No.

44452

Smart Notes
I know that triple quadrupole ICP-MS is the way to
go forward in trace elemental analysis, but what
do I need to know when looking at this technology
more closely?

Since its commercial introduction in the 1980’s, ICP-MS has revolutionized trace
elemental analysis by providing fast, multielement detection for a wide range
of applications. The development of collision/reaction cell (CRC) technology
to overcome polyatomic interferences helped to dramatically reduce detection
limits for key elements such as chromium and arsenic. Nevertheless, challenges
still remained, particularly in the areas of intense polyatomic interferences,
doubly charged ion signals and isobaric isotope overlaps. With the advent of
triple quadrupole ICP-MS instrumentation, many of these challenges can now
be overcome.

Triple quadrupole mass spectrometers were introduced in the early 1980´s to

allow structural elucidation based on fragmentation of a parent ion and analysis
of its daughter ions. Soon after, the advantage of triple quadrupole systems for
quantitation based on single reaction monitoring (SRM) and multiple reaction
monitoring (MRM) was recognized and is nowadays applied in a variety of
different applications. The first commercially available instrument combining
an inductively coupled plasma (ICP) ion source with a triple quadrupole mass
spectrometer (or ICP-MS/MS) was introduced in 2012, and from there on,
the technology has been increasingly accepted, first by research focused
laboratories and more recently by routine analysis laboratories. This is especially
true following the development of dramatically simplified instrument designs and
Safe and
compliant gas easier method set up software.
handling for H₂
and NH₃

QCell CRC with 4 dedicated mass flow

controllers for a variety of cell gases

Mass filtering quadrupole situated

axially in front of the CRC
What is the advantage of using a triple quadrupole
ICP-MS compared to a single quadrupole instrument?
Single quadrupole based ICP-MS systems like the
Thermo Scientific™ iCAP™ RQ ICP-MS are the current
standard in many routine laboratories. Modern generation
instruments feature innovative CRC technology, which
allows analysis of all elements in a single mode based on
kinetic energy discrimination (KED), and hence facilitates
rapid and sensitive multi-elemental analysis1. However,
there are cases where special interferences may not be
fully resolved. Table 1 shows an overview of typical
interferences that cause difficulties with single quadrupole
ICP-MS systems and shows how triple quadrupole ICP-MS
systems, such as the Thermo Scientific™ iCAP™ TQ ICP-MS
can help to overcome these interferences.
Table 1. Overview of different interference types and options for removal with either single quadrupole or triple quadrupole ICP-MS

Type of Technique to remove

Example
interference Single Quadrupole ICP-MS Triple Quadrupole ICP-MS
40
Ar Ar on Se
40 + 80 +

40
Ar16O+ on 56Fe+ KED, often combined with selection of a less
Polyatomic 40
Ar35Cl+ on 75As+ interfered, but also less abundant isotope,
interferences 35
Cl16O+ on 51V+ e.g. 77Se or 57Fe
40
Ar 63Cu+ on 103Rh+ Differential reactivity to reaction
gases (e.g. O2, NH₃ or H₂)
Fe on Ni
58 + 58 +
Isobaric following mass separation before
Rb+ on 87Sr+
87
Mathematical correction
interferences the CRC
204
Hg+ on 204Pb+
150
Nd++ on 75As+ Not possible without full knowledge of
Other 160
Gd++ on 80Se+ which interferences are present (in which
interferences 138
Ba++ on 69Ga+ case, use mathematical correction)

• Some argon based polyatomics are very abundant
(e.g. on 40Ar40Ar+ on 80Se+) and can only be suppressed at
the expense of a severe reduction in detection sensitivity.
Other polyatomic interferences can cause elevated
backgrounds where low level detection is required and
hence lead to false positive results.
• Many elements share isotopes with identical mass
number (corresponding to the total number of protons
and neutrons). These so-called isobaric interferences
can, in most cases, be easily avoided by selection of
a non-interfered isotope or the use of mathematical
correction equations.
• Elements with low 2nd ionization potential (such as
alkaline earth or rare earth elements) can form ions with
two positive charges. Such ions would appear at half of
their nominal mass (as quadrupole mass spectrometers
separate isotopes according to their mass to charge
ratio, or m/z), and therefore may cause unexpected
interferences.
For most elements, there is at least one isotope
available that is free from isobaric interferences (with the
exception of indium), that can be selected for quantitative
measurement. However, the available isotope is not
always attractive for analysis when, for example isotopic
abundance (a factor influencing the achievable detection
sensitivity), is taken into account. Triple quadrupole
ICP-MS systems can permit access to key isotopes that
are inaccessible to single quadrupole systems (such
as 80Se instead of the less abundant 77Se) or remove
interferences which are irremovable with single quadrupole
systems. However, for many elements, there will be no
difference in the way a measurement is performed.
In short, triple quadrupole ICP-MS does not necessarily
offer better detection limits for all elements, but rather
provides significant improvements for key analytes in many
application areas.
What is different for a triple quadrupole mass ICP-MS in TQ mode
spectrometer when having an ICP ion source as
[AsO]+
91
compared to an LC-MS triple quad?
There is a fundamental difference between triple
150
Nd⁺⁺, 150Sm++

quadrupole mass spectrometers using ICP as an ionization

source compared to systems commonly used for LC-MS Q3 set to
product ion mass
applications, such as pesticide screening and quantitation.
For identification and quantitation of a given compound in
a triple quadrupole mass spectrometer, a given precursor
ion is isolated in Q1 and fragmented in a collision cell.
Q2 filled with 75
As⁺ 91
[AsO]+
One or more product ions are subsequently isolated in
reactive gas (O₂)
Q3, and signal intensity is recorded for a single transition
(selected reaction monitoring, SRM) or multiple transitions
(multiple reaction monitoring, MRM) for a given parent ion. 150
Nd⁺, 150Sm⁺,
Due to the potentially numerous combinations of carbon,
91
Zr⁺
Q1 set to
hydrogen, oxygen and nitrogen, there is a high number of analyte mass

molecules fitting to a particular m/z ratio typically resolved

in a quadrupole. This is the typical reason why different
transitions need to be monitored to confirm the presence of
75
As+
a given compound.
SRM Mode for LC-MS
In contrast to this, ICP´s are high energy ion sources that
Q2
cause a complete decomposition of the sample. For the RF Only + Ar
Q1 Set Q3 Scanning
majority of elements, especially metals, singly charged
atomic ions (i.e. [M]+) are produced with a yield of close
to 100%. One of the challenges in ICP-MS is to remove
different types of interferences, potentially appearing at
a similar mass to charge range as the analyte. In these
cases, selective ion molecule reactions can be used in
order to create new product ions. These new product
ions are now different in mass and are separated in an
additional mass filtration step. Figure 1 shows the different
Q3 m/z
operating principles of triple quadrupole LC-MS and
ICP-MS systems. Figure 1. Operation principle for ICP-MS and LC-MS systems with
triple quadrupole mass spectrometers
How does interference removal work on a triple A few examples for elements benefitting from triple
quadrupole ICP-MS? quadrupole interference removal are shown in Table 2.
With a triple quadrupole system, different reactivity of the
Table 2. Selection of analytes and interference combinations
analyte and interference towards different reactive gases is resolved by triple quadrupole ICP-MS
used for interference removal. For example, arsenic reacts Reactive Product
with oxygen to form 75As16O⁺, detectable at m/z 91, through Analyte Interference Mode
gas ion
a “mass shift” reaction. Common interferences, including 31
P 14
N16O1H O₂ 31
P16O Mass shift
polyatomics such as 40Ar35Cl⁺ and doubly charged rare 32
S 16
O O 16
O₂ 32
S O
16
Mass shift
earth elements like 150Nd++, do not react in the same
way and are separated in Q3, despite reaching the CRC.
51
V 35
Cl16O O₂ V O
51 16
Mass shift

Other ions of lower or higher mass (e.g. 91Zr+ or 150Nd⁺) 48

Ti 48
Ca, 32S16O NH₃ 114
[TiNH(NH₃)₃] Mass shift
are filtered out in the first mass filtering quadrupole, so 40
Ar Cl,35
75
As O₂ 91
As16O Mass shift
don’t even reach the CRC. However, the analyte will not
40
Ca35Cl
always react to form a new product ion. In some cases, 40
Ar40Ar,
80
Se O₂ 80
Se16O Mass shift
160
Gd++
interference removal is based on the chemical reaction
of the interference, using a so called “on mass reaction”.
87
Sr 87
Rb O₂ 87
Sr16O Mass shift
Examples for interference removal using triple quadrupole 111
Cd 95
Mo O 16
O₂ 111
Cd On mass
ICP-MS is shown in Figure 2. 137
Cs 137
Ba O₂ 137
Cs On mass
172
Yb 156
Gd16O NH₃ 172
Yb On mass
Scan modes typically applied for structural elucidation
195
Pt 179
Hf16O O₂ 195
Pt On mass
of molecules, such as precursor ion scans, product ion
scans, or neutral loss scans are not applied in ICP-MS
204
Pb 204
Hg NH₃ 204
Pb On mass
since the chemical reactions and hence the resulting
product ions used for interference removal are generally
much easier to interpret.

[AsO]+
91
Cd+
111

150
Nd⁺⁺, 150
Sm ++

40
Ar 35CI+
MoO₂⁺
Q3 set to product Q3 set to product ion
ion mass (m/z 91) mass (m/z 111)

75
As+ is converted
Q2 filled with reactive Q2 filled with Mo16O⁺ forms higher oxide
95
into 75As16O⁺
gas (O₂) reactive gas (O₂) products such as MoO₂

150
Nd⁺, 150Sm⁺,
91
Zr⁺
95
Mo⁺
Q1 set to analyte mass Q1 set to analyte
(m/z 75) mass (m/z 111)

75
As+, 150Nd++, 150Sm++, 40Ar35CI+ Cd+, 95Mo16O+
111

“Mass Shift” “On Mass”

Figure 2. Interference removal for 75As (mass shift reaction) and 111Cd (on mass reaction) using the iCAP TQ ICP-MS
Does this have any implications on the design?
Yes, because far fewer combinations of ions need to be
removed in an ICP-MS compared to an LC-MS system,
this allows for a difference in the design. As per the IUPAC
definition of a tandem mass spectrometer, the iCAP TQ
ICP-MS features “two transmission quadrupole mass
spectrometers in series, with a (non-selecting) RF-only
quadrupole (or other multipole) between them to act as a
collision cell”2. However, in contrast to LC-MS systems, a
short quadrupole is used for the initial selection of a given
m/z ratio before the collision cell.
This allows the design of a true triple quadrupole based
ICP-MS system with the same footprint and size as the
iCAP RQ ICP-MS single quadrupole instrument. There are
important benefits associated with this different design of
an ICP triple quadrupole mass spectrometer:
• The system has a compact footprint and will easily fit into
space limited laboratories
• A smaller quadrupole mass filter can be integrated
into the vacuum system of a single quadrupole mass
spectrometer and hence eliminates the need for an
additional turbo pump
• A more straightforward design of the mass spectrometer
simplifies instrument construction and reduces downtime
for maintenance
The iCAP TQ ICP-MS features the same innovative design
elements as the iCAP RQ ICP-MS, for example, the
RAPID lens, effectively deflecting the ion beam vertically,
and removing unwanted material such as neutrals before
entering Q1 or the CRC. As with the iCAP RQ ICP-MS, this
creates a maintenance free mass spectrometer.
Is the first quadrupole of the iCAP TQ ICP-MS limited
in its resolution capabilities?
The first quadrupole of the iCAP TQ ICP-MS is fully capable
of achieving a resolution of less than 1 amu where required.
The resolution of a quadrupole mass filter is proportional
to the number of alternating potential changes an ion
experiences, as can be seen in the equation below:
fxl
R ∝ N=
VZ
Where R = Mass resolving power
N = Number of RF cycles experienced by the ion
f = RF frequency
l = Quadrupole length
VZ = Initial ion velocity along the quadrupole axis
This again depends on other factors, such as the length of
the device and the frequency in which polarity changes are
applied, as well as the initial ion velocity. As can be seen
from the equation, a reduction in length of the device can
be compensated for by other factors.
What resolution is required in order to resolve all
potentially interfering ions in the first quadrupole?
As always in mass spectrometry, an increase in resolution
goes hand in hand with a reduction in detection sensitivity.
In the case of interference removal using a triple
quadrupole ICP-MS system, there are some important
considerations required to evaluate the impact of the
exposure of other ions to reactive gases in the CRC:
• Ions of higher mass must be removed before the CRC as
they potentially do not react (or at least not quantitatively)
with the reactive gas used for a mass shift reaction of the
analyte. In this case, the intended mass of the product
ion may again be interfered. For example, although
molybdenum reacts with O₂ to form MoO (and other
higher oxides), there may be residual 96Mo⁺ interfering
with mass shifted 80Se (96[80Se16O]⁺).
• Ions of lower mass must be removed to avoid other
elements (equally or even more reactive with a particular
gas) also reacting and forming ions with the same mass
to charge ratio. There can be side reactions with other
ions in the ion beam, which may seriously bias results.
For example, the analysis of selenium in presence of
nickel can be dramatically affected through the formation
of cluster ions of Ni with H₂O⁺ or H₃O⁺ ions³.
• Ions with adjacent mass need to be removed to avoid the
formation of product ions with less abundant isotopes
of the reactive gases. For example, when analyzing
75
As16O⁺, full elimination of 74Se is key to avoid the
potential formation of 74Se17O⁺, having the same nominal
mass as 75As16O⁺. Although 16O is the most abundant
isotope of oxygen (99.76%), the presence of 17O (0.04%)
and 18O (0.20%) must not be neglected, especially for
cases where an element has another isotope of lower
mass, as they would naturally react in the same way.
The determination of isotope ratios is a good way to
prove the full elimination of interferences caused by
adjacent mass4, 5.
The negative impact through possible and unwanted side
reactions is further illustrated for the analysis of 80Se⁺ using
a mass shift reaction. Figure 3 shows which ions with both
lower and higher mass could impact the accurate detection
of the target isotope if they are not fully eliminated in the
first quadrupole:

Figure 3. Impact of other ions for the detection of 80Se

What is Intelligent Mass Selection (iMS)? Table 3 highlights the benefit of using Intelligent Mass
Whereas for some analytes, such as 31P and 32S, there are Selection over a fixed resolution of 1 amu for a variety
potentially many interferences, and a resolution of less than of elements typically analyzed using triple quadrupole
1 amu for Q1 is absolutely required, this is not the case modes. In all cases, full removal of potentially occurring
for the majority of elements typically analyzed in regulated interferences is achieved.
methods. For most analytes, a flexible and dynamic way
Table 3. Sensitivity improvements through the use of iMS in triple
to adjust the resolution of the first quadrupole can be quadrupole based measurement modes
used and leads to a benefit in sensitivity. With Intelligent Relative sensitivity [%]
Mass Selection (iMS), the iCAP TQ ICP-MS features an Analyte
1 amu iMS
innovative control for mass filtration in the first quadrupole,
which intelligently controls ion transmission through Q1 for 48
Ti as [TiNH(NH₃)₃]
114
169
every analyte, leading to complete removal of all potentially 51
V as 51V16O 151
interfering ions with lower or higher mass. At the same 75
As as 75As16O 212
time, iMS improves the transmission in order to increase 80
Se as Se O 80 16
100 181
sensitivity where it is needed – for measurement modes
utilizing triple quadrupole technology for interference
111
Cd as Cd
111
178
removal on key analytes. 138
Ba as 138Ba16O 196
238
U as 238U16O₂ 384
What is the benefit of Reaction Finder?
The effective use of triple quadrupole ICP-MS requires
knowledge of the right reaction pathway for each analyte
or its interferences (in order to select the right isotope,
which may be different from a single quadrupole system),
the right mode (SQ vs. TQ), collision/reaction gas
(KED, O₂, NH₃ etc.) and product ion (where applicable).
In order to enable all laboratory personnel to fully leverage
interference removal, the Reaction Finder Method
Development Assistant was developed. Reaction Finder
is integrated in the graphical user interface of the
Thermo Scientific™ Qtegra™ Intelligent Scientific Data
Solution™ Software, and returns optimized measurement
conditions for each element selected by the user. The
applied selection criteria are based on the lowest detection
limit and assure full removal of interferences. All settings in
Reaction Finder can be modified by the user, e.g. addition
of other measurement modes, selection of other reactive
gases or product ions etc., so that the ability to perform
method development or optimization is not restricted for
experienced operators.
Analyte and Automatic process through Interference free
Interference Reaction Finder detection
m/z m/z
SQ vs. TQ Reactive Gas Product Ion
Mass
Can a triple quadrupole ICP-MS better reduce the
impact of high signals in adjacent masses?
In some cases, samples may contain high concentrations
of certain elements that have isotopes with masses close
to the mass intended for analysis, for example, when
manganese is analyzed in blood, which contains high
amounts of iron (54Fe and 56Fe ‘surround’ 55Mn). In general,
the ability of a mass spectrometer to fully resolve the
contribution of a neighboring signal on the observed
m/z ratio is described by the term abundance sensitivity.
For example, an abundance sensitivity of 1 ppm
(i.e. 1 x 10 -6) corresponds to a false positive signal of
1 cps at an m/z ratio of m+1 or m-1, caused by the
presence of a signal at an m/z of m of 1,000,000 cps.
With triple quadrupole ICP-MS systems, abundance
sensitivity is defined for the combined mass spectrometer
(Q1 and Q3 set to filter for the same ion) and is determined
in standard mode (with no gas in the CRC). Although
it seems evident that abundance sensitivity should be
improved by several orders of magnitude through the
use of a second quadrupole mass filter (e.g. 10 -6 from Q1
multiplied by 10 -6 from Q3), it is in fact normally only slightly
improved (by one or two orders of magnitude) if the initial
characteristics of an ion remain unchanged (e.g. kinetic
energy or direction of travel), as a result of, for example,
using a collision gas in the CRC. While it is true for some
applications highly intense signals of other elements may
cause problems, for some applications there are additional
polyatomic species as well, in which case the use of triple
quadrupole technology can drastically improve the results.
For example, the determination of 129I (a long-lived
radioactive isotope of iodine), which is screened for in
areas that have been historically exposed to radioactive
material released as a result of nuclear power station
accidents. Although the main interference on m/z 129 is
isobaric overlap from xenon (a common impurity in argon
gas), its detection can also be affected by the formation of
127
IH₂ (natural iodine is monoisotopic at m/z 127), especially
when a low amount of 129I needs to be detected in the
presence of even moderate amounts of natural iodine.
Both interferences can be reduced significantly when
using oxygen in the CRC. When used in combination with
mass filtration in the first quadrupole, there is a double-
improvement effect of improving abundance sensitivity and
polyatomic interference suppression. Table 4 shows the
improved efficiency of background reduction on m/z
129 achieved by triple quadrupole operation in comparison
to operation in single quadrupole mode.
Table 4. Reduction of the impact of a high concentration of 127I on
the detection of 129I at ultra-trace levels when analyzing a sample
containing up to 200 mg·L-1 natural iodine. In both cases, O₂ was used
as a reactive gas.
Signal @ 127I [CPS] Signal @ 129I [CPS]
Single quadrupole mode
1 x 10⁹ 3000
Triple quadrupole mode
2 x 10⁹ <2
As can be seen from the data, even differences of up to
nine orders of magnitude (e.g. detection of 10 pg·L-1 of
129
I in presence of 100 mg·L-1 natural iodine) are possible
using a triple quadrupole ICP-MS instrument, whereas the
equivalent analytical range for a single quadrupole system
is lower by at least three orders of magnitude.
Which reactive gases do I need?
The use of different reactive gases has been described for
triple quadrupole ICP-MS. Apart from standard gases such
as He, O₂ or H₂, other gases may be used for selective
chemical reactions in the CRC, such as NH₃, N₂O, CH₃F
or SF₆. Whilst there is almost no limitation to the use of
these gases on the iCAP TQ ICP-MS (given appropriate
safety installations in the laboratory as per country specific
requirements), in most cases special reactive gases only
provide moderate improvements for a single analyte, or a
limited subset of analytes. Therefore, especially for routine
orientated laboratories, the benefits of using gases other
than He or O₂ will be limited. For research orientated
laboratories, a larger selection of reactive gases on
installation of the instrument (e.g. inclusion of H₂ and NH₃
with He and O₂) is recommended.
Conclusion
Whereas single quadrupole ICP-MS systems are perfectly
suited for most routine applications, triple quadrupole
systems such as the iCAP TQ ICP-MS can deliver better
results in many cases. This is due to the higher selectivity
available through the use of reactive gases for removal
of isobaric or doubly charged interferences. Additionally,
sensitivity can be increased in triple quadrupole modes
as compared to KED. For some elements, this permits
significantly improved detection limits. At the same time,
modern software solutions reduce the potential complexity
in method development, so that all laboratories are able
to leverage the full potential of state-of-the-art ICP-MS
technology.
References
1. Smart Note 44415, Thermo Fisher Scientific
2. IUPAC Standard Definitions of Terms Relating to Mass Spectrometry; K. Murray and co.,
Pure Appl. Chem., 2013, Vol. 85, No. 7, pp. 1515-1609
3. Application Note 43404, Thermo Fisher Scientific
4. Application Note 44365, Thermo Fisher Scientific
5. Application Note 44387, Thermo Fisher Scientific

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