated into the cross union,
mixing in the afterglow helium stream. Volatile analytes were
initially chosen for characterization experiments to avoid car-
ryover that might skew trends. Supplementary Figure S2a
shows the highly repeatable extracted ion chronograms for
the protonated monomer of 2,4-lutidine in a concentration
series, and Supplementary Figure S2b displays a select subset
Figure 1. Schematic of vacuum-assisted plasma ionization (VaPI) source assembly. Configuration used for transmission mode
(TM)-VaPI sampling (a). Configuration used for laser ablation (LA)-VaPI sampling (b). Open atmospheric pressure interface arrange-
ment with plasma source (c)

J. D. Keelor et al.: VaPI Source
901
Figure 2. Signal intensities as a function of source gas flow rate (a) and volatile standard concentration (b) for 2,4-lutidine and
DMMP using TM-VaPI with a 20 W DC discharge. Data points and standard deviation error bars represent the average extracted TIC
areas for three consecutive peak traces per point in (a) and five consecutive peak traces per point in (b)
reactions. The high intensity of reactant protonated water clus-
ters persisted for helium flow rates over 2.0 LPM, but measured
analyte signal rapidly disappeared with flow rates beyond
1.8 LPM helium. This result was the consequence of a now
positive pressure at the mesh (≥15 mmHg), which effectively
negated suction and suppressed transmission of desorbed neu-
trals. Additionally, the flood of hot gas into the cross union
when using these higher helium flow rates also heated the
mesh, likely accelerating some sample evaporation into the
environment, thereby contributing to signal loss. Newer, more
sensitive mass analyzers with vacuum systems less robust to
high helium gas loads could potentially operate VaPI at far
lower flow rates or use reduced cell assembly dimensions,
thereby maximizing vacuum draw for improved sample uptake
and ion transmission without much compromise to ionization
efficiency.
the afterglow gas while mixing in the cross union, disrupting
the gas flow profile and vacuum equilibrium to cause tempo-
rary fluctuations in the total ion chronogram. With heating rope
wrapped around the cross union and programmed to 275 °C,
the extracted ion chronogram shapes for each standard ap-
peared more smooth and narrow (Figure 3) compared with
TIC peaks at lower temperatures, with the standard deviation
decreasing more than 2-fold. However, this improvement came
at the expense of lower sensitivity for the volatile analyte, with
the average integrated signal intensity for DMMP being re-
duced by almost half. The signal decrease in response to
excessively heating the cell is easily rationalized. Higher tem-
peratures accelerated sample desorption from the mesh while
simultaneously reducing the net vacuum pull. A near total loss
of cross union vacuum pressure (–2 mmHg) was actually
measured at 1.6 LPM and 275 °C, indicating signal under these
The VaPI linear range was also examined via concentration
series for each standard, Figure 2b. The increasing signal
intensity deviated from linearity after the concentration range
spanned three orders of magnitude, with the protonated ion
signals beginning to plateau at around 100 μM (see Supple-
mentary Figure S4 for this trend forecast using total ion signal
with AC/DC plasmas.) Interestingly, the protonated water pop-
ulation was not fully consumed even at higher analyte concen-
trations, an observation suggesting that fluid dynamics and
ionization reaction kinetics rather than reactant ion depletion
are likely the limiting factors. It is reasoned that evaporative
losses from the slowly aspirating micro-droplets are more
significant at higher volatile concentrations, and dynamic range
linearity may be restored by either amplifying VaPI vacuum
pressure or sealing off the sample mesh after spotting. The
%RSD for volatile standards in Figure 2 still never exceeded
8%, and was under 2% for the majority of data points.
Where sensitivity was not an issue, that sampling reproduc-
ibility could be further improved by controlling cell tempera-
ture. Material aspirated through the sample mesh partially cools
Figure 3. Extracted ion peak traces for 1 mM DMMP at
1.6 LPM helium flow rate with (red) and without (blue) the cross
union heated to 275 °C. (Baseline/time axis for superimposed
consecutive red traces were altered to fit blue trace)

902
J. D. Keelor et al.: VaPI Source
conditions may have depended almost solely on analyte diffu-
sion into the cell. As will be seen in the next section, such
temperature effects also manifest themselves as differences in
performance between AC and DC plasma power regimes.
Since setting the cross union temperature to match the temper-
ature of the discharge gas minimizes hysteresis during sam-
pling, the cross union temperature was set to 200 °C where
vacuum draw was preserved.
discharge, with the net water ion signal consistently equal or
only marginally higher. Even with VaPI parameters optimized,
the largest (H2OnH)+ signal advantage witnessed for AC mode
was <2.5-fold intensity over DC mode, still significantly less
than the order of magnitude higher concentration that could be
expected from metastable atom spectroscopy. Interestingly,
protonated water clusters were observed even when all cross
union openings of the VaPI ion source were sealed off from the
atmosphere. This finding suggests reactant ions were formed in
the discharge from plasma gas impurities and not just He*
Penning ionization of ambient air molecules. More substantive
conclusions may be reached by comparing plasmas in AC/DC
power regimes using even higher quality gases while control-
ling system temperature. Ultimately, since the DC discharge
offered more stable operation and simpler I/V control, it was
selected over AC mode for continued experiments.
Comparison of AC and DC VaPI Operation Modes
A recent study involving high-frequency DBD plasmas and
point-to-plane glow discharges presented spectroscopic evi-
dence suggesting the abundance of helium metastables varies
considerably for different plasma ion source geometries, and
between AC or DC operation modes [41]. Metastable atom
concentration within a plasma was seen to scale proportionally
with plasma power, with lower wattage (10–15 W) DBDs
generating He* populations up to an order of magnitude larger
than those observed for higher power FAPA-type DC dis-
charges. In principle, a greater number of plasma metastable
species should be followed by a higher population of reactant
ions in the AP interface and possibly higher ionization efficien-
cy. Given the reproducible, semiquantitative capabilities of
TM-VaPI, AC and DC discharges were tested in order to
investigate the downstream implications of the spectroscopic
findings, and to determine any performance advantage.
At first glance, the plasma discharges appeared visually
distinct for a given mode; the AC discharge existing as a pink,
focused plasma and the DC discharge as a more diffuse, white
glow. Signal trends observed as a function of helium flow rate
and concentration were almost identical between both power
regimes (Supplementary Figures S5a, b). For comparison, an-
alyte ion intensity ratios for the discharge modes (DC/AC) are
tabulated in Supplementary Figure S5c. Signal intensity grad-
ually shifted in favor of the DC discharge from ≥0.75 times to
over 1.5 times the total AC ion count as the helium flow rate
was increased. Additionally, the signal gain for the DC dis-
charge slowly diminished from around 2 to 1.3 times the AC
ion intensity as analyte concentration increased. The overall
lower signal for the AC plasma in most cases is difficult to
rationalize based on the previously measured metastable den-
sities. Apart from plasma visual appearance, the major observ-
able difference between the two discharges was the VaPI cell
temperature. In Supplementary Figure S6, thermal images of
the source recorded using different helium flow rates showed
temperatures approximately 20 °C higher for AC versus DC
operation, as might be expected because of the 2–3 mA larger
plasma current calculated for the AC discharge. Recalling the
effect of raised gas and cross union temperatures on signal
described previously using this configuration, it is likely that
this small temperature disparity between power modes was
predominantly responsible for decreased ion transmission and
lower volatile signal intensity in AC mode.
TM-VaPI Analysis of Solids
Based on the characterization experiments with volatile stan-
dards, the TM-VaPI ion source is potentially well-suited to MS
applications that require rapid qualitative and semiquantitative
analysis, such as composition screening, reaction monitoring,
and molecular profiling. Using the default transmission mode
geometry, the ion source was amenable to sampling solids
without protracted analyte extraction/dissolution steps. Frag-
ment pieces from a variety of pharmaceutical tablets were
placed on the cross union sample mesh and a stable signal trace
could be achieved (Supplementary Figure S7). Absolute ion
intensity and relative distribution for tablet active ingredients
was again found to depend on both helium flow rate and
plasma temperature, with less detriment than when sampling
volatiles. Desorption and ionization could be effectively tuned
to favor different target analytes by raising the cross union
temperature. Cross union temperature was maintained at ap-
proximately 275 °C, where thermal desorption for heavier
compounds from a solid matrix was efficient, but below the
temperature limit where poor fluid dynamics and vacuum loss
occurred. For a few select cases, it was found that higher
sensitivity was obtained when organic solvent was spotted on
the mesh immediately after removing the larger tablet
fragments.
The spectrum for a single component drug tablet containing
acetaminophen (500 mg) is shown in Supplementary Figure
S8a. Interestingly, both the molecular ion and protonated spe-
cies were detected. The afterglow of the 20 W DC plasma
(~200 °C) was sufficient to thermally desorb the compound
and provide ample signal, but a noticeable 20%–25% increase
in total acetaminophen ion intensity was observed when
heating the cross union to 275 °C, Supplementary Figure
S8b. As expected, the elevated cross union temperature served
to enhance desorption off the mesh and cross union interior
walls, resulting in a stable [M+H]+ intensity but now a more
abundant [2M+H]+ species. A similar effect was seen for
Doralgine tablets containing both caffeine (25 mg) and
noramidopyrine (120 mg), and example spectra are shown here
On average, the protonated water cluster population detect-
ed for the AC plasma was comparable to that of the DC mode

J. D. Keelor et al.: VaPI Source
903
of the tablet pieces and addition of methanol in microliter
aliquots to the mesh screen, the protonated lumefantrine mono-
mer with its chlorine isotopes appeared at m/z = 528 and
m/z=530, accompanied by more intense peaks in the low mass
range. These peaks are associated with M+˙ fragments of
lumefantrine formed by cleavage of the amine moiety and are
identified based on accurate mass as [C8H18N]+
(m/z= 128.1449) and [C9H20N]+ (m/z=142.1604). The obser-
vation of M+˙ ions in addition to [nM+H]+ is not entirely
unexpected, considering the analyte direct exposure to the
highly energetic afterglow reactive species.
in Figure 4. Without external heating, the spectrum featured
primarily the [M+H]+ ions of both ingredients, with caffeine
being the most abundant, Figure 4a. Again, M+˙ molecular ions
of both compounds were also observed. Raising the cross
union temperature to 275 °C had a dramatic effect, where the
signal for caffeine was quickly dwarfed and the protonated
monomer and dimer peaks of the more concentrated
noramidopyrine ingredient dominated the spectrum with an
~4-fold signal increase, Figure 4b. The smaller peaks neigh-
boring the noramidopyrine signals suggest the inclusion of
dipyrone and/or metamizole analogues as lesser tablet constit-
uents, having formulas matching a metamizole protonated
fragment ion [C13H17N3O+H]+ (m/z = 232.1427) and
noramidopyrine/dipyrone fragment dimer complex
[(C13H16N3O)(C12H15N3O)]+ (m/z=447.2500). For both tab-
lets, the increased abundance of dimer species is attributed to a
rise in the overall analyte vapor pressure with higher VaPI cell
temperatures and also partial cooling/clustering of the volatil-
ized analyte in the transfer capillary.
Antimalarial Coartem tablets containing higher mass
artemether (20 mg) and lumefantrine (80 mg) ingredients were
sampled as well, employing additional sample treatment to
improve analysis. Compounds in the artemisinin family are
prone to fragmentation during both electrospray and plasma
ionization, and in Supplementary Figure S8c, the characteristic
ion fragments for artemether are readily seen at m/z= 163, 221,
267, and 281 as previously identified in the literature [42].
Heating the cross union to 275 °C only shifted the relative
intensities of the observed species in greater favor of fragments
at m/z=221 and a lesser fragment at m/z=253 (spectrum not
shown), but otherwise did not alter the total ion signal distri-
bution. Detection of the heavier lumefantrine ingredient re-
quired addition of organic solvent to the mesh, Supplementary
Figure S8d. It is speculated that the solvent vapor acted as a sort
of extractant, similar to a codistillation process, where the
boiled solvent wetted tablet residue and freed material conden-
sate adhering to the mesh or cross union walls. Upon removal
LA-VaPI Characterization
Typical LA-plasma ion source configurations reported in the
literature make use of an open format where fluid dynamic
effects at the mass spectrometer inlet result in significant ion
transmission losses. To investigate if the more controlled sam-
pling capabilities of VaPI could further enhance LA-plasma
ionization approaches, we tested a LA-VaPI configuration, as
depicted in Figure 1b. Performance of the vacuum-assisted LA-
VaPI source design compared with an optimized open air
configuration (Figure 1c) is presented in Figure 5. An amino
acid standard mixture was analyzed by laser ablation of micro-
liter droplets deposited between Teflon spots on a glass slide.
Tentative peak assignments were made for 15 of the 17 mixture
components. Judging by the spectral distribution, ionization
appeared to be decided by compound hydrophobicity and
enthalpy of vaporization rather than gas-phase basicity, favor-
ing amino acids with higher surface activity and evaporation
rates over those with the greatest side-chain proton affinity. The
exception relative to the other undetected basic and hydrophilic
amino acids was proline, primed to dominate the spectrum
owing to a higher predicted volatility over species like histidine
and a rigid structure better able to withstand the energy of glow
discharge ionization compared with the more fragile arginine
[43]. The amino acid ion populations observed were very
similar across spectra for both source configurations, but signal
Figure 4. Mass spectra for a Doralgine drug tablet fragment collected by TM-VaPI using 20 W DC discharge and 1.6 LPM helium (a)
and with cross union heated to 275 °C (b). Spectra were derived from 30 s averages of the TIC signal for each tablet

904
J. D. Keelor et al.: VaPI Source
The Omni slide planar substrate was substituted with a quarter-
inch glass capillary ampoule filled with several hundred mi-
croliters of sample solution. Keeping the cross union tempera-
ture below 250 °C, the sample-loaded ampoule was inserted at
the bottom cross union joint and held in place by system
vacuum. With this sampling strategy, uptake of aerosols gen-
erated in the ablation plume was maximized, allowing heavier
ejecta to be recycled upon recapture in the capillary reservoir.
Figure 6a depicts the LA-VaPI spectrum obtained from an
aqueous PEG solution, showing uniform ion intensity and
Figure 5. Mass spectra of 2.5 mM amino acid standard in
0.1 N HCl sampled by laser ablation and plasma ionization
using either the LA-VaPI scheme from Figure 1b (a) or a tradi-
tional open AP interface arrangement shown in Figure 1c (b).
Standard mixture was ablated from 10 μL droplet on Omni slide
substrate. Spectra are an average of full time until droplets were
consumed (~20 s each). Laser wavelength, frequency, and
effective energy were 2940 nm, 10 Hz, and ~1 mJ. Optimal
helium flow rate for (a) was 1.6 LPM and 1.3 LPM for (b) with
the cross union heated to ~200 °C
intensities were superior using the LA-VaPI scheme shown in
Figure 1b. Total signal intensity was ≥2.5 times higher for all
amino acids detected (Figure 5a) and the protonated reactant
water clusters were almost completely consumed. In contrast,
many of the reactant ions were seen to survive in the spectrum
for the open interface LA-plasma source arrangement,
Figure 5b. As observed previously using a VaPI configuration,
ambient air suctioned through the inlet partly cooled the plasma
gas. This effect in combination with the enclosed nature of the
VaPI ion source also helped reduce spectral complexity in the
low mass range, signified by fewer amino acid fragment ions
appearing under 100 Da (Figure 5b).
Figure 6. Investigation of matrix effects using LA-VaPI with
20 W DC discharge and 1.6 LPM helium. Mass spectra for
~4 mg mL–1 PEG standard (Mn ~400) in 100% aqueous solution
(black trace) and 50:50 methanol/water (red trace) (a). Mass
spectrum of 2.5 mM TAP in deionized water sampled from
200 μL of solution in ampoule (black trace) or 10 μL droplet on
glass substrate (dotted gray trace) (b). Table includes signal
intensity of ions detected for 2.5 mM TAP in aqueous solution
as a function of KCl molar concentration ablating from ampoule.
Unless otherwise specified, ablation was performed from
200 μL solution in capillary ampoule held by vacuum in the
cross union heated to ~200 °C. Laser wavelength, frequency,
and effective energy were 2940 nm, 10 Hz, and ~1 mJ. Spectra
and bar graph intensities were extracted from 1 min average of
stable TIC signal
Following these LA-VaPI experiments, an alternative sam-
pling approach was tested with the goal of further increasing
ablation plume collection and/or controlling evaporative loss.

J. D. Keelor et al.: VaPI Source
905
polymer unit spacing. Interestingly, both analyte signal inten-
sity and peak distribution were enhanced by addition of organic
solvent to the aqueous matrix solution (red dotted trace). Not
only was the net signal significantly higher for polymer
analytes ablated from the mixed solvent system, but the
[M+H]+ peak distribution more accurately reflected the PEG
polydispersity (Mn =395–410). It is conjectured that the higher
organic solvent content facilitated aerosol plume formation by
changing the droplet size distribution [44] and the degree of
analyte enrichment, which in turn promoted more facile
desolvation/ionization in the afterglow region. Experiments
with methanol concentrations in the 20%–90% range showed
largely similar results.
LA-VaPI also proved relatively resistant to the negative
effects associated with high salt concentrations in the sample
medium. For example, LA-VaPI was used to analyze solutions
containing both potassium chloride and 2,4,6-
triamidopyrimidine (TAP), a nucleobase analogue involved in
noncovalent self-assembly structures with cyanuric acid that
are stabilized by cationic salts in aqueous solution [45]. For
KCl concentrations up to 40 mM, the average TAP signal was
relatively unaffected (inset table, Figure 6b), with a moderate
signal enhancement as salt concentrations increased. Similar to
the effect of organic solvent on PEG signal, concentrated salt
ions in the aqueous matrix may influence analyte solubility and
droplet distribution to promote volatilization.
mixtures [49]. In these systems, the products of interest are
often not the most abundant, and product loss can propagate
during sample cleanup with chromatography or extraction
steps. Successful MS analysis of such mixtures necessitates
sensitive instrumentation and efficient sampling measures that
are robust to matrix effects. LA-VaPI was used to monitor
natural and alternative nucleobase products formed in formam-
ide and pyrazine model prebiotic reactions. The synthetic path-
ways postulated for the formamide reaction have been
reviewed in the literature [48, 50, 51], and the reaction pathway
for the predicted pyrazine products is outlined by Scheme 1 in
supporting information. Basic sample preparation involved
collecting portions of the crude product or fractions of the
desalted mixture (see the Experimental section for details),
followed by resuspension in DI water and filtration to remove
large particulates prior to laser ablation from the sample am-
poule. In Supplementary Figure S9a, the nucleobases predicted
to form in the formamide reaction, including purine, adenine,
and cytosine, were all identified for a reaction run to comple-
tion (120 h at 160 °C). Analyzing the same reaction after only
72 h, purine was still seen as the prevailing nucleobase, but the
spectrum was also dominated by low mass species involving
the volatile formamidine precursor, and adenine and cytosine
were far less abundant. Supplementary Figure S9b shows a
spectrum for a reaction mixture containing 2-aminopyrazine
products. The desired 5(6)-dinydroxypropyl-2-aminopyridine
compound at m/z= 170 was barely observable above the noise
threshold, but appreciable amounts of other pyrazine products
were detected, including the protonated monomers of
5-methyl-2-pyrazinamine and 5-amino-2-pyrazineethanol at
m/z = 110 and m/z = 140, respectively. A possible reaction
byproduct of the glycine amidine reagent was also copiously
present and identified with the formula [C4H7N5]+ based on
accurate mass (m/z= 125.0702).
Mass spectra showing the two TAP analytes detected using
the different LA-VaPI sampling approaches are overlaid in
Figure 6b. The protonated TAP monomer and an additional
TAP derivative with accurate mass m/z=140.0583 and formula
[C4H6N5O]+ (alternatively denoted as [TAP-H+O]+) are pres-
+
ent in varying proportions. Reactant ions including N2 ,
O+/O2 , and NO+ have been commonly reported for ambient
+
helium discharge sources like FAPA [5] and PADI [19]. Al-
though far less abundant than the reactant (H2O)nH+ series, the
peak intensity for NO+ was observed to increase (more than
double) in the background spectrum using the enclosed am-
poule sampling method because of enhanced diffusion of at-
mospheric N2 and O2 into the discharge. This same exposure to
the plasma corresponded to an increase of the TAP byproduct
ion (m/z=140) relative to the protonated monomer (m/z=126).
Again, this effect was not an anomaly. As witnessed previously
for 2,4-lutidine, a minor byproduct identified as [M-H+O]+ was
seen at m/z=122 using TM-VaPI, and an NO+ adduct of 2,4-
lutidine was also detected at m/z = 137 (not shown) when
sampling from the LA-VaPI ampoule. It appears that conjugat-
ed cyclic amines of the pyridine/pyrimidine structure are prone
to byproduct formation when sampling with VaPI via plasma
oxidation.
Conclusions
The VaPI source is a highly modular design featuring comple-
mentary sampling techniques, readily adaptable to a number of
sampling scenarios and directly compatible with modern in-
strument inlets incorporating glass transfer capillaries. Acquir-
ing reproducible, quantitative signals with TM-VaPI or LA-
VaPI depends on a balance between source gas temperature
and helium flow rate, which ultimately govern the vacuum
pressure dynamics within the cross union and determine the
available reactant ion population. To this effect, differences in
analyte signal intensity observed between equivalent power
AC and DC discharges were linked to subtle variations in
temperature between power regimes rather than differences in
active metastable concentration. As demonstrated, the VaPI
source is amenable to analyzing both solutions and solids, but
both transmission and laser ablation modes can benefit from
organic solvent addition during sampling to facilitate aerosol
extraction and volatilization. This initial investigation of VaPI
promises to inspire additional modalities in future work, such
Application of LA-VaPI to Reaction Product
Screening
Model prebiotic reactions studied in origins of life chemistry,
such as the Miller-Urey experiment [46, 47] or the formamide
reaction [48], generate highly complex, seemingly intractable

906
J. D. Keelor et al.: VaPI Source
serum metabolomic fingerprinting. J. Am. Soc. Mass Spectrom. 21, 68–
75 (2010)
17. Jones, C.M., Fernandez, F.M.: Transmission mode direct analysis in real
time mass spectrometry for fast untargeted metabolic fingerprinting. Rapid
Commun. Mass Spectrom. 27, 1311–1318 (2013)
18. Kratzer, J., Mester, Z., Sturgeon, R.E.: Comparison of dielectric barrier
discharge, atmospheric pressure radiofrequency-driven glow discharge and
direct analysis in real time sources for ambient mass spectrometry of acet-
aminophen. Spectrochim. Acta B Atom. Spectroscop. 66, 594–603 (2011)
19. McKay, K., Salter, T.L., Bowfield, A., Walsh, J.L., Gilmore, I.S., Bradley,
J.W.: Comparison of three plasma sources for ambient desorption/
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20. Chan, G.C.Y., Shelley, J.T., Wiley, J.S., Engelhard, C., Jackson, A.U.,
Cooks, R.G.: Elucidation of reaction mechanisms responsible for afterglow
and reagent-ion formation in the low-temperature plasma probe ambient
ionization source. Anal. Chem. 83, 3675–3686 (2011)
as TM-VaPI combined with solid phase micro-extraction sam-
ple meshes, LA-VaPI from thin-layer chromatography sub-
strates, direct infusion extractive spray (ES)-VaPI for online
reaction monitoring, and microchip surface acoustic wave neb-
ulization (SAWN)-VaPI.
Acknowledgments
The authors acknowledge support for his study by the NSF and
NASA Astrobiology Program under the NSF Center for Chem-
ical Evolution (CHE-1004570).
21. Song, L., Gibson, S.C., Bhandari, D., Cook, K.D., Bartmess, J.E.: Ioniza-
tion mechanism of positive-ion direct analysis in real time: a transient
microenvironment concept. Anal. Chem. 81, 10080–10088 (2009)
22. Danhelova, H., Hradecky, J., Prinosilova, S., Cajka, T., Riddellova, K.,
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23. Gilbert-Lopez, B., Geltenpoth, H., Meyer, C., Michels, A., Hayen, H.,
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mass spectrometry for pesticide testing: a comparison with atmospheric
pressure chemical ionization and electrospray ionization. Rapid Commun.
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