5th Edition

Handbook of ICP-QQQ
Applications using theAgilent 8800 and 8900
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Foreword
Agilent Technologies launched its 8800 Triple Quadrupole
ICP-MS (ICP-QQQ) at the 2012 Winter Conference on Plasma
Spectrochemistry in Tucson, Arizona, USA.
By the time the first ICP-QQQ was launched, ICP-MS had already been aroundfor almost three decades and was widely praised for its low limits of detection.
In fact, it was considered as the technique-par-excellence for multi-element(ultra-)trace analysis in a wide variety of fields. However, spectral interferenceswere still causing concern in some applications. Significant progress had been
made in providing ICP-MS users with adequate tools to cope with spectral
overlaps compared to the early commercial instruments introduced in 1983.
By using a double-focusing sector-field mass spectrometer instead of aquadrupole filter for mass analysis, many spectral interferences can be resolved,
but this approach requires expensive instrumentation. Quadrupole-based
instruments could be equipped with a multipole-based collision/reaction cell
(CRC), which alleviated spectral interferences to a significant extent, for instance,
by using a non-reactive collision gas such as helium to slow down polyatomic
interfering ions to a larger extent than the atomic analyte ions, such that theformer could be selectively discriminated against on the basis of their lower
kinetic energy. The analytical community first saw Agilent’s 8800 ICP-QQQ
instrumentation as an improved version of a quadrupole-based ICP-MS equippedwith a CRC. But the unique applications being performed using Agilent ICP-QQQ
instruments installed in hundreds of laboratories across industry, research andacademia clearly demonstrates that it is much more than that.
In Agilent’s ICP-QQQ, an octopole CRC is preceded by an additional quadrupole,enabling double mass selection, i.e. before the ions enter the CRC and afterwards.
When the first quadrupole is used as an ion guide only, the ICP-QQQ system
can be used as a “traditional” quadrupole-based ICP-MS instrument. This mode
could be useful for carrying out routine analysis not significantly challenged byspectral interferences. When operated in tandem or MS/MS mode, however,the double mass selection only allows the analyte ion and the interfering ion(s)with the same mass-to-charge ratio to enter the CRC; all ions with a different
mass-to-charge ratio are removed at this stage. Consequently, the control overthe processes in the cell is greatly improved as the reaction of other (e.g. matrix)
ions with the cell gas no longer hinders the desired reaction process. In case ofa mass-shift reaction—i.e. chemical conversion of the analyte ion into a reaction
product ion that can be measured interference-free at another mass-to-charge
ratio—the absence of other ions at the new “location” of the product ion in themass spectrum is guaranteed. As a result, interesting but challenging elements,
such as S and P in biochemical applications, As and Se in environmental andfood applications, or Si in nanoparticle applications can be easily assayed,interference-free.

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Profiting from the analytical advantages offered by MS/MS functionality, some
ICP-QQQ users have demonstrated a larger degree of creativity by using very
reactive gases such as NH3 or CH3F in the CRC and monitoring reaction productions at much higher mass-to-charge ratios than could be adequately exploitedpreviously. Although this might initially sound complicated, the ICP-QQQ’s
software offers tools like product ion scanning, precursor ion scanning anddifferential mass scanning that provide the user with a clear insight into thereactions proceeding in the cell and allow the product ion that will provide thebest, often unprecedented limits of detection to be easily identified. This levelof freedom and ease of use leads to a situation in which every type of spectral
overlap – whether caused by a polyatomic ion, doubly charged ion or isobaric
nuclide – can be successfully overcome. Moreover, ICP-QQQ users have also
been charmed by the additional advantages provided by this type of
instrumentation, such as the unparalleled abundance sensitivity, which is anadded benefit of double mass selection.
In 2016, the 8800 ICP-QQQ was replaced by the Agilent 8900 ICP-QQQ series.
While maintaining the performance to resolve spectral interferences, this second
generation ICP-QQQ instrument provides enhanced sensitivity and a fasterdetector system with a 100 µs minimum dwell time. The latter feature is of
specific importance in single-nanoparticle analysis, a rapidly emerging type of
application, and in handling fast transient signals, such as those generated via
laser ablation systems equipped with ultra-fast ablation cells.
In my opinion, ICP-QQQ has not only fulfilled its initial promises, but has greatly
surpassed the anticipations of the diverse community of ICP-MS users.
Frank Vanhaecke
Department of Analytical Chemistry
Ghent University, Belgium
www.analchem.ugent.be/A&MS

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Table of contents
Title

Elements

Page

Introduction to Agilent Triple Quadrupole ICP-MS

8

Semiconductor

12

Process chemicals
Ultrapure process chemicals analysis by ICP-QQQ with hot plasma conditions

Multiple

13

Determination of ultratrace elements in SEMI Grade 5 high purity hydrogen peroxide

Multiple

19

Automated analysis of semiconductor grade hydrogen peroxide and DI water using ICP-QQQ

Multiple

22

Ultratrace measurement of calcium in ultrapure waterCa

31

Ultratrace measurement of potassium and other elements in UPW using ICP-QQQ in cool
plasma/reaction mode

Multiple

34

Ultralow level determination of phosphorus, sulfur, silicon, and chlorine using the Agilent 8900
ICP-QQQ

P, S, Si, Cl

37

Direct analysis of trace metal impurities in high purity nitric acid using ICP-QQQ

Multiple42

Direct determination of V, Cr, Ge, and As in high-purity 20% hydrochloric acid

Multiple49

Analysis of trace metal impurities in high purity hydrochloric acid using ICP-QQQ

Multiple

52

Determination of Ti, V, and Cr in 9.8% sulfuric acid

Ti, V, Cr

62

Determination of trace elements in ultrapure semiconductor grade sulfuric acid using theAgilent 8900 ICP-QQQ in MS/MS mode

Multiple

64

Multielement nanoparticle analysis of semiconductor process chemicals using spICP-QQQ

Multiple70

Silicon wafer analysis: Determination of phosphorus and titanium in a high silicon matrix

P, Ti

77

Analysis of ultratrace impurities in high silicon matrix samples by ICP-QQQ

Multiple80

Analysis of sulfur, phosphorus, silicon, and chlorine in N-methyl-2-pyrrolidone

S, P, Si, Cl

86

Analysis of silicon, phosphorus, and sulfur in 20% methanol

Si, P, S

90

Automated ultratrace element analysis of isopropyl alcohol with the Agilent 8900 ICP-QQQ

Multiple

93

Analysis of nanoparticles in organic reagents by Agilent 8900 ICP-QQQ in spICP-MS mode

Fe

104

Analysis of 15 nm iron nanoparticles in organic solvents by spICP-MS

Fe

109

GC-ICP-QQQ achieves sub-ppb detection limits for hydride gas contaminants

P, Ge, As, S

112

Determination of trace impurities in electronic grade arsine by GC-ICP-QQQ

Si, P, Ge, S

116

Silicon wafers

Organic chemicals

Semiconductor gases

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Title

Elements

Materials

Page
122

Rare earth oxides
Direct measurement of trace rare earth elements in high purity REE oxides

REEs

123

Removal of MH+ interferences in refined REE material analysis

REEs

126

Direct analysis of trace REEs in high purity Nd2O3

REEs

129

Direct determination of challenging trace rare earth elements in high purity lanthanide REE oxides

REEs

132

Arsenic measurement in cobalt matrix using MS/MS mode with oxygen mass-shift

As

135

Analysis of ultratrace impurities in high purity copper using the Agilent 8900 ICP-QQQ

Multiple

138

Determination of sulfur, phosphorus, and manganese in high purity iron

S, P, Mn

145

The benefits of improved abundance sensitivity with MS/MS for trace elemental analysis
of high purity metals

Multiple

148

Ultratrace copper analysis in a semiconductor grade organometallic titanium complex

Cu

152

Analysis of 10 nm gold nanoparticles using the high sensitivity of the Agilent 8900 ICP-QQQ

Au

155

High sensitivity analysis of SiO2 nanoparticles using the Agilent 8900 ICP-QQQ

Si

158

Accurate determination of TiO2 nanoparticles in complex matrices using the Agilent 8900 ICP-QQQ

Ti

161

MetalsNanomaterials

Environmental

168

Routine soil analysis using the Agilent 8800 ICP-QQQ

Multiple

169

The accurate measurement of selenium in reference materials using online isotope dilution

Se

172

ICP-QQQ with oxygen reaction mode for accurate trace-level arsenic analysis in complex samples

As

176

Avoidance of spectral overlaps on reaction product ions with O2 cell gas: comparison ofquadrupole ICP-MS and ICP-QQQ

Ti

181

Removal of complex spectral interferences on noble metal isotopes

Ru, Rh, Pd, Ag,
Os, Ir, Pt, Au

184

Analysis of platinum group elements (PGEs), silver, and gold in roadside dust using triple
quadrupole ICP-MS

Ru, Rh, Pd, Ag,
Os, Ir, Pt, Au

190

Direct analysis of ultratrace rare earth elements in environmental waters by ICP-QQQ

REE

199

Solving doubly charged ion interferences using an Agilent 8900 ICP-QQQ

Ca, Sc, Zn, As,Se

205

Removal of REE++ interference on arsenic and selenium

As, Se211

Removal of molybdenum oxide interference on cadmium

Cd

215

Rapid analysis of radium-226 in water samples by ICP-QQQ

Ra

218

Feasibility study of fluorine detection by ICP-QQQ

F222

HPLC-ICP-MS/MS: fluorine speciation analysis

F

225

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Title

Elements

Foods and consumer products

Page
228

Elemental analysis
Benefits of the Agilent 8900 ICP-QQQ with MS/MS operation for routine food analysis

Multiple

229

Routine elemental analysis of dietary supplements using an Agilent 8900 ICP-QQQ

Multiple

241

Accurate and sensitive analysis of arsenic and selenium in foods using ICP-QQQ to remove
doubly-charged REE interferences

As, Se250

Analysis of TiO2 nanoparticles in foods and personal care products by single particle ICP-QQQ

Ti

254

Accurate analysis of trace mercury in cosmetics using the Agilent 8900 ICP-QQQ

Hg

263

Sulfur isotope fractionation analysis in mineral waters using an Agilent 8900 ICP-QQQ

S

269

Fast analysis of arsenic species in infant rice cereals using LC-ICP-QQQ

As

275

High throughput determination of inorganic arsenic in rice using hydride generation-ICP-QQQ

As

282

Fast determination of inorganic arsenic (iAs) in food and animal feed by HPLC-ICP-MS

As

286

Multielement analysis and selenium speciation in cattle and fish feed using LC-ICP-QQQ

Multiple295

Arsenic speciation analysis in apple juice using HPLC-ICP-MS with the Agilent 8800 ICP-QQQ

As

304

Speciated arsenic analysis in wine using HPLC-ICP-QQQ

As

312

Fast analysis of arsenic species in wines using LC-ICP-QQQ

As

319

Simultaneous iodine and bromine speciation analysis of infant formula by HPLC-ICP-MS

I, Br

326

Determination of pesticides using phosphorus and sulfur detection by GC-ICP-QQQ

P, S

333

Speciation

Petrochemicals

336

Determination of P, Si and S in acid digested lubricating oil using the Agilent 8800 triple
quadrupole ICP-MS

P, Si, S

337

Accurate sulfur quantification in organic solvents using isotope dilution mass spectrometry

S

342

Determination of chloride in crude oils using an Agilent 8900 ICP-QQQ

Cl

346

Single nanoparticle analysis of asphaltene solutions using ICP-QQQ

Fe, Mo351

Gas chromatographic separation of metal carbonyls in carbon monoxide with detection using
the Agilent 8800 ICP-QQQ

Ni, Fe358

Geology and geochemistry363

Lead isotope analysis: removal of 204Hg isobaric interference on 204Pb using ICP-QQQ MS/MS
reaction cell

Pb

364

Fractionation of sulfur isotope ratio analysis in environmental watersS

368

Measurement of Sr/ Sr isotope ratios in rocks by ICP-QQQ in mass-shift mode

Sr

372

Direct strontium isotopic analysis of solid samples by LA-ICP-MS/MS

Sr

378

Resolution of 176Yb and 176Lu interferences on 176Hf to enable accurate 176Hf/177Hf isotope
ratio analysis using an Agilent 8800 ICP-QQQ with MS/MS

Hf

382

87

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86

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Title

Elements

NuclearPage390

Analysis of radioactive iodine-129 using MS/MS with O2 reaction mode

I

391

Feasibility study on the analysis of radioisotopes: Sr-90 and Cs-137

Sr, Cs395

Determination of trace 236U as UOO+ using ICP-QQQ O2 mass-shift methodU

398

Measurement of neptunium in the presence of uranium: benefits of low abundance sensitivity
and oxygen reaction mode

Np, U

401

Direct analysis of zirconium-93 in nuclear site decommissioning samples by ICP-QQQ

Zr

404

Clinical research

410

Manganese analysis in whole blood: expanding the analytical capabilities of ICP-MS

Mn

411

Measurement of titanium to assess joint replacements

Ti

415

Measurement of selenium in the presence of Gd-based MRI contrasting agents

Se

418

Evaluation of the elemental content of a single cell using fast time-resolved analysis (TRA) ICP-MS

Mg, P, Fe, Zn

421

Life science

428

Simultaneous quantitation of peptides and phosphopeptides by capLC-ICP-QQQ

P, S

429

Analysis of selenoproteins in rat serum using HPLC-ICP-QQQ

Se

432

Absolute quantification of intact proteins in snake venom by capLC-ICP-QQQ

S435

Pharmaceutical

441

Quantitative analysis of active pharmaceutical ingredients using heteroatoms as elemental labels

S, P, Cl

442

Fast and accurate absolute-quantification of proteins and antibodies using ID-ICP-QQQ

S446

Determination of diclofenac and its related compounds using RP-HPLC-ICP-QQQ

Cl

449

Characterization of rare earth elements used for radiolabeling applications by ICP-QQQ

REE

456

Glossary

464

For Research Use Only. Not for use in diagnostic procedures.
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Introduction to Agilent Triple Quadrupole ICP-MS
Agilent introduced the world’s first triple quadrupole ICP-MS(ICP-QQQ) in 2012.
The Agilent 8800 ICP-QQQ signaled a major advance in ICP-MS technology andredefined performance for trace element analysis. Compared to existing
quadrupole ICP-MS instruments, the 8800 ICP-QQQ offered significant analyticalbenefits across many applications in both industry and academic researchlaboratories. Building on this success, the Agilent 8900 ICP-QQQ was launchedfour years later, in 2016.

Configuration of Agilent’s ICP-QQQ instrumentation
According to IUPAC (term 538 from the 2013 Recommendations), a triple
quadrupole mass spectrometer is a “Tandem mass spectrometer comprising
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.”
The cell containing the ion guide—the Octopole Reaction System (ORS) in thecase of Agilent ICP-QQQ—can be pressurized with a collision or reaction gas toallow the selective attenuation of potential interfering ions.
In MS/MS operation, where both quadrupoles are operated as unit mass filters,
ions at the target analyte mass are selected by the first quadrupole (Q1) andpassed to the ORS cell, where the analyte ions are separated from overlapping
interfering ions. The resulting product ions that emerge from the cell are thenfiltered by the second quadrupole (Q2) before being passed to the detector.
This configuration releases the full potential of reaction cell gas methods toresolve spectroscopic interferences including isobaric and doubly-charged
interferences, as well as polyatomic ion overlaps.
As a result, ICP-QQQ can determine a wider range of analytes at much lower
concentrations with greater reliability and higher confidence.

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Figure 1. Cutaway diagram of the Agilent 8900 ICP-QQQ.

9

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ICP-MS/MS technology
Ti+(NH)(NH 3)4 spectrum; ∆m = 2.1 u of Q1
1000000
900000800000Signal (cps)700000600000500000400000300000200000100000
0
127

128

129

130

131

132

133

134

135

Q2

Ti+(NH)(NH 3)4 spectrum; ∆m = 0.7 u of Q1
1000000
900000800000Signal (cps)700000600000500000400000300000200000100000
0
127

128

129

130

131

132

133

134

135

Q2

Figure 2. Ti + (NH)(NH3) 4 product ion spectrumof five Ti isotopes obtained with NH3 cell gas
mode: 46Ti (8.25%), 47 Ti (7.44%), 48Ti (73.72),
49
Ti (5.41%), and 50Ti (4.29%). A Ti standard
solution was analyzed using ICP-QQQ with NH3
cell gas. Top: Q1 was set at Δm = 2.1 u. Bottom:
spectrum was acquired with Q1 set at Δm =0.7 u.

10

The tandem MS configuration of Agilent ICP-QQQ instruments – with two fully
functioning mass filters, one either side of the ORS cell – allows unprecedented
control over the ions that enter the collision/reaction cell (CRC). Q1 rejects all
non-target masses/elements, ensuring more consistent reaction processes in
the CRC, even when the sample composition varies. Precise mass selection by
the first quadrupole, Q1, is crucial to the accurate analytical performancein MS/MS mode. For reliable, consistent control of reaction processes,
Q1 must allow only ions at the target mass-to-charge ratio (m/z) to pass into
the cell. Inefficient mass filtering would cause results to be compromised byinterferences arising from non-target ions entering the cell. To ensure the mosteffective mass filtering and the best quality data, Agilent ICP-QQQ instruments
use the same hyperbolic quadrupole mass spectrometer for Q1 and Q2.
Both quadrupoles are placed in the high vacuum region to ensure optimum massfiltering. This arrangement allows both quadrupoles to operate at unit mass
resolution and low abundance sensitivity while maintaining high transmission
and sensitivity.
The impact of varying Q1 mass filter performance is illustrated in the comparisonof product ion spectra for Ti–NH3 cluster ions shown in Figure 2. The product ion
spectrum (top) was obtained using Q1 settings that provide compromised mass
resolution, with Q1 passing all masses in a 2.1 u window. This wider Q1 mass
window allowed non-target ions to enter the cell, so the reaction processes andproduct ions formed were not under control. In this case, the overlapping ionswere derived from different NH3 clusters formed from the other Ti isotopes.
For example, when 49Ti is the target analyte but Q1 fails to exclude 48Ti from thecell, 48Ti(NH2)(NH3)4+ forms in the cell and overlaps 49Ti(NH)(NH3)4+ at m/z 132.
In contrast, the Ti isotopic pattern (bottom) was obtained with Q1 set to operatewith mass resolution of 0.7 u; i.e. as a true mass filter providing genuine MS/MS
operation. The Ti-NH3 product ions fit the expected Ti isotopic pattern perfectly,
confirming that each Ti isotope entered the cell in isolation to react with the NH3cell gas, i.e. 48Ti+ + NH348Ti(NH)(NH3)4+. The results show that if themass resolution of Q1 is greater than 0.7 u, precise analysis of the specific target
analyte ion/isotope is impossible. Without true MS/MS operation (bothquadrupoles operating with unit mass resolution), analytical results acquired forany analyte could be compromised because unexpected reaction product ionscan be formed and cause overlap on the target product ion.

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Second-generation triple quadrupole ICP-MS:
the Agilent 8900 ICP-QQQ
Building on the success of the 8800, the 8900 ICP-QQQ provides performanceand productivity improvements to address a wider range of applications:– Double the sensitivity of the 8800: users of the 8900 can achieve lower
detection limits or improve matrix robustness by diluting samples, without
degrading detection capability. Note that the sensitivity of the Agilent 8900
Semiconductor configuration ICP-QQQ now exceeds 1Gcps/ppm(1,000,000,000 counts per second per ppm).
– Axial Acceleration on the 8900 Advanced Applications and Semiconductor
configurations controls the energy of ions in the cell. This increases thesensitivity in reaction cell mode and reduces potential product ion overlaps
due to slow moving ions.
– Lower contribution from instrumental background: the 8900 ICP-QQQ is
designed and manufactured to control background signals arising from the
instrument itself. This attention to detail allows users to achieve even lower
BECs than the 8800. The DL specification of the 8900 Advanced Applications
and Semiconductor configurations for sulfur and silicon is < 50 ppt.
– 0.1 ms dwell time: the 8900 ICP-QQQ uses a new fast detector with fast time
resolved analysis (TRA) capability suitable for the accurate analysis of single
nanoparticles (sNPs). High speed is combined with effective interference
removal and specialized software to process the signals and reveal theparticle size and size distribution.
With true triple quadrupole performance, the advanced features and therobustness of the 8900 ICP-QQQ make it a supremely powerful and flexible
multi-element analyzer. Agilent’s Triple Quadrupole ICP-MS instruments willcontinue to open up new possibilities for analysts, especially for the mostchallenging applications.

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Semiconductor
Title

Page

Process chemicals
Ultrapure process chemicals analysis by ICP-QQQ with hot plasma
conditions

13

Determination of ultratrace elements in SEMI Grade 5 high purity
hydrogen peroxide

18

Automated analysis of semiconductor grade hydrogen peroxide and DI
water using ICP-QQQ

22Ultratrace measurement of calcium in ultrapure water

31

Ultratrace measurement of potassium and other elements in UPW using
ICP-QQQ in cool plasma/reaction mode

34

Ultralow level determination of phosphorus, sulfur, silicon, and chlorine using
the Agilent 8900 ICP-QQQ

37

Direct analysis of trace metal impurities in high purity nitric acid using
ICP-QQQ

42

Direct determination of V, Cr, Ge, and As in high-purity 20% hydrochloric acid49

Analysis of trace metal impurities in high purity hydrochloric acid using
ICP-QQQ

52

Determination of Ti, V, and Cr in 9.8% sulfuric acid

62

Determination of trace elements in ultrapure semiconductor grade sulfuric
acid using the Agilent 8900 ICP-QQQ in MS/MS mode

64

Multielement nanoparticle analysis of semiconductor process chemicals
using spICP-QQQ

70

Silicon wafers
Silicon wafer analysis: Determination of phosphorus and titanium in a highsilicon matrix

77

Analysis of ultratrace impurities in high silicon matrix samples by
ICP-QQQ

80

Organic chemicals
Analysis of sulfur, phosphorus, silicon, and chlorine in N-methyl-2-pyrrolidone

86

Analysis of silicon, phosphorus, and sulfur in 20% methanol

90

Automated ultratrace element analysis of isopropyl alcohol with the Agilent
8900 ICP-QQQ

93Analysis of nanoparticles in organic reagents by Agilent 8900 ICP-QQQ in
spICP-MS mode

104

Analysis of 15 nm iron nanoparticles in organic solvents by spICP-MS

109

Semiconductor gases

12

GC-ICP-QQQ achieves sub-ppb detection limits for hydride gas contaminants

112

Determination of trace impurities in electronic grade arsine by GC-ICP-QQQ

116

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Ultrapure Process Chemicals Analysis by ICP-QQQ
with Hot Plasma Conditions
Authors
Kazuhiro Sakai and
Yoshinori Shimamura
Agilent Technologies, Inc.

Meeting single- and sub-ppt guideline levels for ASTM/SEMI
elements in ultrapure water using an Agilent 8900 ICP-QQQ
Introduction
Contamination control is critical in semiconductor device fabrication (FAB)
facilities (1). Contaminants may be introduced via the wafer substrate, or thechemicals and reagents used during the manufacturing process. Impurities—
particularly metal ions and particles – adversely affect device performanceand production yield, so FABs use the highest purity reagents and follow strict
protocols to control contaminants during the manufacturing process.
Ultrapure water (UPW) is used throughout the wafer fabrication processincluding in the RCA standard cleaning (SC-1/SC-2) procedure to remove
chemical contaminants and particulate impurities from the wafer surface.
UPW is one of the most critical process chemicals for contamination-control as
the water is in direct contact with the wafer surface at many stages ofmanufacturing. Any impurities present in the UPW could directly affect theelectrical properties of the finished device, for example, by reducing dielectric
breakdown voltage.
ASTM International and Semiconductor Equipment and Materials International(SEMI) publish standards regarding the specifications for semiconductor
process chemicals and reagents, including UPW. ASTM D5127-13, 2018 and
SEMI F63-0521, 2021 provide guidance for the quality of UPW needed to
produce devices with linewidths < 0.045 microns (2, 3). Both standards requiredetection limits (DLs) of less than 0.5 ppt (boron has a higher limit of 15 ppt)
and background equivalent concentrations (BECs) less than 1 ppt (50 ppt for B).
The semiconductor industry standard method for monitoring trace element
contaminants is ICP-MS, with laboratories increasingly switching to triple
quadrupole ICP-MS (ICP-QQQ or ICP-MS/MS) for its superior detection limits.
The Agilent 8900 ICP-QQQ is a tandem MS instrument, which uses MS/MS
operation to further improve the performance of the technique compared tosingle quadrupole ICP-MS instruments.
The 8900 ICP-QQQ meets the electronic and semiconductor industry’s need fortrace and ultratrace element analysis due to its high sensitivity, low background,and interference removal capabilities. The 8900 has the flexibility to operate inseveral modes to give optimum performance across different applications.
For example, semiconductor labs often use cool plasma conditions to achieve thelowest BECs and DLs for interfered elements and easily ionized elements (EIEs).
Cool plasma reduces EIE backgrounds and suppresses the formation of intense
argon-based interferences such as Ar+, ArH+, and ArO+, allowing low-level analysisof 40Ca, 39K, and 56Fe, respectively.

13

Cool plasma gives excellent results in low matrix samples, such as UPW, H2O2,
HNO3, and HCl (4). However, high matrix samples, such as silicon and metal
digests, are difficult to run using cool plasma due to the higher level of matrix
suppression. More robust, hot plasma (low CeO/Ce ratio) conditions are preferred
for such sample types. For labs wishing to use only hot plasma, the 8900
ICP-QQQ can be fitted with an optional skimmer cone and m-lens that provide
optimum performance in hot plasma conditions. In a recent study, an 8900 fittedwith the optional m-lens was used to determine 38 elements in two digested
silicon samples prepared at 10 and 100 ppm Si (5). The m-lens and the skimmer
cone that it is paired with have an optimized geometry that minimizes EIE
backgrounds when using normal, hot plasma conditions. Using m-lens, the 8900
was able to measure all required elements at ppt levels in the Si matrix without
using cool plasma.
The 8900 with m-lens can also be used to analyze ultratrace elements in low
matrix semiconductor samples – such as UPW – using only normal, hot plasma
conditions. In this study, hot plasma was combined with no gas mode and twocell gas modes to resolve spectral interferences, achieving single- or sub-ppt
BECs and DLs for all analytes.

Experimental
Reagents and sample preparation
UPW (Organo Corp, Tokyo, Japan) was acidified to 0.1% with high purity 68%
HNO3 (TAMAPURE AA-100, Japan). Acidification ensures that elements are
retained as soluble ions in solution, although adding acid can potentiallycontribute to the level of contamination.
Calibration standards
The 8900 ICP-QQQ was calibrated using the method of standard addition (MSA),
as is typical for the analysis of high-purity semiconductor samples. A mixed
multi-element standard (SPEX CertiPrep, NJ, US) was prepared and spiked into
the UPW to give standard additions at 5, 10, 20, and 40 ppt.
Instrumentation
The 8900 Semiconductor Configuration ICP-QQQ was fitted with standard
components including a PFA-100 MicroFlow nebulizer, quartz spray chamber,quartz torch with 2.5 mm injector, and Pt sampling cone. The standard s-lens
was replaced with an optional m-lens (part number G3666- 67500) and optional
Pt-tipped, Ni-based skimmer cone for m-lens (part number G3666-67501).
The 8900 includes the ORS4 collision/reaction cell (CRC) and two quadrupoles(Q1 and Q2), one either side of the CRC, enabling double mass selection(MS/MS). Q1 rejects all nontarget ions before they enter the cell, allowing only
analyte ions and on-mass interference ions to pass to the cell. The analyte andinterfering ions can then be separated using predictable, consistent, andreproducible reaction chemistry (6, 7). Q2 then ensures that only the analyte ions(on-mass mode) or analyte-product ions (mass-shift mode) pass to the detector,
free of interferences.

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Agilent ICP-MS MassHunter instrument control software for the 8900 provides
simple method setup to measure analytes in different cell gas modes using asingle multitune acquisition. In this analysis no gas mode, ammonia reaction
mode (using a mixture of ammonia and hydrogen cell gases), and oxygen
reaction mode were used to remove interferences using a combination of
on-mass and mass-shift measurement. During data acquisition, the cell gases
and measurement modes were switched automatically, giving a fast andautomated analysis using the best mode for each analyte. Instrument acquisitionand operating parameters are given in Table 1.
Table 1. Agilent 8900 ICP-QQQ operating conditions.
No GasNH3+H2O2

Acquisition Parameters
Scan Mode

MS/MS

Replicates (standards)

3

Replicates (blank)

10

Integration Time per Mass (s)1.0PlasmaRF Power (W)1600

Sampling Depth (mm)8.0

Nebulizer Gas (L/min)

0.70

CeO+/Ce+ (%)

2

Cell
He Flow Rate (mL/min)

-

1

-

H2 Flow Rate (mL/min)

-

2

-

*NH3 Flow Rate (mL/min)-

2.0 (20%)-

O2 Flow Rate--

0.45 (30%)

KED (V)

3

–10

–7

*Mix of 10% NH3 in 90% He

Results and discussion
Calibration curves
Four representative MSA calibration curves for K, Ca, Fe, and Ni in UPW are
shown in Figure 1. No background subtraction or blank correction was
performed. The four analytes are representative of the EIEs (K), elements withsevere background interferences (Ca), elements of particular importance for thesemiconductor industry (Fe), and elements that could indicate contaminationfrom the ICP-MS interface (Ni). All the SEMI element calibrations showed
excellent linearity (r > 0.999) and low BECs. This performance confirms thehigh sensitivity of the 8900 and the effectiveness of the reaction cell methodwith m-lens to control elemental backgrounds and resolve interferences.

15

Figure 1. Representative MSA calibration plots for K, Ca, Fe, and Ni in UPW.

BECs and DLs
BECs and DLs for 26 elements were calculated automatically by the ICP-MS
MassHunter software (Table 2). BECs below 0.5 ppt and DLs below 0.3 ppt wereobtained for 25 SEMI elements, easily meeting the limits for UPW specified by
ASTM and SEMI. The higher specified limits for boron (50 ppt BEC and DL of 15ppt) were also easily achieved (measured BEC of 1.11 ppt and DL of 1.18 ppt).
Backgrounds are highly dependent on water quality, but the BEC achieved in thiswork was a factor of 50 lower than the SEMI guideline, easily meeting current
industry requirements. Critical metallic (conductive) contaminants such as Al, Cr,
Fe, Co, Ni, Cu, Zn, and Mo were measured with BECs and DLs substantially below
0.5 ppt, again easily meeting industry requirements.
The results, which are also shown in Figure 2, demonstrate the suitability of the8900 ICP-QQQ using hot plasma for the analysis of ultratrace contaminants inhigh purity semiconductor process chemicals.

Figure 2. BECs and DLs for SEMI specified elements in UPW measured using the 8900 ICP-QQQ
with hot plasma conditions.
16

Conclusion
The study has demonstrated the suitability of the Agilent 8900 ICP-QQQ with
optional m-lens for the measurement of ultratrace-level contaminants in
low-matrix semiconductor reagents such as UPW. The m-lens ensured thatbackground signals for the EIEs – K, Na, Ba, and Li – were minimized, allowing
all 26 SEMI-critical elements to be measured at ppt levels using hot plasma
conditions (CeO/Ce ratio < 2%). All potential spectral interferences were resolvedby operating the 8900 in MS/MS mode using a single multitune method with nogas and two reaction gas modes.
Standard addition calibration curves from 0 ppt to 40 ppt concentration range
showed excellent linearity and sensitivity for all elements. The low BECs showedthat the method successfully removed all spectral interferences, including
argon-based interferences that typically form under hot plasma conditions.
The 8900 method resolved the intense interferences such as Ar+, ArH+, and ArO+,
allowing sub-ppt analysis of 40Ca, 39K, and 56Fe, respectively.
The BECs and DLs for all elements were well below the recommendations set by
ASTM and SEMI for the quality of UPW related to semiconductor-industry
manufacturing at < 0.045 m linewidths.
Table 2. Agilent 8900 ICP-QQQ DLs and BECs and ASTM/SEMI requirements for 26 elements in UPW.
Measured in UPW
by 8900

ASTM D5127-13(2018)
Requirements

SEMI F63-0521(2021)
Requirements

BEC (ppt)

BEC (ppt) MDL (ppt)

AnalyteTune ModeLi

No gas

7

0

0

<1

<1

B

No gas

11

1.18

1.11

<50

<50

15

Na

No gas

23

0.26

0.23

<1

<1

0.5

Mg

NH3+H2

24

0.05

0.02

<1

<1

0.5

Al

NH3+H2

27

0.11

0.06

<1

<1

0.5

K

NH3+H2

39

0.12

0.13

<1

<1

0.5

Ca

NH3+H2

0.17

0.38

<1

<1

0.5

Ti

O2

0

0

<10

<1

0.5

V

NH3+H2

51

0.04

0.01

<10

<1

0.5

Cr

NH3+H2

52

0.24

0.38

<1

<1

0.5

Mn

NH3+H2

55

0.08

0.09

<10

<1

0.5

Fe

NH3+H2

56

0.23

0.36

<1

<1

0.5

Co

NH3+H2

59

0.05

0.01

<1

<1

0.5

Q1

Q2

40
48

64

DL (ppt)

BEC (ppt)

0.5

Ni

NH3+H2

60

0.14

0.07

<1

<3

1.6

Cu

NH3+H2

63

0.22

0.24

<1

<1

0.5

Zn

NH3+H2

64

0.15

0.06

<1

<1

0.5

As

O2

0.23

0.02

<1

<1

0.5

Sr

NH3+H2

88

0.01

0.002

<1

<1

0.5

Mo

NH3+H2

98

0.04

0.01

<1

<1

0.5

Cd

NH3+H2

114

0.04

0.004

<10

<1

0.5

Sn

NH3+H2

118

0.12

0.03

<10

<1

0.5

Sb

NH3+H2

121

0.05

0.01

<1

<1

0.5

Ba

NH3+H2

0.03

0.003

<1

<1

0.5

W

O2

0.20

0.30

<1

<1

0.5

75

91

138
184

216

Pt

O2

195

0.20

0.40

<1

<1

0.5

Pb

NH3+H2

208

0.05

0.005

<1

<1

0.5

BEC and DL values of “0” are reported for Li and Ti because zero counts per
second were measured for these elements in all 10 replicates of the blank UPW.
17

References

18

1.

Applications of ICP-MS: Measuring Inorganic Impurities in Semiconductor
Manufacturing, Agilent publication 5991-9495EN

2.

ASTM D5127-13, Standard Guide for Ultra-Pure Water Used in the Electronics
and Semiconductor Industries, https://www.astm.org/Standards/D5127.htm

3.

SEMI F63 - Guide for Ultrapure Water Used in Semiconductor Processing,https://store-us.semi.org/products/f06300-semi-f63-guide-for-ultrapurewater-used-in-semiconductor-processing

4.

Kazuo Yamanaka, Determination of Ultratrace Elements in High Purity
Hydrogen Peroxide with Agilent 8900 ICP-QQQ, Agilent publication
5991-7701EN

5.

Yu Ying, Analysis of Ultratrace Impurities in High Silicon Matrix Samples by
ICP-QQQ, Agilent publication 5994-2890EN

6.

Technical Overview of Agilent 8900 Triple Quadrupole ICP-MS, Agilent
publication 5991-6942EN

7.

Naoki Sugiyama and Kazumi Nakano, Reaction data for 70 elements using
O2, NH3 and H2 with the Agilent 8800 Triple Quadrupole ICP-MS, Agilent
publication 5991-4585EN

> Return to table of contents> Search entire document

Determination of Ultratrace Elements in SEMI Grade 5High Purity Hydrogen Peroxide
AuthorIntroduction

Kazuo Yamanaka
Agilent Technologies, Japan

Hydrogen peroxide (H2O2) is one of the most important process chemicals usedin semiconductor device manufacturing. As a strong oxidizer, it is used forcleaning silicon wafers, removing photoresists, and etching metallic copper on
printed circuit boards.

Keywords
SEMI, H2O2, hydrogen peroxide,
semiconductor, high purity chemicals

Semiconductor Equipment and Materials International (SEMI) publishes standards
regarding the specifications for semiconductor process chemicals including H2O2(SEMI C30-1110). SEMI Grade 5 is the highest purity level, with maximum
contamination levels of 10 ppt for most trace elements. The industry therefore
requires analytical methods capable of measuring the trace elements at single- or
sub-ppt level background equivalent concentrations (BECs). SEMI C30-1110 also
includes specifications for the maximum concentrations of sulfate and phosphateallowed in high purity H2O2, with a limit of 30 ppb. This limit equates to elemental
concentrations of sulfur and phosphorus of 10 ppb. These two contaminants are
not currently measured by ICP-QMS. However, the recent development of triple
quadrupole ICP-MS (ICP-QQQ) permits much lower limits of detection for S and P.
It is now possible to monitor all SEMI elements using a single technique.

Experimental
Instrumentation: Agilent 8900 Semiconductor configuration ICP-QQQ.
Tuning: To achieve the lowest DLs, a multi-tune method was used. The tuning
parameters are summarized in Table 1. For data acquisition, a 2 s integration time
was used for all isotopes with three replicates (10 replicates for the blank to
calculate the DLs).
Table 1. ICP-QQQ tuning conditions.
Cool
Scan mode

Cool-NH3(1)

Cool-NH3 No gas(2)Single Q

RF power (W)

H2

He

600

4.5

3.5

1500
0.70

Make-up gas flow (L/min.)

0.90

0.48

Sampling depth (mm)

18.0

8.0

Ex1 (V)-150.0-18.0-100.0-17.0

Omega (V)-70.0

Omega Bias (V)2.0

Q1 Entrance (V)Cell gasO2 (2)MS/MS

Nebulizer gas flow (L/min)

Ex2 (V)O2 (1)

4.2

-12.0

4.2

-250.0-120.0-140.0

-70.0

10.0

8.0

–

H2

He

7.0

5.0

-15.0

-10.0

10.5

4.0

-50.0

–

Cell gas flow (ml/min)

4.7

NH3
2.0

2.0

Axial Acceleration (V)

0.0

1.5

KED (V)

15.0

-5.0

0.0
5.0

0.0

O2
0.3

0.3
1.0

3.0

-7.0
19

Sample Preparation
TAMAPURE-AA-10 hydrogen peroxide (35%, Tama Chemicals, Japan) was usedas the sample matrix. To stabilize the spiked elements, ultrapure nitric acid
(TAMAPURE-AA-10) was added to the H2O2 samples at one part of 70% HNO3
to 1000.

Results and discussion
Table 2 shows quantitative results and detection limits for the SEMI specification
elements in high purity 35% H2O2. Comparative quantitative results and DLs arealso shown for the same elements in ultrapure water. Long-term stability wasevaluated by measuring a H2O2 sample spiked at 10 ppt for most elements and
100 ppt for sulfur. Calibration curves were generated at the beginning of thesequence. The spiked samples were then run as unknown samples for a total
analysis period of 3 h 40 min. The RSDs of the 13 results are shown in Table 2(Stability RSD %).
Table 2. ICP-QQQ tuning conditions.
Hydrogen peroxide
Element Q1

Q2

Scan mode

Tune

Conc.
(ppt)

DL
(ppt)

Stability
RSD (%)

Conc.
(ppt)

DL
(ppt)

Li

7

single quad

Cool

< DL

0.003

4.7

< DL

0.004

11

MS/MS

No gas

7.7

0.69

8.1

4.6

0.57

Na

23

single quad

Cool

0.39

0.031

3.3

0.5

0.069

Mg

24

single quad

Cool

0.017

0.017

4.1

< DL

0.012

Al

27

single quad

Cool

0.39

0.071

2.9

0.11

0.11

B

20

Ultrapure water

11

P

31

47

MS/MS

O2 (1)

4.2

0.89

3.3

3.4

0.91

S

32

48

MS/MS

O2 (1)

190

5.1

7.8

41

3.8

K

39

39

MS/MS

cool+NH3 (2)

0.21

0.11

2.2

0.2

0.088

Ca

40

40

MS/MS

cool+NH3 (2)

< DL

0.23

1.9

< DL

0.10

Ti

48

64

MS/MS

O2 (2)

0.097

0.045

2.6

< DL

0.028

V

51

67

MS/MS

O2 (2)

0.067

0.027

2.6

< DL

0.023

Cr

52

52

MS/MS

cool+NH3 (1)

0.13

0.075

3.5

< DL

0.031

Mn

55

55

MS/MS

cool+NH3 (1)

< DL

0.012

2.7

< DL

0.004

Fe

56

56

MS/MS

cool+NH3 (1)

0.13

0.074

3.3

< DL

0.027

Ni

60

60

MS/MS

cool+NH3 (1)

0.16

0.14

3.7

< DL

0.030

Cu

63

63

MS/MS

cool+NH3 (1)

< DL

0.048

5.0

0.19

0.18

Zn

64

64

MS/MS

He

0.22

0.14

4.5

0.35

0.17

As

75

91

MS/MS

O2 (2)

< DL

0.087

3.5

< DL

0.081

Cd

114

114

MS/MS

No gas

< DL

0.02

2.3

< DL

0.017

Sn

118

118

MS/MS

No gas

0.088

0.063

2.0

< DL

0.037

Sb

121

121

MS/MS

H2

< DL

0.015

1.6

< DL

0.022

Ba

138

138

MS/MS

H2

0.061

0.033

1.2

< DL

0.004

Pb

208

208

MS/MS

No gas

0.081

0.053

1.0

0.056

0.035

Conclusion
All the elements specified in SEMI C30-1110 were measured at sub-ppt to ppt
levels in high purity 35% hydrogen peroxide using the Agilent 8900 ICP-QQQ.
For almost all elements, sub ppt quantitative results were obtained, with theremaining elements having single-ppt detection limits (except Si, 25 ppt).
Reproducibility between 1.0 – 8.1 % RSD was obtained at the 10 ppt level (100ppt for S) for the spiked analytes in a high purity 35% hydrogen peroxide sample
analysis sequence that lasted 3 hours 40 minutes. This performance
demonstrates the suitability of the Agilent 8900 Semiconductor configuration
ICP-QQQ instrument for the routine analysis of the highest-purity semiconductor
reagents and process chemicals.

More information
Determination of ultratrace elements in high purity hydrogen peroxide with
Agilent 8900 ICP-QQQ, Agilent publication, 5991-7701EN

21

> Return to table of contents> Search entire document

Automated analysis of semiconductor grade hydrogen
peroxide and DI water using ICP-QQQ
Authors
Kazuhiro Sakai
Agilent Technologies, Japan
Austin Schultz
Elemental Scientific, USA

Online MSA calibration using prepFAST S automated sample
introduction and Agilent 8900 ICP-QQQ
Introduction
Maximizing product yield and performance of semiconductor devices requires
manufacturers to address the potential for contamination at every stage of the
production process. Contamination from particles, metals, and organic residues
can affect the electrical properties of the semiconductor, reducing the quality andreliability of the final product. For example, following each photolithography stepduring wafer processing, the organic photoresist mask must be completely
removed from the silicon wafer surface. A mixture of sulfuric acid (H2SO4) andhydrogen peroxide (H2O2) known as a sulfuric/peroxide mix (SPM) is used for thiscleaning procedure. SPM is also used for degreasing the wafer surface. H2O2 is also
used in the RCA Standard Clean steps (SC-1 and SC-2) used to clean silicon wafers,
and for etching metallic copper on printed circuit boards.
Ultrapure water (UPW) is used throughout the wafer fabrication process. As well asworking as a rinse solution between processing steps, UPW is also the diluent for
many process chemistries such as SC-1 and SC-2 solutions. As these chemicals
are in frequent and prolonged contact with the wafer surface, minimizing metal
impurities is essential to prevent wafer surface contamination.
Semiconductor Equipment and Materials International (SEMI) publishes standards
for semiconductor process chemicals. The standard for H2O2 is SEMI C30-1110 –Specifications for Hydrogen Peroxide (1). SEMI Grade 5 is the highest purity level,with maximum contamination levels of 10 ppt for most trace elements.
Quadrupole ICP-MS (ICP-QMS) is the standard technique used to monitor traceelement contaminants in the semiconductor industry. However, the drive for eversmaller device architectures and higher yields requires an increasing number ofcontaminant elements to be monitored at lower concentrations.
In addition to trace elements, SEMI Standard C30-1110 specifies the maximum
concentration of sulfate and phosphate allowed in high purity H2O2, with a limit of
30,000 ppt. This limit equates to an elemental concentration of sulfur (S) andphosphorus (P) of 10,000 ppt. Due to the relatively high detection limits achievablewith conventional single quadruple ICP-MS, these two elements are not currently
measured using ICP-MS.
Triple quadrupole ICP-MS (ICP-QQQ) provides much lower limits of detection for
S and P (among many other elements). Uniquely, the technique offers the potential
for the sulfate and phosphate analysis to be combined with the other trace metals.
The adoption of ICP-QQQ therefore enables all SEMI specified elements to bemonitored using a single technique (2, 3).

22

Contamination control
Ultratrace analysis at the pg/g (ppt) or fg/g (ppq) level is susceptible tocontamination from the lab environment, reagents, or errors arising from manualtasks, such as pipetting. To deliver consistently accurate results at these ultratrace
concentrations, a skilled and experienced analyst is typically required.
One approach to simplifying the analysis for less expert analysts is to use an
automated sample introduction system. These systems automate typical sample
handling steps such as dilution, acidification, and spiking. They can also
automatically generate a calibration curve using either external standards or
Method of Standard Additions (MSA).
In this study, an automated procedure was developed to quantify ultratraceelemental impurities in de-ionized (DI) water and H2O2 using an Agilent 8900
ICP-QQQ fitted with an ESI prepFAST S automated sample introduction system.
The prepFAST S automates sample preparation and calibration, saving time andminimizing the risk of sample-contamination from manual sample handling
operations.

Experimental
Reagents and samples
TAMAPURE-AA-10 hydrogen peroxide (35%, Tama Chemicals, Japan) andultrapure DI water (Milli-Q water, Molsheim, France) were used as the samples.
Standard stock solution for MSA: a 1000 ppt mixed multi-element standard
solution was prepared by diluting a 10 ppm mixed multi-element standard
solution (SPEX CertiPrep, NJ, US) with 1% HNO3.
Nitric acid for sample acidification: a 10% nitric acid solution was prepared bydiluting 68% ultrapure HNO3 (TAMAPURE-AA-10) with DI water. HNO3 wasautomatically added the H2O2 samples, giving a final concentration of 0.5% HNO3
to stabilize the spiked elements. UPW samples are often also acidified to ensure
trace element stability (see reference 2). However, in this work, the DI water was
analyzed unacidified, without the addition of a HNO3 spike, providing results thatcan be compared with the earlier work.
The standard stock and HNO3 spike solutions were loaded on the prepFAST S.
All solutions run in the analysis were automatically prepared from these stock
solutions by the prepFAST S system. The prepFAST S method used DI (Milli-Q)
water as the carrier solution, at a flow rate of 100 μL/min.
All preparation and analysis steps were performed in a Class 10,000 clean room.
Instrumentation
A standard Agilent 8900 semiconductor configuration ICP‑QQQ instrument was
equipped with a PFA concentric nebulizer that is included with the prepFAST S
automated sample introduction system. The semiconductor configuration
ICP-QQQ is fitted with a Peltier cooled quartz spray chamber, quartz torch(2.5 mm id), platinum-tipped sampling and skimmer cones, and s-lens.
The 8900 ICP-QQQ was connected to the ESI prepFAST S automated sample
introduction system. The prepFAST S is a specialized, semiconductor version of
the standard ESI prepFAST. The S version has a high purity, low-contamination,
inert sample path and features an automated MSA spike addition mode. ICP-QQQ
23instrument operating conditions are given in Table 1.Tuning: To achieve thelowest DLs, a multi-tune method was used. The tuning parameters are
summarized in Table 1. For data acquisition, a 2 s integration time was used for
all isotopes with three replicates (10 replicates for the blank to calculate the DLs).
Table 1. ICP-QQQ operating conditions.
Cool-nogas
Acquisition mode

Cool-NH3(1)

Cool-NH3 No gas(2)Single Q

RF power (W)H2He

O2 (2)

4.5

3.5

MS/MS
600

1500

Carrier gas (L/min)

0.70

Make-up gas (L/min.)

0.90

0.48

Sampling depth (mm)

18.0

8.0

Ex1 (V)Ex2 (V)O2 (1)-150.0-18.0-100.0-17.0

Omega bias (V)-70.0

Omega lens (V)2.0

Q1 entrance (V)

4.2

4.7

-12.0

10.0

-15.0

4.2

-250.0-120.0-140.0

-70.0

8.0

10.0

10.5

4.0

-50.0

NH3 flow (mL/min)*-

3.0 (30%)**

-

-

-

-

-

He flow (mL/min)

-

1.0

-

-

5.0

-

-

H2 flow (mL/min)

-

-

-

-

7.0

-

-

-

-

-

-

-

-

4.5 (45%)**

O2 flow (mL/min)-

Axial acceleration (V)

0.0

1.5

Energy discrimination (V)

15.0

-5.0

0.0
5.0

0.0

1.0
3.0

-7.0

*10% NH3 balanced with 90% He* Values in parentheses are % of the maximum flow of the gas controller, as displayed in the tuning pane of
ICP-MS MassHunter software

The most advanced semiconductor manufacturing facilities require the lowest
possible levels of contamination, so they require analytical techniques that candeliver the lowest possible detection limits (DLs). This requirement is critical in
the analysis of trace contaminants in process chemicals such as UPW and H2O2,
which are used at multiple stages of the wafer fabrication process. UPW andH2O2 also come into direct contact with the wafer surface.
The 8900 ICP-QQQ satisfies this requirement by offering the flexibility to optimize
the measurement parameters (plasma conditions, quadrupole scan mode, cellgas type, and flow rate) to give the highest sensitivity and lowest background foreach analyte.
In this work, several reaction cell gases (He, H2, O2, and NH3) were used in thecollision/reaction cell (CRC) of the 8900, as appropriate for the large number ofanalytes being measured. Since DI water and H2O2 are low-matrix samples, cool
plasma conditions were also applied for the elements where this mode provides
the lowest background equivalent concentrations (BECs).
The tuning steps were applied sequentially during the measurement of eachsolution. This approach allows the tuning conditions to be optimized for theremoval of different types of interferences, while maintaining maximum
sensitivity for the analytes. Q1 and Q2 settings are shown in Table 2 along with
DLs, BECs, and quantification results.
24

ESI prepFAST S operation
The prepFAST S automated sample introduction system combines anautosampler with a system of ultrapure valves (S1 -5), and a set of high precisionsyringe pumps. Undiluted chemicals can be placed on the autosampler and thesystem will perform the actions—such as dilution, acidification, and spiking—required to prepare the sample for introduction to the ICP-MS or ICP-QQQ. The
operation of the prepFAST S is outlined in the four schematics shown in Figure 1.
1. Loading of sample: Syringe S5 loads a precise amount of sample to the loopof valve 1 (V1).

2. Sample dilution and sample spiking: Syringes S1, S2, S3, and S4 mix the acid,sample, diluent, and spike solution into a loop connecting V1 and V2.

3. Sample injection: The prepared sample is introduced into the ICP-QQQ via thecarrier solution pumped by S2. S2 provides a precise flow rate regardless ofsample type. The V1 loop is washed simultaneously.

25

4. Valve wash: UPW or acidified UPW is used to clean the lines between V1 and V2.

Figure 1. ESI prepFAST S system schematic, illustrating four distinct steps: sample loading during
spray chamber rinse, sample preparation, injection, and cleaning.

The prepFAST S removes the need for analyst intervention in the analysis ofsemiconductor grade chemicals, reducing the risk of sample contamination.
The integrated system offers the following advantages for the ultratraceelemental analysis of semiconductor samples:
1. Automated dilution of samples
2. Automated creation of external or MSA calibrations
3. Automated acidification of samples
4. Injection of samples at a precise flow rate
5. High speed rinsing of the ICP-MS sample introduction system

Results and discussion
Figures 2 and 3 show calibration curves for Na, K, Si, P, and S in DI water and Ca,
Zn, and As in H2O2, respectively. All elements were measured using the MSA
calibration prepared automatically using the prepFAST S. These elements are
difficult to analyze at low levels due to raised backgrounds. The analytes Si, P,
and S are not commonly measured with conventional single quadrupole ICP-MS,
due to the presence of intense polyatomic interferences. However, the controlled
reaction chemistry of the 8900 ICP-QQQ operating in MS/MS mode gives far
superior control of background interferences. MS/MS mode allows theseelements to be calibrated and quantified at ppt concentrations.
Good linearity at the ppt level was observed for all elements measured in both
sample matrices, although Si, P, and S had relatively high BECs of 85, 10, and 118
ppt, respectively. These elements are typically present at higher levels than the
trace metals, as they are more difficult to control in the lab environment and inreagents. They are also less critical contaminants, as reflected in the higher levels
for P and S (of 30 ppb for phosphate and sulfate) permitted in high purity H2O2.
However, despite the higher BECs, the calibration curves for Si, P, and S were still
linear over the calibration range from 10 to 50 ppt. The same calibration levels
were used for all analytes, as the mixed stock standard contained all elements atthe same concentration.

26

23 Na [No gas]x104

31 ➝ 47 P [Ox]y = 425.4809* x + 148.7000
R = 0.9996
DL = 0.07685 ppt
BEC = 0.3495 ppt

x103

y = 14.5463* x + 151.6000
R = 0.9997
DL = 4.421 ppt
BEC = 10.42 ppt

1

CPS

CPS

2

0.5
1

0

0
20.0

40.0
Conc (ppt)

60.0

39 ➝ 39 K [Cool NH 3-2]
x103
6

20.0

40.0
Conc (ppt)

60.0

40.0
Conc (ppt)

60.0

32 ➝ 48 S [Ox]x104

y = 92.7607* x + 12.3000
R = 0.9997
DL = 0.04893 ppt
BEC = 0.1326 ppt

y = 45.8456* x + 5385.4010
R = 0.9937
DL = 2.267 ppt
BEC = 117.5 ppt

2
CPS

CPS

4

1

1

0

0
20.0

40.0
Conc (ppt)

60.0

40.0
Conc (ppt)

60.0

20.0

28 ➝ 28 Si [H 2]

CPS

x103

y = 10.5488* x +895.1300
R = 0.9898
DL = 3.821 ppt
BEC = 84.86 ppt

1

0
20.0

Figure 2. Calibration plots for Na, K, Si, P, and S in DI water. All values in ng/L (ppt).

27

40 ➝ 40 Ca [Cool NH 3-2]x102

75 ➝ 91 As [softOx]

y = 10.1753* x + 6.8333
R = 0.9994
DL = 0.5958 ppt
BEC = 0.6716 ppt

x103
1

y = 15.5825* x + 2.1667
R = 0.9993
DL = 0.147 ppt
BEC = 0.139 ppt

4

CPS

CPS

6

0.5

2

0

0
20.0

40.0
Conc (ppt)

60.0

40.0
Conc (ppt)

60.0

20.0

40.0
Conc (ppt)

60.0

64 ➝ 64 Zn [He]

CPS

x102

y = 5.6426* x +2.6667
R = 0.9994
DL = 0.4061 ppt
BEC = 0.4726 ppt

2

0
20.0

Figure 3. Calibration plots for Ca, Zn, and As in H2O2. All values in ng/L (ppt).

DLs and quantitative results
Forty-nine elements in total, including all the elements listed in SEMI C30-1110,
were measured by MSA in DI water and H2O2, using the 8900 multi-tune mode
method. Data was acquired in an automated sequence of cool plasma, no gas,
and gas modes, during a single visit to the sample vial. Data for each of themodes was combined automatically into a single report for each sample.
Quantitative results, DLs, and BECs for all analytes—including all the SEMI
specified elements—are shown in Table 2. Detection limits were calculated as
3-sigma of 10 replicate measurements of the blank DI water or H2O2 sample.
DLs <1 ng/L (ppt) were obtained for 46 elements in DI water. The DLs for theremaining 3 elements, Si, P, and S, were at the single-ppt level. Measured
concentrations of all elements apart from B, Si, P, and S were <1 ng/L or <DL,
confirming the purity of the sample. This analytical performance easily meets therequirements for monitoring UPW in semiconductor manufacturing.
In H2O2, DLs <1 ng/L were obtained for 45 elements. The DLs for B, P, and S, wereat the single-ppt level, while the DL for Si was 26 ppt. All elements were measured
at <1 ng/L or <DL apart from B (22 ppt), Na (1.1 ppt), Si (500 ppt), P (9.4 ppt), andS (220 ppt) in 35% H2O2. Only B and Si exceed the 10 ppt maximum limit in the
SEMI specifications, and of these, only B is a SEMI specified element. P and S
were quantified well below the 10,000 ppt SEMI specified limit in H2O2.
28

Table 2. Quantification of trace elements in DI water and 35% H2O2. SEMI specification elements are in bold.
Q1

Li
Be

9

B

11

Q2

Scan type

Tune mode

Dl WaterDL (ng/L)

BEC (ng/L)

H2O2
Conc (ng/L)

DL (ng/L)

BEC (ng/L)Conc (ng/L)

7

SQ

Cool no gas

0.003

0.001

<DL

0.025

0.022

<DL

9

MS/MS

No gas

0.096

0.040

<DL

0.089

0.017

<DL

11

MS/MS

No gas

0.52

1.7

1.7

1.9

22

22

Na

23

SQ

Cool no gas

0.077

0.35

0.35

0.11

1.1

1.1

Mg

24

SQ

Cool no gas

0.015

0.009

<DL

0.040

0.053

0.053

27

SQ

Cool no gas

0.040

0.028

<DL

0.22

0.63

0.63

Si

Al
28

28

MS/MS

H2

3.8

85

85

26

500

500

P

31

47

MS/MS

O2

4.4

10

10

2.6

9.4

9.4

S

32

48

MS/MS

O2

2.3

120

120

7.5

220

220

K

39

39

MS/MS

Cool NH3 (2)

0.049

0.13

0.13

0.19

0.45

0.45

Ca

40

40

MS/MS

Cool NH3 (2)

0.082

0.044

<DL

0.60

0.67

0.67

Ti

48

64

MS/MS

O2 (2)

0.042

0.021

<DL

0.24

0.21

<DL

V

51

67

MS/MS

O2 (2)

0.021

0.026

0.026

0.058

0.068

0.068

Cr

52

52

MS/MS

Cool NH3 (1)

0.085

0.047

<DL

0.24

0.69

0.69

Mn

55

55

MS/MS

Cool NH3 (1)

0.010

0.010

0.010

0.039

0.020

<DL

Fe

56

56

MS/MS

Cool NH3 (1)

0.070

0.076

0.076

0.29

0.17

<DL

Co

59

59

MS/MS

Cool NH3 (1)

0.017

0.002

<DL

0.025

0.005

<DL

Ni

60

60

MS/MS

Cool NH3 (1)

0.080

0.016

<DL

0.24

0.18

<DL

Cu

63

63

MS/MS

Cool NH3 (1)

0.12

0.11

<DL

0.17

0.12

<DL

Zn

64

64

MS/MS

He

0.063

0.28

0.28

0.41

0.47

0.47

Ga

71

SQ

Cool no gas

0.011

0.001

<DL

0.032

0.031

<DL

Ge

74

74

MS/MS

He

0.36

0.32

<DL

0.27

0.20

<DL

As

75

91

MS/MS

O2 (2)

0.072

0.035

<DL

0.15

0.14

<DL

Se

78

78

MS/MS

H2

0.20

0.14

<DL

0.40

0.13

<DL

85

SQ

Cool no gas

0.031

0.015

<DL

0.052

0.035

<DL

Rb
Sr

88

88

MS/MS

He

0.024

0.002

<DL

0.000*

0.000*

0.000*

Nb

93

93

MS/MS

He

0.018

0.010

<DL

0.030

0.029

<DL

Mo

98

98

MS/MS

He

0.093

0.045

<DL

0.065

0.063

<DL

Ru

101

101

MS/MS

He

0.077

0.058

<DL

0.075

0.014

<DL

Rh

103

103

MS/MS

O2 (2)

0.057

0.10

0.10

0.018

0.097

0.097

Pd

105

105

MS/MS

No gas

0.078

0.12

0.12

0.055

0.090

0.090

Ag

107

107

MS/MS

No gas

0.099

0.14

0.14

0.031

0.016

<DL

Cd

114

114

MS/MS

No gas

0.045

0.021

<DL

0.047

0.009

<DL

In

115

115

MS/MS

No gas

0.009

0.003

<DL

0.022

0.019

<DL

Sn

118

118

MS/MS

No gas

0.038

0.059

0.059

0.20

0.17

<DL

Sb

121

121

MS/MS

H2

0.029

0.032

0.032

0.028

0.005

<DL

Te

125

125

MS/MS

No gas

0.18

0.043

<DL

0.000*

0.000*

0.000*

133

MS/MS

Cool no gas

0.074

0.020

<DL

0.088

0.059

<DL

Cs
Ba

138

138

MS/MS

H2

0.023

0.014

<DL

0.039

0.018

<DL

Ta

181

181

MS/MS

No gas

0.024

0.041

0.041

0.12

0.28

0.28

W

182

182

MS/MS

No gas

0.037

0.009

<DL

0.044

0.044

0.044

Re

185

185

MS/MS

No gas

0.040

0.037

<DL

0.062

0.056

<DL

Ir

193

193

MS/MS

H2

0.023

0.016

<DL

0.040

0.027

<DL

Pt

195

195

MS/MS

No gas

0.28

0.33

0.33

0.088

0.39

0.39

Au

197

197

MS/MS

No gas

0.051

0.048

<DL

0.22

0.15

<DL

Tl

205

205

MS/MS

No gas

0.036

0.082

0.082

0.015

0.010

<DL

Pb

208

208

SQ

No gas

0.042

0.066

0.066

0.056

0.035

<DL

Bi

209

209

MS/MS

No gas

0.034

0.048

0.048

0.027

0.054

0.054

U

238

238

MS/MS

No gas

0.004

0.001

<DL

0.012

0.008

<DL

SQ: single quadrupole. *Measured value was zero counts in all replicates.

29

Conclusion
By combining ultra low detection limits with a high degree of automation,
the Agilent 8900 ICP-QQQ fitted with ESI’s prepFAST S automated sample
introduction system provides performance ideally suited to the high demandsof the semiconductor industry. The method also simplifies the elemental
analysis of semiconductor process chemicals.
User handling of the samples is limited to loading the multielement stock
standards, acid used for spiking, and samples into the prepFAST S automatedsample introduction system. All subsequent steps, including introduction of
the sample to the ICP-QQQ, are performed automatically by the prepFAST S.
Benefits of the method include:– Autodilution of samples– Auto-acidification of samples– Auto-creation of MSA calibrations– Injection of samples at a precise flow rate
– High-speed rinsing of the ICP-MS sample introduction system.
A complete analysis of the two samples, measured using separate, automated
MSA calibrations, was achieved in less than 30 minutes.
Automating the sample handling steps speeds up the analytical procedure,
while also making the overall analysis easier for the analyst to perform.
Eliminating manual tasks such as sample dilution and spiking lowers the risk ofcontamination during ultratrace analysis. Limiting the handling of reagents andsamples also reduces the likelihood of errors arising during the experimental
procedure, leading to an increased confidence in the data quality.
All the elements specified in SEMI C30-1110, including P and S, were measured at
sub-ppt to ppt levels in DI water and high purity 35% H2O2. The results easily meetthe current SEMI Grade 5 specifications for H2O2.

References
1.	SEMI C30-1110, Specifications for hydrogen peroxide, 2010.
2.	Kazuo Yamanaka, Determination of ultratrace elements in high purity hydrogen
peroxide with Agilent 8900 ICP‑QQQ, Agilent publication, 2016, 5991-7701EN
3.	Kazumi Nakano, Ultra-low level determination of phosphorus, sulfur, silicon,
and chlorine using the Agilent 8900 ICP-QQQ, Agilent publication, 2016,
5991-6852EN

30

> Return to table of contents> Search entire document

Ultratrace Measurement of Calcium in Ultrapure Water
Authors

Introduction

Albert Lee, Vincent Yang, Jones Hsu,
Eva Wu and Ronan Shin, BASF Taiwan
Ltd., Taipei, Taiwan

In the semiconductor industry, the control of metal impurities in the process
chemicals used in the manufacture of semiconductor devices is critical toachieve the required product performance and yield. As device performance iscontinually increasing, the required impurity control becomes ever more stringent.
For example, metal content of the ultra-pure water (UPW) used in the
manufacturing process must be at the sub-ppt level. ICP-MS is the standard
technique used for the trace metals analysis of semiconductor chemicals anddevices. The most common instrument and measurement technique used in
the semiconductor industry is single quadrupole ICP-MS (ICP-QMS) withcool plasma. The cool plasma technique [1], developed in the mid 1990s,
enables the quantification of key contaminant elements at the single ppt level.
Collision and reaction cell ICP-QMS, developed from 2000 onwards, enabled the
direct analysis of more complex semiconductor matrices, but did not improve on
the DLs or BECs of cool plasma for low-matrix samples. To achieve measurement
at the sub-ppt level, reduction of the BEC is required. As outlined in this paper,
the Agilent 8800 ICP-QQQ provides new reaction cell technology that enables asignificant reduction in the BEC that can be achieved for Ca, to 100 ppq.

Katsuo Mizobuchi, Agilent
Technologies, Japan

Keywords
semiconductor, process chemicals,
ultra pure water, UPW, calcium, methodof standard additions, hydrogenon-mass

Table 1. Cool plasma operating conditions.
Parameter

Unit

Tuning value

RF

W

600

Sampling depthmm

18

Carrier gas flow

L/min

0.7

Make-up gas flow

L/min

1.0

Spray chamber temp.

°C

2

Experimental
Instrumentation: Agilent 8800 #200.
Plasma conditions: For the ultratrace measurement of Ca, cool plasma operating
conditions were used (Table 1). The sample was self-aspirated at a carrier gas
flow rate of 0.7 L/min.
Reagents and sample preparation: A Ca standard was prepared in UPW acidified
with 0.1% high purity HNO3. This was used to make 50 ppt and 100 ppt additions
to a UPW blank acidified with 0.1% high purity HNO3.

31

Results and discussion
Ultra-low BEC for Ca using MS/MS mode
Figure 1 shows the BECs obtained for Ca, measured at its major isotope of
40
Ca, using the method of standard additions (MSA) under three different
operating conditions on the 8800 ICP-QQQ: Single Quad mode with no cell gas,
MS/MS mode with no cell gas, and finally MS/MS mode with a H2 cell gas flowof 1 mL/min. The Single Quad mode uses operating conditions with Q1 acting
as an ion guide, to emulate the Agilent 7700 ICP-QMS. The obtained BEC of
6.8 ppt is similar to that routinely achieved with the Agilent 7700 operated in cool
plasma mode.
Using MS/MS mode (without cell gas) improved the Ca BEC to 1.4 ppt. MS/MS
mode with H2 at 1 mL/min in the cell further improved the BEC down to 0.041 ppt(41 ppq). The obtained MSA plot is shown in Figure 2. The Agilent 8800 ICP-QQQ
in MS/MS mode with H2 cell gas achieved a BEC for Ca in UPW two orders ofmagnitude lower than the BEC obtained using conventional ICP‑QMS.
Figure 3 shows the spectrum obtained for UPW using cool plasma conditions inSingle Quad mode with no cell gas. As can be seen, Ar+ (m/z 40) is suppressed
under the lower temperature plasma conditions, but two intense backgroundpeaks are observed at m/z = 19 and 30. These are (H2O)H+ and NO+ respectively.
In Single Quad mode, all ions formed in the plasma, including these two intense
ions, pass through to the cell. Even with no gas added to the cell, a reaction
occurs in the cell which causes a new interfering ion at m/z = 40. The likely
reaction occurring in the cell is: NO+ + Ar Ar+ + NO (charge transfer reaction),
which increases the BEC for Ca by several ppt. Although the ionization potential(IP) of NO (IP = 9.26 eV) is lower than that of Ar (IP = 15.7 eV), a metastable ion,
NO+, exists close to the ionization potential of Ar [2]. So it is reasonable to assume
that the charge transfer reaction shown occurs in the cell.
With MS/MS mode on the 8800 ICP-QQQ, Q1 rejects all non-target ions such as
NO+ and (H2O)H+, preventing unwanted reactions from occurring in the cell, which
lowers the Ca BEC. The addition of H2 in the cell also removes any residual 40Ar+
that is formed even under cool plasma conditions.

32

40 ➝ 40 Ca [Cool-H 2 (1mL) (MSMS)]

8

x103

7

6

y = 49.5084 *x + 2.0200
R = 0.9999
DL = --BEC = 0.0408 ppt

6

CPS

5
4

4

3
2

2
1
0

Single quadH 2 flow = 0 mL/min

MS/MS

H 2 flow = 0 mL/min

0

MS/MS

50.0

H 2 flow = 1 mL/min

Figure 1. BECs for Ca obtained using
Single Quad mode with no cell gas [6.8 ppt],
MS/MS mode with no cell gas [1.4 ppt],
and MS/MS mode with an H2 cell gas flowof 1 mL/min [0.041 ppt].

100.0
Conc (ppt)

Figure 2. MSA calibration plot for Ca using
MS/MS mode with H2 flow of 1 mL/min.

[1] Spectrum No. 1 [187.530 sec]DIW_COOL.D/Tune#1[CPS][Log]
1.E10
1.E9
1.E8
1.E7
1.E6
1.E5
1.E4
1000
100
10
m/z–>

10

20

30

40

50

60

70

80

90

100

Figure 3. Spectrum of UPW acquired using cool plasma conditions in Single Quad modewith no gas mode.

References
1.	K. Sakata and K. Kawabata, Reduction of fundamental polyatomic ions in
inductively coupled plasma mass spectrometry, Spectrochimica Acta, Part B,
1994, 49, 1027.
2.	R. Marx, Y.M. Yang, G. Mauclaire, M. Heninger, and S. Fenistein, Radioactive
lifetimes and reactivity of metastable NO+(a3Σ+,v) and O+2(α4 Πu,v) , J.Chem.
Phys., Vol. 95, No. 4, 2259-2264, 1991.

33

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Ultratrace Measurement of Potassium and Other Elements
in UPW Using ICP-QQQ in Cool Plasma/Reaction Mode
Authors

Introduction

Katsuo Mizobuchi and
Masakazu Yukinari
Agilent Technologies, Tokyo, JapanThe level of metal contaminants is strictly controlled in semicon device
manufacturing processes, but the elements K, Ca and Fe are difficult to determine
by ICP-MS due to argide interferences e.g. ArH+ on 39K+, Ar+ on 40Ca+ and ArO+ on
56
Fe+. Cool plasma employs a relatively low temperature plasma to remove theargide interferences allowing the analyst to measure these elements at tracelevels. The low temperature plasma also reduces the background signal from any
Easily Ionized Elements (EIEs) such as Li and Na that may deposit of on theinterface of the ICP-MS. Even after the introduction of high concentration of EIEs,
cool plasma ensures a low background level of these elements is maintained.

Keywords
semiconductor, process chemicals,
ultra pure water, UPW, potassium, cool
plasma, ammonia on-mass

The Agilent 8800 ICP-QQQ provides improved cool plasma performance in
combination with reaction cell technology, to enable a BEC of 30 ppq for K to beachieved in ultrapure water (UPW), and BECs at the ppq level for all the otherelements studied: Li, Na, Mg, Al, Ca, Cr, Mn, Fe, Ni and Cu.
Table 1. Cool plasma operating conditions.
Parameter

Unit

Tuning value

RF

W

600

Carrier gas

L/min

0.7

Make-up gas

L/min

0.8

Sampling depth

(mm)

18

NH3 (10% in He) cell gas flow rate

mL/min1

Experimental
Instrumentation: Agilent 8800 #200 (semiconductor configuration).
Plasma conditions: Cool plasma operating conditions (Table 1).
Reagents and sample preparation: The blanks and samples were acidified using
high purity HNO3 (TAMAPURE-AA-10, TAMA Chemicals Co. Ltd. Kanagawa,Japan). Standard solutions were prepared by serial dilution from a SPEX 331
mixed standard (SPEX CertiPrep, NJ, USA).
Cool plasma/NH3 reaction cell mode
Investigation of the signal at m/z 39 under cool plasma conditions indicated thepresence of 38ArH+ which decreases with lowering plasma temperature, indicatinga reduction in the ionization of the polyatomic ion. However, there was also acontribution from a water cluster ion, (H3O+)(H2O), which is likely to form under
low temperature plasma conditions. The combination of these two interferencesmeans that there is no plasma temperature at which both interferences can be
minimized (Figure 1). As the water cluster ion is known to react with deuterated
ammonia (ND3) via a fast proton transfer reaction [1], it was assumed thatreaction with NH3 would proceed at a similar rate, so this cell gas mode wasinvestigated in order to remove the water cluster ion in cool plasma conditions.
34

39K

50

40Ca

56Fe

45
40

Normalized signal

35
30
25
20
15
10
5
0
0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

MUGS (L/min)Figure 1. Investigation of the background signal under cool plasma conditions.
BEC of K, Ca and Fe as a function of make-up gas (MUGS) flow rate.

Results and discussion
Ultra-low BEC for K using MS/MS mode
Ammonia reaction gas mode under cool plasma conditions was used todetermine K in UPW. The BEC of K was measured at 30 ppq. A comparative study
carried out using a 7500cs quadrupole ICP-MS in cool plasma/NH3 reaction
mode achieved a BEC of 500 ppt for K [2]. It would be reasonable to attribute theimprovement of BEC achieved with the 8800 to the MS/MS reaction capability of
the ICP-QQQ. In conventional quadrupole ICP-MS, ions formed under cool plasma
conditions enter the reaction cell and react with NH3 or with impurity residues
present in the cell to form product ions at m/z 39. MS/MS prevents any unwanted
precursor ions from entering the cell, thus minimizing the production of undesired
product ions.
Multielement analysis
The cool plasma/NH3 reaction mode method was applied to the multielement
analysis of UPW. As can be seen from the results in Table 2, a BEC < 150 ppq wasachieved for all elements, including K, Ca and Fe.

35

Table 2. DL and BEC of elements in UPW.
Mass/Element

Sensitivity, cps/ppt

DL, ppt

BEC, ppt

7 Li

6.2

0.000

0.000

23 Na

94.0

0.014

0.035

24 Mg

44.0

0.010

0.005

27 Al

42.7

0.010

0.002

39 K

96.8

0.000

0.030

40 Ca

42.5

0.035

0.091

52 Cr

36.5

0.029

0.037

55 Mn

64.5

0.020

0.011

56 Fe

42.2

0.488

0.134

60 Ni

13.4

0.270

0.101

65 Cu

15.5

0.014

0.029

Conclusion
The Agilent 8800 ICP-QQQ was used to show the background signal at m/z 39
under cool plasma conditions was due to a water cluster ion, H3O(H2O)+, which
was removed using NH3 cell gas. The ICP-QQQ BEC for 39K was more than afactor of 10 lower than that achieved using a conventional quadrupole ICP-MS.
This demonstrates the benefit of MS/MS mode for reaction gas methods:
MS/MS mode prevents all non-target ions from entering the cell, and thereby
eliminates the possibility of unwanted reactions from occurring.

References
1.	V. G. Anicich (2003.11), An Index of the Literature for Bimolecular Gas Phase
Cation-Molecule Reaction Kinetics (p369), NASA
2.	Junichi Takahashi et al., Use of collision reaction cell under cool plasma
condition in ICP-MS, Asia Pacific Winter Plasma Conference 2008 (O-10)

More information
Ultratrace measurement of potassium and other elements in ultrapure waterusing the Agilent 8800 ICP-QQQ in cool plasma reaction cell mode, Agilent
publication 5991-5372EN

36

> Return to table of contents> Search entire document

Ultralow level determination of phosphorus, sulfur, silicon,
and chlorine using the Agilent 8900 ICP-QQQ
AuthorIntroduction

Kazumi Nakano,

Quadrupole ICP-MS (ICP-QMS) is one of the most sensitive and versatile
analytical tools used in inorganic analysis. With sensitivity approaching 1,000
million counts per second/part per million (1 G cps/ppm) and background signals
typically less than 1 cps, the latest instrumentation achieves detection limits (DL)in the ppq (pg/L) range for most of the elements in the periodic table. Detection
limits tend to be lowest for elements at masses higher than 80 u, while somelower mass elements are more difficult to measure at trace levels due to thepresence of spectral overlaps from polyatomic interferences. ICP-QMS can utilize
cool plasma and/or collision/reaction cell methods to address the problem ofbackground interferences, with successful results in many applications.

Agilent Technologies, Japan

More recently, the introduction of triple quadrupole ICP-MS (ICP-QQQ) has
dramatically improved the reliability and performance of reaction cell methods by
allowing a double mass filter (MS/MS) to be applied to control reaction chemistry
in the cell. This now allows analysts to resolve interferences on a wide range ofelements in a controlled and effective manner.
With the introduction of Agilent’s second generation ICP-QQQ instrument, theAgilent 8900 Triple Quadrupole ICP-MS, reaction cell operation with MS/MS mode
has been further refined. This note describes the performance of the 8900
ICP-QQQ for the analysis of some of the most challenging elements for ICP-MS:
phosphorus (P), sulfur (S), silicon (Si), and chlorine (Cl). The first ionization
potentials of these elements are relatively high, which reduces the degree ofionization and therefore the analyte signal. Furthermore, the background signals
are elevated due to plasma-, solvent- and matrix-based polyatomic ions, making
low-level analysis even more difficult. As ICP-MS technology has developed, there
has been a growing demand and expectation to measure these difficult elements
together with more conventional elements in high purity chemicals and materials.
Details of the methods used to control the interferences on the four elements arepresented, together with background equivalent concentrations (BECs) anddetection limits (DLs) for P, S, Si and Cl in ultra-pure water (UPW), and P, S and Si
in the highest grade hydrogen peroxide (H2O2).

Experimental
Instrumentation
An Agilent 8900 ICP-QQQ (#200, Semiconductor Configuration) was used for all
measurements. The sample introduction system comprised a PFA concentric
nebulizer, a quartz spray chamber and torch, and platinum interface cones. The
8900 #200 ICP-QQQ is fitted with a new argon gas flow control system speciallydesigned to minimize sulfur/silicon contamination from the gas line components.
Normal, hot plasma conditions were used throughout. Extraction lens voltages
were optimized for maximum sensitivity using an Agilent 1 ppb tuning solution
containing Li, Y, Ce and Tl. Operating and tuning parameters are summarized inTable 1.
37

Table 1. Agilent 8900 ICP-QQQ operating parameters.
Parameter

Unit

Value

RF power

W

1500

Sampling depth

mm

8.0

Carrier gas flow rate

L/min

0.70

Make-up gas flow rate

L/min

0.52

Extraction lens 1

V

4.0

Extraction lens 2

V

-210

Omega lens bias

V

-80

Omega lensV

8.0

Method and cell tuning
Based on previous studies, oxygen (O2) mass-shift mode was used for the
analysis of P and S, hydrogen (H2) on-mass mode was used for Si, and Cl
was determined using H2 mass-shift mode [1]. The reaction processes used forremoval of the primary interference on each analyte were as follows:
Sulfur by oxygen mass-shift mode
The intense polyatomic interference from 16O2+ on the primary isotope of S, 32S+
at m/z 32, is avoided by shifting S+ away from the interfering O2+ ion, using an
O-atom addition reaction. S+ reacts readily with O2 cell gas to form the product ion
SO+, which can be measured free of interference at M + 16 u (m/z 48 for the
primary 32S16O+ isotope product ion), as shown in the following equations:32

S+ + O2 <cell gas>  32S16O+ + O

16

O2+ + O2 <cell gas>  no reaction

Phosphorus by oxygen mass-shift mode
A similar mass-shift approach is used for the measurement of P as PO+.
The native mass of P (m/z 31) suffers an intense background interference
from 14N16O1H+, 15N16O+, and 14N17O+. These background polyatomic ions are
avoided by reacting P+ with O2 cell gas, shifting the P+ away from the interfering
ions, and measuring it as the PO+ product ion at m/z 47:
31

P+ + O2 <cell gas>  31P16O+ + O

NOH+/NO+ + O2 <cell gas> no reaction

Silicon by hydrogen on-mass mode
The analysis of Si uses on-mass measurement with H2 cell gas, as theprimary interferences on the major Si isotope at m/z 28, 14N2+ and 12C16O+,
react readily with H2, while Si+ does not react. Thus, the N2+ and CO+ interferences
can be removed, and 28Si+ can be measured free from the interferences at its
original mass:38

28

Si+ + H2 <cell gas>  no reaction

14

N2+ + H2 <cell gas> 

12

C16O+ + H2 <cell gas>  COH+ + H

N2H+ + H

Chlorine by hydrogen mass-shift mode
Cl is a difficult element to analyze at low concentrations using ICP-MS, because it
is a common contaminant and is often present in reagents used in the laboratoryenvironment. In addition, its first ionization potential of 12.967 eV is higher thanthat of any other commonly measured element, meaning that Cl is very poorly
ionized, so the sensitivity for Cl+ is extremely low. A further issue for low-level
Cl analysis is the presence of a polyatomic interference from 16O18O1H+ on the
primary Cl isotope at m/z 35. The O2H+ overlap can be avoided by measuring Cl
as a ClH2+ product ion, produced from sequential reaction with H2 reaction gas:35

Cl+ + H2 <cell gas>  35Cl1H+ + H

Followed by 35Cl1H+ + H2 <cell gas>  35Cl1H2+ + H
16

O18O1H+ + H2 <cell gas>  no reaction

In all of these methods, the Agilent 8900 ICP-QQQ was operated in MS/MS mode
(where both Q1 and Q2 function as mass filters) ensuring that only the target ion
or product ion was measured. MS/MS means that potentially overlapping ionsare excluded from the collision/reaction cell, so the reaction chemistry iscontrolled and consistent, even if other matrix elements or analytes are present in
the sample. For example, in the case of 32S16O+ product ion measured at m/z 48,
the product ion mass could be overlapped by other ions, such as 48Ca+, 48Ti+, and36
Ar12C+, if these ions were not rejected by Q1. This is the main reason for the
improved reaction mode performance of ICP-QQQ compared to ICP-QMS, as
ICP-QMS has no mass filter step before the collision/reaction cell.
The ORS4 collision/reaction cell of the 8900 #200 instrument has the facility toutilize an axial acceleration voltage, which was found to be effective to increase
sensitivity in the O2 mass-shift method used for the determination of P and S.
Cell parameters were optimized separately for each mode while aspirating a
1 ppb standard solution of each of the elements. Cell tuning parameters are
summarized in Table 2.
Table 2. Cell mode related tuning parameters.
Parameter

Unit

Element
Mass pair31(Q1  Q2)

P, 32S(31  47), (32  48)

H2 on-mass
28

H2 mass-shiftSi

35(28  28)Cl

(35  37)

O2

H2

mL/min0.41

5.0

Cell gas
Flow rate

O2 mass-shift

OctpBias

V

-3

-18

KED

V

-8

0

Axial acceleration

V

1

0

Cell exit

V

-90

-70

Deflect

V

8-6

Plate bias

V

-60

39

Reagents
Standard solutions for P, S and Si were prepared from single element standards
purchased from SPEX CertiPrep (NJ, USA), by serial dilution with UPW. The UPW
was supplied from ORGANO Corp (Tokyo, Japan). The Cl standard was preparedfrom high purity HCl purchased from Wako Pure Chemicals Industries Ltd (Osaka,
Japan). The highest purity grade H2O2, TAMAPURE-AA-10, was purchased fromTAMA Chemicals Co Ltd (Kanagawa, Japan). The calibration standard addition
spikes were added directly to the undiluted H2O2. A 1% TMAH alkaline rinse wasused during the analysis of Cl to maximize the effectiveness of the washout
between samples and prevent any carryover. All pipette tips, vials and bottles were
thoroughly cleaned using diluted high purity acids and rinsed in UPW prior to use.

Results and discussion
To prepare the ICP-QQQ for the analysis, a 1% HNO3 solution was aspirated
overnight to thoroughly clean the sample introduction system. Running theplasma for several hours would also help to remove any contaminants in the
Ar gas flow line. P, S and Si were measured together, and Cl was analyzed in a
separate batch since it benefited from an alkaline rinse between solutions.
Figures 1 and 2 show the calibration curves of the four elements in UPW and
P, S and Si in H2O2, respectively, measured using the method of standard addition(MSA). The background level of Cl present in the H2O2 sample was too high topermit accurate analysis at the spike levels used.
Good linearity at low and sub-ppb levels was observed for all elements measured
in both of the sample matrices. The DL for each element was calculated as
3 times the standard deviation of 10 replicates of the blank using an integration
time of 1 sec for each element. The results are summarized in Table 3.
31 ➝ 47 P [O2]CPS

228 ➝ 28 Si [H 2]y = 15458.4854 *x + 162.9000
R = 0.9999
DL = 0.003261 ppt
BEC = 0.01054 ppt

x105

CPS

x104

1

0

y = 27123.9812 *x + 7027.9950
R = 0.9999
DL = 0.01467 ppt
BEC = 0.2591 ppt

2

0
0.5

1.0

5.0

Conc (ppt)

32 ➝ 48 S [O2]
x105
3

10.0
Conc (ppt)

35 ➝ 37 Cl [H2]y = 22744.7396 *x + 1715.8070
R = 0.9999
DL = 0.005491 ppt
BEC = 0.07544 ppt

x103

y = 176.1898 *x + 321.6000
R = 0.9989
DL = 0.2752 ppt
BEC = 1.825 ppt

2
CPS

CPS

2

1

1

0

0
5.0

10.0
Conc (ppt)

5.0

10.0
Conc (ppt)

Figure 1. Calibration plots of P, S, Si and Cl in UPW. All values in ug/L (ppb).
40

31 ➝ 47 P [O2]28 ➝ 28 Si [H 2]y = 14686.8534 *x + 238.1000
R = 0.9999
DL = 0.002336 ppt
BEC = 0.01621 ppt

x105

CPS

CPS

x104
2

1

0

y = 26151.7841 *x + 12863.3990
R = 0.9999
DL = 0.01875 ppt
BEC = 0.4919 ppt

2

0
0.5

1.0

5.0

Conc (ppt)

10.0Conc (ppt)

32 ➝ 48 S [O2]x105
3y = 22260.5380 *x + 5424.7810
R = 1.0000
DL = 0.0125 ppt
BEC = 0.2437 ppt

CPS

2

1

0
5.0

10.0
Conc (ppt)

Figure 2. Calibration plots of P, S and Si in H2O2.
Table 3. BEC and DL of P, S, Si and Cl in UPW and P, S and Si in the highest grade H2O2.
P
(ppt)

S
(ppt)

Si
(ppt)

Cl
(ppt)

Element

BEC

DL

BEC

DL

BEC

DL

BEC

DL

UPW

10.5

3.3

75.4

5.5

259

14.7

1.83

0.28

H 2O 2

16.2

2.3

244

12.5

492

18.8

Conclusion
The Agilent 8900 ICP-QQQ operating in MS/MS mode with O2 and H2 cell gases
successfully eliminated problematic spectral interferences on non-metallic
impurities P, S, Si and Cl in UPW and P, S and Si in H2O2. The results highlight theadvanced performance of the second generation ICP-QQQ for the analysis ofchallenging elements, by achieving the lowest ever reported BECs for the four
elements in UPW.

References
1.	N. Sugiyama, Trace level analysis of sulfur, phosphorus, silicon and chlorine
in NMP using the Agilent 8800 Triple Quadrupole ICP-MS, Agilent applicationnote, 2013, 5991-2303EN

41

> Return to table of contents> Search entire document

Direct analysis of trace metal impurities in high purity
nitric acid using ICP-QQQ
Authors

Introduction

Kazuo Yamanaka and Kazuhiro Sakai

The manufacturing yield of semiconductor devices has always been susceptible
to contamination from trace metals. As the industry continues to progress
towards devices with smaller features and a higher density of integration,susceptibility to contamination in microfabrication processing presents anincreasing challenge. Controlling contamination at these small scales requires
ever-higher purity of process chemicals and manufacturing conditions.

Agilent Technologies, Tokyo, JapanThe semiconductor device fabrication industry uses well-established cleaning
procedures to remove organic and metallic residues and impurities from thesurface of silicon wafers. The purity of reagents used during manufacturing
processes and the air quality in the fabrication plant are important considerations.
Nitric acid (HNO3) plays an important role in the fabrication of semiconductor
devices so needs to be of ultrahigh purity. A mix of nitric and hydrofluoric acid isused to etch single crystal silicon and polycrystalline silicon. HNO3 is also
combined with phosphoric acid and acetic acid for wet etching of aluminum.
As a reagent, HNO3 is used in the preparation of other semiconductor materials.
SEMI standard C35-0708 Tier-B protocol for HNO3 (69.0–70.0%) specifies
contaminant levels of <1 μg/L (ppb) for several elements [1]. The concentration ofindustrial grade HNO3 is usually 60–68%, depending on the method of production.
In this study, undiluted HNO3 was analyzed directly by triple quadrupole ICP-MS(ICP-QQQ). This approach simplified sample preparation and avoided thepotential introduction of contaminants during dilution.

Experimental
Samples and standards
Two samples of HNO3 were used in this study:– Sample 1: 68 % HNO3 (high purity-grade)– Sample 2: 61 % HNO3 (electronic-grade - lower purity)
No further sample preparation was necessary as all samples were introduced
directly into the ICP-QQQ.
Calibration and quantification were done using the method of standard additions(MSA). Standard solutions were prepared by spiking a multi-element standard
solution (SPEX CertiPrep, NJ, US) into each HNO3 sample to give spike levels of 5,
10, 20, 30 and 40 ppt. The density of the nitric acid solution varies with theconcentration of the acid, which affects the sample transport, nebulization anddroplet evaporation processes in the ICP-MS sample introduction. Therefore, for themost accurate analysis, the acid grade (concentration) used for the spiked MSA
calibration solutions should be approximately matched to the acid concentration of
the samples. ICP-MS MassHunter allows an MSA calibration to be converted to an
external calibration to determine contaminant levels in other nitric acid samples
with similar acid concentration. The solutions were prepared just before analysis.
All preparation and analyses were performed in a Class 10,000 clean room.
42

Instrumentation
An Agilent 8900 Semiconductor configuration ICP-QQQ instrument was usedin this study. The instrument is fitted as standard with a PFA-100 nebulizer,
Peltier-cooled quartz spray chamber, quartz torch, platinum-tipped sampling andskimmer cones, and s-lens. The nebulizer was operated in self-aspiration mode
to minimize the potential for sample contamination from contact with theperistaltic pump tubing. If large numbers of undiluted HNO3 samples are run
routinely, it is recommended that the large (18 mm) insert Pt cone is fitted.
Long-term corrosion of internal ICP-MS components can be minimized by fitting
the dry pump option and ball-type interface valve kit.
In advanced semiconductor applications, the key requirement is to deliver theabsolute lowest possible detection limits (DLs) for each analyte. To achieve thisgoal, laboratories measuring ultratrace levels of contaminants can use a
multitune method, where several tuning steps are applied sequentially during themeasurement of each solution. This approach allows the tuning conditions to be
optimized for the removal of different types of interferences, while maintaining
sensitivity for each analyte. In this work, several reaction cell gases (He, H2, O2,
and NH3) and both hot and cool plasma conditions were used as appropriate forthe large number of analytes being measured. Tuning conditions are shown in
Table 1 and other acquisition parameters are shown in Table 2.
Table 1. ICP-QQQ operating conditions.
Cool-NH3

No gasH2

Acquisition modeO2

O2 -soft

MS/MS

RF power (W)600

Sampling depth (mm)

18.0

1500
8.0

Nebulizer gas (L/min)
Make-up gas (L/min)

He

0.70
0.78

0.36

Ex1 (V)-150

Ex2 (V)-17.0-250.0-120.0Omega bias (V)-70.0-140.0-70.0

Omega lens (V)2.0

Q1 entrance (V)-15.0

He flow (mL/min)

1.0

4.2

10.0

4.7

8.0

4.2

10.0

4.5

3.5

10.5

4.0

-

-

-50.0
-

-

5.0

H2 flow (mL/min)

-

-

7.0

-

-

-

*NH3 flow (mL/min)

2.0 (20%)**

-

-

-

-

-

O2 flow (mL/min)

-

-

-

-

4.5 (30%)**

3.0

-7.0

Axial acceleration (V)1.5

Energy discrimination (V)

-5.0

0.0
5.0

0.0

1.0

*10% NH3 balanced with 90% He** Values in parentheses are % of the maximum flow of the gas controller, as displayed in the tuning paneof ICP-MS MassHunter

43

Table 2. Acquisition parameters.
Parameter

Setting

Q2 peak pattern

1 point

Replicates3 (spiked samples)
10 (unspiked solution for DL measurement)

Sweeps/replicate

10Integration time

2 s for all isotopes

Results and discussion
DLs and BECs
In total, 49 elements were measured using the 8900 ICP-QQQ operating in
multiple tune modes, switched automatically during a single visit to each sample
vial. Data for each of the modes was combined automatically into a single reportfor each sample. DLs and Background Equivalent Concentrations (BECs) inundiluted 68% HNO3 (Sample 1) are given in Table 3. The stability test results are
discussed in the “long-term stability” section of the report.
Table 3. DLs and BECs in high purity 68% HNO3.

44

Element

Tune

Q1

Q2

DL
(ng/L)

BEC(ng/L)

30 pptRecovery %Stability test
RSD %

Be

No gas

9

9

0.12

0.071

92

3.5

B

No gas

11

11

0.43

3.5

94

6.3

Na

Cool-NH3

23

23

0.53

2.3

93

3.1

Mg

Cool-NH3

24

24

0.085

0.049

93

2.0

Al

Cool-NH3

27

27

0.10

0.16

93

3.6

P

O2

31

47

8.1

83

95

―**

S

O2

32

48

2.6

65

93

―**

K

Cool-NH3

39

39

0.38

0.73

93

2.9

Ca

Cool-NH3

40

40

0.54

0.38

93

1.2

Sc

O2

45

61

0.007

0.013

93

0.5

Ti

O2-soft

48

64

0.039

0.081

93

3.3

V

O2-soft

51

67

0.041

0.17

93

1.5

Cr

Cool-NH3

52

52

0.42

0.25

93

3.0

Mn

Cool-NH3

55

55

0.084

0.014

93

2.5

Fe

Cool-NH3

56

56

0.75

1.1

92

4.7

Co

Cool-NH3

59

59

0.21

0.075

93

4.3

Ni

O2-soft

60

60

0.067

0.38

93

2.0

Cu

Cool-NH3

63

63

0.12

0.50

94

3.8

Zn

He

64

64

0.52

0.46

93

2.9

Ga

Cool-NH3

71

71

0 cps

0 cps

92

2.5

Ge

H2

74

74

0.060

0.10

93

1.4

As

O2-soft

75

91

0.082

0.081

93

1.8

Se

H2

78

78

0.78

0.41

93

5.5

Rb

Cool-NH3

85

85

0.089

0.030

93

3.0

Sr

He

88

88

0.014

0.012

93

0.8

Element

Tune

Q1

Q2

DL
(ng/L)

BEC(ng/L)

30 pptRecovery %Stability test
RSD %

Zr

O2

90

106

0.22

1.0

93

0.4

Nb

He

93

93

0.012

0.014

93

0.8

Mo

He

98

98

0.088

0.10

93

1.0

Ru

He

101

101

0.032

0.034

93

1.2

Pd

No gas

105

105

0.066

0.14

92

1.0

Ag

No gas

107

107

0.029

0.025

93

0.9

Cd

No gas

114

114

0.058

0.046

92

1.4

In

No gas

115

115

0.004

0.004

93

0.6

Sn

No gas

118

118

0.099

0.35

93

0.9

Sb

H2

121

121

0.056

0.028

93

1.6

Te

H2

125

125

0.57

0.45

93

5.2

Cs

Cool-NH3

133

133

0 cps

0 cps

93

2.4

Ba

H2

138

138

0.014

0.010

93

0.4

Hf

No gas

178

178

0.014

0.005

93

0.9

Ta

He

181

181

0.052

0.065

93

0.5

W

No gas

182

182

0.030

0.022

93

0.7

Ir

No gas

193

193

0.016

0.011

93

0.9

Au

No gas

197

197

0.049

0.068

93

1.7

Tl

No gas

205

205

0.090

0.46*

93

0.6

Pb

No gas

208

208

0.060

0.21

93

0.7

Bi

No gas

209

209

0.018

0.025

93

0.4

Th

No gas

232

232

0.004

0.003

93

0.8

U

No gas

238

238

0.025

0.013

93

0.6

DLs were calculated as 3-sigma of 10 replicate measurements of a blank HNO3 sample (cps refers counts per
second).
*The BEC of Tl was higher than expected, most likely due to residual signal from the ICP-MS tuning solution.
**P and S concentration in the mixed spike (30 ppt) was too low for reliable quantification above the blank (83ppt and 65 ppt, respectively).

Table 4 shows quantitative data for all SEMI specification elements [1] inhigh purity 68% HNO3 and electronic-grade 61% HNO3 determined by MSA.
For the greatest accuracy, the two different concentration grades of nitric acidmeasured in this study were calibrated using separate MSA calibrations.
However, if additional samples of similar grade (acid concentration) aremeasured, the MSA calibration can be easily and automatically converted to an
external calibration plot. External calibration allows subsequent samples to bemeasured without requiring MSA spike additions into each additional sample.
Good linearity was obtained for all SEMI target elements, as shown in the
representative calibration curves for B, Na, Al, K, Ca, As, and Pb (Figure 1).
Normally, the concentration in each sample is obtained by multiplying thequantitative value by the dilution factor (usually about 10 times for nitric acid).
However, in this study, the quantitative value equals the sample concentration in
the original sample, as the acids were measured undiluted. The results given in
Table 4 show that all 49 elements studied can be analyzed at significantly lower
levels than the <1 ppb maximum limit specified for HNO3 in SEMI standard
C35-0708 Tier-B [1].

45Table 3. Quantitative results for SEMI specification elements [1] in high purity 68% HNO3 andelectronic-grade 61% HNO3.
High-purity grade
68% HNO3,
ng/L

Electronic grade
61% HNO3,
ng /L

SEMI C35-0708
Tier-B max limit,
ng/L

Li

<0.061

0.19

<1000

B

3.5

270

<1000

Na

2.3

130

<1000

Mg

<0.085

11

<1000

Al

0.16

93

<1000

K

0.73

6.5

<1000

Element

Ca

<0.54

50

<1000

Ti

0.081

1.1

<1000

V

0.17

0.24

<1000

Cr

<0.42

70

<1000

Mn

<0.084

3.4

<1000

Fe

1.1

270

<1000

Ni

0.38

28

<1000

Cu

0.50

0.99

<1000

Zn

<0.52

3.8

<1000

As

<0.082

0.25

<1000

Cd

<0.058

0.80

<1000

Sn

0.35

13

<1000

Sb

<0.056

0.11

<1000

Ba

<0.014

0.43

<1000

Pb

0.21

0.31

<1000

Measured values shown as “<” indicate that the measured concentration was below the detection limit.

46

11 ➝ 11 B
x103
2

23 ➝ 23 Na

y = 37.5393 *x + 130.1429
R = 0.9984
DL = 0.4308 ppt
BEC = 3.467 ppt

x103

y = 52.8238 *x + 122.0714
R = 1.0000
DL = 0.5278 ppt
BEC = 2.311 ppt

CPS

CPS

2
1

1

0

0
20.0

40.0

20.0

Conc (ppt)

27 ➝ 27 Al
x103
2

40.0
Conc (ppt)

39 ➝ 39 K

y = 24.8165 *x + 3.8571
R = 0.9994
DL = 0.103 ppt
BEC = 0.1554 ppt

x103

y = 45.5539 *x + 33.1429
R = 0.9998
DL = 0.3848 ppt
BEC = 0.7276 ppt

CPS

CPS

2

1

0.5

0

0
20.0

40.0

20.0

Conc (ppt)

40 ➝ 40 Ca

CPS

2

75 ➝ 91 As

y = 11.0417 *x + 4.2143
R = 0.9993
DL = 0.5426 ppt
BEC = 0.3817 ppt

x103
1

CPS

x102

40.0
Conc (ppt)10

y = 19.4600 *x + 1.5714
R = 0.9997
DL = 0.0824 ppt
BEC = 0.08075 ppt

0.5

0
20.0

40.0
Conc (ppt)

20.0

40.0
Conc (ppt)

208 ➝ 208 Pb

CPS

x104

y = 177.5962 *x + 37.0000
R = 1.0000
DL = 0.05952 ppt
BEC = 0.2083 ppt

0.5

0
20.0

40.0
Conc (ppt)

Figure 1. Calibration curves for several SEMI specification elements in high purity 68% HNO3.

47

Long-term stability
Long-term stability was evaluated by measuring a 68% HNO3 sample spiked at
30 ppt for all elements. Calibration curves were generated at the beginning of thesequence. The spiked samples were then run as unknown samples for a total
analysis period of 6.5 hours. The RSDs of the 21 analysis results are shown in
Table 3 (stability test RSD (%)). Good stability was maintained throughout the run,with RSDs between 0.4 and 5.5 %. S and P gave less reliable long-term results
due to the low concentration of the spike (30 ppt) measured above the relatively
high concentration (83 ppt for P; 65 ppt for S) in the unspiked sample.

Conclusion
The Agilent 8900 ICP-QQQ operating in MS/MS mode provides the sensitivity,
low backgrounds, and effective control of interferences required for the analysis
of ultratrace elements in high purity nitric acid.
Forty-nine elements were measured at sub-ppt to ppt levels in undiluted highpurity 68% HNO3. Calibrations were linear for all elements between 0–40 ppt.
SEMI-specified elements were quantified at the single-figure ppt or sub-ppt levelin high purity 68% HNO3. The reproducibility results for 30 ppt spikes in high purity
undiluted 68% HNO3 were between 0.4–5.5 % RSD for all elements except P and
S, in a sequence lasting 6.5 hours.
The results demonstrate the suitability of the Agilent 8900 Semiconductor
configuration ICP-QQQ for the routine analysis of the highest-purity
semiconductor-grade reagents and process chemicals.

References
1. SEMI C35-0708, Specifications and guidelines for nitric acid (2008).

More information
For more information on Agilent ICP-MS products and services, visit our website
at www.agilent.com/chem/icpms
When analyzing 61–68 % HNO3 on a routine basis, it is recommended to use thefollowing options:– G3280-67056 Pt sampling cone (18 mm insert)– G4915A

Upgrade to dry pump

– G3666-67030 Interface valve kit – ball type valve

48

> Return to table of contents> Search entire document

Direct Determination of V, Cr, Ge, and As in
High-Purity 20% Hydrochloric Acid
AuthorIntroduction

Junichi Takahashi
Agilent Technologies, Japan

Since the 1970s, the RCA Standard Clean (SC) method has been used extensively
in many countries for cleaning silicon wafer surfaces. SC-2 refers to a mixture of
HCl and H2O2 that is used to remove ionic and metallic contaminants from thesurface of silicon wafers. Because cleaning solutions are in direct contact withsemiconductor devices, ultra high purity is required for these solutions. The SEMI
standard Tier-D protocol for HCl defines the contaminant level to be <10 ppt foreach element. Some elements have been very difficult to determine at ppt levelby quadrupole ICP-MS (ICP-QMS) due to significant spectral interferences arisingfrom the Cl matrix, even when analyzed by ICP-MS equipped with a collision/
reaction cell (CRC). Consequently, some methods for the analysis of high purity
HCl by ICP-MS have recommended sample pre-treatment steps to remove
the chloride matrix, which can lead to analyte loss and sample contamination.
In this study, ICP-QQQ was used to analyze undiluted HCl directly. Using MS/MS
mode with mass-shift to remove polyatomic ions, the most problematicelements, such as V, Cr, Ge and As could be determined in HCl at single-figure
ppt detection limits.

Keywords
semiconductor, RCA Standard Clean,silicon wafer, hydrochloric acid,vanadium, chromium, germanium,
arsenic, ammonia on-mass, ammonia
mass-shift, oxygen mass-shift

Experimental
Instrumentation: Agilent 8800 #200. Operating parameters are given in Table 1.
Reagents: 20% TAMAPURE-AA-100 HCl (metallic impurities are guaranteed to be
below 100 ppt) was purchased from Tama Chemicals Co., Ltd. (Kanagawa,Japan). The undiluted HCl was introduced directly into the ICP-QQQ.
Table 1. ICP-QQQ operating conditions.
O2 MS/MS1)NH3 MS/MS2)

RF power

W

1600

Sampling depthmm8Carrier gas flow rate

L/min

0.8

Make-up gas flow rate

L/min

0.41

Octopole bias V

V

-20

KED

V

-20

He

mL/min3

1

O2

mL/min

0.4

0

NH3

mL/min0

31) 100% O2 (purity 99.995%)
2) 10% NH3 balanced with 90% He (purity 99.995%)

49

Results and discussion
Determination of BECs of V, Cr, Ge, and As in high purity HCl
ICP-QMS with a CRC using He collision mode can successfully eliminate somepolyatomic ions such as ArCl [1], and the use of NH3 as a reaction gas also works
to remove the ClO+ ion for the determination of V. However, ICP-QMS has someserious limitations when highly reactive cell gases (such as NH3) are used in the
CRC. Principal among these limitations is the fact that all ions enter the CRC,
so predicted reaction pathways can be disrupted and new reaction product ion
overlaps can be formed if the analyte levels in the sample change. ICP-QQQ with
MS/MS removes this limitation, as the first quadrupole mass filter (Q1) allows
precise selection of the ions that are allowed to enter the cell. This ensures thatreaction processes and product ions are strictly controlled, dramatically
improving detectability of the analyte ions shown in Table 2.
Table 2. Spectral interferences arising from the Cl matrix on some key elements.
Polyatomic interferencem/zAnalyte ion

ClO+

51, 53

51

V+

ClOH+

52, 5452

Cr+, (54Fe+)*

ClCl+

70, 72, 74

70

Ge+, 72Ge+, 74Ge+

ArCl+

75, 7775

As+, (77Se+)**Alternative isotopes can be chosen to avoid spectral interferences on Fe and Se.
51 ➝ 51 V [NH 3MM)]
The MS/MS acquisition mode using O2 or NH
as the reaction gas enables the3x10
y = 8.5726 *x + 2.2000
using
NH3 cell gas), Cr as
determination of trace 51V (measured directly as VRDL+==0.9996
0.523 ppt
BEC = 0.2566 ppt75
52
16 +
74
14
+
Cr O (using O2), Ge as Ge NH2 (using NH3) and As as As16O+ (using O2).
(which is set to the As+ precursor
In the case of As, the 91Zr+ ion is removed by Q1
4ion mass of m/z 75), so the potential overlap from Zr on the AsO+ product ion atm/z 91 is also removed. The complete cut-off of cluster ions by Q1 also
2in the cell, so the potential new
eliminates the possibility that 14NH235Cl is created51
product ion interference on V is avoided. Representative calibration curves for V
and Ge are shown in Figure 1. BECs and DLs determined by the ICP‑QQQ for V, Cr,0
Ge, and As are given in Table 3.
20.0
40.0
60.0
CPS

2

Conc (ppt)

51 ➝ 51 V [NH 3MM)]

74 ➝ 90 Ge [NH 3MM)]y = 8.5726 *x + 2.2000
R = 0.9996
DL = 0.523 ppt
BEC = 0.2566 ppt

x101

4

y = 0.5342 *x + 0.8000
R = 1.0000
DL = 4.43 ppt
BEC = 1.498 ppt

CPS

CPS

x102

2
2

0
20.0

40.0
Conc (ppt)

60.0

0
20.0

40.0

60.0

Conc (ppt)

74 ➝ 901.Ge[NH 3MM)] curves of V (NH3 on-mass mode) and Ge (NH3 mass-shift mode) in 20% HCl.
FigureCalibration
x101

CPS

50
2

y = 0.5342 *x + 0.8000
R = 1.0000
DL = 4.43 ppt
BEC = 1.498 ppt

Table 3. BECs and DLs for V, Cr, Ge and As in 20% HCl.
Element

Ti

Cr

Ge

As

Mode (cell gas)

MS/MS (NH3)

MS/MS (O2)

MS/MS (NH3)

MS/MS (O2)

Measured ion

51

Mass pair

Q1 = Q2 = 51

Q1 = 52,
Q2 = 68

Q1 = 74,
Q2 = 90

Q1 = 75,
Q2 = 91

BEC - ppt

0.3

8.0

1.5

19.7

DL - ppt

0.5

1.1

4.4

3.4

V+

52

Cr16O+

74

Ge14NH2+

52

Cr16O+

Investigation of arsenic contamination
As the BEC for arsenic in high purity HCl was relatively high (Table 3), the signal
count at m/z 91 was investigated further. The signals of the mass-pairs 75/75,
77/77, 75/91 and 77/91 were measured by ICP‑QQQ with MS/MS, the mass pairnumber represents the set mass of Q1 followed by the set mass of Q2, so an
MS/MS mode acquisition of mass pair 75/91 represents a mass-shift modewith Q1 = 75 and Q2 = 91, for example. The four mass pairs were measured in
HCl blanks from three different lots, and the results are shown in Table 4.
The following observations were made:1.	The ratio of the signal of 75/75 to 77/77 is around four, which is close to theratio of the abundance of 35Cl to 37Cl, i.e. 3.13.
2.	The ratio of the signal of 75/91 to 77/93 is 200–1000, which is far in excess of
the ratio of 35Cl to 37Cl.
3.	While the signals of 75/75 and 77/77 are similar for the three HCl blanks, thoseof 75/91 and 77/93 vary.
Table 4. Comparison of background counts (cps) in 3 different lots of 20% HCl*.
Mass pair75->75

77->77

75->91

77->93Sample A

509.3

133.5

584.4

2.5

Sample B

508.4

126.0

1172.6

1.9

Sample C

612.7

130.0

3175.6

2.6*All the samples were obtained from the new bottles of high purity HCl.

Finding #1 suggests that the remaining signal on 75/75 and 77/77 was mostly
from ArCl+. This is a reasonable assumption since ArCl+ doesn’t react with O2very efficiently so most ArCl+ remains at the original masses of 75 and 77.
Finding #2 suggests that the signal of 75/91 is not due to ArCl+. Assuming that
all counts of 77/93 arise from 40Ar37Cl, the contribution of 40Ar35Cl to the signal of
75/91 in the HCl blank is estimated to be just 7-8 cps, which is two orders ofmagnitude lower than the signal that is actually observed. Observation #3,
together with #1 and #2, suggests the high count obtained for 75/91 in HCl isdue to As impurity in the acid.

Reference
1.	Direct analysis of trace metallic impurities in high purity hydrochloric acid by
Agilent 7700s ICP-MS, Agilent application note, 5990-7354EN.
51

> Return to table of contents> Search entire document

Analysis of trace metal impurities in high purity
hydrochloric acid using ICP-QQQ
Authors

Introduction

Kazuo Yamanaka and Kazuhiro Sakai

Hydrochloric acid (HCl) is a component of the standard RCA cleaning process used
to remove organic and metallic residues and impurities from the surface of siliconwafers used in semiconductor manufacturing. The cleaning steps are performed
before high temperature processing steps such as oxidation and chemical vapor
deposition (CVD). RCA Standard Clean 2 (SC-2) removes ionic contaminants fromthe wafer surface. SC-2 follows SC-1, which removes organic residues andparticles. SC-2 consists of HCl combined with hydrogen peroxide (H2O2) andde-ionized water (DIW). Since the cleaning solutions are in direct contact with thesilicon wafer surface, ultrahigh purity reagents are required for these solutions.

Agilent Technologies, JapanSEMI standard C27-0708 Tier-C protocol for HCl specifies a maximum contaminantlevel of 100 ppt for each element (HCl 37.0 - 38.0 %) [1]. The concentration ofindustrial grade HCl is usually 20 or 35%, depending on the method of production.
The Cl matrix leads to the formation of several polyatomic ions, which causesignificant spectral interferences on some key elements. For example, H237Cl+ on
39 + 35 16 +K , Cl O on 51V+, 35Cl16OH+ on 52Cr+, 37Cl16O+ on 53Cr+, 35Cl37Cl+ on 72Ge+, 37Cl2+ on
74
Ge+, and 40Ar35Cl+ on 75As+. As a result of these polyatomic interferences, it has
been difficult to determine these elements at the required levels using conventional
single quadrupole ICP-MS (ICP-QMS). Even ICP-QMS instruments fitted with acollision/reaction cell (CRC) or bandpass filter can only offer limited reduction of
the spectral interferences arising from the Cl matrix. Consequently, some methods
for the analysis of high purity HCl by ICP-QMS have recommended sample
pretreatment steps to remove the chloride matrix, which can lead to analyte loss
and/or sample contamination.
In this study, triple quadrupole ICP-MS (ICP-QQQ) was used to analyze 50 elements
in HCl, using MS/MS mode to resolve the polyatomic interferences. All analytes,
including the most problematic elements such as K, V, Cr, Ge, and As, could bedetermined directly in the undiluted HCl with single digit ppt detection limits.

Experimental
Instrumentation
An Agilent 8900 Semiconductor configuration ICP-QQQ was used in this study.
The instrument was fitted with a PFA-100 nebulizer, Peltier-cooled quartz spraychamber, quartz torch, platinum-tipped sampling and skimmer cones and s-lens.
The nebulizer was operated in self-aspiration mode to minimize the potential forsample contamination from the peristaltic pump tubing. In advanced
semiconductor applications, the key requirement is to deliver the absolute lowest
possible detection limits (DLs) for each analyte. To achieve this goal, laboratories
measuring ultratrace levels of contaminants can use a multi-tune method, where
several tuning steps are applied sequentially during the measurement of eachsolution. This approach allows the tuning conditions to be optimized for theremoval of different types of interferences, while maintaining maximum sensitivity
for each analyte. In this work, several reaction cell gases (H2, O2, and NH3) were52

used as appropriate for the large number of analytes being measured. He was used
as a buffer gas in the NH3 reaction gas modes. Tuning conditions are shown in
Table 1 and other acquisition parameters are shown in Table 2.
Table 1. ICP-QQQ operating conditions.
Cool

Cool-NH3

No gasH2

Acquisition mode

O2

600

1500

Sampling depth (mm)

18.0

18.0
8.0

Nebulizer gas (L/min)

0.70
0.90

Extract 1 (V)Extract 2 (V)O2 -soft

MS/MS

RF power (W)Make-up gas (L/min)

NH3

0.48
-150

4.2

-18.0

4.7

-17.0

Omega bias (V)-70.0

Omega lens (V)2.0

Q1 entrance (V)

-15.0

4.5

3.5

-250.0-120.0-140.0
10.0

-70.0

8.0

10.5

4.0

-50.0

He flow (mL/min)

-

1.0

-

-

-

1.0

-

H2 flow (mL/min)

-

-

-

7.0

-

-

-

2.0
(20%)

-

-

-

2.0
(20%)

-

-

-

0.45
(30%)

NH3 flow (mL/min)
O2 flow (mL/min)--

Axial acceleration (V)

0.0

1.5

Energy discrimination (V)

15.0

-5.0

0.0
5.0

1.0
0.0

0.45
(30%)
0.2

1.0

-7.0

Table 2. Acquisition parameters.
Parameter

Setting

Q2 peak pattern

1 point

Replicates3 (spiked samples)
10 (unspiked solution)

Sweeps/replicate

10Integration time

2 s for all isotopes

Samples and standards
The samples of HCl used in this study included:– Sample 1: 20% HCl (high purity grade).
– Sample 2: 36% HCl (non-high purity grade).
– Sample 3: 20% HCl (34% high purity grade diluted to 20% with DIW).
No further sample preparation was necessary as all samples were introduced
directly into the ICP-QQQ. To run undiluted HCl routinely, it is recommended thatthe large (18 mm) insert Pt cone is fitted. Long-term corrosion of internal ICP-MS
components can be minimized by fitting the dry pump option.
53

Calibration and quantification were done using the method of standard additions(MSA). Standard solutions were prepared by spiking a multi-element standard
solution (SPEX CertiPrep, NJ, US) into each HCl sample type to give spike levelsof 10, 20, 30, and 40 ppt. The MSA calibrations were then automaticallyconverted to external calibrations in the ICP-MS MassHunter data analysis table.
This conversion allows other samples of the same type (HCl concentration) tobe quantified without requiring separate MSA spike additions into each sample.
All solutions were prepared just before analysis.
All preparation and analysis was performed in a Class 10,000 clean room.

Results and discussion
DLs and BECs
In total, 50 elements including all SEMI specification analytes were measured
using the 8900 ICP-QQQ operating in multiple tune modes. Data for each mode
was combined automatically into a single report for each sample. Detection limits(DLs) and background equivalent concentrations (BECs) in 20% HCl are given in
Table 3.
Table 3. DLs and BECs in high purity 20% HCl*.
Element
Li

Cell gas mode

Q1 mass

Q2 mass

DL ng/L

BEC ng/L

Cool-NH3

7

7

0.032

0.016

Be

No gas

9

9

0.022

0.021

B

No gas

11

11

0.55

4.1

Na

Cool-NH3

23

23

0.064

0.15

Mg

Cool-NH3

24

24

0.077

0.056

Al

Cool-NH3

27

27

0.20

0.19

P

O2-soft

31

47

1.1

2.6

K

Cool-NH3

39

39

0.087

0.17

Ca

Cool-NH3

40

40

0.44

0.68

Sc

O2-soft

45

61

0.014

0.012

Ti

O2-soft

48

64

0.051

0.074

V

NH3

51

51

0.11

0.19

Cr

Cool-NH3

52

52

0.18

0.12

Mn

Cool-NH3

55

55

0.016

0.006

Fe

Cool-NH3

56

56

0.24

0.27

Co

Cool-NH3

59

59

0.10

0.038

Ni

Cool-NH3

60

60

0.66

0.26

Cu

Cool-NH3

63

63

0.10

0.12

Zn

NH3

66

66

0.14

0.097

Ga

NH3

71

71

0.015

0.026

Ge

NH3

74

107

0.90

3.0

Ge

NH3

74

107

0.32

0.77

As

O2

75

91

1.4

48

As

O2

75

91

0.73

6.2

Se

H2

78

78

0.44

0.52

* Shaded rows for Ge and As indicate results measured in Sample 3, due to suspected contamination for theseelements in Sample 1.

54

Element
Rb

Cell gas mode

Q1 mass

Q2 mass

DL ng/L

BEC ng/L

Cool-NH3

85

85

0.041

0.013

Sr

NH3

88

88

0.003

0.001

Y

O2-soft

90

106

0.010

0.006

Zr

O2-soft

93

125

0.012

0.004

Nb

O2

93

125

0.004

0.005

Mo

He

98

98

0.13

0.57

Ru

He

101

101

0.016

0.003

Pd

He

105

105

0.010

0.001

Ag

He

107

107

0.032

0.014

Cd

He

114

114

0.090

0.10

In

He

115

115

0.035

0.021

Sn

He

118

118

0.57

3.3

Sb

He

121

121

0.66

1.5

Te

H2

125

125

0.37

0.31

Cs

NH3

133

133

0.008

0.019

Ba

NH3

138

138

0.005

0.005

Hf

No gas

178

178

0.005

0.004

Ta

He

181

181

0.013

0.010

W

No gas

182

182

0.039

0.062

Re

No gas

185

185

0.12

0.50

Ir

No gas

193

193

0.017

0.012

Au

He

197

197

0.027

0.022

Tl

No gas

205

205

0.007

0.004

Pb

H2

208

208

0.028

0.023

Bi

No gas

209

209

0.024

0.030

Th

No gas

232

232

0.017

0.021

U

No gas

238

238

0.009

0.005

Quantitative results
Table 4 shows quantitative data for all SEMI specification elements in high purity
20% HCl and non-high purity 36% HCl determined by MSA. The results show thatthe 8900 ICP-QQQ can measure contaminants in HCl at a much lower level than
the 100 ppt maximum limit specified in the SEMI specifications. It is important tonote that the concentration specified by SEMI is for 37–38% HCl while the data
presented here is for 20 and 36% HCl. Even taking this difference into account,the 8900 ICP-QQQ is clearly able to measure contaminants at levels far lower
than current industry requirements for high-purity HCl.

55

Table 4. Quantitative results for SEMI specification elements in high purity 20% HCl (Sample 1) andnon-high purity 36% HCl (Sample 2).
Element
Li

Cell gas mode

Q1

Q2

Sample 1
20% HCl, ng/L

Sample 2
36% HCl, ng/L

DL, ng/L

Cool-NH3

7

7

<DL

<DL

0.032

B

No gas

11

11

4.1

15

0.55

Na

Cool-NH3

23

23

0.15

6.4

0.064

Mg

Cool-NH3

24

24

<DL

6.5

0.077

Al

Cool-NH3

27

27

<DL

23

0.20

K

Cool-NH3

39

39

0.17

1.5

0.087

Ca

Cool-NH3

40

40

0.68

13

0.44

Ti

O2-soft

48

64

0.074

1.4

0.051

V

NH3

51

51

0.19

4.6

0.11

Cr

Cool-NH3

52

52

<DL

0.55

0.18

Mn

Cool-NH3

55

55

<DL

0.071

0.016

Fe

Cool-NH3

56

56

0.27

7.6

0.24

Ni

Cool-NH3

60

60

<DL

<DL

0.66

Cu

Cool-NH3

63

63

0.12

0.57

0.10

Zn

NH3

66

66

<DL

1.1

0.14

As

O2

75

91

48

39

0.73*

Cd

He

114

114

0.10

0.34

0.090

Sn

He

118

118

3.3

2.3

0.57

Sb

He

121

121

1.5

0.95

0.66

Ba

NH3

138

138

0.005

<DL

0.005

Pb

H2

208

208

0.023

0.13

0.028

*DL for As measured in Sample 3, due to suspected contamination for this element in Sample 1.

Cr and K determination
Cool plasma is a proven technique used to remove plasma-based interferences.
Although it has been largely superseded by CRC methodology, cool plasma
remains the most effective analytical mode for some elements in certain
matrices. Combining cool plasma with CRC technology has been shown to be a
powerful mode for interference removal [2]. Because the major isotope ofchromium (52Cr+) suffers an interference from 35Cl16OH+ in high purity HCl, Cr wasdetermined using cool plasma with ammonia cell gas. The calibration curve for52
Cr shows that 35Cl16OH+ interference was removed successfully, allowing a
BEC of 0.12 ng/L (ppt) to be achieved, with a detection limit of 0.18 ppt (Figure 1).
The DL and BEC displayed in the ICP-MS MassHunter calibration plots are basedon the 10 replicates of the unspiked high-purity 20% HCl sample.

56

52 ➝ 52 Cr [Cool-NH 3]

CPS

x103

y = 17.4775* x + 2.0714
R = 0.9999
DL = 0.1816 ppt
BEC = 0.1185 ppt

0.5

0
20.0

40.0
Conc (ppt)

Figure 1. 52Cr calibration curve obtained using cool plasma and NH3 cell gas, showing low BEC
and good linearity.

The same approach is effective for the determination of other interferedelements such as K. Figure 2 shows that the interference from H237Cl+ on
39 +K was suppressed using cool plasma and NH3 cell gas, giving a BEC and
DL for K of 0.17 ppt and 0.09 ppt, respectively.
39 ➝ 39 K [Cool-NH 3]x103
6

y = 113.1886* x + 18.7857
R = 0.9996
DL = 0.08685 ppt
BEC = 0.166 ppt

CPS

4

2

0
20.0

40.0
Conc (ppt)

Figure 2. 39K calibration curve obtained using cool plasma and NH3 cell gas.

V and Ge determination
ICP-QMS fitted with a CRC operating in helium collision mode can successfully
eliminate many polyatomic ions using He collision cell gas and kinetic energy
discrimination (KED) [3]. However, ICP-QMS has some serious limitations whenhighly reactive cell gases, such as NH3, are used in the CRC.
ICP-QMS has no mass selection step before the cell, so all ions enter the CRC.
It is likely, therefore, that new reaction product ions will form in the CRC that may
overlap the target analyte mass of interest. Bandpass ICP-QMS instruments,
where all ions within a certain mass range (usually about 10 u) of the target
analyte can enter the cell and react, have similar limitations to traditional
ICP-QMS in terms of controlling reaction chemistry with highly reactive cell gases.
ICP-QQQ with MS/MS removes this limitation, as the first quadrupole mass filter(Q1), which is located before the CRC, allows precise selection of the specificmass of ions that are allowed to enter the cell. This extra mass selection step
ensures that reaction processes in the cell are controlled, which removes the57potential for non-target product ion overlaps and dramatically improves thedetectability of the analyte ions.
MS/MS acquisition mode using NH3 as the reaction cell gas was used for the
trace determination of V and Ge. The ClO+ interference on 51V was removed using
NH3 on-mass mode. Potentially, 14NH235Cl+ could form in the cell and interferewith V at m/z 51. However, the unit mass resolution of Q1 on the 8900 ICP-QQQ
ensures that only ions at m/z 51 can enter the cell. All other matrix and analyteions, e.g. 35Cl+, are prevented from entering the cell and cannot, therefore,
contribute to the signal at the analyte mass. This simple approach avoids theformation of any new product ion interferences on 51V.
The ClCl+ interference on 74Ge was avoided by measuring a Ge-ammonia cluster
ion, 74Ge[14NH2(14NH3)]+, in mass-shift mode at mass 107. Q1 (set to m/z 74 toallow the 74Ge+ precursor ions to enter the cell) rejects all non-target masses,
including 107Ag+, which would otherwise overlap the Ge-NH3 product ion mass.
Q1 (in contrast to a bandpass filter) also rejects all other nearby analyte ions,70
Zn+, 71Ga+, 73Ga+, 75As+, 78Se+, etc., preventing them from forming potentiallyoverlapping ammonia clusters at the target product ion mass.
Representative calibration curves for V and Ge are shown in Figure 3, again
illustrating the low BEC (0.19 ppt for V and 0.77 ppt for Ge) and DL (0.11 ppt for V
and 0.32 ppt for Ge) achieved with the 8900 with NH3 cell gas in MS/MS mode.
51 ➝ 51 V [NH 3]x103

y = 49.5575* x + 9.5000
R = 0.9998
DL = 0.1077 ppt
BEC = 0.1917 ppt

CPS

2

1

0
20.0

40.0
Conc (ppt)

74 ➝ 107 Ge [NH 3]x103

y = 21.8313* x + 16.9000
R = 0.9998
DL = 0.3219 ppt
BEC = 0.7741 ppt

CPS

1

0.5

0
20.0

40.0
Conc (ppt)

Figure 3. 51V and 74Ge calibration curve obtained using NH3 cell gas.

58

Determination of As
Arsenic has a single isotope at m/z 75 that suffers an interference from thepolyatomic ion 40Ar35Cl+. Since ArCl+ readily forms in a chloride matrix, thepolyatomic interference compromises the determination of As at ultratracelevels in concentrated HCl using ICP-QMS. Oxygen can be used as the cell gas to
avoid this overlap, with As being measured as the AsO+ product ion at m/z 91.
However, with ICP-QMS, the AsO+ product ion at mass 91 suffers an interference
from 91Zr+. Helium collision mode in the Agilent ORS cell can reduce ArCl+
effectively, allowing a BEC of less than 20 ppt to be achieved by ICP-QMS [3].
But, as semiconductor industry demands become more stringent, this sensitivity
may not be sufficient for the lowest level of ultratrace analysis.
Using the 8900 ICP-QQQ with MS/MS, the 91Zr+ ion is removed by Q1, which is
set to the As+ precursor ion mass of 75. MS/MS mode allows O2 cell gas to be
used successfully, with As being measured as the AsO+ product ion at m/z 91
without overlap from 91Zr+. A further benefit of O2 cell gas is that measuring
AsO+ provides more sensitivity that direct measurement of As+ in He mode.
A calibration curve for As in 20% HCl (Sample 3) is shown in Figure 4,
demonstrating a BEC of 6.17 ppt and a DL of 0.73 ppt. While lower than theindustry requirements for high-purity HCl, this BEC doesn’t represent the best
performance that can be achieved with the 8900 ICP-QQQ, so further
investigation was done to identify the cause of the relatively high background.
75 ➝ 91 As [Ox]x103y = 44.0143* x + 271.5000
R = 0.9998
DL = 0.7272 ppt
BEC = 6.168 ppt

CPS

2

1

0
20.0

40.0
Conc (ppt)

Figure 4. 75As MSA calibration curve obtained in Sample 1 using O2 cell gas.

Investigation of arsenic contamination
As the measured result for As was relatively high in high purity HCl Sample 1(Table 4), the signal count at m/z 91 (mass of the product ion AsO+) wasinvestigated further. In a high Cl matrix, the polyatomic ion 40Ar35Cl+ forms in theplasma and during ion extraction. This polyatomic ion has the same nominal
mass as the target 75As+ precursor ion, so it passes through Q1 and enters thecell. While not thermodynamically favored, the ArCl+ might react with the O2 cellgas to form ArClO+, which would therefore remain as an interference on AsO+ at
m/z 91. This possibility can be checked by comparing the isotopic signature of
the Cl-based product ions observed in the mass spectrum. Since chlorine has
two isotopes, 35 and 37, the ratio of the natural abundances of these isotopes(75.78%: 24.22%) can be used to confirm whether a product ion is Cl-based.
59

The signals of the mass-pairs 75/91 and 77/93, representing the potential Cl
interferences 40Ar35Cl16O+ and 40Ar37Cl16O+ respectively, were measured by ICP-QQQ
with MS/MS. A neutral gain scan spectrum (where Q1 and Q2 are scanned
synchronously, with a fixed mass difference between them) was measured and thescan is presented in Figure 5. For this neutral gain scan, Q1 was scanned across themass range from 74 to 78 u to pass any precursor ions to the CRC, and Q2 wasscanned synchronously at Q1 + 16, monitoring any product ions formed by O-atom
addition. The peak at mass-pair m/z 75/91 that caused the relatively high BEC for As
in Sample 1 is clearly visible. However, if the signal at 75/91 was due to interference
from 40Ar35Cl16O+, there would also be a corresponding signal from 40Ar37Cl16O+ at
mass-pair 77/93. Since there was no signal observed at 77/93, we can conclude
that the signal at m/z 75/91 is not due to any contribution from ArClO+, and the highreported concentration of As in Sample 1 is due to contamination.
Tune Mode = Ox : 007SMPL.d
x103

ArCIO

CPS

4

2

0
74->9075->91

76->92Mass pair

77->9378->94

Figure 5. Neutral gain scan spectrum for 20% high purity HCl showing the theoretical isotope templatefor 40Ar35Cl16O+ and 40Ar37Cl16O+. Q1 was scanned from m/z 74 to 78, while Q2 was set to Q1 + 16.

Conclusion
The high performance of Agilent ICP-QQQ systems for the analysis of trace
metallic impurities in concentrated HCl has been described previously [4].
Now, the Agilent 8900 Semiconductor configuration ICP-QQQ with flexible cellgas support, powerful MS/MS capability, and proven cool plasma performance,
further improves the detection limits for the analysis of a wide range of trace
metal contaminants in high purity acids. The advanced reaction cell methodology
supported by the 8900 ICP-QQQ allows the SEMI elements, including thoseelements with potential matrix-based interferences such as K, V, Cr, Ge, and As,
to be determined at lower concentrations in a chloride matrix than waspreviously possible.

60References
1.	SEMI C27-0708, Specifications and guidelines for hydrochloric acid (2008)
2.	Junichi Takahashi and Katsuo Mizobuchi, Use of Collision Reaction Cell under
Cool Plasma Conditions in ICP-MS, 2008 Asia Pacific Winter Conference on
Plasma Spectroscopy
3.	Junichi Takahashi, Direct analysis of trace metallic impurities in high purity
hydrochloric acid by Agilent 7700s/7900 ICP-MS, Agilent publication, 2017,5990-7354EN

More information
When analyzing 20–36% HCl on a routine basis, it is recommended to use thefollowing options:– G3280-67056 Pt sampling cone (18 mm insert)– G4915A

Upgrade to dry pump

– G3666-67030 Interface valve kit – ball type valve
Since hydrochloric acid is corrosive, avoid placing open sample bottles near the
instrument.

61

> Return to table of contents> Search entire document

Determination of Ti, V, and Cr in 9.8% Sulfuric Acid
AuthorIntroduction

Junichi Takahashi
Agilent Technologies, Japan

High purity H2SO4 is frequently used in the manufacturing of semiconductor
devices, in processes such as the removal of organic substances from thesurface of silicon wafers. The required metallic impurity level is lower than
100 ppt in the concentrated (usually 98%) acid. ICP-MS is the technique of choicefor the measurement of trace metal impurities in semiconductor process
chemicals. There are, however, some limitations for the measurement ofelements such as Ti, V and Cr in H2SO4. Because of its high viscosity of 27 cP, it is
not possible to introduce H2SO4 directly into the ICP without dilution. A 10 times
dilution in UPW is normally applied, thus the BEC of the calibration curve must be
lower than 10 ppt in the 9.8% H2SO4 solution measured. In addition, spectralinterferences from SO+, S2+ and ArS+ originating from H2SO4 make it difficult todetermine elements such as Ti and Cr at low concentration even by quadrupole
ICP-MS (ICP-QMS) equipped with collision/reaction cell (CRC). As outlined in thisreport, the Agilent 8800 ICP-QQQ with MS/MS mode allows the successful
determination of the most problematic elements including Ti, V and Cr in H2SO4.

Keywords
semiconductor, process chemicals,
ultra pure water, UPW, calcium, methodof standard additions, hydrogenon-mass

Experimental
Instrumentation: Agilent 8800 #200. Operating parameters are given in Table 1.
Reagents and sample preparation: Highly purified H2SO4, TAMAPURE-AA-100(98% H2SO4) was purchased from Tama Chemicals Co., Ltd. (Kanagawa, Japan).
5 g of H2SO4 was diluted by a factor of 10 in a chilled PFA bottle.
Table 1. ICP-QQQ operating conditions.
O2 MS/MS1)
RF powerW

NH3 MS/MS2)
1600

Sampling depthmm8Carrier gas flow rate

L/min

0.8

Make-up gas flow rate

L/min

0.41

Octopole bias V

V

-20

KED

V

-20

He

mL/min3

1

O2

mL/min

0.4

0

NH3

mL/min0

31) 100% O2 (purity 99.995%)
2) 10% NH3 balanced with 90% He (purity 99.995%)

Results and discussion
Of the potential polyatomic interferences formed from the H2SO4 matrix, the SO+ ion isvery stable and difficult to eliminate because its dissociation energy is as high as 5.44
eV. In addition, its ionization potential is 10.3 eV, which is almost the same as that of S,
10.36 eV. The spectral interferences caused by SO+ and SOH+ overlap with 48Ti (32S16O),
51
V (33S18O, 34S16OH and 32S18OH) and 52Cr (34S18O). Quadrupole ICP-MS operating in He
62

collision mode provides BECs of 60 ppt for 47Ti (the BEC for the preferred isotope 48Ti
is much higher), 3 ppt for V and 8 ppt for Cr in 9.8% H2SO4. The BEC of Ti, in particular,
is not acceptable for producers and users of semiconductor grade H2SO4.
Appropriate reaction gases to remove SO+ successfully in ICP-QMS are difficult
to find. NH3 can reduce SO+ by two orders of magnitude but the background signal
remains too high for this application. Additionally, cluster ions of NH3 such as NmHn
produced by the reaction between Ar+ and the NH3 cell gas lead to new reaction
product ion interferences that increase the background at m/z 51, for example.
The 8800 ICP-QQQ operating in MS/MS mass-shift mode with NH3 or O2 reaction gas
provides reliable and consistent measurement of Ti as 48Ti14NH(14NH3)3 (Figure 1) andCr as 52Cr16O in H2SO4. Furthermore, in MS/MS mode, the Ar+ ion is removed by Q1,
preventing it from reacting with NH3 to form new product ion interferences in the cell.
This reduces the background at m/z 51 improving the BEC for V, as shown in Figure 2.
The final BECs obtained by ICP-QQQ in 9.8% high purity H2SO4 are summarized inTable 2.
48 ➝ 114 Ti [NH 3MM)]

51 ➝ 51 V [NH 3MM)]x103

y = 1.1606 *x + 0.8333
R = 0.9960
DL = 0.7462 ppt
BEC = 0.718 ppt

3

5

CPS

CPS

x101

y = 45.2034 *x + 3.0000
R = 1.0000
DL = 0.06637 ppt
BEC = 0.06637 ppt

2

1

0

0
20.0

40.0

60.0

20.0

Conc (ppt)

40.0

60.0

Conc (ppt)

Figure 1. Calibration curve of Ti in 9.8% H2SO 4.

Figure 2. Calibration curve of V in 9.8% H2SO 4.

Table 2. BECs of Ti, V and Cr in 10x diluted 98% H2SO 4, measured by ICP-QQQ.
Element

Ti

VC

Mode (cell gas)

MS/MS (NH3)

MS/MS (NH3)

MS/MS (O2)

Measured ion

48

Mass pair

Q1 = 48,
Q2 = 114

Q1 = Q2 = 51

Q1 = 52,
Q2 = 68

BEC - ppt

0.72

0.07

3.70

Ti14NH(14NH3)3+

51

V+

52

Cr16O+

Conclusion
ICP-QQQ operating in MS/MS mode provides a reliable means for manufacturersof high purity H2SO4 to guarantee all metallic impurity concentrations at less than
100 ppt in the concentrated acid.

More information
Determination of challenging elements in ultrapure semiconductor grade sulfuric acidby Triple Quadrupole ICP-MS, Agilent publication, 5991-2819EN

63

> Return to table of contents> Search entire document

Determination of trace elements in ultrapure
semiconductor grade sulfuric acid using theAgilent 8900 ICP-QQQ in MS/MS mode
Authors

Introduction

Michiko Yamanaka, Kazuo Yamanaka
and Naoki Sugiyama,

In the semiconductor industry, it is extremely important to reduce contamination
within the manufacturing process, as particle-, metallic-, or organic-based
contaminants degrade the quality and reliability of the final device. Organic
materials, such as photoresist polymer patterns, must be thoroughly removed
from the surface of the silicon wafer following ion implantation; this cleaning
step is performed using a piranha solution; a mixture of sulfuric acid (H2SO4) andhydrogen peroxide (H2O2). Ensuring a low level of metal impurities in thesechemicals is vital to ensure that contamination of the wafer surface is avoided at
this stage in the manufacturing process.

Agilent Technologies, Japan

Since its inception, ICP-MS has been widely utilized for the analysis of elemental
impurities in chemicals and materials used by semiconductor-related industries.
More recently, collision/reaction cell (CRC) technology, which was first developedfor quadrupole ICP-MS (ICP‑QMS), has been implemented to remove polyatomic
ions that cause problematic spectral interferences on many analytes. In certain
sample matrices, however, not all polyatomic species can be completely removed
using CRC-ICP-QMS, hindering accurate measurement of a few importantelements at low-levels. For example, high concentration sulfur matrices generatepolyatomic ions with a low ionization potential, such as SO+, which interferes with
Ti. Since SO+ has a high dissociation energy of 5.4 eV, it is not easily dissociatedusing a CRC operating in collision mode with an inert cell gas.
The Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) has a unique tandem MS
configuration, comprising two quadrupole mass filters (Q1 and Q2), separated byan octopole reaction system (ORS4) cell. The MS/MS configuration allows
reaction chemistry to be applied to the most complex and challenging
interference problems that hinder ICP-QMS. As more reactive gases (e.g. NH3 or
O2) can be used in ICP-QQQ in a controlled way, the reaction pathways andproduct ions formed in the cell are not affected by changes in the sample matrix
or by other co-existing analyte ions. Using MS/MS, Ti can be analyzed in a sulfur
matrix, using NH3 reaction gas mode, by measuring a suitable ammonia cluster
product ion that is free from polyatomic ion interference. In addition, the new axial
acceleration technology of the 8900 ICP-QQQ, which accelerates product ionsgenerated in the ORS4 cell, leads to an increase in sensitivity of product ions,
including Ti/NH3 cluster ions.
In this study, the Agilent 8900 ICP-QQQ was used for the analysis of 42 analytes
in sulfuric acid, including Ti and other elements which are difficult to determine attrace levels in a high sulfur matrix.

64Experimental
Sample preparation
All sulfuric acid samples were prepared using pre‑cleaned PFA containers.
High purity 98% H2SO4 (TAMA Chemicals Co. Ltd. Japan) was diluted ten‑foldwith ultrapure water (UPW). All calibration and quantification was done using themethod of standard additions (MSA). Standard solutions were prepared from a
mixture of XSTC-331, XSTC-7, XSTC-8 (SPEX CertiPrep, USA) and a Si single
element standard (Kanto Chemical Co., Inc., Japan).
Instrumentation
An Agilent 8900 ICP-QQQ (#200, Semiconductor configuration) was usedthroughout. The sample introduction system comprised a quartz torch with a
2.5 mm i.d. injector, quartz spray chamber, a PFA concentric nebulizer andplatinum-tipped interface cones. The sample was self-aspirated using an Agilent
I-AS autosampler. MS/MS mode, in which Q1 and Q2 both act as unit mass filters,
was used for all measurements. To run ten-fold diluted sulfuric acid routinely,
it is recommended that the large (18 mm) insert Pt cone is fitted. Long-term
corrosion of internal ICP-MS components can be minimized by fitting the dry
pump option and ball-type interface valve kit.
Evaluation of different reaction gases
For multi-element trace analysis, O2, NH3, H2 and He were evaluated as cell gases.
O2 is often used in mass-shift methods to move the target analyte from its
elemental ion mass to its oxide product ion mass (MO+) by setting Q2 to 16 amu
higher than Q1 [1]. NH3 is highly reactive and used as a cell gas in both on-massmode and mass-shift mode depending on the interference to be removed.
H2 and He were used with O2 or NH3, to assist the cell gas reaction process.
He cell gas was used in collision mode to eliminate many common backgroundpolyatomic interferences.
Results and discussion
As is typical with analyses at the ultra-trace level, the optimum plasma mode
(normal or cool plasma) and cell gas type was selected for each element.
Most higher-mass analytes are free from significant interference in high-purity
reagents, but element-specific optimization is particularly important for theultra-trace analysis of Ti, V, Cr, Zn, Ge and As, which suffer from S-basedpolyatomic interferences in a sulfur-matrix. Instrument operating parameters
used are shown in Table 1.
Oxygen mass-shift mode detects analyte ions (M+) as reaction product ions at
the oxide ion mass (MO+). For example, 75As+ is detected as AsO+ at m/z 91.
This method is used when the analyte ion reacts efficiently with O2 gas to forman oxide ion, while the interfering ion reacts slowly or not at all with the O2 gas,so does not contribute significantly to the signal at the new mass of the analyte
product ion. The lowest detection limits (DLs) and background equivalentconcentrations (BECs) for Si, As and Se were obtained with a relatively highO2 cell gas flow rate (0.7 mL/min), which encourages the formation of O-atom
addition product ions for these analytes, especially Se.

65

Table 1. ICP-QQQ operating parameters.
Cool-NH3
RF power, W

600

Sampling depth, mm

18.0

NH3-1
(for Ti and V)

NH3-2(for Zn)O2

O 2+ H 2(for P)He mode1

1600
8.0

Carrier gas, L/min

0.7

Makeup gas, L/min

0.75

Extraction lens 1, V

-150

Extraction lens 2, V

-15

Octopole bias, V-10.0

Axial acceleration, V

0.49
5.3

5.1
-200

-17.0

-13.5

1.0

5.0

4.5

-250

-190

-155

-11.0

-4.0

-100.0

0.2

1.0

0.0

Energy discrimination, V

-5.0

-18.2

-20.0

-13.0

-8.0

5.0

NH3 flow1, mL/min

2

1

4.5

-

-

-

O2 flow, mL/min

-

-

-

0.7

0.2

-

He flow, mL/min

1

9

1

-

-

9

H2 flow, mL/min

-

-

-

-

1

-

High engergy He mode conditions
10% NH3 balanced with 90% He

12

O2 + H2 mass-shift mode for P
In a sulfur matrix, on-mass measurement of 31P is affected by the peak tail of thelarge adjacent 32S peak. This can be addressed using ICP-QQQ, which benefits
from the high abundance sensitivity (AS) of MS/MS mode. The AS in MS/MS
mode is the product of the AS of the two quadrupoles, so Q1 AS x Q2 AS. On the
Agilent 8900, each of the two quadrupoles has an AS specification of 10-7, so theoverall AS is theoretically 10-14, meaning that peak tailing, even from very intense
background peaks, is practically eliminated. However, on-mass measurement(e.g. using He mode) does not give sufficiently low backgrounds for themeasurement of P at ultra-trace levels. As an alternative, O2 mass-shift mode canbe used to effectively eliminate the NO+ or NOH+ interference on P+, since theoxidation of P+ is exothermic, while the oxidation of NO+ or NOH+ is endothermic.
Hence, these background polyatomic ions are avoided by shifting the P+ awayfrom the interfering ions, and measuring it as the PO+ product ion at m/z 47.
Interestingly, P sensitivity was improved 1.5 times by adding H2 gas to the cell
together with O2. In this study, O2 + H2 mass-shift mode was used for P analysis
to obtain maximum sensitivity. However, O2 alone would deliver sufficientperformance for the analysis of semiconductor grade H2SO4. Optimum gas
conditions were 0.2 mL/min of O2 and 1 mL/min of H2.
NH3 mass-shift mode for Ti
The two most abundant isotopes of titanium, 48Ti and 46Ti, suffer interferencesfrom 32S16O and 32S14N respectively, so the minor isotope, 47Ti, is usually selected
for analysis using ICP-QMS. However, MS/MS mode with ICP-QQQ allows controlof the complex reaction chemistry that occurs with ammonia cell gas, allowing
the major Ti isotopes to be measured as a suitable Ti-NH3 cluster ion and thereby
avoiding the S-based interferences. Single ng/L level BECs can be achieved using
this approach [2]. 48Ti could also potentially suffer an isobaric overlap from theminor 48Ca isotope (0.187% abundance), but this is not a problem in semiconductor
reagents as the concentration of Ca is low.
When a heavy cell gas such as O2 or NH3 is used at a high flow rate, analyte ionsentering the cell significantly slow down due to suffering multiple collisions withthe cell gas molecules, resulting in an increased transit time through the cell.
66

Some ions may even lose so much energy that their progress through the cellstops, which causes a loss of sensitivity. Furthermore, product ions formed in
the cell are generally very slow as a result of the reaction with cell gas molecules.
If the transmission of these product ions through the cell reduces, so does thesensitivity. The ORS4 CRC of the 8900 Semiconductor configuration ICP-QQQ
benefits from axial acceleration; an electrical field is established by a potential
gradient in the axial direction of the cell so that positively charged analyte ionsare accelerated towards the cell exit. Axial acceleration can improve thetransmission of slow-moving product ions, and thus increase the sensitivity forcertain analytes. In practice, changing the axial acceleration voltage from 0 V to
+1 V resulted in a 5-fold increase in the sensitivity of the ammonium cluster ion
selected for titanium analysis, 48TiNH(NH3)3+ (m/z = 114). An axial acceleration
voltage of 1 V was used for Ti analysis using MS/MS mass-shift mode with
NH3 cell gas.
Multi-element analysis
Representative calibration curves obtained using MSA are shown in Figure 1.
Good linearity was observed for all analytes (R > 0.9995), and sub-ppt detection
limits were achieved for all elements apart from Si (44 ppt), P (3 ppt), and Zn(1.5 ppt). The quantitative results of the analysis of 9.8% H2SO4 are shown in
Table 2. The DLs were determined from 10 x replicate measurements of theblank 9.8% H2SO4 solution. Recoveries and RSDs were determined from10 replicate measurements of a 20 ng/L spiked solution of 9.8 % H2SO4.
Excellent performance was achieved for all elements, including Ti, V and Zn,
indicating the effective suppression of S-based matrix interferences.

Figure 1. Calibration curves of P, Ti, V and As in 9.8% H2SO 4
67

Table 2. Quantitative results for 42 elements in 9.8% H2SO4.
AnalyteMode

Q1 Mass

Q2 MassDL (ng/L)

BEC (ng/L)

20 ng/L Spike
Recovery (%)

20 ng/L RSD (%)

Li

Cool-NH3

7

7

0.13

0.13

104

2.1

Na

Cool-NH3

23

23

0.37

0.73

102

1.8

Mg

Cool-NH3

24

24

0.15

0.05

106

2.4

Al

Cool-NH3

27

27

0.18

0.09

107

1.8

Si

O2

28

44

44

480

*98

*1.7

P

O2 + H2

31

47

2.8

15

96

3.5

K

Cool-NH3

39

39

0.36

0.66

104

2.1

Ca

Cool-NH3

40

40

0.57

0.18

106

1.8

Ti

NH3-1

48

114

0.76

0.81

99

2.9

V

NH3-1

51

51

0.05

0.10

101

0.5

Cr

Cool-NH3

52

52

0.51

0.37

106

2.8

Mn

Cool-NH3

55

55

0.16

0.11

103

3.0

Fe

Cool-NH3

56

56

0.40

0.28

101

2.7

Ni

Cool-NH3

58

58

0.12

0.02

100

3.6

Co

Cool-NH3

59

59

0.23

0.03

102

2.3

Cu

Cool-NH3

63

63

0.57

0.58

101

2.8

Zn

NH3-2

68

85

1.5

1.8

99

4.1

Ga

Cool-NH3

69

69

0.08

0.01

102

2.0

Ge

He

74

74

0.40

0.24

101

3.3

As

O2

75

91

0.08

0.08

101

1.1

Se

O2

78

94

0.14

0.22

103

2.0

Rb

Cool-NH3

85

85

0.12

0.03

102

2.6

Sr

He

88

88

0.02

0.004

100

1.9

Zr

He

90

90

0.03

0.005

101

1.1

Nb

He

93

93

0.03

0.05

100

1.3

Mo

He

98

98

0.19

0.12

104

1.9

Ru

He

101

101

0.19

0.10

101

3.6

Pd

He

105

105

0.04

0.004

102

3.1

Ag

He

107

107

0.16

0.15

99

1.2

Cd

He

114

114

0.16

0.04

102

3.5

In

He

115

115

0.02

0.008

101

1.1

Sn

He

118

118

0.35

0.33

102

2.3

Sb

He

121

121

0.09

0.03

101

3.1

Cs

He

133

133

0.10

0.17

103

1.7

Ba

He

138

138

0.03

0.007

102

1.3

Ta

He

181

181

0.26

0.42

100

1.6

W

He

182

182

0.28

0.07

99

4.4

Au

He

197

197

0.41

0.30

99

3.3

Tl

He

205

205

0.09

0.07

100

2.6

Pb

He

208

208

0.56

0.93

95

4.1

Bi

He

209

209

0.03

0.004

100

2.2

U

He

238

238

0.02

0.003

101

2.7

*2 µg/L spike

68Conclusions
Forty-two elements were determined successfully at ultra-trace levels insemiconductor grade H2SO4 using the Agilent 8900 Semiconductor configuration
ICP-QQQ. Excellent spike recoveries for all elements were achieved at the 20 ppt
level (2 ppb for Si) in the 1/10 diluted H2SO4, demonstrating the suitability of the8900 ICP-QQQ method for the routine analysis of high purity process chemicals.
Problematic spectral interferences that hinder the measurement of some key
elements by ICP-QMS were eliminated using ICP-QQQ in MS/MS mode withsuitable reaction cell gas conditions. The axial acceleration function of the 8900
ICP-QQQ provided significant improvements in the product ion sensitivity used forthe determination of Ti, Zn and P etc. Sub-ppt level DLs and BECs were obtained
for almost all analytes in 9.8 % H2SO4.

References
1.

‘Agilent 8800 Triple Quadrupole ICP-MS: Understanding oxygen reaction
mode in ICP-MS/MS’, Agilent publication, 2012, 5991-1708EN.

2.

J. Takahashi, ‘Determination of challenging elements in ultrapure
semiconductor grade sulfuric acid by Triple Quadrupole ICP-MS’, Agilent
publication, 2015, 5991-2819EN

More information
When analyzing 9.8% sulfuric acid on a routine basis, it is recommended to use
the following options:– G3280-67056 Pt sampling cone (18 mm insert)– G4915A Upgrade to dry pump
– G3666-67030 Interface valve kit - ball type valve

69

> Return to table of contents> Search entire document

Multielement Nanoparticle Analysis of Semiconductor
Process Chemicals Using spICP-QQQ
Authors
Yoshinori Shimamura, Donna Hsu,
and Michiko Yamanaka
Agilent Technologies, Inc.

Characterization of Ag, Fe3O4, Al2O3, Au, and SiO2 NPs
in TMAH in a single analytical run
Introduction
Technologies such as smartphones, cloud computing, the Internet of Things(IoT), and development of autonomous vehicles continue to drive demand forsemiconductor products. To meet the requirements for higher integrated circuit(IC) performance and improved device yield, contamination must be controlled
in the wafer substrate and on the surface of the device during fabrication.
Given the nanometer scale of device features, there is a critical need to monitor
metallic nanoparticles (NPs), as well as dissolved metals. Analysis of NPs present
in bulk chemicals, silicon wafers, and cleaning bath solutions is important. If aparticle is present between two metal lines, it may cause electrical shorting tooccur, and surface defects can affect the growth of new layers on the siliconwafer. To fully investigate the cause/source of any particle contamination,
multi-element analysis of NPs is necessary. ICP-MS is used increasingly tomeasure nanoparticles directly in sample solutions, using single particle
inductively coupled plasma mass spectrometry (spICP-MS). With growinginterest in characterizing NPs in various semiconductor samples, the technique
is currently being evaluated within the industry.
The Single Nanoparticle Analysis software module available for ICP-MS
MassHunter provides the method setup, analysis, and data interpretation tools
for single particle ICP-MS analysis. spICP-MS has been used for a range ofstudies, from the analysis of gold NPs in simple matrices to TiO2 NPs in complex
samples (1–4). To facilitate multiple element NP analysis, Agilent has developed
Rapid Multi-Element Nanoparticle Analysis software. The software can collectdata sequentially for up to 16 elements in a single sample analysis, using
optimum conditions for the measurement of each individual element (6).
This function saves time and reduces the risk of sample contaminationcompared to conventional spICP-MS analysis, as data for multiple elements canbe obtained with only one visit to the sample vial.
In this study, multiple element NPs including Ag, Fe3O4, Al2O3, Au, and SiO2 were
measured in semiconductor grade tetra methyl ammonium hydroxide (TMAH).
TMAH is widely used as a basic solvent in the development of photoresist in thephotolithography processing of ICs. Since TMAH comes into direct contact withthe wafer surface, avoiding contamination of the chemical is critical. The Agilent
8900 Triple Quadrupole ICP-MS (ICP-QQQ) was used for the analysis because of
its high sensitivity, low background, and effective interference removal capability.

70Experimental
Sample reagents and NP standards
A 60 nm silver NP (Sigma Aldrich, P/N 730815) reference material (RM) was used
to measure the nebulization efficiency, which is required for the calculation ofparticle size and particle concentration. The value was calculated using RM size
and the sensitivity of an ionic Ag solution (Kanto Chemical, Japan).
Solutions containing 30 nm iron oxide (Fe3O4) NPs (Sigma Aldrich, P/N 747408),
30~60 nm aluminum oxide (Al2O3) NPs (Sigma Aldrich, P/N 642991), 200 nm
silica (SiO2) NPs (nanoComposix, P/N SISI200), and 60 nm gold NPs (NIST 8013)
were used as NP standards. The sample comprised 25 wt% TMAH diluted to
1 wt % (25 times dilution) with de-ionized water (Organo, Japan).
Sample preparation
To verify the method for the measurement of multiple element NPs, the Ag RM
and four NP standards were dispersed in 1 wt % TMAH using the preparation
procedure shown in Figure 1. To prepare the intermediate solutions, 1% TMAH
was used as the diluent for Al2O3 NPs, while DIW was used for the other NPs.
Better dispersion was obtained for Al2O3 NPs using TMAH as the diluent.
Instrumentation
An Agilent 8900 ICP-QQQ (Semiconductor configuration) was used for all
measurements. The sample introduction system comprised a quartz torch witha 1.5 mm i.d. injector, quartz spray chamber, a PFA concentric nebulizer, andplatinum-tipped interface cones. The samples were self-aspirated using an
Agilent I-AS integrated autosampler.
The 8900 ICP-QQQ was operated in MS/MS mode for all measurements, with
Q1 and Q2 acting as unit mass filters. Q1 selects which elements enter the ORS4
collision/reaction cell (CRC), allowing controlled reaction chemistry to take place inthe cell when a reactive cell gas such as hydrogen (H2) or ammonia (NH3) is used.
The 8900 can also operate in helium (He) collision mode, which is effective for theelimination of many common polyatomic ions using kinetic energy discrimination(KED).

Figure 1
NP original
solutionsIntermediate
solutions

Ag 60 nm20 ppm20 ppb in DIW

Fe3O4 30 nm
1000 ppm

10 ppm in DIW

Al2O3 30 ~ 60 nm
20 wt%

Au 60 nm
50 ppm200 ppm in 1 %TMAH
2 ppm in 1 %TMAH

SiO2 200 nm
10000 ppm

100 ppm in DIW
50 ppb in DIW
1 ppm in DIW

10 ppb in DIW
20 ppb in 1 %TMAH
Measuredsolutions

20 ppt in
1 %TMAH

10 ppt in
1 %TMAH

200 ppt in 1 %TMAH

50 ppt in
1 %TMAH

1 ppb in 1 %TMAH

Figure 1. Sample preparation procedure.

71 1

NPs containing 28Si, 197Au, 27Al, 56Fe, or 107Ag were measured in fast Time Resolved
Analysis (fast TRA) mode. Fast TRA allows single element acquisition at asampling rate of 100 μs (10,000 measurements per second) with no settling time
between measurements (7). All elements were measured on-mass in MS/MS
mode, with Q1 and Q2 set to the same mass. H2 cell gas was used to eliminate
any on-mass polyatomic interferences on 28Si, such as 12C16O and 14N2. NH3 mode
was used to control the ArO and C2O2 interference on Fe at m/z 56 and the C2H3
and CNH interferences on Al at m/z 27. NH3 was also used to eliminate any ofpotential interferences from the carbon matrix on Ag at m/z 107. Au is lesssusceptible to polyatomic interference so can be measured using He or no gas
mode. During the analysis, ICP-MS MassHunter changes between each tune step
sequentially, ensuring that optimum conditions are used for the measurement ofeach element.
Multiple element NP data acquisition and analysis were performed using the Rapid
Multi-Element Nanoparticle Analysis mode of the Single Nanoparticle Application
Module of ICP-MS MassHunter. In Rapid Multi-Element Nanoparticle Analysis
mode, multi-element data is collected sequentially from a single sample acquisition,with the multi-element data being combined into a single data file. This approachsaves time, as only one sample uptake and rinse time is required for all analytes.
Data quality is likely to be improved, as the risk of sample contamination using asingle analysis-approach is significantly reduced compared to performing multiple,
separate analyses.
The operating conditions of the Agilent 8900 ICP-QQQ are detailed in Table 1.
Table 1. ICP-MS operating conditions.
ParameterValue
H2 modeRF power (W)1200

Sampling depth (mm)12

Nebulizer gas (L/min)

0.70

Makeup gas (L/min)

NH3 mode

0.20

Sample uptake rate (mL/min)

0.216 (self aspiration)

Spray chamber temp. (°C)

2

Extraction lens 1 (V)–100

Extraction lens 2 (V)–10Octopole bias (V)

–18

–8

–8

Axial acceleration (V)

1

1

1.5

Energy discrimination (V)

3

3

–10

H2 cell gas flow rate (mL/min)

6

0

0

He cell gas flow rate (mL/min)

0

2

1

0

3.0 (30 %of full scale)

NH3* cell gas flow rate (mL/min)0

Dwell time (μs)

Masses monitored (m/z)

Data acquisition time (s/element)

72

He mode100
Si(Q1:28, Q2:28)

Au(Q1:197, Q2:197)
30

Al (Q1:27, Q2:27)
Fe (Q1:56, Q2:56)
Ag (Q1:107, Q2:107)

Results and discussion
Nebulization efficiency measurement
To convert the signals measured using spICP-MS to the particle content of theoriginal sample, it is necessary to calculate the nebulization efficiency.
The nebulization efficiency is the ratio of the amount of analyte entering theplasma to the amount of analyte delivered to the nebulizer. Here, the nebulization
efficiency was calculated by measuring a reference material (Ag NP) of known
particle size. A 60 nm Ag NP RM dispersed in 1% TMAH and an ionic Ag solution(in 1% TMAH base) were measured. The Single Nanoparticle software
automatically calculated the nebulization efficiency as 0.081 (8.1%). The signal
distribution and the size distribution graphs of Ag NPs in 1% TMAH are shown in
Figure 2.

Figure 2. Signal distribution (left) and size distribution (right) of Ag NPs in 1% TMAH solution.

Analysis of various kinds of NPs in TMAH
Blank TMAH and TMAH solution spiked with Fe3O4, Al2O3, Au, or SiO2 NPs were
measured using the multi-element spICP-MS method. The time resolved signal,
signal distribution, and size distribution for Fe3O4, Al2O3, Au, and SiO2 NPs areshown in Figure 3.
The Rapid Multi-Element Nanoparticle Analysis software enabled multiple
element NP data to be quickly collected. Less than six minutes were required forthe measurement of all elements, which equates to a saving of 7 minutes
compared to separate, single sample analyses. The time-saving per sample canbe calculated using the following equation, which means that more time can besaved if more elements are measured.
Time saving per sample = (number of measured elements -1)
× (sample uptake time + rinse time)
The improved Single Nanoparticle Application Module software automaticallysets the signal baseline in the TRA data, which is shown in light blue in the time
charts in Figure 3. The improved software also sets the particle threshold,which separates particle-generated signals from the background or ionic signals.
The particle threshold is shown by the vertical red/pink line in the signal
distribution graphs in Figure 3.
The measured size and size distribution data for all four spiked NP samples
agreed with the expected results (Figure 3). The results for Fe3O4 and SiO2 NPs
show that both NPs were present in the blank TMAH solution analyzed in thisstudy, although not all TMAH solutions are likely to contain NPs.
73

Figure 3 - AlTime (sec)

TMAH blank

Time (sec)Particle size (nm)Signal intensity (cps)Figure 3 - SiTime (sec)

Signal intensity (cps)Time (sec)Particle size (nm)30 - 60 nm
Al2O3 NPs

Normalized Frequency

Frequency

count (cps)30 nm
Fe3O4 NPs

Normalized Frequency

Frequency

count (cps)Particle size (nm)Signal intensity (cps)

Al2O3 NP spike

Fe3O4 NP spike

Particle size (nm)Signal intensity (cps)

2

SiO2

Au

1

Signal intensity (cps)Frequency

Signal intensity (cps)Particle size (nm)count (cps)Time (sec)Particle size (nm)

200 nmSiO2 NPs

Signal intensity (cps)Normalized Frequency

SiO2 NP spike
Normalized Frequency

Frequency

count (cps)Time (sec)

6 0 nmAu NPsTime (sec)Particle size (nm)Signal intensity (cps)

Au NP spikecount (cps)Normalized Frequency

Frequency

count (cps)Time (sec)Normalized Frequency

TMAH blank

TMAH blank

Frequency

Au

Frequency

count (cps)Frequency

count (cps)Al2O3

threshold

TMAH blank

Normalized Frequency

Fe3O4

Normalized Frequency

Fe

Particle size (nm)3

Figure 3. Time resolved signal, signal distribution, and size distribution graphs for Fe3O 4, Al2O3, Au, and SiO2 NPs. The upper graphs for each NP show
the results from 1% TMAH without NP spike; the lower graphs show the results with NP spike.

Figure 4 summarizes the size data for multiple element NPs in 1% TMAH.
The blue histograms show NPs present in the unspiked (original) TMAH solution.
The green histograms show NPs present in the spiked TMAH solution. The
results show that all five NPs were detected separately, even in the mixed NP
TMAH solution. Using the multiple element spICP-MS method, small particles(e.g. 30 nm Fe3O4) can be clearly measured with good accuracy even in thepresence of larger particles (e.g. 200 nm SiO2).
Long-term stability test
Figure 5 shows the stability of particle concentration and particle size for fiveNPs in 1% TMAH over 10 hours. For Ag NPs, both the particle concentration andthe size decreased over time, suggesting that Ag NPs are easily dissolved in
1% TMAH solution. For Fe3O4 NPs, the size was constant, but the particle
concentration decreased over time. Rather than being dissolved in TMAH, Fe3O4
NPs are likely to settle or be adsorbed onto the surface of the sample container.
Al2O3 and SiO2 NPs were stable in terms of particle concentration and size over
10 hours. The size profile of the Au NPs remained constant over 10 hours, while
the particle concentration remained broadly stable over 10 hours after a slightchange during the first three hours.
74

4Figure 4
200nm

56nm

30nm

30nm

60nm

Figure 4. Size distribution overview for multiple element NPs in 1% TMAH. The results for the unspiked TMAH solution are shown in blue and the
spiked TMAH solution results are shown in green.

3

Figure 5. Long-term stability of NP solutions of Ag, Fe3O 4, Al2O3, Au, and SiO2. The blue line shows
the particle concentration and the red line shows the average particle size.

75

Conclusion
Multiple element nanoparticles were determined and characterized in 1% TMAH
using the Agilent 8900 ICP-QQQ operating in multi-element spICP-MS mode.
The MS/MS method delivered the low background, high sensitivity, andinterference control necessary for the analysis of multiple element NPs insemiconductor grade chemicals.
Using specially developed Rapid Multi-Element Nanoparticle Analysis software,
multi-element data for Ag, Al2O3, Fe3O4, Au, and SiO2 NPs were collected from asingle sample acquisition and combined into a single table of results. The tableprovides comprehensive information about the nanoparticles containing eachof the measured elements. The results showed that small particles such as
30 nm Fe3O4 NPs could be measured in solutions containing larger particles,
such as 200 nm SiO2 NPs. The particle size and particle concentration of Al2O3
and SiO2 NPs were stable in 1% TMAH solution over 10 hours, while the particle
concentration of Fe3O4 and Ag NPs decreased over time. The results suggestthat Fe3O4 and Ag NPs in TMAH solutions should be measured as soon as they
are prepared. While the particle size of Fe3O4 NPs remained stable in 1% TMAH,
the variation in the concentration of NPs over time requires further investigation.
The study showed that samples containing nanoparticles composed of different
and/or multiple elements can be determined quickly and accurately using
spICP-MS. Compared to acquiring data separately for each NP, the Rapid MultiElement Nanoparticle Analysis software simplifies the analytical method andshortens the sample run times by seven minutes. If more elements are measured,
more time can be saved.

References

76

1.

Susana Nunez, Heidi Goenaga Infante, Michiko Yamanaka, Takayuki Itagaki,
Steve Wilbur, Analysis of 10 nm gold nanoparticles using the high sensitivityof the Agilent 8900 ICP-QQQ, Agilent publication, 5991-6944EN

2.

Jenny Nelson, Michiko Yamanaka, Francisco Lopez-Linares, Laura Poirier,
Estrella Roge, Single Nanoparticle Analysis of Asphaltene Solutions using theAgilent 8900 ICP-QQQ: ICP-MS MassHunter software module simplifies
spICP-MS analysis, Agilent publication, 5991-9498EN

3.

Michiko Yamanaka, Steve Wilbur, Accurate Determination of TiO2
Nanoparticles in Complex Matrices using the Agilent 8900 ICP-QQQ,
Agilent publication, 5991-8358EN

4.

Michiko Yamanaka, Takayuki Itagaki, Steve Wilbur, High sensitivity analysis
of SiO2 nanoparticles using the Agilent 8900 ICP-QQQ in MS/MS mode,
Agilent publication, 5991-6596EN

5.

Michiko Yamanaka and Steve Wilbur, Measuring Multiple Elements in
Nanoparticle using spICP-MS: Acquire NP data for up to 16 elements in
Rapid Multi-Element Nanoparticle Analysis Mode, Agilent publication,
5994-0310EN

6.

Craig Jones, Emmett Soffey, Mark Kelinske, Rapid Multielement Nanoparticle
Analysis Using Single-Particle ICP-MS/MS, Spectroscopy, 2019, 34, 5, 10–20.
Link.

7.

Steve Wilbur, Michiko Yamanaka, and Sebastien Sannac, Characterizationof nanoparticles in aqueous samples by ICP-MS, Agilent publication,
5991-5516EN

> Return to table of contents> Search entire document

Silicon Wafer Analysis by ICP-QQQ: Determination of
Phosphorus and Titanium in a High Silicon Matrix
AuthorIntroduction

Junichi Takahashi
Agilent Technologies, JapanThe semiconductor industry first used ICP-MS for trace element analysis in theearly 1980s. Nowadays the technique is widely used for control of trace impurities
in materials and chemicals, particularly by silicon device manufacturers. The major
challenge for quadrupole ICP-MS (ICP-QMS) is the presence of spectroscopic
interferences on key contaminant elements, although performance has been
gradually improved through developments such as cool plasma and collision/
reaction cells (CRC), and improved performance has also been provided by highresolution ICP-MS. Consequently, metallic impurity control of silicon wafers can be
successfully monitored by ICP-MS in the case of low silicon samples such as
Vapor Phase Decomposition (VPD) of native silicon wafers. However, difficulties ofSi-based spectral interferences, particularly on P and Ti, still affect the analysis ofsamples that contain high concentrations of Si, such as VPD samples of thermally
oxidized wafers and samples relating to bulk silicon wafers. These interferences
cannot be reduced adequately by ICP-QMS and have required HR-ICP-MS. In thispaper, we evaluate triple quadrupole ICP-MS with MS/MS technology for thedetermination of ultratrace P and Ti in a high Si matrix.

Keywords
semiconductor, silicon wafer,phosphorus, titanium, Vapor Phase
Decomposition, VPD, oxygen massshift

Experimental
Instrumentation: Agilent 8800 #200 with an inert sample introduction kit
including a low flow nebulizer (PFA-20) and a Pt/Ni skimmer cone. The actual
sample uptake rate was 36 µL/min. The sample was self-aspirated from an
Agilent I-AS autosampler.
Plasma conditions: Robust tuning conditions were applied as summarized inTable 1.
Ion lens tune: Extract 1 = 0 V was used and other lens voltages were optimized
using Auto tune.
Sample preparation: Silicon wafer samples were dissolved in TAMAPURE
HF/HNO3 and the final Si concentration was adjusted to 2000 ppm.
Table 1. Robust tuning conditions.
O2 MS/MSH2 MS/MS

RF power

W

1600

Sampling depthmm8Carrier gas flow rate

L/min

0.6

Make-up gas flow rate

L/min

0.6

He

mL/min30

O2

mL/min0.4

0H2

mL/min0

1077Results and discussion
Phosphorus is monoisotopic at m/z 31, and suffers an interference from 30SiH.
While P+ can be detected as PO+ under cool plasma conditions, it is difficult tomaintain cool plasma when the matrix concentration is high. Si sample solutions
always contain HF, so Si will form SiF (IP: 7.54 eV) that also interferes with Ti.
Table 2 shows the Si-based spectral interferences on P and Ti. Using the 8800
ICP-QQQ operating in MS/MS mode with O2 mass-shift, P and Ti can be
determined as their oxide ions, avoiding the Si-based interferences.
Table 2. Spectral interferences of Si on P and Ti.
Polyatomic interferencem/zAnalyte ion

30

SiH+

31

31

P+

30

Si16O+

46

46

Ti+

28

Si19F+, 30Si16OH+

47

47

Ti+, 31P16O+

29

Si19F+, 30Si18O+

48

48

Ti+

30

Si19F+

49

49

Ti+

For Ti analysis, Q1 is set to m/z 48, and so will transmit 48Ti+ and any otherinterfering ions at mass 48, such as 29Si19F+ and 30Si18O+. But only 48Ti reacts withoxygen in the CRC, producing the product ion 48Ti16O+, which is transmitted by
setting Q2 to m/z 64. NH3 can be used as an alternative reaction gas, as it
produces 48Ti14NH+ that can be detected at m/z 63.
P+ reacts readily with O2 to form 31P16O+. The selection of ions at m/z 31 by Q1
eliminates the spectral interference of 28Si19F. However, 30SiH passes through Q1
and reacts with O2 to create 30Si16OH. In order to determine P in a high Si matrix,
H2 mass-shift is a preferred option, despite the relatively low efficiency of
production of PH3+ or PH4+ ions. The MSA calibration curves for P and Ti in amatrix of 2000 ppm Si are shown in Figure 1. The calculated BECs are
summarized in Table 3. A long term stability test was carried out by analyzing a
spiked sample repeatedly over five hours (Figure 2).
31

Table 3. BECs of P and Ti in 2000 ppm Si.

78

Element

P

Ti

Mode (cell gas)

MS/MS (H2)

MS/MS (O2)

Measured ion

31

Mass pair

Q1 = 31, Q2 = 35

Q1 = 48, Q2 = 64

BEC - ppt

227

13

PH4+

48

Ti16O+

31 ➝ 35 P [H2MS/MS]
x102

48 ➝ 64 Ti (O2MS/MS)
x103

y = 80.2115 x + 18.2000
R = 0.9996

y = 25.2585 x + 337.0000
R = 0.9937

CPS

CPS

4

2

0

2

0
0.0

2.0

4.0

0.0

50.0

Conc (ppt)

100.0Conc (ppt)

Figure 1. MSA curves of P and Ti in 2000 ppm Si.
31 ➝ 35 P [H 3MS/MS] 4 ppb
48 ➝ 64 Ti [O2MS/MS] 100 ppt
140%
120%

Normalized signal

100%
80%
60%
40%
20%
20%
0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

300

320

Elapsed time (min)Figure 2. Five-hours test of P and Ti spiked in 2000 ppm Si.

Conclusion
The MS/MS mass-shift mode of the ICP-QQQ is effective for the determinationof P, Ti and other trace elements in high purity silicon matrices, providing effective
removal of the potential Si-based polyatomic interferences.

More information
Improvement of ICP-MS detectability of phosphorus and titanium in high purity
silicon samples using the Agilent 8800 Triple Quadrupole ICP-MS, Agilent
publication 5991-2466EN

79

> Return to table of contents> Search entire document

Analysis of Ultratrace Impurities in High Silicon Matrix
Samples by ICP-QQQ
AuthorsYu Ying
Agilent Technologies (China) Co., Ltd.

Determination of 38 elements in high matrix samples using an
Agilent 8900 ICP-QQQ with optional m-lensIntroduction
Rapid developments in the emerging fields of artificial intelligence (AI) and theInternet of Things (IoT) are driving innovation in the integrated circuit (IC) sectorof the semiconductor industry. IC fabrication plants (known as FABs or IC
foundries) are increasing production of ICs to meet the requirements of thisexpanding market, as well as serving ongoing demand from other high-techindustries. Silicon (Si) is essential to the IC industry, as most modern electronics
are based on Si semiconductors. These devices are made from millions ofindividual transistors (or switches) packed onto a Si wafer chip. Smallertransistors give higher core density, faster processing speed, lower power
consumption, and less heat generation, critical factors for mobile devices.
Currently, FABs are producing chips with transistor "gates" 10, 7, or even5 nanometers (nm) long, with ongoing research projects to reduce the gate
length even further. Manufacturing ICs at this small scale and high density
requires excellent control of the quality of the Si substrate and process
chemicals. It is important that the performance of the analytical instruments
used to detect metallic impurities in raw materials evolves to meet the needs ofthe semiconductor industry.
Single quadrupole ICP-MS is the most widely used atomic spectrometry
technique for the measurement of trace elements in many semiconductor
applications due to its sensitivity and multi-element capability (1). However,more advanced semiconductor processes require elemental impurities on the
Si wafer to be less than 1.0 x 107 atom/cm2 level. While it is difficult to meetthese specifications using single quadrupole ICP-MS, triple quadrupole ICP-MS(ICP-QQQ) with MS/MS operation has further improved the sensitivity,
background, and interference removal capabilities of the technique. Withdetection limits (DLs) for many elements at the sub-ppt level, ICP-QQQ is
increasingly used in the semiconductor industry for the accurate analysis of thehighest purity semiconductor materials (1).
Another challenge of measuring trace metal impurities in a high Si matrix by
ICP-MS relate to physical effects arising from the matrix. The high levels of Si in
the sample can lead to deposition of Si on the sampling cone and suppressionof analytes, leading to instability and signal drift. Operating single quadrupole
ICP-MS with a “cool” or reduced-energy plasma has been widely used in thesemiconductor industry for many years for the analysis of high-purity chemicals
and materials. Cool plasma suppresses the formation of intense argon-based
interferences such as Ar+ and ArO+, allowing low-level analysis of 40Ca and 56Fe,
respectively. A lower-temperature plasma also causes less re-ionization of tracesof easily ionized elements (EIEs) from the cones and ion lens, giving lower

80

background signals for these elements than normal plasma conditions. However,the lower power used with cool plasma conditions provides insufficient energy to
decompose some sample matrices, including high Si matrix samples.
The Agilent 8900 ICP-QQQ fitted with an optional “m-lens” ion lens uses normal
plasma conditions to analyze silicon-rich samples. The m-lens has an optimized
geometry that minimizes background signals from EIEs deposited on the
ICP-MS interface components. The 8900 with m-lens provides ppt-levelbackground equivalent concentrations (BECs) for the elements of interest in thesemiconductor industry, including the easily-ionized alkaline elements. The low
BECs enable the monitoring of ultra-trace ppt-level impurities in high Si matrices
using high-power, robust, matrix tolerant plasma conditions.
In this study, the 8900 ICP-QQQ was used to analyze two Si samples preparedat matrix levels that are typically analyzed in the semiconductor industry.
Excellent precision was achieved for the measurement of 50 ppt spikes in the
Si matrix samples over a 1 hour analytical run, demonstrating the effectiveness,robustness, and sensitivity of the method.

Experimental
Reagents
All samples and standards were prepared in semiconductor grade TAMAPURE
AA-100 nitric acid (HNO3) and hydrofluoric acid (HF) bought from Tama
Chemicals Co. Ltd, Kanagawa, Japan. The ultrapure water (UPW) was supplied
from Organo Corp (Tokyo, Japan).
Sample preparation
Pieces of electronic grade (9N purity) poly-silicon were weighed to the nearest
0.05 g and the sample surfaces were cleaned with HNO3 and rinsed with UPW.
To prepare a 1000 ppm Si matrix solution, the Si pieces were digested in a
1:1 (w/w) acid mix of 38% HF and 55% HNO3. The Si matrix solution was thendiluted to provide two typical Si matrix samples. A 10 ppm Si solution was used
to represent the Si matrix level in a sample prepared by scanning the wafer
using a vapor phase decomposition (VPD) device. A 100 ppm Si matrix solution
was used to represent the matrix level that would be present in a digested
poly-silicon sample.
Calibration standards
Simple, aqueous (no Si matrix) calibration standards were prepared in the sameacid concentration as the 10 and 100 ppm Si samples using Agilent stock
solutions. Multi-element calibration standards included “2A” (p/n 8500-6940) and“4” (p/n 8500-6942). Single element standards at 1000 μg/mL were used for
antimony (p/n 5190-8562) and tin (p/n 5190-8583).
A multi-element spike solution containing all elements was also prepared fromthe stock solutions. The spike solution was added to the 10 and 100 ppm Si
matrix samples at 50 ng/L (ppt).

81

Instrumentation
An Agilent 8900 ICP-QQQ was used for the analysis. The 8900 was fitted withan inert (HF-resistant) sample introduction system comprising a 200 μL/min
MicroFlow PFA nebulizer, a PFA spray chamber, endcap, and connector tube, anda demountable torch with a 2.5 mm internal diameter (i.d.) sapphire injector.
A Pt-tipped sampling cone was used, together with the optional m-lens (G366667500), and Pt-tipped, Ni-based skimmer cone for m-lens (G3666-67501).
The PFA nebulizer and Pt tipped sampling cone are standard on the 8900 #200
(Semiconductor Applications model). The other sample introduction parts (PFA
spray chamber, endcap, connecting tube, and demountable torch) are included in
the Inert Kit (G4912A #001). The sample introduction and interface parts listed
are also compatible with the 8900 #100 (Advanced Applications model).
A high Si matrix leads to the formation of several polyatomic ions, which causesignificant spectral interferences on some important elements such as Ti, Fe, Ni,
Cu, and Ge (Table 1). To achieve the lowest BEC for each analyte in the siliconrich samples, optimized ICP-QQQ acquisition conditions were used for different
elements. Using ICP-MS MassHunter instrument control software, it is simple tomeasure different analytes in different cell gas modes using a single multitune
method. During data acquisition, the ORS4 cell gases and measurement modes
are switched automatically, giving a fast and automated analysis using the bestmode for each analyte.
In this study, several reaction cell gases (He, H2, O2, and NH3) were used as
appropriate for the large number of analytes being measured. Details of theconfiguration and principles of ICP-QQQ and MS/MS are explained elsewhere(2, 3). The operating parameters of the 8900 ICP-QQQ are given in Table 2.

Results and discussion
Background equivalent concentrations
The blank, 10 ppm, and 100 ppm Si samples were measured by external
calibration method and the BECs of each sample were calculated using ICP-MS
MassHunter. The BECs of all 38 analytes were lower than 50 ng/L in both the
10 and 100 ppm Si matrix blank samples, with most below 5 ng/L (Table 3).
The low BECs show the effectiveness of the ICP-QQQ method at removing
interferences on all analytes, including Si-based interferences on Ti, Fe, Ni, Cu,
and Ge (Table 1). The relatively high BECs for some analytes may be due to thecontamination during sample preparation.
Spike-recovery and stability test
The stability, robustness, and matrix tolerance of the instrument and method
were tested over an hour of continual measurements. The unspiked (blank) Si
samples were measured three times and each spiked sample was measured
11 times over the 60 minute run. The average recoveries of the 50 ng/L spikes
ranged from 90 to 110% for all elements apart from Fe at 112% in the 10 ppm Si
sample (Table 3). The slightly higher recovery of Fe was likely due to sample
contamination from the laboratory environment. The 8900 ICP-QQQ also provided
excellent sensitivity and accuracy for all elements, including EIEs, as shown by
the spike recoveries in both Si matrices.

82

The relative standard deviation (RSD) of the measurements (n=11) was <6% for
all 38 elements in both Si matrices, indicating minimal signal drift during the runusing the 8900 with m-lens. Figure 1 shows the stability test results of sometypical elements of importance to IC foundries such as Fe in the 100 ppm Si
matrix sample.
Table 1. Potential spectral interferences in a Si matrix digest with HF.
Analyte Ion
46

Ti+

Interference

56

Si F
Si16OH+

63

Cu+

Si19F+
Si18O+

65

Cu+

Si19F+

72

28

47

Ti+

30

48

Ti+

30

49

Ti+

58

Ni+

60

Ni+

Analyte Ion

Si16O+

30

19 +

29

30
28
29
28

Si Si
Si29Si+30+

74Interference

Fe+

28

28

Si16O19F+

30

Si16O19F+
Si18O19F+

28

Ge+
Ge+

Si28Si+28

Si28Si16O

28

Si28Si18O
Si28Si16O

30

Si16O2+
Si30Si+30

Table 2. ICP-QQQ operating conditions.
No Gas

H2

15

25

NH3

He

25

20

Acquisition Parameters
Scan Mode
Stabilization Time (s)MS/MSReplicates3

Sweeps/Replicate

100

Integration Time (s)0.6PlasmaRF Power (W)1550

Sampling Depth (mm)8.0

Carrier Gas (L/min)

0.8

Makeup Gas (L/min)

0.4

LensesExtract 1 (V)1.5

Extract 2 (V)–70

Omega Bias

–20

Omega Lens

6

Cell
He Flow Rate (mL/min)

4.0

H2 Flow Rate (mL/min)

10.0*NH3 Flow Rate (mL/min)

2.0

Octopole Bias (V)

–8

–18

–6

–20

Axial Acceleration (V)

0

1

1.5

0

KED (V)

3

–8

–10

5

83

Table 3. Analysis results of 10 and 100 ppm Si matrix samples and matrix-spiked samples, n = 11.
10 ppm Si Matrix Sample
Element84

Q1/Q2

Cell Gas

BEC(ng/L)

100 ppm Si Matrix Sample%RSD of50 ppt-Spiked
Samples

50 ppt Spike
RecoveryAverage (%)

BEC(ng/L)%RSD of50 ppt-Spiked
Samples

50 ppt Spike
RecoveryAverage (%)

Li

7/7

No gas

0.38

3.7

101.4

0.60

3.4

107.3

Be

9/9

No gas

0.00

3.6

99.4

0.87

4.7

105.7

B

11/11

No gas

16.1

4.0

105.9

30.2

3.2

109.7

Na

23/23

H2

5.13

5.6

101.8

13.3

2.9

96.7

Mg

24/24

H2

1.45

3.0

93.9

5.82

4.4

108.2

Al

27/27

H2

8.52

3.8

103.1

46.6

2.6

97.7

K

39/39

H2

10.8

2.3

93.6

10.3

2.6

105.1

Ca

40/40

H2

7.99

2.1

95.8

7.79

3.3

108.9

Ti

48/114

NH3

5.35

5.4

101.3

4.55

5.4

101.7

V

51/67

NH3

0.00

2.5

90.8

0.30

4.6

102.3

Cr

52/52

NH3

4.30

2.5

95.9

9.71

2.8

101.4

Mn

55/55

NH3

35.7

3.8

103.8

43.3

1.5

96.2

Fe

56/56

H2

21.6

6.0

112.0

23.6

3.9

106.9

Ni

58/58

NH3

6.75

2.4

90.0

4.69

3.2

99.1

Co

59/59

NH3

2.37

4.0

92.2

5.56

2.3

96.7

Zn

64/64

NH3

1.92

5.6

99.4

34.8

5.9

94.5

Cu

65/65

NH3

4.19

5.1

101.1

33.6

5.7

95.7

Ga

69/69

H2

0.34

2.4

94.8

6.13

2.8

109.8

Ge

74/74

H2

4.26

2.0

90.7

4.30

1.7

98.1

As

75/75

H2

0.86

4.7

90.3

0.29

5.9

100.4

Se

78/78

H2

1.24

5.0

90.4

1.60

4.5

97.2

Rb

85/85

H2

0.62

2.0

96.5

18.4

4.5

100.6

Sr

88/88

H2

0.02

2.0

95.3

0.03

2.5

101.2

Zr

90/90

H2

0.08

1.9

94.9

0.03

2.3

102.2

Nb

93/93

He

0.43

2.6

91.5

0.12

2.7

98.2

Mo

95/95

He

0.12

2.9

93.8

0.53

4.3

98.0

Ag

107/107

No gas

0.12

1.9

98.2

0.18

1.6

100.8

Cd

114/114

NH3

0.02

1.7

95.9

0.00

2.5

98.1

Sn

118/118

NH3

0.51

2.5

96.7

1.12

2.1

97.6

Sb

121/121

NH3

0.14

2.3

93.9

0.24

2.6

95.3

Cs

133/133

He

0.03

2.7

94.6

0.03

1.8

97.0

Ba

138/138

H2

0.42

2.3

97.6

0.43

1.9

98.4

Ta

181/181

He

0.17

2.2

98.8

0.09

1.6

96.4

W

182/182

He

3.48

4.2

99.2

0.12

2.2

96.1

Re

185/185

He

0.00

2.9

95.8

0.01

1.9

95.9

Tl

205/205

No gas

0.15

3.0

104.2

0.12

1.3

103.2

Pb

208/208

NH3

0.31

2.2

98.0

0.19

1.9

96.1

U

238/238

No gas

0.00

3.3

103.2

0.00

1.0

101.2

Normalized signal

Sample number

Figure 1. Stability results for multiple elements spiked at 50 ppt in a 100 ppm Si matrix sample.

Conclusion
The robustness of the Agilent 8900 ICP-QQQ with m-lens was demonstrated
for the determination of 38 elements in two digested silicon samples containing
10 and 100 ppm Si. The optional m-lens ensured that the background signals
for the EIEs were minimized, allowing all elements to be measured at ppt levels
using matrix tolerant, high-power plasma conditions.
The best BECs for all elements were achieved by operating the 8900 ICP-QQQ in
MS/MS mode using a single multitune method with different cell gases. The low
BECs showed that the method successfully removed all spectral interferences,including Si-based interferences on Ti, Fe, Ni, Cu, and Ge.
The reproducibility (stability) results for the 50 ppt spikes in the two high siliconsamples were between 1 and 6% RSD for all elements in a sequence lasting
1 hour. These results showed that there was minimal signal suppression or driftcaused by Si deposition on the interface under the robust plasma conditions.
The study demonstrates the suitability of the 8900 ICP-QQQ for thecharacterization of trace metals in silicon-matrix samples. The method has thepotential to meet the evolving needs and future specifications of the mostadvanced manufacturing processes that are required to meet the demand forhigher IC performance.

References1.

Applications of ICP-MS: Measuring Inorganic Impurities in Semiconductor
Manufacturing, Agilent publication, 5991-9495EN

2.

Eduardo Bolea-Fernandez, Lieve Balcaen, Martin Resano, Frank Vanhaecke.
Overcoming spectral overlap via inductively coupled plasma-tandem mass
spectrometry (ICP-MS/MS). A tutorial review, J. Anal. At. Spectrom., 2017, 32,
1660–1679

3.

Ed McCurdy, Glenn Woods, Naoki Sugiyama. Method Development with
ICP-MS/MS: Tools and Techniques to Ensure Accurate Results in Reaction
Mode, Spectroscopy, 2019 (9):20–27, http://www.spectroscopyonline.com/
method-development-icp-msms-tools-and-techniques-ensure-accurateresults-reaction-mode

85

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Analysis of Sulfur, Phosphorus, Silicon, and Chlorine in
N-methyl-2-pyrrolidone
AuthorIntroduction

Naoki Sugiyama
Agilent Technologies, Japan

N-Methyl-2-Pyrrolidone (NMP), chemical formula: C5H9NO, is a stable, water-solubleorganic solvent that is widely used in the pharmaceutical, petrochemical, polymer
science and especially semiconductor industries. Electronic grade NMP is used bysemiconductor manufacturers as a wafer cleaner and photo resist stripper and assuch the solvent comes into direct contact with wafer surfaces. This requires
NMP with the lowest possible trace metal (and non-metal) contaminant levels.
ICP-MS is the technique of choice for the measurement of trace metal impurities
in semiconductor process chemicals. It is a challenge, however for ICP-MS tomeasure non-metallic impurities such as sulfur, phosphorus, silicon, and chlorine
in NMP. The low ionization efficiency of these elements greatly reduces analytesignal, while the elevated background signal (measured as background equivalentconcentration, BEC) due to N-, O-, and C-based polyatomic ions formed from the
NMP matrix makes low-level analysis even more difficult (Table 1).

Keywords
N-methyl-2-pyrrolidone, NMP,
semiconductor, process chemicals,
sulfur, phosphorus, silicon, chlorine,
method of standard additions, oxygenmass-shift

Table 1. ICP-QMS BECs obtained in no gas mode for selected analytes in NMP.
Element

m/z

Ionization
potential (eV)

Ionization ratio (%) BEC without cell
(ppm)

Interference

Si

28

8.152

87.9

>100

14

N2+, 12C16O+

P

31

10.487

28.8

0.39

14

N16OH+, COH3+S32

10.360

11.5

9.5

16

O2+, NOH2+

Cl

35

12.967

0.46

0.26

16

O18OH+

Experimental
Instrumentation: Agilent 8800 #200 with narrow injector (id =1.5 mm) torch(G3280-80080) typically used for the analysis of organic solvents. A C-flow 200
PFA nebulizer (G3285-80000) was used in self-aspiration mode. An option gas
flow of 20% O2 in Ar was added to the carrier gas to prevent carbon build up on
the interface cones.
Plasma conditions: NMP analysis requires hotter plasma conditions than normal.
This was achieved by reducing Make-up Gas (MUGS) by 0.2 L/min. Plasma tuning
conditions are summarized in Table 2.
Table 2. Plasma conditions for NMP analysis.

86

Parameter

Unit

Tuning value

RF

W

1550

Sampling depth

mm

8.0

Carrier gas flow

L/min

0.50

Make-up gas flow

L/min

0.10

Option gas flow

L/min

0.12 (12% of full scale)

Spray chamber temperature°C

0CRC conditions: Table 3 summarizes the cell tuning parameters (gas flow rate
and voltages) used.
Table 3. CRC operating conditions.
ParameterUnit

O2 reaction cell

H2 reaction cell

Method-On-mass

Cell gas

-

O2

H2

Gas flow rate

mL/min0.30

4.0

Octopole bias

V

-14

-10

KED

V

-5

Mass-shift-5

On-mass0

Mass-shift-5

Reagents and sample preparation: Electronic industry grade NMP was distilled
at 120 °C and acidified by adding high purity HNO3 to a concentration of 1% w/w.

Results and discussion
NMP was analyzed directly using the method of standard additions (MSA).
Three replicate measurements (ten replicates for the blank) were acquired for S,
P, Si and Cl using an integration time of 1 s per isotope.
P and S measurement in NMP
The mass-shift method using O2 worked well for P and S measurement in NMP.
The reactions of P and S with O2 are exothermic, indicated by the negative value for
ΔH, as shown below; therefore P+ and S+ are efficiently converted to their oxideions, PO+ and SO+. P and S can be measured as the product ions, avoiding theoriginal spectroscopic interferences on their elemental masses, m/z 31 and m/z 32.
P+ + O2  PO+ + O ΔHr = -3.17 eV
S+ + O2  SO+ + O ΔHr = -0.34 eV
In MS/MS mode, Q1 rejects 36ArC+ before it can enter the cell, preventing it fromoverlapping SO+. This allows ICP-QQQ to control the reaction chemistry pathways
and reaction product ions, ensuring that the analyte product ion is measured
free from overlap, regardless of the levels of other co-existing analyte (or matrix)
elements. MS/MS mode with the O2 mass-shift method achieved BECs of 0.55
ppb and 5.5 ppb for P and S respectively in NMP. The low BECs and linear
calibration plots achieved in MS/MS mode also prove that the matrix-based
interferences do not react with O2, allowing the analytes to be separated fromthe interferences.
Si measurement in NMP
H2 cell gas was applied to the measurement of Si in NMP. The reaction kinetics
for Si and its major interferences with H2 cell gas are shown below. The reaction
rate data suggests that Si does not react with H2 cell gas (endothermic reaction
indicated by the positive value for ΔH), and so could be measured in NMP using
the direct, on-mass method. While the reaction of Si+ with H2 is endothermic,
the reactions of the major interfering ions on Si at mass 28 (N2+ and CO+) areexothermic, and these interferences are therefore neutralized or reacted away.

87Si+ + H2  SiH+ + H

ΔHr = 1.30 eV

N 2 + H2  N 2H + H

ΔHr = - 0.60 eV

CO+ + H2  COH+ +H

ΔHr = - 1.63eV++

The results obtained are shown in Figure 2 (top). The H2 on-mass method
achieved a BEC of 15.8 ppb for Si in NMP.
Oxygen cell gas was also tested of the measurement of Si in NMP. As shown
below, the reaction of Si+ with O2 to form SiO+ is endothermic. However, collisional
processes in the cell provide additional energy which promotes the reaction,
enabling the O2 mass-shift method to be applied.
Si+ + O2  SiO+ + O ΔHr = 0.11 eV
Unfortunately, a major interference on Si at m/z 28 (CO+) also reacts with O2,
so the BEC achieved using the O2 mass-shift method to measure Si as SiO+
(Q1 = 28, Q2 = 44) was not satisfactory. Fortunately, another Si reaction production (SiO2+) also forms and this can be measured at m/z 60 (Q1 = 28, Q2 = 60)
giving a BEC of 11.9 ppb for Si in NMP (Figure 2, bottom).
31 ➝ 47 [O2MSMS]

28 ➝ 28 [H 2KED=0]y = 3327.3981 *x + 1840.2144
R = 0.9995
DL = 0.06424 ppb
BEC = 0.553 ppb

x106
2

y = 3306.7272 *x + 52295.8767
R = 0.9999
DL = 0.4502 ppb
BEC = 15.81 ppb

CPS

CPS

x106

2

2
2

0

0
500.0

500.0

Conc (ppt)

32 ➝ 48 [O2MSMS]
x106

Conc (ppt)

28 ➝ 60 [O230%]

y = 1075.2813 *x + 5878.2456
R = 0.9997
DL = 0.2534 ppb
BEC = 5.467 ppb

x105

y = 541.0307 *x + 6441.6833
R = 1.0000
DL = 0.4752 ppb
BEC = 11.91 ppb

CPS

CPS

3

2

0.5

1

0

0
500.0
Conc (ppt)

Figure 1. Calibration curve using MS/MS with
O2 mass-shift for P (top) and S (bottom) in NMP.

88

500.0
Conc (ppt)

Figure 2. Calibration plots for Si in NMP.
Top: H2 on-mass method (Q1=Q2=28).
Bottom: O2 mass-shift method (Q1=28, Q2=60).

Cl in NMP
Cl+ reacts exothermically with H2 to form ClH+ as shown below. ClH+ continues toreact via a chain reaction to form ClH2+.
Cl+ + H2  ClH+ + H

ΔHr = -0.17 eV

ClH+ + H2  ClH2+ + H

ΔHr = -0.39 eV

Figure 3 (left) shows calibration plots obtained for Cl in NMP using the H2 massshift method. The plot obtained using the O2 mass-shift method (Figure 3, below)
is also shown for comparison. A slightly better BEC of 34.2 ppb was achieved withmuch higher sensitivity for Cl in NMP using the H2 mass-shift method.
35 ➝ 37 [H2]
x104
1.5

35 ➝ 51 [O2]y = 21.1975 *x + 725.6867
R = 1.0000
DL = 3.614 ppb
BEC = 34.23 ppb

x102

y = 0.6662 *x + 24.2222
R = 0.9993
DL = 26.33 ppb
BEC = 36.36 ppb

4

CPS

CPS

1

2
0.5

0
500.0
Conc (ppt)

500.0Conc (ppt)

Figure 3. Calibration plots for Cl in NMP. Left: H2 mass-shift method (Q1 = 35, Q2 = 37).
Right: O2 mass-shift method (Q1=35, Q2=51).

More information
Trace level analysis of sulfur, phosphorus, silicon and chlorine in NMP
using the Agilent 8800 Triple Quadrupole ICP-MS, 2013, Agilent publication,
5991-2303EN

89

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Analysis of Silicon, Phosphorus, and Sulfur in
20% Methanol
Authors

Introduction

Emmett Soffey, Bert Woods andSteve Wilbur
Agilent Technologies, Japan

Analysis of organic solvents for trace metals presents a number of challenges to
ICP-MS, many of which have been overcome to varying degrees on Agilent’s 7700
Series quadrupole ICP-MS systems. However, even with these advances, several
elements remain challenging in organic solvents, particularly silicon, phosphorus
and sulfur. All three elements are subject to intense interferences frompolyatomic ions based on carbon, nitrogen and oxygen, which are difficult tocompletely remove using conventional quadrupole ICP‑MS (ICP‑QMS). Examples
include CO+, COH+, N2+ and NO+ on silicon 28, 29 and 30; COH+, NOH+, N2H+, NO+
and CO+ on phosphorus 31 and O2+, NO+, NOH+ and NOH2+ on sulfur 32 and 34.
Additionally, phosphorus and sulfur have high first ionization potentials (IP) of
10.5 eV and 10.4 eV respectively, resulting in relatively poor sensitivity comparedto more typical elements whose IPs are in the range of ~6 – 8 eV.

Keywordsorganic solvents, methanol, silicon,
phosphorus, sulfur, hydrogen on-mass,
oxygen mass-shift

Experimental
Instrumentation: Agilent 8800 #200.
Plasma conditions and ion lens tune: RF power =1550 W, Sampling depth = 8.0mm and Carrier gas flow rate = 1.05 L/min were used with soft extraction tune,
Extract 1 = 0 V and Extract 2 = -190 V.
Ultra pure methanol was spiked with silicon (Si), phosphorus (P) and sulfur (S) at
1, 5, 10 and 50 ppb and measured using the ICP-QQQ in several operationalmodes in order to evaluate the optimum conditions for the simultaneous analysisof all three analytes. Hydrogen and oxygen reaction gases were evaluated, with
H2 cell gas used in both Single Quad (SQ) and MS/MS modes. In addition, helium
collision gas was investigated in both SQ and MS/MS mode to determine theeffects of using MS/MS with a non-reactive cell gas.
The CRC conditions are outlined in Table 1, which includes the five analysis modes
evaluated. Two Single Quad modes were tested, using both He and H2 in the cell, tosimulate the capability of a single quadrupole ICP-MS. In addition, three conditions
using MS/MS mode were tested using H2, He and O2 as cell gases.
Table 1. 8800 ICP-QQQ acquisition conditions tested, including five operational modes.
Parameter

90

Unit

He SQ

H2 SQ

H2
MS/MS

He
MS/MS

O2
MS/MS

Acquisition mode

SQ

SQ

MS/MS

MS/MS

MS/MS

Cell gas

He

H2

H2

He

O2

Cell gas flow rate

mL/min

5.0

7.0

7.0

7.0

0.40

KED

V

5

0

0

5

-7

Results and discussion
The BECs and DLs results are summarized in Tables 2–4, for silicon, phosphorus
and sulfur respectively, for all 5 analysis modes tested. SQ and optimum MS/MS
results are in bold type for comparison. A few mass‑pairs were measured in eachmode as shown. For example, Table 2 shows silicon monitored in MS/MS modewith O2 cell gas, using a mass-pair of Q1 = 28 and Q2 = 44. With Q1 set to m/z 28,
only silicon 28 and any on‑mass interferences are allowed to enter the ORS cell.
The silicon 28 in the cell reacts with the oxygen cell gas to form SiO+, and Q2 is
set to measure at Q1 + 16 (m/z = 44), ensuring that only the M + 16O reaction
transition is measured.
Table 2. DLs and BECs for silicon. Silicon was not measurable at the spiked concentrations inhelium mode.

Mode

Mass or mass pair

BEC (ppb)

DL (ppb)

H2 SQ

Q2=28

25.46

0.12

H2 MS/MS

Q1=28, Q2=28

2.17

0.03

O2 MS/MS

Q1=28, Q2=44

85.54

28.21

O2 MS/MS

Q1=29, Q2=45

N/A

N/A

O2 MS/MS

Q1=30, Q2=46

99.09

21.26

Table 3. DLs and BECs for phosphorus. Phosphorus was not measurable at the spiked
concentrations in H2 Single Quad mode.
Mode

Mass or mass pair

BEC (ppb)

DL (ppb)

He SQ

Q2=31

3.81

0.63

He MS/MS

Q1=31, Q2=31

2.99

0.72

H2 MS/MS

Q1=31, Q2=33

0.56

0.07

H2 MS/MS

Q1=31, Q2=34

0.58

0.67

O2 MS/MS

Q1=31, Q2=47

0.40

0.05

O2 MS/MS

Q1=31, Q2=63

0.41

0.02

Table 4. DLs and BECs for sulfur using MS/MS mode with O2 cell gas. Sulfur was not measurable atthe spiked concentrations in helium or hydrogen mode.

Mode (cell gas)

Mass or mass pair

BEC (ppb)

DL (ppb)

MS/MS (O2)

Q1 = 34, Q2 = 34

51.17

4.37

MS/MS (O2)

Q1 = 32, Q2 = 48

3.13

0.10

MS/MS (O2)

Q1 = 34, Q2 = 50

3.11

0.20

Sample calibration plots are displayed in Figure 1. They are displayed in pairs
showing the results obtained using SQ mode with a typical cell gas (upper
calibration), compared to MS/MS mode using the optimum conditions (lower
calibration).
91

28 Si [H 2]x105

31 P [He]x103y = 1280.1006 *x + 32594.8367
R = 0.9995
DL = 0.1156
BEC = 25.46

34 S [He]x102y = 32.7647 *x + 124.8667
R = 0.9993
DL = 0.6334
BEC = 3.811

y = -0.0162 *x + 603.3433
R = -0.3947
DL = -4617
BEC = -3.713E+04

2

CPS

CPS

CPS

1

1

0.5

0

0
20.0

40.0

0

60.0

20.0

Conc (ppt)

40.0

60.0

20.0

Conc (ppt)

28 ➝ 28 Si [H 2 MSMS]x104

5

31 ➝ 63 P [O2]
x103
1.5

y = 1152.1621 *x + 2501.6633
R = 1.0000
DL = 0.03134
BEC = 2.171

40.0

60.0

Conc (ppt)

32 ➝ 48 S [O2]x105y = 21.7410 *x + 8.8667
R = 0.9999
DL = 0.01593
BEC = 0.4078

y = 6821.2872 *x + 21359.7600
R = 1.0000
DL = 0.1023
BEC = 3.131

4
1
CPS

CPS

CPS

5

2
0.5

0

0
20.0

40.0

60.0

0
20.0

Conc (ppt)40.0Conc (ppt)

60.0

20.0

40.0

60.0

Conc (ppt)

Figure 1. Calibration curves for Si, P and S showing SQ results (upper) compared with MS/MS results (lower). 32S was not measurable at the spiked
concentrations in methanol in SQ mode due to the intense 16O2+ polyatomic interference.

Conclusion
It can be seen that in all cases the use of MS/MS mode significantly improves
both the BEC and instrument detection limit when compared to Single Quad
mode. The most notable improvement was for sulfur which cannot be measured
at the spiked concentrations (1, 5, 10, 50 ppb) in SQ He mode due to the intensepolyatomic background resulting from the methanol matrix. By contrast, on the8800 ICP-QQQ using MS/MS mode with O2 mass-shift, S can be measured witha DL of 0.1 ppb.

More information
Analysis of silicon, phosphorus and sulfur in 20% methanol using the Agilent
8800 Triple Quadrupole ICP‑MS, Agilent publication, 5991-0320EN

92

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Automated ultratrace element analysis of isopropyl alcoholwith the Agilent 8900 ICP-QQQ
Authors
Kazuhiro Sakai and Katsuo Mizobuchi
Agilent Technologies, Japan
Riro Kobayashi
IAS Inc, Japan

Online calibration using the IAS Automated Standard Addition
System (ASAS)
Introduction
Contamination control is critical in the semiconductor industry. Inorganic
impurities are of particular concern, as they affect the electrical properties of theinsulating and conducting layers from which semiconductor devices are made.
Trace element contamination during wafer fabrication can therefore reducethe manufacturing yield and operational reliability of semiconductor devices.
To minimize contamination, process chemicals must be monitored for ultratrace(ng/L; ppt) levels of elemental impurities.
Isopropyl alcohol (IPA) is an important organic solvent used in semiconductor
manufacturing to remove organic and metallic residues and impurities from thesurface of silicon wafers. Since IPA comes into direct contact with the wafer
surface, the concentration of trace metals present in the solvent should be
extremely low. For high purity Grade 4 IPA, SEMI standard C41-0705 specifies amaximum contaminant level of 100 ppt for each element (1). Delivering accurate
analysis at these low concentrations requires a highly sensitive analytical
instrument, together with a suitable clean laboratory environment, and advanced
sample handling skills. Modern ICP-MS systems include predefined settings andauto-optimization routines to simplify operation. But the sample preparation,
sample processing, and calibration steps still require a highly skilled analyst.
Automating these steps would simplify the method, reducing the level of skill
required for analysts to reliably perform the analysis.
Agilent ICP-MS systems can be integrated with various automated sample
introduction systems, depending on a laboratory’s requirements. Systems areavailable that automate a range of sample handling steps such as dilution,
acidification, spiking, and calibration. One of the simplest, easiest-to-use andmost cost-effective systems for automating semiconductor sample handling is
the Automated Standard Addition System (ASAS) from IAS Inc. The ASAS canautomatically add online spikes to generate a method of standard additions(MSA) or external calibration curve. In addition to simplifying the analysis, theautomated sample introduction system decreases manual sample handling,
reducing errors, and lowering the potential for sample contamination.
In this study, trace element impurities in IPA were quantified by online MSA using
an IAS ASAS (Tokyo, Japan) and Agilent 8900 Triple Quadrupole ICP-MS (ICPQQQ). The method allows the accurate and reliable quantification of ultratracelevel impurities in IPA without requiring a highly skilled analyst.

Experimental
Reagents and samples
High purity IPA was prepared for analysis by distilling electronic-grade IPA in thelab. The IPA samples were introduced into the ICP-QQQ undiluted, to minimize therisk of contamination and to achieve the lowest possible detection limits (DLs).
93

A 1 μg/L (ppb) mixed multi-element standard solution was used to create the
MSA calibration spikes. The working standard solution was prepared by diluting a
10 ppm mixed multi-element standard (SPEX CertiPrep, Metuchen, NJ, US) with
distilled IPA. To stabilize the spiked elements, nitric acid (68% ultrapure HNO3)
was added to the IPA samples at a final acid concentration of 1%.
The 1 ppb working standard solution was placed into a clean sample bottle andconnected to the standard line of the ASAS. All MSA calibration (spike) solutions
required for the analysis were automatically prepared and added online by the
ASAS. Spike concentrations of 0, 5, 10, 20, and 50 ppt were added to the IPA
sample. The sample preparation and analysis steps were performed in a Class
10,000 clean-room.
Instrumentation
An Agilent 8900 Semiconductor configuration ICP-QQQ instrument was used.
The instrument was fitted with a glass concentric nebulizer (G1820-65138)
self-aspirating with PFA sample tubing (G1820-65478; 0.3 mm id, 1.6 mm od).
A Peltier-cooled quartz spray chamber, quartz torch, platinum-tipped samplingand skimmer cones, and s-lens were used.
When organic solvents are analyzed, carbon in the sample aerosol can bedeposited on the sampling cone, causing instability and signal drift. To prevent
carbon deposition during the analysis of solvents such as IPA, oxygen is added
to the carrier gas to oxidize the carbon in the plasma. Volatile organic solvents
also cause a very high solvent vapor pressure in the spray chamber, leading toplasma instability. To reduce solvent vapor pressure and ensure reliable plasma
ignition and operation, the spray chamber temperature is reduced to below zero
degrees. In this work, the spray chamber was cooled to –5 °C using the Peltier
device that is standard on all Agilent ICP-MS systems. For stable operation of theplasma, a torch with a narrow (1.5 mm) injector replaced the standard 2.5 mm
injector torch.
Combining cool plasma with collision/reaction cell (CRC) operation has beenshown to be a powerful mode for interference removal in ICP-MS (2).
These conditions can also be used for the analysis of organic solvent samples,but such samples require more plasma energy to decompose the organic matrix.
The analyst must balance reducing the plasma temperature enough to control
the ionization of interfering species, while maintaining sufficient energy to
decompose the matrix. With Agilent ICP-MS systems, the ShieldTorch Systemprovides effective reduction of the plasma potential, so ionization of polyatomic
ions is minimized, even at higher forward power. “Cool plasma” conditions provide
better robustness and matrix tolerance on Agilent ICP-MS systems than on
systems that do not have such effective control of plasma potential.
Furthermore, all Agilent ICP-MS systems have two separate gas controls
contributing to the total “carrier” gas flow passing through the central, injector
tube. The nebulizer gas flow (the flow that passes through the nebulizer
and aspirates the sample) is adjusted to give optimum sample aspiration.
The make-up gas flow is then optimized to control the total carrier gas flowthat transports the sample aerosol through the central channel of the plasma.
This total carrier flow, combined with the plasma power and sampling depth,
determines the “coolness” of the plasma conditions.

94

In advanced semiconductor applications, the key requirement is to deliver theabsolute lowest possible detection limits for each analyte. Laboratories
measuring ultratrace levels of contaminant metals often use a multitune method,where several tuning steps are applied sequentially during the measurement ofeach solution. This approach allows the tuning conditions to be optimized for theremoval of different types of interferences, while maintaining sensitivity for eachanalyte. In this work, several reaction cell gases (He, H2, O2, and NH3) were used
for the analytes being measured.
Instrument tuning conditions are shown in Table 1 and other acquisition
parameters are shown in Table 2.
Table 1. Agilent 8900 ICP-QQQ operating conditions.
H2 (cool
plasma*)NH3 (cool
plasma*)

O2 He

H2

Scan type

MS/MS

RF power (W)1500

Sampling depth (mm)18.0

Nebulizer gas flow rate (L/
min)

0.70

20% O2 Ar balance gas flowrate (L/min)

0.30 (30%)**Spray chamber temp (°C)

–5.0

Make-up gas flowrate (L/min)

0.80

0.70
-100

Extract 2 (V)-10.0

Omega bias (V)-70.0

Omega lens (V)4.0

Q1 entrance (V)

-50.0
-

H2 cell gas flow rate (mL/min)

No gas0.50

Extract 1 (V)He cell gas flow rate (mL/min)

He

1.0

12.0

-

5.0

-

5.0

-

-

10.0

-

-

NH3 cell gas flow rate (mL/min)***-

2(20%)**

-

-

-

-

O2 cell gas flow rate (mL/min)

-

-

0.075
(5%)**---OctP bias (V)

-18

-5

-3

-30

-20

-10

Axial acceleration (V)1.0

Energy discrimination (V)

0

0
-10

3

Table 2. Acquisition parameters.
Parameter

Setting

Q2 peak pattern

1 point

Replicates3 (spiked samples)
10 (unspiked sample)

Sweeps/replicate

10Integration time (s)1 (all elements except phosphorus)
10 (phosphorus)* Optimum cool plasma conditions were achieved by adjusting the make-up gas flow while maintaining a highforward power setting.
** Values in parentheses are % of the maximum flow of the gas controller, as displayed in the tuning paneof ICP-MS MassHunter.
*** 10% NH3 balanced with 90% He.
95Automated Standard Addition System (ASAS)
The IAS ASAS is an automated online sample processing device. It uses a
precise, microflow syringe pump to add specific volumes of spike solutions ordiluent to the sample flow as it passes to the ICP-MS nebulizer. The small
footprint of the ASAS allows it to be easily positioned between the autosampler
and ICP-MS, as shown in Figure 1. This arrangement is beneficial in the small
workspace typically available in semiconductor clean-rooms. Once connected inline, the ASAS can be used to automatically generate a calibration curve using
either external standards or MSA.
MSA calibrations have the advantage of exact matrix matching, since thecalibration is created in the actual sample matrix. However, conventional manual
MSA spiking is often regarded as complicated and time-consuming. With
automatic spike additions using ASAS, the complexity is eliminated. Also, theAgilent ICP-MS MassHunter software allows an MSA calibration in one sample tobe automatically converted to an external calibration. This function allows othersamples of the same type to be run against the MSA calibration, without requiring
the subsequent samples to be spiked individually. With these two improvements,
MSA can be as fast and easy to run as conventional external calibration.
Spike recoveries are typically carried out as a routine performance check during
semiconductor chemical analysis. This can be automated to simplify and speed
up the analysis. The ASAS microvolume syringe pump adds the spike to thecontinuously flowing sample stream, so the risk of sample contamination anderrors is minimized.

Figure 1. An Agilent ICP-MS fitted with an IAS ASAS automated standard addition system and theAgilent I-AS integrated autosampler.

96

ASAS operation consists of the following four steps:
Step 1: Loop is filled with the standard solution.
“Valve IN” in the standard line opens and the syringe pump activates. This loads
the standard solution along a dedicated uptake line from the standard bottle tothe loop.

Step 2: Excess standard solution is pumped to waste.
“Valve OUT” in the standard line opens, “Valve IN” closes, and the syringe pumpdischarges, pumping the remaining standard solution to the waste bottle—
bypassing the loop.

Step 3: Sample flow rate is measured to allow calculation of MSA spikevolumes.
To minimize the potential for contamination from peristaltic pump tubing,high-purity samples are usually introduced using self aspiration. This meansthat the flow rate varies, depending on the sample viscosity and tubing length.
To allow the MSA spike additions to be calculated accurately, the ASAS system
first measures the sample flow rate, as follows:– When the autosampler probe moves to the sample vial, it triggers
measurement of the sample uptake rate.
– An air bubble is introduced via the “Air inlet valve”.
– Optical fiber sensors measure the elapsed time between the air bubble
passing Sensor 1 and Sensor 2. The elapsed time is inversely proportional to
the sample flow rate, allowing the actual solution flow rate to be calculated.
97

Step 4: MSA spikes are added automatically.
The syringe pump delivers the standard solution from the loop into the sample
line via the “Mix Block”. The standard solution flow rate needed to give each of therequired MSA spike levels is calculated automatically, as explained later in theworked example.
The MSA spike solution is mixed with the sample online and the spiked sample ispassed to the ICP-MS nebulizer.

Worked example: Addition of a 50 ppt MSA spike to a sample flowing at 200 μL/min.
– A 1 ppb spike standard is prepared and placed in a sample bottle connected to
the Standard line of the ASAS.
– The microflow syringe loads the spike standard into the ASAS loop via thededicated uptake line.
– The autosampler moves to the next sample vial.
– The ASAS measures the sample uptake line flow rate (as previously outlined in
Step 3). In this example, we will use a nominal flow rate of 200 μL/min.
– Based on the measured sample flow rate, the ASAS software calculates theflow rate of the 1 ppb stock standard required to give a 50 ppt spike
concentration. In this case, to achieve a spike level of 50 ppt in the sample
flow of 200 μL/min, the standard would need to be introduced at a flow rate of
10.0 μL/min (20x dilution of the 1 ppb standard).
– The standard in the loop is added to the sample via the “Mix Block” at thecalculated flow rate. The mixed, spiked sample then passes to the ICP-MS
for analysis.
98

The ASAS can accurately add the standard solution at any flow rate between 0.10
and 99.99 μL/min. However, to avoid over diluting the sample, the recommended
standard flow rate is between 1.00 and 10.00 μL/min. This assumes a typicalnebulizer self-aspiration flow rate of 200 μL/min.
The volume of the ASAS microflow syringe is about 800 μL, and the loop volume
is 700 μL. When the volume of the standard solution remaining in the syringe falls
below a set value, the syringe is automatically refilled. This happens after thecurrent set of standard additions has completed.
If the total volume of standard solution required for the spike additions exceeds
the loop volume, the syringe automatically refills the loop to ensure continuous
operation.
Integrating the ASAS with the Agilent 8900 ICP-QQQ offers the following
advantages for ultratrace elemental analysis of semiconductor samples:– Compatibility with the Agilent I-AS autosampler and self-aspirating nebulizers– Compact, easy-to-use, online system– Automated creation of MSA or external calibrations– Automated spike addition for spike recovery studies– The ASAS can also be installed as part of the IAS Continuous Chemical
Samples Inspection (CSI) system. This system provides online monitoring ofmultiple streams, baths, and containers of semiconductor process chemicals.

Results and discussion
DLs and BECs
In total, 47 elements—including all 22 elements specified in SEMI standard
C41-0705—were measured using the 8900 ICP‑QQQ. The instrument was
operated in multiple tune modes, which were switched automatically during asingle visit to each sample vial. Data for each of the modes was combined
automatically into a single report for each sample. Detection Limits (DLs) andBackground Equivalent Concentrations (BECs) in undiluted IPA are given in
Table 3. The DLs were calculated from 3 x the standard deviation (SD) of 10
replicate measurements of the blank (unspiked) IPA sample. The DLs and BECs
for all SEMI required elements (shown in bold) were all well below the grade 4
requirements of 100 ppt; many were below 0.1 ppt. These results illustrate how
the 8900 ICP-QQQ provides performance that ensures compliance with higher
chemical purities that will be required for semiconductor manufacturing in the
future. DLs and BECs for Hf and Re could not be calculated, as the measured
background signal was zero counts per second in all replicates of the blank IPA.
The BEC for Cu reported using the normal, preferred isotope of Cu-63 was
unexpectedly high, at 6.4 ppt. This result was compared to the BEC measured
using the secondary isotope, 65Cu, and the two measured concentrations werein agreement. This suggests the high BEC observed using 63Cu was due to trace
Cu contamination in the IPA sample rather than any interference on 63Cu.
The ASAS was used to perform an automatic spike recovery test. Ten separate IPA
solutions were spiked at 20 ppt and measured against an external calibration thatwas created automatically by converting the MSA calibration. The spike recovery
accuracy and repeatability (%RSD) results are also shown in Table 3. Excellent spikerecoveries of between 91–108% were achieved for all elements at the 20 ppt level,99and RSDs (n=10) were between 1.6 and 8.9%. The results show the excellent
reproducibility of the ASAS spike additions, as well as the good stability of the8900 ICP-QQQ when aspirating organic solvents. This demonstrates the suitabilityof the ASAS-ICP-QQQ method for the routine analysis of ppt-level contaminantelements in IPA.
Table 3. DLs, BECs, and spike recoveries in IPA. Analytes shown in bold are SEMI grade 4 elements.

100

AnalyteQ1

Q2

Tune modeDL(ng/L)

BEC(ng/L)

20 ng/L
Recovery(%)

20 ng/L
n=10
RSD (%)SEMI standard C41-0705
Grade 4(ng/L)

Li

7

7

*H2

0.010

0.040

99

2.4

< 100

Be

9

9

No gas

0.023

0.005

99

2.4

B

11

11

No gas

1.2

12

96

8.0

< 100

Na

23

23

*NH3

0.060

0.97

109

5.7

< 100

Mg

24

24

*NH3

0.020

0.082

102

2.7

< 100

Al

27

27

*NH3

0.042

0.16

100

2.8

< 100

P

31

47

O2 He

2.6

43

99

7.9

<16,000*

K

39

39

*NH3

0.64

1.1

107

4.9

< 100

Ca

40

40

*NH3

0.19

0.62

108

4.7

< 100

Ti

48

64

O2 He

0.23

1.3

99

2.4

< 100

V

51

67

O2 He

0.020

0.030

99

2.3

< 100

Cr

52

52

*NH3

0.16

0.48

92

1.7

< 100

Mn

55

55

*NH3

0.030

0.030

102

2.4

< 100

Fe

56

56

*NH3

0.16

0.72

101

2.5

< 100

Co

59

59

He

0.020

0.020

99

2.1

Ni

60

60

He

0.43

0.80

101

2.0

<100

Cu

63

63

O2 He

0.38

6.4

97

2.3

<100

Zn

64

64

He

0.71

0.72

98

6.9

<100

Ga

71

71

O2 He

0.013

0.005

100

2.8

Ge

74

74

He

0.30

0.070

96

8.1

As

75

91

O2 He

0.41

0.26

108

2.7

Rb

85

85

H2

0.17

0.59

101

2.4

Sr

88

88

O2 He

0.005

0.002

98

2.4

Zr

90

90

O2 He

0.030

0.020

99

2.7

Nb

93

93

H2

0.14

0.41

102

4.0

Mo

98

130

O2 He

0.17

0.11

103

4.1

Ru

101

101

He

0.080

0.03

99

2.9

Rh

103

103

O2 He

0.070

0.18

99

2.1

Pd

105

105

O2 He

0.070

0.040

100

2.5

Ag

107

107

O2 He

0.014

0.006

97

2.6

Cd

111

111

O2 He

0.035

0.004

98

4.0

In

115

115

O2 He

0.012

0.008

99

1.8

<100

<100

Sn

118

118

O2 He

0.058

0.034

100

4.9

<100

Sb

121

121

O2 He

0.056

0.009

103

2.3

<100

Te

125

125

O2 He

0.78

0.29

97

8.9

Cs

133

133

*H2

0.060

0.022

96

4.2

Ba

138

138

O2 He

0.009

0.004

99

2.4

<100

Analyte

Q1

Q2

Tune modeDL(ng/L)

BEC(ng/L)

20 ng/L
Recovery(%)

20 ng/L
n=10
RSD (%)

Hf

178

178

He

0.000

0.000

105

5.1

W

182

214

O2 He

0.21

0.049

97

5.7

Re

185

185

O2 He

0.000

0.000

96

3.0

Ir

193

193

No gas

0.060

0.006

101

6.7

Pt

195

195

O2 He

0.51

0.45

100

3.0

Tl

205

205

O2 He

0.018

0.008

99

2.1

Pb

208

208

O2 He

0.047

0.042

100

2.7

Bi

209

209

O2 He

0.021

0.004

98

1.6

Th

232

248

O2 He

0.11

0.022

97

4.6

U

238

254

O2 He

0.18

0.048

91

6.6

SEMI standard C41-0705
Grade 4(ng/L)<100* High-power cool plasma conditions: the temperature of the plasma was adjusted by changing the make-up
gas flow rate.
** < 16,000 ppt is the concentration limit for elemental P that is equivalent to the SEMI specified limit of 50 ppb(50,000 ppt) for PO4.

Resolving polyatomic interferences on Mg, Al, and Cr
In this work, high-power cool plasma conditions were combined with reaction cellgases to provide the most effective control of intense background and matrixbased interferences. Cool plasma conditions were obtained by adjusting the
make-up gas flow, while maintaining plasma energy with normal “hot plasma” RFpower of 1500 W. These plasma conditions ensured sufficient plasma robustness
to allow long-term analysis of the organic matrix, while providing effective controlof carbon-based interferences on analytes such as Mg, Al, and Cr (Table 4).
Table 4. Main interferences arising from organic solvent matrix.
AnalyteInterferences

DL (ng/L)

BEC (ng/L)

0.020

0.082

0.042

0.16

24

Mg

12

C2+

27

Al

12

C N, C N, C NH

31

P

15

N16O+,14N17O+,13C18O+

2.6

43

52

Cr

40

Ar12C+

0.16

0.48

15

+ 13

14

+ 12

14

1

+

The major isotope of magnesium, 24Mg+, suffers an intense polyatomic
interference from 12C2+ in organic samples. Cool plasma conditions can suppress
the ionization of C2, and CRC mode can also be employed successfully to resolve
the interference. In this work, the lowest DLs for Mg were achieved using a
combination of high-power cool plasma conditions and on-mass measurementin MS/MS mode with NH3 cell gas. The calibration curve for 24Mg shows that the12
C2+ interference was removed successfully, achieving a BEC less than 0.1 ng/L(ppt), and a detection limit of 0.020 ppt (Figure 2).

10124 ➝ 24 Mg [NH 3]

27 ➝ 27 Al [NH 3]

y = 822.8617* x + 67.1000
R = 1.0000
DL = 0.02037 ppt
BEC = 0.08154 ppt

x104

x104

y = 476.0745* x + 227.1000
R = 0.9991
DL = 0.1601 ppt
BEC = 0.477 ppt

CPS

4

CPS

4

52 ➝ 52 Cr [NH 3]

y = 820.7953* x + 129.7000
R = 0.9999
DL = 0.04224 ppt
BEC = 0.158 ppt

2

CPS

x104

2

0

2

1

0

0

50.0

50.0

Conc (ppt)

Conc (ppt)50.0Conc (ppt)

Figure 2. MSA calibration curves for 24Mg, 27Al, and 52Cr.

The same approach was effective for the determination of other elements that suffercarbon-based polyatomic interference in organic solvents, such as 27Al and 52Cr.
The calibrations shown in Figure 2 demonstrate that the interferences from 12C15N+,
13 14 + 12 14
C N , C NH+ on 27Al+ and 40Ar12C+ on 52Cr+ were minimized using high-power cool
plasma conditions and NH3 cell gas. These conditions gave BECs and DLs of 0.16
and 0.042 ppt for Al, and 0.48 and 0.16 ppt for Cr, respectively (Table 4).
P determination
SEMI Standard C41-0705 specifies the maximum concentration of phosphateallowed in high purity IPA, with a limit of 50 μg/L (ppb) or 50,000 ppt. This limit
equates to an elemental concentration of about 16,000 ppt for phosphorus (P).
The analysis of P in IPA needs an ORS cell mode that can resolve P from thenormal plasma background polyatomic ions formed from N and O – 14N16O1H+,
15 16 +N O , and 14N17O+. In addition, potential carbon-based interferences that overlap
P+ at m/z 31 must also be resolved. MS/MS mass shift operation with oxygen
reaction cell gas has been shown to be suitable for the analysis of P. Using thismethod, the P+ ions react with O2 cell gas to form a reaction product ion PO+ at
m/z 47, mass-shifted away from the original on-mass interferences.
A previous study (3) demonstrated that a relatively high octopole bias (–3 V) witha mix of cell gases comprising 0.075 mL/min oxygen plus 12 mL/min helium
could be used successfully for low-level analysis of P. The relative cell gas flow
rates mean that the density of helium atoms in the cell is 160 (12/0.075) times
greater than that of oxygen. Most of the ions entering the cell will therefore collide
multiple times with helium atoms before they collide (and react) with an oxygen
atom. Helium works as a buffer gas, reducing the kinetic energy of the ions before
they react with the O2 cell gas. This low collision energy should reduce the in-cellformation of certain unwanted reaction product ions, for example, 13C18O+ + O2
13C18O16O+ + O. Suppressing these reactions reduces the formation of interfering
product ions that could overlap the analyte product ion 31P16O+ at
m/z 47. Using these mixed cell gas conditions, a minimum BEC for P of 27 ppt
in IPA was reported (3).
The measurement conditions for P described in reference 3 were also used in thisstudy. The calibration curve in Figure 3 shows good linearity from 5 to 50 ppt for
P. The BEC was 43 ng/L (ppt) and the DL was 2.6 ppt (Table 3). Given the muchhigher typical contaminant levels for P compared to the other trace metals, itwould be reasonable to calibrate P at a higher concentration level than the otherelements. This modification could easily be applied to the ASAS methodology10231 ➝ 47 P [O2He]
x102

CPS

3

y = 2.6697* x + 114.1700
R = 0.9991
DL = 2.573 ppt
BEC = 42.76 ppt

2

1

0
50.0
Conc (ppt)

Figure 3. MSA calibration curve for 31P.

described here, if a higher P concentration was added to the working stock
standard solution. The ASAS would then prepare and inject the online MSA spikes
from the mixed standard, including the higher P spike levels. The upper limit for
P defined in SEMI Grade 4 purity chemicals is also much higher than for theother trace elements. The relatively high BEC of 43 ppt is still several orders ofmagnitude lower than the 16,000 ppt concentration limit specified for P.

Conclusion
By automating the processes of sample preparation and standard spiking,the IAS ASAS automated-MSA system simplifies the elemental analysis ofsemiconductor process chemicals using the Agilent 8900 ICP-QQQ. The multielement standard is prepared and connected to the ASAS, and the samples areloaded into the I-AS autosampler. The ASAS system then automatically performs
all required steps, including online MSA spike additions and introduction of thesample to the ICP-QQQ.
Eliminating manual sample handling steps during ultratrace analysis lowers
the risk of contamination. Limiting the handling of reagents and samples also
reduces the likelihood of errors arising during the experimental procedure.
Automating calibration and spike addition leads to increased consistency andhigher confidence in the quality of the results.
The Agilent 8900 ICP-QQQ was operated using optimized plasma conditions and
MS/MS mode to measure 47 elements in IPA. BECs at sub-ppt to ppt levels wereacquired for all analytes – including all the elements specified in SEMI C41-0705.
The results easily meet the current SEMI grade 4 specifications for all elements,
including P, in IPA.
The excellent spike recovery and repeatability results for all elements at the
20 ppt level show the suitability of the automated ASAS method for the routine
analysis of semiconductor process chemicals. The long-term robustness of
this method is enhanced by using high-power cool plasma conditions.
These conditions provide superior matrix decomposition and improved analyte
ionization in the presence of the organic solvent matrix.

References
1.	SEMI C41-0705, Specifications and Guidelines for 2-Propanol, 2005.
2.	J. Takahashi and K. Mizobuchi, Asia Pacific Winter Conference on Plasma
Spectroscopy 2008.
3.	K. Mizobuchi, N. Yamada and M. Yukinari, The Japan Society for Analytical
Chemistry, 66th Nenkai, 2017.

103

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Analysis of Nanoparticles in Organic Reagents by
Agilent 8900 ICP-QQQ in spICP-MS Mode
Authors
Donna Hsu, Yoshinori Shimamura,
Brian Liao, and Michiko Yamanaka1

Determination of 25 and 30 nm Fe3O4 NPs in low particle
concentration solutions

Chun-Hua Chen and Chiu-Hun Su2

Introduction

Ching Heng Hsu3

Semiconductor device manufacturing involves several processes including
lithography, etching, ion implantation, and peeling. Even small amounts ofimpurities present in processing reagents such as developer, rinse solution, andetching liquid can cause defects, resulting in a reduction of product yield anddegradation of product reliability. Metallic nanoparticles (NPs), especially iron (Fe)NPs, can lead to the occurrence of ‘cone defects’ on the surface of wafers, whichcause shorting of electrical signals (1). To prevent these problems from arising,an accurate analytical method is required to determine metallic NPs insemiconductor process chemicals.

1 Agilent Technologies, Inc.
2 Industrial Technology ResearchInstitute of Taiwan, Taiwan
3 BASF Taiwan Ltd., Taiwan

Single particle ICP-MS (spICP-MS) is a powerful tool that is used increasingly tocharacterize the NP content of various types of samples (2–4). spICP-MS allows
the simultaneous determination of the number, concentration, and size ofparticles, plus the dissolved element concentration. It can be applied to themeasurement of semiconductor grade organic solvents such as isopropyl alcohol(IPA), propylene glycol methyl ether acetate (PGMEA), and butyl acetate (BuAc),
as well as aqueous solutions (3). To detect very small-sized NPs using spICP-MS,
an instrument with a low background and high sensitivity such as the Agilent
8900 Triple Quadrupole ICP-MS (ICP-QQQ) is needed. Also, since some metallic
NPs suffer from spectral interferences, the advanced interference removal
capability of the 8900 ICP-QQQ is advantageous for the application.
In this study, Fe NPs were measured in semiconductor grade IPA, PGMEA, andBuAc using the Agilent 8900 ICP-QQQ operating in spICP-MS mode.

Experimental
Sample preparation
Two kinds of Fe3O4 NP (Fe NP) solutions, 25 nm (Sigma Aldrich, p/n 900027)
and 30 nm (Sigma Aldrich, p/n 747408), were used as NP standards. The Fe NPs
were spiked into IPA, PGMEA, and BuAc. These organic solvents were introduced
directly to the ICP-QQQ. To measure the ionic sensitivity of Fe, an aqueous Fe
standard (1000 ppm, Kanto Chemicals, Japan) was diluted with each organic
solvent.
Instrumentation
An Agilent 8900 ICP-QQQ (#200, Semiconductor configuration) and Agilent SPS 4
autosampler were used for all measurements. The sample introduction systemcomprised a quartz torch with a 1.5 mm i.d. injector, quartz spray chamber, andplatinum-tipped interface cones. The SPS 4 autosampler was fitted with a sample
rack (produced in Taiwan) designed to accommodate larger sample bottles (100to 500 mL). Being able to load the same bottles used for sample preparation into
104

the SPS 4 rack reduces the risk of contamination as the samples don’t need to betransferred to smaller bottles. Also, larger bottles are convenient for the long-term
stability test. The samples were self-aspirated using an Agilent PFA nebulizer,
which is part of the SPS 4 probe kit (p/n G3139-68000). Clean argon gas waspurged into the cover of the autosampler and there was a constant flow ofultrapure water via a continuous flow rinse port fitted to the SPS 4.
The 8900 ICP-QQQ was operated in MS/MS mode for all Fe measurements.
Both Q1 and Q2 (unit mass filters) were set to m/z 56. Q1 selects which elements
enter the ORS4 collision/reaction cell (CRC), allowing controlled reaction
chemistry to take place in the cell when a reactive cell gas is introduced.
Ammonia cell gas was used to control the ArO and C2O2 interferences thatoverlap Fe at m/z 56.
The signal generated by a single NP lasts for about 1 ms, so Fast Time
Resolved Analysis (TRA) mode of the 8900 ICP-QQQ was used to acquire thedata. Fast TRA allows single element acquisition at a sampling rate of 100 μs(10,000 measurements per second) and no settling time is needed between
measurements. Data analysis was performed using the Single Nanoparticle
Application Module of the Agilent ICP-MS MassHunter software.
The operating conditions of the Agilent 8900 ICP-QQQ are detailed in Table 1.
As shown, slightly different parameters were used to achieve optimum sensitivity
for the determination of Fe NPs in each solvent. To enable the direct injection oforganic solvents to the ICP-QQQ without the deposition of carbon on the cones,
oxygen gas (20%, Ar balanced) was added to the sample gas flow.
Table 1. ICP-QQQ operating conditions.
Parameter

RF power (W)

Value
IPA

PGMEA

BuAc

1400

1500

1500

Sampling depth (mm)18.0

Nebulizer gas (L/min)

0.70

Makeup gas (L/min)

0.50

0.60

0.45

*Option gas (L/min)

0.40 (40%)

0.20 (20%)

0.40 (40%)

Spray chamber temp. (°C)

2

Extraction lens 1 (V)

-150

-125

-125

Extraction lens 2 (V)

-10

-15

-15

Octopole bias (V)

-10

-3

-3

Axial acceleration (V)Energy discrimination (V)

1.5
-10

-7

2 (20%)

3 (30%)

He flow rate (mL/min)**NH3 flow rate (mL/min)-7

1

Dwell time (μs)
Masses monitored
Data acquisition time (s)3 (30%)

100
Fe (Q1: 56, Q2: 56)
60*20% O2 balanced with Ar added using the option gas mass flow controller,
which is fitted as standard on the Agilent 8900 Semiconductor ICP-QQQ.
**10% NH3 balanced with He.

105

Results and discussion
Analysis of Fe NPs in IPA, PGMEA, and BuAc
Solutions of IPA, PGMEA, and BuAc containing 30 nm Fe NPs spiked at 5 ppt
were measured using the 8900 ICP-QQQ. The signal distribution and size
distribution plots for Fe NPs in each of the samples are shown in Figure 1.
The signals generated from the Fe NPs were clearly separated from thebackground signals. Also, the mean measured particle size was around 30 nm inall spiked solvents, which is consistent with the nominal Fe NP diameter (30 nm).
The Single Nanoparticle Application Module software automatically sets theparticle threshold, which is shown by the pink line in the signal distribution plots.
The spICP-MS software automatically calculates the nebulization efficiency,
which is the ratio of the amount of analyte entering the plasma to the amountof analyte delivered to the nebulizer. By measuring 30 nm Fe NP, the nebulization
efficiency (calculated by size) was found to be around 0.30 (30%) for all threeorganic solvents. The sensitivity of ionic Fe ranged from 1500 cps/ppt to 2400
cps/ppt depending on the solvent. The background equivalent concentration(BED) of the blank reagents was around 6 nm.
IPA

PGMEA

BuAc

20

20

Frequency

30

Frequency

Frequency

30

10

10

20

10

0

0
10000

1000001000000
Signal (CPS)

10000000

0
10000

1000001000000
Signal (CPS)

10000000

10000

1000001000000
Signal (CPS)

10000000

100

100

50

0

Normalized frequency

Normalized frequency

Normalized frequency

100

50

0
10

20

30
40
50
60
Particle size (nm)

70

80

50

0
10

20

30
40
50
60
Particle size (nm)

70

80

10

20

Figure 1. Signal distribution (upper) and size distribution (lower) of 30 nm Fe NPs in solutions of IPA, PGMEA, and BuAc.

106

30

40 50 60 70
Particle size (nm)80Linearity of detected particle number concentration in terms of spiked
concentration
Figure 2 shows the size distribution of 25 nm Fe NPs dispersed in IPA solution
at several concentrations (0, 0.1, 0.5, 1, and 2 ppt). The graph clearly indicates a
Gaussian distribution for 0.5, 1, and 2 ppt of Fe NPs. It wasn’t possible to detect
NPs smaller than 18 nm due to the background signal from the small amountof ionic Fe present in the sample (BEC = 0.6 ppt).
8.E+06

Particle concentration (particle/L)

2 ppt
7.E+061 ppt

6.E+06

0.1 ppt

0.5 pptblank

5.E+06
4.E+06
3.E+06
2.E+06
1.E+06
0.E+000

2

4

6

8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
0 48
0 50 52 54 56 58 60 62
Particle size (nm)Figure 2. Size distribution data for 25 nm Fe NPs spiked at 0, 0.1, 0.5, 1, and 2 ppt in IPA.
The vertical axis shows the particle number concentration for each range of particle sizes(each bar represents a size range of 2 nm).

Figure 3 shows the relationship of measured particle number concentration(particle/L) against the spiked concentration of Fe NPs in IPA. Almost perfectlinearity (R2 = 0.998) was obtained across the concentration range of 0.1 to 2 ppt.
These results show that 25 nm Fe NPs can be determined in IPA solutions
containing very low concentrations of Fe NPs using the 8900 ICP-QQQ operatingin spICP-MS mode.
Measured particle concentration (particles/L)

4.0E+07
3.5E+073.0E+07R 2 = 0.998

2.5E+072.0E+07
1.5E+07
1.0E+07
5.0E+06
0.0E+00
0

0.5
1
1.5
Spiked concentration (ppt)2

Figure 3. Relationship between the spiked
concentration of 25 nm Fe NPs and measured
particle number concentration in IPA.

107

Long-term stability test
Figure 4 shows the stability of detected particle number (representing particle
number concentration) and particle size for 30 nm Fe NPs in the three solvents
over 12 hours. Both the detected particle number and the size were constant over
12 hours, as indicated by the %RSDs. The stability of Fe NPs in each solvent means
they can be measured accurately, even a long time after sample preparation.

IPA (3%)3500

PGMEA (4%)

35

BuAc (6%)

3000

PGMEA (4%)

BuAc (6%)

25

2500
2000
1500
1000

20
15
10
5

500
0
0:00

IPA (2%)30

Particle size (nm)Detected particle number (particles/min)

4000

0
2:24

4:48

7:12

9:36

12:00

Time (hour)

14:24

0:00

2:24

4:48

7:12

9:36

12:00

14:24

Time (hour)

Figure 4. Long-term stability of 30 nm Fe NPs in IPA, PGMEA, and BuAc over 12 hours. The left graph shows the detected particle number and theright graph shows the average particle size. The numbers in parentheses are RSD%.

Conclusion
Using an spICP-MS method, the Agilent 8900 ICP-QQQ operating in MS/MS mode
was used for the determination and characterization of iron-based nanoparticles
in IPA, PGMEA, and BuAc.
Standards containing 25 or 30 nm Fe3O4 nanoparticles were spiked into theorganic solvents and the particle size and the particle number concentration
were determined using the spICP-MS method. The small-sized particles weresuccessfully measured in solutions with a particle concentration ranging from
0.1 to 2 ppt. Also, the particle size and particle concentration of Fe NPs werestable in each of the three organic solvents over 12 hours.
Overall, the method delivered the low background, sensitivity, and spectralinterference removal necessary for the analysis of small-sized NPs insemiconductor grade organic solvents.

References
1.	Takuya Hagiwara, Kentaro Saito, Hiraku Chakihara, Shuji Matsuo, Masao Inoue,
Seiji Muranaka, Yuki Ota, Masazumi Matsuura, Study on Cone-defects during
the Pattern Fabrication Process with Silicon Nitride, J. Photopolym. Sci.
Technol., 28, No.1, 2015, 17–24
2.	Michiko Yamanaka and Steve Wilbur, Measuring Multiple Elements in
Nanoparticle using spICP-MS: Acquire NP data for up to 16 elements in Rapid
Multi-Element Nanoparticle Analysis Mode, Agilent publication, 5994-0310EN
3.	Yoshinori Shimamura, Donna Hsu, and Michiko Yamanaka, Multielement
Nanoparticle Analysis of Semiconductor Process Chemicals Using spICP-QQQ:
Characterization of Ag, Fe3O4, Al2O3, Au, and SiO2 NPs in TMAH in a single
analytical run, Agilent publication, 5994-0987EN
4.	Michiko Yamanaka and Steve Wilbur, Accurate Determination of TiO2
Nanoparticles in Complex Matrices using the Agilent 8900 ICP-QQQ, Agilent
publication, 5991-8358EN
108

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Analysis of 15 nm Iron Nanoparticles in
Organic Solvents by spICP-MS
Authors
Donna Hsu1
Yoshinori Shimamura1
Katsuo Mizobuchi1
Brian Liao1
Kuo-Lin Wang2
Chiu-Hun Su3
Ching Heng Hsu4
Agilent Technologies, Inc.
Shiny Chemical Industrial Co., Ltd.,
Taiwan3
Industrial Technology ResearchInstitute of Taiwan
4
BASF Taiwan Ltd.
1

2

Using the exceptional sensitivity and low background of theAgilent 8900 ICP-QQQ
Monitor metallic nanoparticles in process chemicals
In semiconductor device manufacturing, even small amounts of impurities
present in processing reagents can affect product yield and reliability. There is
growing awareness that metallic nanoparticles (NPs), especially Fe NPs, can leadto the occurrence of defects on the surface of wafers. Single particle ICP-MS(spICP-MS) is a powerful tool that is used increasingly to characterize the NP
content of various types of samples, including semiconductor process chemicals.

Measurement of 15 nm Fe NPs using spICP-MS
The Agilent 8900 ICP-QQQ (semiconductor configuration) was fitted with aquartz torch with a 1.5 mm i.d. injector. Interferences on 56Fe from ArO and C2O2
were resolved using oxygen as the cell gas. The Agilent SPS 4 autosampler wasused, so large bottles (100 to 500 mL) could be used for long-term stability tests.
The samples were self-aspirated using an Agilent PFA nebulizer with SPS 4 probe
kit (G3139-68000). Data analysis was performed using the optional Single
Nanoparticle Application module of Agilent ICP-MS MassHunter software.
Table 1. 8900 ICP-QQQ operating parameters used for spICP-MS method.
Parameter

SettingParameter

Setting

RF Power (W)1200

Energy Discrimination (V)–8.0

Sampling Depth (mm)16

Cell gas (O2) Flow (mL/min)

0.38 (25%)

Neb Gas Flow (L/min)

0.75

Dwell Time (us)100

Makeup Gas Flow (L/min)

0.5

Scan Mode

Single quad mode

*Option Gas (O2) Flow (L/min)

0.12 (12%)

Mass Monitored

56 (Fe)Spray Chamber Temp (deg)–2Data Acquisition Time (s)60

Axial Acceleration (V)2*Direct injection of organic solvents was possible by adding oxygen (50% balanced with Ar) to prevent the depositionof carbon on the cones.

The spICP-MS method was used to measure isopropyl alcohol (IPA), propylene
glycol methyl ether acetate (PGMEA), and propylene glycol monomethyl ether(PGME) spiked with 15 nm Fe2O3 NPs (Sigma Aldrich). Figure 1 shows the signal
distribution (upper) and size distribution plots (lower) for Fe NPs in each of thesamples. The NP signals were clearly separated from the background signals.
Also, the mean measured particle size was around 15 nm in all spiked samples,
which is consistent with the nominal Fe NP diameter of 15 nm.

109

PGMEAPGME

Frequency

Frequency

Frequency

IPA

Signal (CPS)

Signal (CPS)
Normalized frequency

Normalized frequency

Normalized frequency

Signal (CPS)

Particle size (nm)Particle size (nm)Particle size (nm)Figure 1. Signal distribution (upper) and size distribution (lower) of 15 nm Fe NPs in solution of IPA,PGMEA, and PGME.

Size ratio of 15 and 30 nm particles
Table 2 shows the average signal intensities from one particle with a 30 nm
diameter and one particle with a 15 nm diameter, and the ratio of these intensities(30 nm/15 nm). As the signal intensity is proportional to the cube of the diameterof the particle, the ratio of signal intensities from the 15 and 30 nm NPs should be
8. The measured ratio was 8.44, which is acceptable, considering the accuracy ofthe nominal diameters.
Table 2. Average particle signal intensities and ratio of the intensities.
Ratio(30 nm/15 nm)

Average signal intensity from one particle (cps)5,216,482

617,736

8.44

IPA 4000# of particles (min-1)

Long-term stability tests

25
20

3000

Figure 2 shows the stability of detected number (representing particle number15
2000
of Particles
RSD: 4% over 10
concentration) and particle size for 15 nm Fe NPs in two of# thesolvents
1000
Mean Size RSD: 2%
10 hours. Both the detected particle number and the size were constant over 5
0
0
0
2
4
6
8
10
12
10 hours, as indicated by the %RSDs.

15

2000
1000
0

0

2

# of Particles RSD: 4%

10

Mean Size RSD: 2%

5

4

6

8

10

12

4000

0

25
20

3000

15

2000
1000
0

Time (hour)

PGMEA# of particles (min-1)

20

3000

Time (hour)

PGMEA

25
Mean size (nm)# of particles (min-1)

IPA 400002# of Particles RSD: 6%

10

Mean Size RSD: 3%

5

4

6

Time (hour)

15

2000
1000
0

110

20

0

2

# of Particles RSD: 6%

10

Mean Size RSD: 3%

5

4

6

Time (hour)

8

10

12

0

Mean size (nm)# of particles (min-1)

25 in IPA and PGMEA over 10 hours.
Figure 4000
2. Long-term stability of 15 nm Fe NPs
3000

Mean size (nm)

15 nm

8

10

12

0

Mean size (nm)

30 nm

Figure 3 shows the size distribution profiles of 30 nm Fe NPs in IPA on the dayof sample preparation and six months later. After six months, the signals from30 nm Fe NPs were clearly observed and the shape of the size distribution isalmost the same as the one in the fresh solution. The results show that Fe NPs
are stable in IPA for a long period, suggesting that they don’t dissolve into or
precipitate out of the solvent.

Six months later

Normalized frequency

Normalized frequency

Day 1

Particle size (nm)Particle size (nm)Figure 3. Size distribution of 30 nm Fe NPs in IPA on the day of preparation (left) andsix months later (right).

Single particles in high purity solvents
The 8900 spICP-MS method satisfies the emerging needs of the semiconductor
industry to monitor low concentrations of small sized particles in high purity
solvents.

111

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GC-ICP-QQQ Achieves Sub-ppb Detection Limits for
Hydride Gas Contaminants
Authors

Introduction

William Geiger, ConSci Corporation,
Pasadena, Texas, USA

Hydride gases, such as phosphine and arsine, are important contaminants inprocess chemicals used in both the petrochemical and semiconductor industries.
The presence of phosphine, arsine, hydrogen sulfide, and carbonyl sulfide inpolymer grade ethylene or propylene can have a deleterious effect on catalysts
used in the production of polypropylene plastics. In the semiconductor industry,
phosphine is used as a precursor for the deposition of group III-V compound
semiconductors, and as a dopant in the manufacturing of semiconductor
devices, such as diodes and transistors. The presence of unwanted hydride gas
impurities can have a profound effect on the performance of the final device.

Emmett Soffey, Steve Wilbur and Chris
Scanlon, Agilent Technologies Inc.,
USA

Keywords
semiconductor, petrochemical,
phosphine, arsine, hydrogen sulfide,
carbonyl sulfide, germane, silane,
oxygen mass-shift, hydrogen on-mass

To date, measurement of these contaminants at ppb levels has been sufficient,
but increasing competition within the industry and evolving performance criteria
are pushing specifications ever lower. In addition, high purity gas manufacturers
often require analytical detection limits 5-10 times lower than reported
specifications. In anticipation of increasing industry demand for lower level
detection, a new high sensitivity GC-ICP-QQQ method was developed for thisapplication.

Experimental
Instrumentation: An Agilent 7890 GC was coupled to an Agilent 8800 #200 using
the Agilent GC-ICP-MS interface.
Acquisition conditions: MS/MS mass-shift mode using oxygen as the cell gas forthe measurement of Ge, As, P and S. MS/MS mode with hydrogen cell gas wasused for the on-mass measurement of the primary isotope of Si at m/z 28.
Table 1. Agilent 8800 ICP-QQQ operating conditions.
O2 modeH2 modeRF power (W)1350

Sample depth (mm)8.4Argon carrier (make-up ) gas flow (L/min)

0.85

Extract 1 (V)-150

Extract 2 (V)-190

Kinetic Energy Discrimination (V)-40Cell gas/flow (mL/min)

0.35

5.0

Reagents and sample preparation: Gas standards of silane, phosphine, germane,arsine (all balanced with H2), and hydrogen sulfide and carbonyl sulfide (balancedwith Ar) were supplied by Custom Gas Solutions at a nominal value of 10 ppmv.
These standards were dynamically diluted in helium using a pressure/fixed
restrictor based diluter supplied by Merlin MicroScience.
112

Results and discussion
Low level phosphine analysis
The purpose of this experiment was to establish a detection limit for phosphine(PH3) using GC-ICP-QQQ under ideal conditions. Q1 was set to m/z 31 (theprecursor ion 31P+) and Q2 was set to m/z 47 to measure the product ion 31P16O+.
Since the eluting peaks are relatively narrow, with duration of no more than
~12 seconds, a maximum of 1 second was set for the total scan time. For the
single element analysis of phosphine (measured as PO+), an integration time of
1.0 second was used. A multi-point calibration curve was generated for PH3 atconcentrations of 8.2, 18.8 and 50.8 ppb. This covers the representative
concentration range required for the measurement of this contaminant.
31 ➝ 47 PH 3

CPS

x106

y = 20438.647728 *x + 0.000000E+000
R = 1.0000
DL = --BEC = 0

1

0.5

0
20.0

40.0

60.0

Conc (ppt)

Figure 1. Phosphine calibration curve with an R value of 1.000 over the concentration range.

A low level phosphine standard (~0.42 ppb) was also prepared, to allow thedetection limit (DL) to be calculated. Two different methods for DL calculation
were used:i.	Two times the signal to noise (S/N) of the phosphine peak in the low levelstandard based on “Peak to Peak” noise methodii.	The standard deviation of the concentrations measured in seven replicate
analyses of the low level standard.
Full Time Range EIC (31 ➝ 47) : 030SMPL.d
x103

2

0
2.0

4.0
RT(min)Figure 2. Chromatogram of 0.42 ppb PH3 standard. S/N: 96.9.

113

In the chromatogram shown in Figure 2, a S/N ratio of 96.9 was determined forthe phosphine peak. Using the equation DL = 2 x ((concentration of standard) /(S/N)), a detection limit approximation of 8.67 ppt was calculated based on 2 x((0.42 ppb) / (96.9)). Using the standard deviation method, where multiple
replicates of the low level standard were analyzed, the detection limit was 19 ppt.
Analysis of additional hydride gases
The GC-ICP-QQQ method was applied to the multielement analysis of germane,arsine and phosphine within a single analysis. Ge and As were measured
as their O2 reaction product ions, GeO+ and AsO+, as was the case with P (PO+).
Hydrogen sulfide (H2S) and carbonyl sulfide (COS) were also analyzed using O2
mass-shift mode, based on the ICP-QQQ measurement of sulfur as the 32S16O+
reaction product ion at m/z 48. For the analysis of silane, Si was measured
directly (on-mass) at its major isotope 28Si, using H2 cell gas. The primarypolyatomic interferences on 28Si+ are 12C16O+ and 14N2+, due to the presence of CO2,N2 and O2 in the argon supply and from air entrainment into the plasma. H2 wasselected as the reaction gas as both the CO+ and N2+ interferences react readily
with H2 cell gas. Si+ remains unreactive and so can be measured, free frominterferences, at its original mass.
Comparison of GC-ICP-QQQ and GC-ICP-MS DLs
For comparison purposes, H2S, COS, PH3, GeH4, AsH3, and SiH4 were analyzed byboth GC-ICP-QQQ with the 8800 ICP-QQQ, and GC-ICP-MS using the same GC
method with an Agilent 7900 conventional quadrupole ICP-MS. A summary of thedetection limits (DLs) for both techniques is given in Table 1. For analytes where
the background noise is very low (Ge-74, As-75), single digit ppt level detection
limits are easily achieved using either GC-ICP-MS or GC-ICP-QQQ. However,for analytes that are prone to higher backgrounds (P-31 and S-32), significantly
lower detection limits can be achieved by using MS/MS with O2 cell gas andmeasuring the oxygen addition reaction product ions PO+ and SO+ in mass-shiftmode. In addition, MS/MS mode with H2 cell gas provides effective removal of
background interferences at mass 28, allowing on-mass measurement of Si at its
primary isotope.

114

Table 1. Detection limit comparison between GC-ICP-QQQ and GC-ICP-MS.
Hydride gas

8800 ICP-QQQ

H 2S

32 -> 48 (O2)7900 ICP-MS
DL, ppb

COS

PH3

GeH4

AsH3

SiH4

DL, ppb
32 (No gas)

MDL 7 reps

0.21

MDL 7 reps

0.62

MDL 2 X S/N

0.11

MDL 2 X S/N

0.22

32->48 (O2)

32 (No gas)

MDL 7 reps

0.12

MDL 7 reps

0.51

MDL 2 X S/N

0.11

MDL 2 X S/N

0.21

31->47 (O2)

31 (No gas)

MDL 7 reps

0.019

MDL 7 reps

0.139

MDL 2 X S/N

0.009

MDL 2 X S/N

0.077

74->90 (O2)

74 (No gas)

MDL 7 repsNA

MDL 7 reps

0.013

MDL 2 X S/N

0.0038

MDL 2 X S/N

0.001375->91 (O2)75 (No gas)

MDL 7 repsNA

MDL 7 reps

0.016

MDL 2 X S/N

0.0013

MDL 2 X S/N

0.006

28->28 (H2)

28 (H2)

MDL 7 reps

0.14

MDL 7 reps

1.09

MDL 2 X S/N

0.196

MDL 2 X S/N

1.18

NA = not available

GC-ICP-QQQ sets benchmark detection limits
The significantly lower background and higher sensitivity of the Agilent 8800
ICP-QQQ resulted in a GC-ICP-QQQ method that shows a clear advantage forthe determination of a range of contaminants in high purity gases at the low
detection levels demanded by the industry. Compared to GC-ICP-MS withconventional quadrupole ICP-MS, GC-ICP-QQQ DLs for silane, phosphine,hydrogen sulfide, and carbonyl sulfide were lower by a factor of 5 to 10, withsilane detection limits in the ~200 ppt range and phosphine detection limits inthe ~15 ppt range.

More information
Sub-ppb detection limits for hydride gas contaminants using GC-ICP-QQQ.
Agilent Publication 5991-5849EN
Find out more about CONSCI at www.consci.com or contact William Geiger atbill@conscicorp.com

115

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Determination of Trace Impurities in Electronic Grade
Arsine by GC-ICP-QQQ
Authors
William M. Geiger, Blake McElmurry,Jesus Anguiano1
Mark Kelinske2
1
2

CONSCI, Ltd., Pasadena, Texas, USA
Agilent Technologies Inc., USA

Sub-ppb detection limits for hydride gas contaminants using asingle column, single injection volume, and multi-tune method
Introduction
Most electronic devices use silicon-based semiconductors. However certain
applications can benefit from alternative semiconductor materials, such as III-V
compound semiconductors. These compounds are made of elements fromgroups III and V of the periodic table, usually Al, Ga, or In combined with N, P, As,or Sb. The appeal of these compounds is that they have much higher “carrier
mobility” than silicon, which means they offer high performance and greater chipdensity with lower power consumption and less heat generation. These are
critical factors in microelectronics, leading to increased use of III-V compound
semiconductors in high electron mobility transistors (HEMT) and field effecttransistors (FET).
Unlike Si semiconductors, III-V compound semiconductors are also able to emit
light, which makes them essential for the large and growing field ofoptoelectronics. Light emitting diodes (LED) are widely used in lighting, displays,
illuminated switches, and infrared remote controls. Other III-V compound
semiconductor devices include vertical-cavity surface-emitting lasers (VCSEL),
which are used in optical fiber communications.
Among the most widely used III-V compounds are gallium arsenide (GaAs),
aluminum gallium arsenide (AlGaAs), and indium gallium arsenide nitride(InGaAsN), all of which require arsine gas as a precursor for manufacture.
Dopants are added deliberately to modify the electrical properties ofsemiconductor materials, but incorporation of unwanted dopant elements into
III-V compound semiconductor structures can be problematic, even at trace levels(1). The unwanted dopants will introduce energy levels in the energy gap of thesemiconductor, altering the electrical and optical properties of the semiconductor
substrate through an increase in electron mobility, leakage current, or
photoluminescence.
For example, n-type dopants such as Ge, Si, P, and S increase leakage current andreduce the gain of transistors. Therefore, it is critical to determine theconcentration of germane (GeH4), silane (SiH4), phosphine (PH3), and hydrogensulfide (H2S) impurities in arsine to prevent them affecting the performance of the
final device. There may be some slight variation in the gas purity levels required
for the manufacture of each type of device, but, in general, process gases need tobe free of dopant impurities. Because Ge is of particular concern in the
manufacture of many devices, there is a need to measure GeH4 impurities at or
below single digit ppb levels in arsine. However, the ability to detect such low level
impurities requires a highly sensitive analytical method.

116

Gas chromatography (GC) coupled with ICP-MS is currently the only techniquecapable of measuring germane in arsine at sub-ppb levels (2–4). The nonatmospheric molecular impurities typically determined by GC-ICP-MS are H2S,
SiH4, PH3, and GeH4. Occasionally, stibine (SbH3), hydrogen selenide (H2Se), andstannane (SnH4) are also of interest.
The goal of this work was to measure as many of the critical hydride gas
impurities as practically possible in arsine, using a single GC-ICP-MS injection anda multi-tune "time program" acquisition method. This approach avoids the need touse different detectors, columns, methods, and even instruments to cover the fullrange of impurities.

Experimental
Sample and standard preparation
Standards of SiH4, PH3, GeH4, and H2S were made using a 10 ppm standard mixture(Custom Gas Solutions, Durham, NC, USA) and dynamically diluting it to a value of
24 ppb using a UHP-MMSD dilution system (CONSCI, Pasadena, TX). Standards for
H2Se, SbH3, and SnH4 are difficult to obtain due to the labile nature of thesecompounds. Only qualitative retention time standards were made using hydride
generation with sodium borohydride. Although H2Se, SbH3, and SnH4 can be
determined by GC-ICP-MS, they were not studied quantitatively in this investigation.
Instrumentation
An Agilent 7890B GC was used for the separation of impurities in arsine and an
Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) was used as the detector.
The standard Agilent GC-ICP-MS interface was modified using a high flow Deansswitch, as shown in Figure 1. This configuration allowed the arsine matrix to bevented at its elution time, preventing the matrix from entering the ICP-MS torch.
The column was selected based on a previous study that used an Agilent 8800
ICP-QQQ (3). The GC operating parameters are given in Table 1.

Figure 1. Schematic of the Deans switch used to vent arsine eluted by the GC column, preventing
the matrix from being passed to the 8900 ICP-QQQ.
Table 1. GC operating parameters.
Parameter

Setting

ColumnTwo 100 m x 0.53 mm x 5.0 µm DB-1

Carrier Gas (psig Ar)

20

Oven Temperature (°C)

30 (isothermal)

Sample Size (µL)

60

Transfer Line Temperature (°C)

120

117

Standard instrument operating parameters for the ICP-MS recommended by
Agilent were used. To optimize the ICP-QQQ, a standard containing 5 ppm sulfur
hexafluoride, xenon, and krypton in argon (CSI Gas, Texas City, TX) was used.
The standard was introduced into the argon dilution gas flow path at 2 mL/min
and the signal at m/z 32 was maximized. The S, Kr, and Xe peaks were used to
optimize torch position and confirm mass calibration.
As described in a previous study (3), Agilent ICP-QQQ instruments feature two
identical, full-sized quadrupole mass filters (Q1 and Q2), situated either side of theOctopole Reaction System (ORS) collision/reaction cell (CRC). This configuration
enables double mass selection (MS/MS), which is vital for successful interference
removal using reactive cell gases. Like Q2, Q1 operates in a high vacuum region,
so it provides excellent resolution and abundance sensitivity while also
maintaining high transmission. This allows precise selection of the ions that enter
the cell, ensuring the reactions used to remove interferences on analyte ions are
consistent and predictable. A reactive cell gas such as hydrogen, oxygen, orammonia is used to react with either the interfering ion or the analyte ion (M+) toattain interference-free measurement. Analytes are measured in ‘on-mass’ or‘mass-shift’ mode. When the cell gas reacts with the interferent, but not theanalyte ion, the analyte is measured at its natural mass (on-mass) and theinterference ions are removed by Q2. When the analyte ion reacts more readily
with the cell gas than the interference ions do, the analyte forms a reaction
product ion e.g. MH+ or MO+. These product ions are then measured at a newmass, away from the interfering ion overlaps.
The ICP-QQQ can also be operated in no gas mode or the ORS cell can bepressurized with a collision gas, such as helium (He). He mode removes many
common polyatomic ion interferences by kinetic energy discrimination (KED) orby collision-induced dissociation (CID).
Compared to the 8800 ICP-QQQ used in the previous study (3), the 8900 uses
newer technology, such as an ORS 4 cell, which provides higher sensitivity andlower backgrounds. In addition, the 8900 #100 (Advanced Applications) model
used in this work includes inert, low sulfur and silicon argon gas lines, which
reduce instrumental backgrounds for these elements. To identify the best
method conditions for the application, three different MS/MS tune modes were
investigated: no gas, hydrogen, and oxygen with and without a mass-shift.
Instrument operating conditions are listed in Table 2.
Table 2. ICP-QQQ operating parameters.
Parameter

No GasRF Power (W)

O2

1450

Sampling Depth (mm)3Dilution Gas Flow (L/min)

0.7

Extract 1 (V)–20

Extract 2 (V)–250

Kinetic Energy Discrimination (V)5Cell Entrance (V)

118

H2

2

–7

–50

Cell Exit (V)–80

Cell Gas Flow RateNA

–70
2 mL/min

0.6 mL/min(40% of full scale)Method development
The method conditions that provided the best detection limits (DLs) for eachcompound are summarized using bold text in Table 3. The DLs were calculated fromsignal-to-noise value multiplied by three (as described later). For analytes where thebackground noise is low due to the absence of interferences (e.g. 74Ge), single digit
ppt level DLs were easily achieved using GC-ICP-QQQ operating in no gas, H2, or O2
mode. For analytes that are prone to higher backgrounds, such as 31P, 32S, and 28Si,
lower DLs were achieved using a reactive cell gas method. The presence of CO2, N2,
and O2 in the argon supply and from air entrainment into the plasma leads to theformation of spectral interferences. These interferences include 12C18OH+, 14N16OH+,
15
N2H+, 15N16O+ and 13C18O+ on 31P+, 16O2+ and 14N18O+ on 32S+, and 12C16O+ and 14N2+ on
28 +Si . P and S react quickly with O2, so both analytes were measured as reaction
product ions, 31P16O+ and 32S16O+, at m/z 47 and 48, respectively, in mass-shift mode.
H2 cell gas provided effective removal of the background interferences at mass 28,
allowing on-mass measurement of 28Si+ at m/z 28.
The measurement of different analytes in different reaction modes is simple to set
up and run using a single multi-tune method on the 8900. In the acquisition method,
the cell gases and measurement modes are switched automatically during theanalysis, giving a fast and automated analysis using the optimum mode for eachanalyte. Switching conditions during the run allows the analyst to use the best cellconditions, as well as increase the analyte acquisition times to improve sensitivity.
Increasing the injection volume would provide even lower DLs for all compounds
except for H2S. A 60 µL (or smaller) sample size is needed for the separation of H2Sfrom the arsine matrix.
Table 3. Comparison of GC-ICP-QQQ method conditions for each gas mode.
No Gas
Mass

Integration
Time (s)Area of
24 ppb Standard

S/N

3 sigmaDL, ppbv

Silane28 > 280.2

165967

14

5

Germane74 > 740.24474358260

0.01

Phosphine

31 > 31

0.2

32118

870

0.08

Hydrogen sulfide

32 > 320.2

234053

175

0.41

Mass

Integration
Time (s)Area of
24 ppb Standard

S/N

3 sigmaDL, ppbv

Silane28 > 28

0.2

79068

42

1.7

Germane74 > 740.22720068300

0.01

Phosphine

31 > 31

0.2

17919

650

0.11

Hydrogen sulfide

32 > 320.2145124180

0.40

Hydrogen

OxygenMass

Integration
Time (s)Area of
24 ppb Standard

S/N

3 sigmaDL, ppbv

Silane28 > 28

0.2

51499

34

2

Silane28 > 44

0.2

34201

37

2

Germane74 > 740.24223598000

0.01

Germane74 > 90

0.2

15577

1240

0.06

Phosphine

31 > 31

0.2

0

0

NA

Phosphine

31 > 47

0.2

29011

1500

0.05

Hydrogen sulfide

32 > 32

0.2

22579

13

6

Hydrogen sulfide

32 > 480.2

218640

290

0.24

119

Figure 2. Overlaid chromatograms of SiH4, PH3, H2S, and GeH4 in arsine by GC-ICP-QQQ obtainedusing a multi-tune method.

Multi-element analysis of SiH4, PH3, H2S, and GeH4
Since the best sensitivity (peak area) was obtained using different cell gas
conditions for each analyte compound, a time program method was used where
the acquisition conditions were changed during the run. The optimized singlemethod parameters are given in Table 4 and the chromatograms are shown in
Figure 2. If analysts preferred to simplify the analysis and use a single cell gas,
O2 would provide acceptable data, with some loss of sensitivity compared to themulti-tune method.
Table 4. Multi-tune method parameters.
Acquisition
Time (s)SilaneGermanePhosphine
HydrogensulfideRetention Time
(s)

Gas
Mode

Q1 -> Q2

Integration
Time/Mass (s)

1008
77
89

992

H2

28 -> 28

0.8

1037

O2

74 -> 74

0.2

1057

O2

31 -> 47

0.4

1112

O2

32 -> 48

0.8

Table 5. DLs for SiH4, GeH4, PH3, and H2S.
Mass

Integration
Time (s)

Gas
Mode

S/N

3 sigma DL,
ppbv

Silane28 > 280.8

H2

Germane74 > 74

0.2

O2308146140

0.514383748000

Phosphine

31 > 47

0.4

0.01

O2

60451

4700

0.02

Hydrogensulfide32 > 480.8

O2883099490

0.15Area of 24
ppb Standard

Results and discussion
The DLs reported for SiH4, GeH4, PH3, and H2S (Table 5) were determined using
the chromatograms (Figure 2) that were obtained using the parameters outlinedin Table 4. The ICP-MS MassHunter software signal-to-noise (S/N) tool was used.
The software divides the concentration of the analyte by the S/N value followedby multiplication by three to determine the DL. The EPA protocol MDL and aStudent T-test could have been applied if a standard 10 times or less than the
expected DL had been available (5). That level standard was not available forthis work.
120

Other compounds of potential interest in the quality control testing of arsine
including H2Se and SbH3 eluted well beyond the arsine retention time (not shownin Figure 2). The relative retention time of SnH4 and arsine prevented SnH4 frombeing separated on a boiling point column, so an Agilent Select Low Sulfur
column (p/n CP8575) was used instead. DLs for SnH4, H2Se, and SbH3 were
estimated at 1 ppb or lower, based on their relative response in aqueous samples
and their first ionization potentials.

Conclusion
GC-ICP-QQQ was used to separate and measure all hydride gas contaminants inarsine at or below single digit ppbv levels. Germane, which is probably the mostcritical contaminant in semiconductor-grade arsine, was determined at low ppt
levels. Measurements of SiH4, PH3, H2S, GeH4, H2Se, and SbH3 were performed
using a single GC column and a single injection.
The best detection limits for all compounds were achieved by operating the 8900
ICP-QQQ in MS/MS mode with H2 and O2 cell gases. Using a single multi-tune
method allowed us to maximize signal averaging, and therefore achieve low DLs
with a single injection.
The determination of dopants/contaminants in arsine provides extra processcontrol to aid in the quality of the manufacturing process, thus improving the yieldand performance of micro-electronic and opto-electronic devices.

References
1.

J. Feng, R. Clement, M. Raynor, Characterization of high-purity arsine andgallium arsenide epilayers grown by MOCVD. J. of Chrystal Growth, 2008,
310, 23, 4780–4785

2.

C. J. Meyer and W. M. Geiger, The Chromatographic Analysis of Trace
Atmospheric Gases. In J. D. Hogan (Ed.), Specialty Gas Analysis: A Practical
Guidebook. 1997, 76–77. New York: Wiley-VCH.

3.

W. M. Geiger and E. Soffey, GC-ICP-QQQ Achieves Sub-ppb Detection Limits
for Hydride Gas Contaminants. In Agilent 8800 ICP-QQQ Application
Handbook, Fourth edition, 2020, 37–40, Agilent publication 5991-2802EN

4.

D. Decker and L. M. Sidisky, Gas Chromatographic Column Considerations.
In W. M. Geiger, & M. W. Raynor (Eds.), Geiger, W. M., and Raynor, M. W.
(2013). Trace analysis of specialty and electronic gases. (pp. 251–274).
Hoboken, N.J: John Wiley & Sons, Inc.

5.

G. Wells, H. Prest, C. W. Russ IV, Signal, Noise, and Detection Limits in
Mass Spectrometry, Agilent publication, 5990-7651EN

121

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Materials
Title

Page

Rare earth oxides
Direct measurement of trace rare earth elements in high purity REE oxides

123

Removal of MH+ interferences in refined REE material analysis

126

Direct analysis of trace REEs in high purity Nd2O3

129

Direct determination of challenging trace rare earth elements in highpurity lanthanide REE oxides

132

MetalsArsenic measurement in cobalt matrix using MS/MS mode with oxygenmass-shift

135

Analysis of ultratrace impurities in high purity copper using the Agilent 8900
ICP-QQQ

138

Determination of sulfur, phosphorus, and manganese in high purity iron145

The benefits of improved abundance sensitivity with MS/MS for traceelemental analysis of high purity metals

148

Ultratrace copper analysis in a semiconductor grade organometallic
titanium complex

152

Nanomaterials

122

Analysis of 10 nm gold nanoparticles using the high sensitivity of the Agilent
8900 ICP-QQQ

155High sensitivity analysis of SiO2 nanoparticles using the Agilent 8900
ICP-QQQ

158

Accurate determination of TiO2 nanoparticles in complex matrices using theAgilent 8900 ICP-QQQ

161

> Return to table of contents> Search entire document

Direct Measurement of Trace Rare Earth Elements inHigh Purity REE Oxides
AuthorIntroduction

Kazumi Nakano
Agilent Technologies, JapanThe rare earth elements (REEs) are widely used in advanced technologies
including high-power permanent magnets, lasers, phosphors used in fluorescentlamps, radar screens and plasma displays. REEs are also used in petroleum
refining, automobile catalytic converters and batteries, and in high-technology
glasses. It is clear from these examples that REEs play a key role in many typesof materials used in high-technology industries. However, the presence of other
REEs as contaminants in a purified single-element REE material often impacts
the functionality of the final product, so impurities in the REE oxide raw materialmust be carefully controlled.

Keywords
Rare Earth Elements, REE, rare earthoxide, REO, samarium oxide,
gadolinium oxide, oxygen mass-shift,ammonia on-mass

ICP-MS is the most commonly used atomic spectrometry technique for themeasurement of trace REEs due to its simple REE spectra — particularly whencompared to emission techniques. The measurement of mid- and high-mass REEs
in a low-mass REE matrix is, however, very challenging for ICP-MS because REEs
have among the highest metal-oxide (M-O) bond strengths of any element, and theoxide ions of the low mass REE overlap the preferred isotopes of the mid-massand high-mass REEs. Table 1 shows the interferences observed in the analysis oftrace REEs in high-purity samarium (Sm) oxide and gadolinium (Gd) oxide.
Separation of the trace REE analytes from the REE matrix can be performed
utilizing a chelating resin, but this technique is time-consuming and customizationis needed according to the analyte and matrix element. The direct analysis of trace
REEs in a variety of high-purity REE matrices is therefore desired. In this work,
an Agilent 8800 Triple Quadrupole ICP-MS was used for the direct analysis of trace
REE in two high-purity REE materials: Sm2O3 and Gd2O3. Operating the ICP-QQQ in
MS/MS mode effectively removes the challenging interferences, enabling thedetermination of REE impurities at trace levels in these two materials.
Table 1. Preferred isotope for ICP-MS analysis of each REE, and the potential interferences caused by
Sm2O3 and Gd2O3 matrices.
Element

La

Ce

Pr

Nd

Sm

Eu

Gd

Tb

Dy

Ho

Er

Tm

Yb

Lu

Mass

139

140

141

146

147

153

157

159

163

165

166

169

172

175

N/A

GdH+

Gd2O3
Sm2O3

N/A

SmH+

GdO+ GdOH+
SmO+ SmO+ SmO+ SmOH+

123

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/General purpose.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -180 V.
Acquisition parameters: Three cell modes were used with MS/MS acquisition:
No gas, O2 mass-shift, and NH3 on-mass mode. In MS/MS O2 mass-shift mode,
the REEs were determined as their oxide ions. REE ions react efficiently with theO2 cell gas and are converted to the oxide ion REE-O+. For example, in themeasurement of 153Eu+, Q1 is set to m/z 153 (153Eu+) and Q2 is set to m/z 169(153Eu16O+). Cell tuning parameters are summarized in Table 2.
Table 2. CRC tuning parameters.
Cell mode

Unit

Scan mode

MS/MS

Cell gas

No gas

O2

*NH3

N/A

O2

NH3

Cell gas flow rate

mL/min

N/A

0.35

9.0

Octopole bias

V

-8

-5

-18

KED

V

5

-8

-8

Cell exit

V

-80

-90

-110

Deflect lens

V

20

10

-3

Plate

V

-80

-90

-110

*10% NH3 balanced in Ar

Results and discussion
Two high purity REE oxide materials Gd2O3 (5N) and Sm2O3 (4N8) were gently
dissolved in semiconductor grade HNO3 and diluted to a concentration of 1 ppm(as the REE). The other (trace) REEs were measured in each matrix solution using
the three cell modes. The results are given in Figure 1 and Figure 2. As expected,
analysis of the 1 ppm Gd solution in no gas mode gave positive errors on someelements due to interferences from Gd polyatomic ions: GdH+ interferes with
159
Tb+, GdO+ interferes with 172Yb+ and GdOH+ interferes with 175Lu+.
Preliminary studies showed that NH3 cell gas reacts with many of the polyatomic
ions that interfere with the REE. However, NH3 also reacts quickly with some of
the REE ions, leading to reduced sensitivity of < 1 cps/ppt [1], so this mode is only
suitable for the measurement of the less reactive analytes: Pr, Eu, Dy, Ho, Er, Tm
and Yb. For these elements, NH3 on-mass mode gave excellent results, including
for Yb in the Gd matrix, where the measured Yb background concentration was
reduced by four orders of magnitude (Figure 1) indicating effective removal of the
GdO+ overlap. Background signals for Dy, Ho, Er and Tm in the Sm matrix werealso dramatically improved (Figure 2).

1241.E+03
No gasDetermined conc. (ppb)

1.E+02O2 – mass-shift

1.E+01GdO+

NH3 – on mass

1.E+00GdOH +

1.E-01GdH +1.E-02
1.E-03
1.E-04
La

139

Ce

140

Pr

141

Nd

146

Sm

147

Eu

153

157

Gd

Tb

159

Dy

163

Ho

165

Er

166

Tm

169

Yb

172

Lu

175

Figure 1. Measured concentration of REE impurities in 1 ppm Gd solution. Gd based interferences are observed on Tb, Yb and Lu. Only the elements
in red were measured in NH3 on-mass mode.
1.E+03
No gasDetermined conc. (ppb)

1.E+02O2 – mass-shift

1.E+01NH3 – on mass

SmO+

1.E+00

SmO+

SmO+

1.E-01

SmOH +
SmH

1.E-02+

1.E-03
1.E-04
La

139

Ce

140

Pr

141

Nd

146

Sm

147

Eu

153

157

Gd

Tb

159

Dy

163

Ho

165

Er

166

Tm

169

Yb

172

Lu

175

Figure 2. Measured concentration of REE impurities in 1 ppm Sm solution. Sm based interferences are observed on Eu, Dy, Ho, Er, Tm and Yb.
Only the elements in red were measured in NH3 on-mass mode.

For the REEs that react with NH3 (La, Ce, Nd, Sm, Gd, Tb and Lu), O2 mass-shiftmode and measurement of the target analyte as its REE-O+ ion is the preferredapproach. Most REEs are effectively converted to the oxide ion via reaction with
O2 cell gas [1], and this mode was applied to the measurement of Lu in the Gd
matrix, avoiding the GdOH+ interference on the Lu+ isotope and giving a good
improvement in the background signal. Compared to no gas mode, O2 mass-shiftmode also gave a good improvement in the background signals for Dy, Ho, Er, Tm
and Yb in the Sm matrix, but for all these analytes the backgrounds in NH3 mode
were lower still.

Reference
1.	Direct measurement of trace rare earth elements (REEs) in high-purity REE
oxide using the Agilent 8800 Triple Quadrupole ICP-MS with MS/MS mode,
Agilent application note, 5991-0892EN.

125

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Removal of MH+ Interferences in Refined REE
Material Analysis
AuthorIntroduction

Naoki Sugiyama
Agilent Technologies, JapanThe measurement of Rare Earth Elements (REEs) is of great importance ingeochemistry, mining and material science. Manufacturers of high purity REE
materials need to quantify metal impurities, including trace levels of the other
REEs, in the refined, single element REE matrix. ICP-MS is the technique of choicefor the measurement of REEs, but most of the REE isotopes suffer frominterference by polyatomic species (predominantly hydride ions, MH+ and oxideions, MO+) derived from other, lower-mass REE elements. While MH+ interferences
are lower in intensity than MO+ interferences, they present a more challenging
problem for REEs that have no isotope free from interference. For example, 139La+
is interfered by 138BaH+ and 140Ce+ by 139LaH+. These interferences are too close inmass to be resolved by high-resolution (HR-)ICP-MS [1]. In this paper, we describe
the removal of the MH+ interferences using an Agilent 8800 ICP-QQQ in MS/MS
mass-shift mode, with oxygen as the reaction gas.

Keywords
Rare Earth Elements, REE,
geochemistry, mining, materialscience, lanthanum, barium, cerium,
method of standard additions, MSA,
oxygen mass-shift

Experimental
Instrumentation: Agilent 8800 #100. The standard glass nebulizer was replacedwith a C-flow nebulizer (G3285-80000) for optimal washout between the highmatrix samples.
Plasma conditions: Preset plasma/General purpose.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -180 V.
CRC conditions: O2 gas at 0.3 mL/min, Octopole bias = -5 V, KED = -5 V.
Acquisition parameters: MS/MS mode with O2 mass-shift method.
Figure 1 illustrates the mechanism of MS/MS O2 mass-shift mode used formeasuring Ce in a La matrix sample. The major isotope of Ce at m/z 140 suffers
an interference from 139LaH+. Q1 is set to m/z 140, allowing only the analyte ion
140
Ce+ and any other ions at m/z 140 to pass through to the cell. All other ions
not at m/z 140 are rejected. In the cell, Ce reacts with oxygen to form CeO+ at
m/z 156. Q2 is set to m/z 156, allowing CeO+ to pass to the detector. Since
139
LaH+ does not react with O2 to form 139LaOH+, it remains as LaH+ at m/z 140
and is rejected by Q2. The same principle is used for the separation of 139La+
from 138BaH+ in a Ba matrix.

Results and discussion
Oxygen

LaH +
Ce +

139

140

La+, 139LaOH +,other ions

CeO +

140

139

Q1=140Cell

Q2=156Detector

Figure 1. MS/MS mass-shift method with O2 reaction gas; used for the measurement of Ce,
as CeO at m/z 156, in a La matrix.

126

Using the Method of Standard Addition (MSA), the BECs and DLs of La in a matrixof 50 ppm Ba, and Ce in a matrix of 50 ppm La were determined. Data was
acquired using MS/MS mode with O2 mass-shift, and also using Single Quad (SQ)
mode with O2 reaction gas to emulate conventional quadrupole ICP-MS (ICPQMS) for comparison.
As shown in Figures 2A and 2B, SQ mode with O2 reaction gas suffers frominterferences that prevent the measurement of La in the Ba matrix and Ce in the
La matrix, respectively. In contrast, the calibration plots shown in Figures 2C and2D demonstrate that MS/MS mode with O2 mass-shift can successfully remove
the matrix overlaps to permit the trace quantitation of La in a Ba matrix and Ce ina La matrix. The BECs and DLs achieved were 8.5 ppt and 2.5 ppt respectively for
La in a 50 ppm Ba solution, and 10.6 ppt and 0.8 ppt respectively for Ce in a 50
ppm La solution.
155 [02 singl Q]
x107

156 [02 singl Q]
x106

B

y = -878371.1611 * x + 2585277.2917
R = -0.7625
DL = -0.2243 ppb
BEC = -2.943 ppb

CPS

3

CPS

1

A

y = -1955617.5667 * x + 8468888.2500
R = -0.7679
DL = -0.323 ppb
BEC = -4.331 ppb

2

0.5

1

0

0
0.1

0.2

0.1

Conc (ppp)

139 ➝ 155 [O2 MSMS]
x104

C

y = 121678.7045 * x + 1038.0357
R = 1.0000
DL = 0.002523 ppb
BEC = 0.008531 ppb

140 ➝ 156 [O2 MSMS]
x104

2

CPS

CPS

3

0.2
Conc (ppp)D

y = 128483.1740 * x + 1359.7590
R = 1.0000
DL = 0.0008282 ppb
BEC = 0.01058 ppb

2

1

0

0
0.1

0.2
Conc (ppp)

0.1

0.2
Conc (ppp)

Figure 2. Top: Calibration plots up to 0.2 ppb for La in 50 ppm Ba matrix (A) and Ce in 50 ppm La
matrix (B), acquired in SQ mode with oxygen reaction gas (emulating conventional quadrupole
ICP-MS). Bottom: Calibration plots up to 0.2 ppb for La in 50 ppm Ba matrix (C) and Ce in 50 ppm
La matrix (D) acquired in MS/MS mode with oxygen mass-shift.

127

Investigation of unexpected product ion observed at m/z 156 in the 50 ppm
La matrix
The background signals that contributed to the poor result obtained for Ce in the
La matrix using SQ mode with O2 reaction gas (Figure 2B) were investigated bycarrying out a precursor ion scan for product ion mass 156. The precursor ion
scan capability of the 8800 ICP-QQQ provides a uniquely powerful approach toidentifying the source of potential polyatomic and reaction product interferences.
Oxygen cell gas was introduced into the cell and a precursor ion spectrum was
obtained by scanning Q1 from 2 to 260 u (Figure 3) with Q2 fixed at mass 156.
From the spectrum, we can identify which precursor ions react with O2 to produce
product ions at mass 156, overlapping 140CeO+ in SQ mode.
Figure 3 shows the precursor ion scan spectrum for product ion mass 156 forthe 50 ppm La matrix, with intense peaks at m/z 139 (139La+) and 156 (139La16OH+).
In SQ mode, as with conventional ICP‑QMS, these ions all enter the cell, andwith Q2 set to 156 u, the 139La16OH+ polyatomic ions contribute to thesignal measured at m/z 156 (140Ce measured as analyte product ion 140CeO+).
These unwanted precursor ions cannot be rejected by a CRC operating as a
bandpass filter in ICP-QMS, as they are too close in mass to the target analyte
precursor ion. Only by using MS/MS mode on the 8800 ICP-QQQ, where Q1
operates as a unit mass filter, can non-target masses (like 139La16OH+ in thisexample) be prevented from entering the cell.

Figure 3. Precursor ion scan from 2-260 u for product ion mass 156, in a 50 ppm La matrix.
Six peaks are seen at m/z = 138, 139, 140, 155, 156 and 157, with the intense peaks at m/z 139 andm/z 156 being due to 139La+ and 139La16O1H+ respectively.

Reference
1.	Sabine Becker and Hans Joachim Dietze, J. Anal. At. Spectrom., 1997, vol.12,
p881.

More information
Removal of hydride ion interferences (MH+) on Rare Earth Elements using theAgilent 8800 Triple Quadrupole ICP-MS, Agilent publication, 5991-1481EN

128

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Direct Analysis of Trace REEs in High Purity Nd2O3
Authors

Introduction

Juane Song1, Xiang-Cheng Zeng1,
Dong Yan1 and Wei-ming Wu2

Advanced technology products containing Rare Earth Elements (REEs) are
increasing at a rapid rate. However, the presence of other REEs as contaminants
in a purified single-element REE material may affect the functionality of the final
product, so impurities in the REE oxide raw material must be carefully controlled.

Agilent Technologies, China,
Jiangxi University of Science andTechnology, Jiangxi, China

1
2

Keywords
Rare earth elements (REE), high purity
metals, neodymium, neodymium (III)oxide, oxygen mass-shift, ammonia
on-mass, ammonia mass-shift,geochemistry, mining, materials
science

The measurement of mid- and high-mass REEs in a low-mass REE matrix ischallenging for ICP-MS because REEs have high metal-oxide (M-O) bondstrengths, and the oxide ions of the low mass REEs overlap the preferred isotopesof the mid-mass and high-mass REEs. For example, in the analysis of trace REEs
in high purity Nd2O3, 145Nd16OH2+ and 146Nd16OH+ overlap the preferred isotope ofdysprosium (163Dy+), 143Nd16O+ overlaps the only isotope of terbium (159Tb+) and148
Nd16OH+ overlaps the sole isotope of holmium (165Ho+). While separation of
the trace REEs from the REE matrix can be performed using a chelating resin,
this technique is time-consuming and needs to be customized to the particularanalyte and matrix under investigation. Clearly there is a requirement for amethod capable of the direct analysis of trace REEs in a variety of high purity
REE matrices.

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/HMI-L.
Acquisition parameters:
Five operational modes were evaluated:– No gas– Helium mode, 5 mL/min– O2 mass-shift, 0.3 mL/min– NH3 on-mass, 8 mL/min (NH3 as 10% NH3 in He)– NH3 mass-shift, 3 mL/min, (NH3 as 10% NH3 in He).
Sample and sample prep: High purity Nd2O3 (99.999%, purchased from the
Baotou Research Institute of Rare Earths, China) was dissolved gently insemiconductor grade HNO3, and diluted to 500 ppm as Nd2O3.

Results and discussion
Thirteen trace REEs were measured in the Nd2O3 sample using the five different
cell modes, and the results are summarized in Table 1. As expected, the BEC oflow- and mid-mass REEs, such as La, Ce, Pr, Sm, Eu and Gd (Pr and Sm were
present as impurities) were comparable in all modes, as these elements are freefrom interferences due to Nd. In contrast, the BECs for high-mass REEs in He
mode were lower in He mode than in no gas mode, suggesting that high mass
REEs suffered interferences from Nd-derived polyatomic ions.

129

Table 1. BECs of 13 REEs in 500 ppm Nd2O3. All units ug/kg (ppb).
Element

IsotopeNo gasHe

O2 mass-shift

NH3 on-mass

NH3 mass-shift

La

139

0.143

0.127

0.143

-

-

Ce

140

0.018

0.012

0.011

-

-

Pr

141

1.376

1.202

1.056

-

-

Sm

152

1.061

0.950

0.999

-

-

Eu

153

0.032

0.026

0.028

-

-

Gd

155

0.035

0.046

0.033

-

-

Tb

159

442.6

74.6

1.258

-

0.022

Dy

163

250.3

196

1.161

0.040

-

Ho

165

20.43

16.2

0.101

0.004

-

Er

170

0.065

0.020

0.013

-

-

Tm

169

0.084

0.031

0.003

-

-

Yb

174

0.251

0.120

0.058

-

-

Lu

175

0.014

0.006

0.004

-

-

O2 mass-shift mode
All 13 REEs react with O2 efficiently to form REE-oxide ions, as shown below.
REE+ + O2  REE-O+ + O
The MS/MS capability of the 8800 ICP-QQQ enables the removal of spectralinterferences on each element using "mass-shift". For example in O2 mass-shiftmode, all 13 REEs can be detected as REE-O+ ions at 16 u higher than the original
elemental mass (M+16). From Table 1, it can be seen that O2 reaction mode with
mass-shift further reduced the BEC for Tb, Dy, Ho, Er, Tm, Yb, and Lu, compared to
He mode.
While the improvement in O2 mass-shift mode is significant for Tb, Dy and Ho that
suffer intense interference from NdO+, the BECs of the other high-mass REEs
such as Er, Tm, Yb and Lu were also improved in this mode, indicating that theseelements also suffer interferences from Nd-based polyatomic ions: 150NdOH3+
interferes with 169Tm+, 142NdN2+ (or 142NdCO+) and 144NdCN+ with 170Er+, 142NdO2+
with 174Yb+, 143NdO2+ and 144NdONH+ (or 144NdC2H+) with 175Lu+. The contributionof the above mentioned interferences on Er, Tm, Yb and Lu are not overly
significant. However, O2 mass-shift mode was shown to be an effective approachfor the removal of all polyatomic ion interferences, typically leading to a 5-10x
lower BEC compared to no gas mode.

130

NH3 on-mass mode for Dy and Ho
A previous study showed that NH3 cell gas reacts with many of the polyatomic
ions that interfere with the REEs. However, NH3 also reacts quickly with someof the REE ions, leading to reduced sensitivity of < 1 cps/ppt for La, Ce, Nd, Sm,
Gd, Tb and Lu. NH3 on-mass mode is valuable for the determination of a limited
number of REEs; Pr, Eu, Dy, Ho, Er, Tm and Yb [1]. The results in Table 1 showthat NH3 on-mass mode gave excellent results for Dy and Ho in the Nd2O3 matrix,
with an improvement in BECs of 20x compared to O2 mass-shift mode.
NH3 mass-shift mode for Tb
For the REEs that react efficiently with NH3 (La, Ce, Nd, Sm, Gd, Tb and Lu),NH3 mass-shift mode can be used. In this study, NH3 mass-shift mode wasinvestigated for the determination of Tb, and the reaction product ion TbNH+(m/z 174) was found to give the lowest BEC. A BEC of 22 ppt for Tb in a 500 ppm
Nd2O3 solution was achieved, which is 50x lower than the result achieved in O2
mass-shift mode, indicating the effective removal of the NdO+ overlap.

Conclusion
The Agilent 8800 ICP-QQQ with MS/MS capability was used to successfullymeasure 13 REE impurities in a high-purity Nd2O3 sample solution. Tandem MS
with MS/MS mode is essential for accurate reaction mode analysis in a complex
matrix. On conventional quadrupole ICP-MS, there is no additional quadrupole(Q1) to select which ions can enter the cell. As a result, all ions enter the cell so,when a reactive cell gas is used, a complex and variable population of reaction
product ions is created, depending on the sample matrix and other analytes.
With ICP-QQQ, the first quadrupole selects only the target mass to pass into thecell, so the reaction chemistry is controlled and consistent. With the combinationof HMI and MS/MS reaction cell mode, the 8800 ICP-QQQ provided effective
removal of the polyatomic interferences from the Nd matrix.

Reference
1.	Naoki Sugiyama and Glenn Woods, Direct measurement of trace rareearth elements (REEs) in high-purity REE oxide using the Agilent 8800
Triple Quadrupole ICP-MS with MS/MS mode, Agilent publication, 2012,
5991-0892EN.

More information
Application note: Routine determination of trace rare earth elements in high purity
Nd2O3 using the Agilent 8800 ICP-QQQ. Agilent publication 5991-5400EN

131

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Direct Determination of Challenging Trace Rare EarthElements in High Purity Lanthanide REE Oxides
Authors

Introduction

Juan-e Song and Xiang-cheng Zeng
Agilent Technologies, China

ICP-MS is widely used for trace impurity analysis of high purity rare earth element(REE) oxide materials. But the analysis of trace REEs in high purity REE oxidematerials remains challenging. Matrix-based polyatomic ions such as REEO+,
REEOH+, and REEH+ cause severe spectral interferences on some REE elements.
Trace REE analytes can be separated from the REE matrix using a chelating resin,but this technique is time-consuming, and customization is needed per the
analyte and matrix element.

Keywords
Rare Earth Elements, REE, rare earthoxides, REO, oxygen mass-shift,ammonia on-mass, ammonia massshift

In this study, trace REEs in lanthanide oxide materials were determined using an
Agilent 8900 ICP-QQQ with O2 and NH3 reaction cell gases. Since the analysis of
La2O3, Tm2O3 and Lu2O3 is relatively interference free, these matrices weren’t
included in the study.

Experimental
Instrumentation: An Agilent 8900 Advanced Applications configuration ICP-QQQ
was used without any modification. For the analysis of 500 ppm REE matrix
samples, ‘general-purpose plasma’ conditions were selected in the MassHunter
software. The preset plasma function automatically sets all plasma-relatedparameters, simplifying instrument set-up.
Five cell modes were investigated: no gas, helium (He), oxygen (O2), and ammonia(20% NH3 in He). Tuning conditions are summarized in Table 1. In NH3 mass-shiftmode, a pre-study was done using ‘product ion scan’ to identify the mostabundant NH3 cluster ion. The masses of the cluster ions used for the analysis
are given in Tables 2 and 3, together with the analytical results.
Table 1. Cell gas mode-related tuning parameters.
Cell gas modeNo gasScan ModeO2 mass-shift NH3 on-mass

Single Quad

NH3 mass-shift

MS/MS

Octopole bias (V)

-8

-18

-3

-5

-5

Octopole RF (V)

140

180

180

180

180

KED (V)

+5

+4

-7

-7

-7

Axial Acceleration (V)

0

1

1.5

0.5

0.5

1

1

4.0 ~ 6.0

1.0 ~ 8.0

He (mL/min)
O2 (mL/min)
NH3 (mL/min)

132

He

5
0.45

Results and discussion
Ten REE oxide materials of the highest-grade purity (5N) including Ce2O3, Pr6O11,
Nd2O3, Gd2O3, Sm2O3, Eu2O3, Tb4O7, Dy2O3, Er2O3, and Yb2O3 were dissolved insemiconductor grade HNO3 and diluted to 500 ppm (as REE oxide). H2O2 wasadded during the dissolution of Ce2O3 and Tb4O7. REEs were measured in eachmatrix solution using the five cell modes specified in Table 1. The results are
given in Tables 2 and 3.
As expected, in no gas mode, the BECs for the REEs were relatively high due tospectral interferences. He collision cell mode was able to alleviate some of theinterferences, but not all. Previous studies have shown that both O2 and NH3 areeffective for the removal of polyatomic ions that interfere with the REEs [1, 2].
A drawback of NH3 mode has been low sensitivity. However, Axial Accelerationof cluster ions in the cell of the 8900 ICP-QQQ increases sensitivity. The results
reported in Tables 2 and 3 show that the BECs for all REEs were dramatically
improved using a reactive cell gas. The improvement factor data relates to thedifference in BEC obtained in reaction mode compared to no gas mode.
Table 2. BECs of REE impurities in 500 ppm Ce, Pr, Nd, and Gd oxide solutions.
SampleCe2O3

PrO

Analyte

Pr

Gd

Tb

Tb

Isotope

141

160

159

159

Interference
BEC (ppb)

140

CeH+

142

Ce18O+

142

Ce16OH+141

Pr18O+

Nd2O3

Gd2O3

Tb

Dy

Ho

Tb

Yb

Lu

159

163

165

159

172

175

NdOH+,
143
NdO+

145

142

Nd18O+

148

NdOH+

158

GdH+

156

GdO+

159

GdOH+

No gas

6.17

3.36

29.2

10.3

721

163

13.4

2.23

3420

75.0

He

3.79

11.9

0.725

2.50

234

36.6

3.06

2.16

1200

66.4

O2

0.064

0.030

9.76

0.001

1.95

0.804

0.070

0.106

284

0.444

NH3

BEC

0.284

0.055

0.039

0.255

0.021

0.030

7.16

mass pair(159/174)(159/244)(159/174)(163/163)(165/165)(172/172)(175/260)x100

x10,000

x20,000

x1000

x1000

x20

x100,000

x200

Improvement factor

x100

x100

Table 3. BECs of REE impurities in 500 ppm Sm, Eu, Tb, Dy, Er, and Yb oxide solutions.
SampleSm2O3

AnalyteDy

Isotope162

Interference
BEC (ppb)

147

SmO+

Ho
165
148
149

SmOH ,
SmO+
+

Eu2O3

Tb4O7

Dy2O3

Er2O3

Yb2O3

Er

Tm

Tm

Lu

Ho

Tm

Lu

167

169

169

175

165

169

175

150

SmOH+

152

SmOH+

141

EuO+

159

TbO+

164

DyH+

168

ErH+

174

YbH+

No gas

0.408

185

44.9

39.0

64.8

3270

2.13

1.26

0.97

He

0.169

61.9

18.1

13.6

38.20

1670

1.28

1.57

1.38

O2

0.083

0.158

0.916

0.240

2.73

26.1

0.057

0.025

0.195

BEC

0.035

0.055

0.092

0.127

0.002

0.244

0.074

mass pair(162/162)(165/165)(167/167)(169/169)(169/169)(175/260)(165/165)

x10

x3000

x500

x200

x30,000

x10,000

x50

x50

x5

NH3

Improvement factor

133

Conclusion
The Agilent 8900 ICP-QQQ method was used to measure REE impurities in highpurity REE oxide materials. REE matrix-based hydride, oxide, and hydroxide
polyatomic ion interferences were removed by operating the ICP-QQQ in MS/MS
mode with O2 and NH3 reaction cell gases. The BECs were improved by one tofour orders of magnitude using reactive cell gases compared to no gas mode.
The method is suitable for the direct analysis of trace REEs in the presence ofhigh concentration matrix-REEs.

References
1.	Direct measurement of trace rare earth elements (REEs) in high-purity REE
oxide using the Agilent 8800 Triple Quadrupole ICP-MS with MS/MS mode,
Agilent application note, 2012, 5991-0892EN
2.	Routine determination of trace rare earth elements in high purity Nd2O3 using
the Agilent 8800 ICP-QQQ, Agilent application note, 2015, 5991-5400EN

134

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Arsenic Measurement in Cobalt Matrix using MS/MS
Mode with Oxygen Mass-Shift
AuthorIntroduction

Katsuo Mizobuchi
Agilent Technologies, Japan

Measuring the purity of materials such as high purity metals is of interest acrossadvanced technology industries, to support the development of new materials
and/or improve the performance of existing products. ICP-MS is widely used for
determining elemental impurities in these materials due to its unique features:High sensitivity, low DLs, multi element analysis capability, wide dynamic range,
fast analysis and minimal sample preparation requirements.

Keywords
arsenic, high purity metals, cobalt,
zirconium, oxygen mass-shift

For many applications, the errors caused by spectral interferences in quadrupole
ICP-MS have been adequately addressed by the introduction of CRC technology.
However, the analysis of trace contaminants in high purity materials presents aparticular challenge due to the high matrix levels and the need to determine
impurities at the trace level. For example, the determination of As in Co is difficultfor quadrupole ICP-MS due to the signal from CoO+ that overlaps the only isotope
of arsenic at m/z 75. Although only about
0.01% of the Co ions in the plasma are present as CoO+ ions, the Coconcentration in a 1000 ppm solution is 6 or 7 orders of magnitude higher than
the trace levels of As that are of interest in this application. Consequently, theCoO+ interference is still very significant relative to the As+ signal. This note
describes the measurement of trace As in a 1000 ppm Co solution using an
Agilent 8800 ICP‑QQQ in MS/MS mass-shift mode, using oxygen as thereaction gas.

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/HMI-mid.
CRC conditions: O2 gas at 0.3 mL/min,
Octopole bias = -5 V, KED = -7 V.
Acquisition conditions: Three oxygen (O2) mass-shift operational modes
were compared:– Single Quad mode A with low mass cut off at m/z < 59
– Single Quad mode B with low mass cut off at m/z = 59
– MS/MS mode with Q1 as a 1 u mass filter, Q1 = 75 and Q2 = 91
Sample: SPEX CLCO2-2Y (SPEX CertiPrep Ltd., UK) was used as 1000 ppm
Co solution.

135

Results and discussion
BEC of As in 1000 ppm Co solution using O2 mass-shift method
From the equation and reaction enthalpy below, it can be seen that arsenic reacts
readily with O2 cell gas via an O-atom transfer reaction. This creates the reaction
product ion AsO+ at m/z 91, moving the analyte away from the CoO+ interference
on As+ at m/z 75.
As+ + O2  AsO+ + O ΔHr = -1.21 eV
The reaction enthalpy for CoO+ with the O2 cell gas is much less favorable,
so the overlap from the CoO+ polyatomic interference is successfully avoided.
To evaluate the effectiveness of MS/MS mode for this application, the 8800
ICP-QQQ was operated in three acquisition modes: MS/MS mode and two“Single Quad” modes, in which Q1 functions as a bandpass filter rather than aunit (1 u) mass filter. In Single Quad mode A, Q1 was set to allow most of theplasma-formed ions to enter the cell; in Single Quad mode B, Q1 was set with alow mass cutoff around m/z 59 to allow only ions with a mass greater than 59 toenter the cell (most 59Co+ ions are rejected); and finally in MS/MS mode Q1 was
set to allow only ions at m/z 75 to enter the cell (all 59Co+ rejected).
The BECs for As obtained using the three acquisition modes are shown in Figure
1. MS/MS mode achieved the lowest BEC for As of 330 ppt in 1000 ppm Co.
The BEC obtained by the Single Quad modes were orders of magnitude higher,
which suggests the occurrence of the following undesired reactions in the celland indicates the incomplete rejection of Co+ by Single Quad mode B:
59

Co+ + O2 59CoO+ + O; 59CoO+ + O2  59CoO2+ + O

Note that this sequential reaction chemistry leads to a relatively intense signal for
CoO2+, because the number of precursor ions for the reaction (the Co+ ions fromthe plasma) is so high (10000 times higher intensity than the CoO+ signal in theplasma). Consequently, in Single Quad mode, the CoO+ overlap cannot be
successfully avoided by moving the As+ to its AsO+ product ion at m/z 91 using
O2 cell gas, because CoO2+ (also at m/z 91) is formed relatively easily when alarge number of Co+ ions are allowed to enter the cell.
1.E=07

BEC of As (ppt)

1.E=06
1.E=05
1.E=04
1.E=03
1.E=02Single Quad A

Single Quad B

MS/MS

Figure 1. BEC of As in 1000 ppm Co solution with O2 mass-shift method using three acquisition
modes (note log intensity scale).

136

AsO+ in the presence of zirconium
To successfully avoid interferences using the mass-shift method, the mass of
the analyte product ion must itself be free from interference. For example, in thisapplication the AsO+ product ion is measured at m/z 91 where it could beoverlapped by an isotope of zirconium (91Zr+). The presence of Zr in a sample may
therefore cause an error in the results for As measured as AsO+ using O2 reaction
mode on ICP-QMS. The potential effect of co-existing Zr on AsO+ measurement
using ICP-QMS was investigated.
Figure 2 is a spectrum of 10 ppm Zr obtained using Single Quad mode A with
O2 mass-shift. Zr reacts with O2 very efficiently (ΔHr = -3.84) and is converted to
ZrO+. However not all the Zr+ ions are converted to ZrO+ so some Zr+ remains,interfering with the measurement of AsO+ at m/z 91. In contrast, in MS/MS modethe 91Zr+ ion is rejected by Q1, so the potential overlap on the AsO+ product ion atm/z 91 is removed.
ZrO
ZrO
108

3 Orders
Zr
Zr

CPS

106

104

102

100
85

90

95

100
m/z

105

110
Q2

Figure 2. Spectrum of 10 ppm Zr obtained using Single Quad mode A with O2 mass-shift-method.

Conclusion
Trace levels of arsenic in a 1000 ppm cobalt matrix can be successfullymeasured (BEC of 330 ppt) using the 8800 ICP-QQQ operating in MS/MS
mass-shift mode, with oxygen as the reaction gas. There are two main
advantages of using MS/MS compared to ICP-QMS:
1.	In MS/MS mode, Co+ is prevented from entering the cell by Q1, which is set tom/z 75. In ICP-QMS, CoO2+ is formed in the cell via a chain reaction and willinterfere with AsO+ at m/z 91.
2.	In MS/MS mode, the potential 91Zr+ overlap on the AsO+ product ion at m/z 91
is eliminated, as 91Zr+ ions (and all other ions apart from m/z 75) are rejectedby Q1.

137

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Analysis of ultratrace impurities in high purity copper
using the Agilent 8900 ICP-QQQ
AuthorNaoki Sugiyama
Agilent Technologies, Japan

Low-ppt determination of alkali metals in high matrix samples
using the optional "m-lens"Introduction
Metals such as copper (Cu), aluminum (Al), tantalum (Ta), tungsten (W), andhafnium (Hf) are essential for the manufacture of semiconductor devices.
Metal sputtering targets are used to form conducting or insulating (dielectric)layers by thin film deposition using chemical vapor deposition (CVD) or physicalvapor deposition (PVD). Conducting metals, originally Al but now typically Cu,
are used as interconnects within wiring levels and as “vias” between layers.
A complex, large-scale integrated circuit (IC) microprocessor chip may containtens of layers of interconnect “wires” with a total length up to about 100 km (1, 2).
To ensure high performance and high production-yield of the final devices, very
high purity metals are required for these components.
Semiconductor manufacturers may require high-purity, electronic-grade metals
at grades of 5N (5 9s – 99.999% purity) up to 9N (99.9999999% purity) or above,
depending on the proposed application. A 6N metal (99.9999% purity) contains
a total of only 1 mg/kg (ppm) of the impurities of interest, so each individual
impurity element would typically be certified as <0.01 or <0.005 ppm in thesolid metal.
Determination of trace contaminants in high-purity metals is often performed
using glow discharge mass spectrometry (GD-MS). However, GD-MS is expensive
and requires the availability of solid metal calibration standards containing thetrace elements of interest. GD-MS also has relatively slow speed of dataacquisition leading to low sample throughput—around 10 minutes or more persample—often longer when a cryo-cooled source is used. The fact that solid
samples are analyzed also makes automation of sample changeover forunattended analysis more problematic than for liquid sample digests.
ICP-MS is widely used for quality-control of semiconductor materials, but someelements are difficult to measure at ultratrace levels in the presence of a highmatrix. ICP-MS operating with a “cool” or reduced-energy plasma has been widely
employed since the 1990s as a powerful mode for the analysis of high-purity
chemicals and materials. Cool plasma suppresses the formation of intense
argon-based interferences such as Ar+ and ArO+, allowing low-level analysis of40
Ca and 56Fe, respectively. Cool plasma conditions are also beneficial in theanalysis of the alkali metal elements, providing lower background equivalentconcentrations (BECs) than hot plasma conditions. A lower-temperatureplasma causes less re-ionization of traces of easily-ionized elements (EIEs)
from the cones and ion lens, giving lower background signals for these elements.
Cool plasma is not universally applicable, though, as the lower power plasma
has less energy, which reduces its ability to decompose the sample matrix.
Poor tolerance of high matrix levels is especially problematic for the analysis ofhigh matrix, high-purity samples such as electronic-grade metals.

138

This note describes a new approach to the measurement of ultratrace impurities
in high-purity copper using triple quadrupole ICP-MS (ICP-QQQ). An optional ion
lens (called the "m-lens") has been developed for the Agilent 8900 ICP-QQQ toallow ultra-low-level measurement of alkali metals under matrix tolerant, highpower plasma conditions. The m-lens has an optimized geometry that minimizes
background signals from EIEs deposited on the ICP-MS interface components.
matrix samples using the optional "m-lens".

Experimental
Sample preparation
All samples and standards were prepared in 5% semiconductor grade
TAMAPURE AA-100 nitric acid (HNO3) bought from Tama Chemicals Co. Ltd,
Kanagawa, Japan. Solutions were prepared and analyzed in PFA vials, whichwere cleaned with diluted HCl and HNO3 and then rinsed using ultrapure water(UPW) before use.
A 0.1% copper (Cu) solution was prepared for analysis. A sample of 9N high purity
copper was cleaned in diluted HNO3, rinsed with UPW, weighed (about 0.05 g),
and dissolved in 5 mL of 50% HNO3 (1:1 concentrated HNO3:UPW). The solution
was brought up to volume (50 mL) with UPW, giving a total dilution of 1000x,
and a matrix level of 0.1%. The 8900 ICP-QQQ can tolerate % levels of dissolved
solids, but higher dilutions allow non-matrix-matched calibrations to be used.
This removes the need for certified metal standards containing every element ofinterest. The exceptionally low detection limits of the 8900 ICP-QQQ (sub-ppt formost elements) enable ultratrace analysis even in higher sample dilutions.
The 1000x dilution factor simplifies conversion of the measured concentrationsin ng/L (ppt) in the digest solution to the concentrations in μg/kg (ppb) in theoriginal solid.
Calibration standards for 49 elements were prepared from several mixed,
multi-element stock standards (SPEX CertiPrep, NJ, USA). To minimize signal
suppression due to physical sample transport and nebulization effects, thecalibration standards were matrix matched to the HNO3 concentration (5%) of theCu sample digest.
All samples and standards were spiked with a mix of three internal standard(ISTD) elements, Be, Sc, and In, at 5.0, 0.5, and 0.5 ppb, respectively. ISTDs wereadded to compensate for matrix differences between the standards (no Cu) andthe 0.1% Cu solutions, and to correct for any long-term signal drift.
Instrumentation
An Agilent 8900 Semiconductor configuration ICP-QQQ was used for all
measurements. The standard PFA nebulizer was used in self-aspiration mode,connected to the standard quartz spray chamber and quartz torch with 2.5 mm
i.d. injector. The 8900 ICP-QQQ was fitted with the standard Pt-tipped sampling
cone, optional m-lens (part number G3666-67500), and optional Pt-tipped,
Ni-based skimmer cone for m-lens (part number G3666-67501). The skimmer
cone for m-lens also requires a non-standard skimmer cone base (part number
G3666-60401).

139

Tuning and method
Hot plasma conditions (1% CeO+/Ce+) were used to ensure good tolerance of thehigh concentration of Cu matrix. A single collision/reaction cell (CRC) tuning
mode was used to measure all 49 analyte elements in the Cu samples. A cell gas
mixture of oxygen (O2) and hydrogen (H2) was used to remove interferences using
a combination of MS/MS on-mass and mass-shift modes. Operating conditions
are summarized in Table 1, and acquisition parameters and given in Table 2.
Table 1. Agilent 8900 ICP-QQQ operating parameters.
Parameter

Setting

RF power (W)1550

Sampling depth (mm)8.0

Carrier gas flow rate (L/min)

0.70

Make-up gas flow rate (L/min)

0.46

Extract 1 (V)0.0

Extract 2 (V)-70

Omega bias (V)-60

Omega lens (V)8.0
O2 = 0.2; H2 = 7.0

Cell gas flow rate (mL/min)
Octopole bias (V)-10

KED (V)-10

Axial acceleration (V)+2.0

Table 2. Acquisition parameters.
Element

140

Q1/Q2

Main
interferencesScan
methodMeasuredion

Integration
time (s)

ISTD

Li

7/7

On-mass

Li+

0.5

Be

B

11/11

On-mass

B+

2.0

Be

Na

23/23

On-mass

Na+

0.5

Sc

Mg

24/24

On-mass

Mg+

0.5

Sc

+

Al

27/27

On-mass

Al

0.3

Sc

Si

28/28

N2+, CO+On-mass

Si+

0.5

Sc

P

31/47

NOH , Cu

Mass shift

PO

+

2.0

Be

S

32/48

O2 , Cu

Mass shift

SO

+

2.0

Be

K

39/39

ArH+

On-mass

K+

0.5

Be

Ca

40/40

+

Ar

On-mass

+

Ca

0.3

Sc

Ti

48/48

SO+

On-mass

Ti+

0.5

Sc

V

51/51

+

(ClO )

On-mass

+

V

0.3

Sc

Cr

52/52

ArC+

On-mass

Cr+

0.3

Sc

Mn

55/55

ArNH

On-mass

Mn

+

0.3

Sc

Fe

56/56

ArO+

On-mass

Fe+

0.3

Sc

+

++

++

+

+

Co

59/59

On-mass

Co

0.3

Sc

Ni

60/60

On-mass

Ni+

0.5

Sc

Zn

68/68

On-mass

Zn+

2.0

Sc

Ga

71/71

On-mass

Ga

0.5

In

ArNN+, CuHHH+++

Element

Q1/Q2

Main
interferencesScan
methodMeasuredion

Integration
time (s)

ISTD

Ge

72/72

ArAr+

On-mass

Ge+

0.5

In

As

75/91

(ArCl+)

Mass shift

AsO+

1.0

In

Se

78/78

ArAr

Rb

85/85

Sr

On-mass

+

Se

3.0

In

On-mass

Rb+

0.3

In

88/88

On-mass

Sr+

0.5

In

Zr

90/106Mass shift

ZrO+

0.5

In

Nb

93/125CuNO+

Mass shift

NbOO

+

0.3

In

Mo

95/127

CuOO+

Mass shift

MoOO

0.5

In

Ru

99/99

ArCu+

On-mass

Ru+

0.5

In

Rh

103/103+

ArCu

On-mass

Rh

+

0.3

In

Pd

105/105

ArCu+

On-mass

Pd+

0.5

In

+

+

+

Ag

107/107

On-mass

Ag

0.3

In

Cd

111/111On-mass

Cd+

1.0

In

Sn

118/118

On-mass

Sn

0.5

In

Sb

121/121On-mass

Sb+

0.5

In

Te

125/125

On-mass

Te+

3.0

In

Cs

133/133

On-mass

Cs+

0.5

In

Ba

137/137

On-mass

Ba+

0.5

In

Hf

178/194

Mass shift

HfO+

0.5

In

Ta

181/213Mass shift

TaOO

0.5

In

W

182/214Mass shift

WOO

0.5

In

Re

185/185

On-mass

Re+

0.5

In

Ir

193/193On-mass

Ir+

0.5

In

Pt

195/195

On-mass

Pt+

0.5

In

+

+

+

+

Au

197/197

On-mass

Au

0.5

In

Tl

205/205

On-mass

Tl+

0.3

In

Pb

208/208

On-mass

Pb

0.3

In

Bi

209/209

On-mass

Bi+

0.3

In

Th

232/248

Mass shift

ThO+

0.3

In

U

238/270

Mass shift

UOO+

0.3

In

+

Results and discussion
BECs and DLs in 5% HNO3 blank
Background equivalent concentrations (BECs) in 5% HNO3 were obtained fromthe calibration plots for each analyte. Calibration plots for three alkaline elements(Li, Na, and K) are shown in Figure 1. The BECs for the three elements were 0.1,
6.1, and 5.4 ppt, respectively, indicating very low background signals obtainedusing the m-lens. Calibration plots for Si, P, and S are also given in Figure 1.
The BECs for these challenging elements were 231, 7.2, and 84 ppt, respectively.
P and S have relatively high first ionization potentials (IPs) and so are poorly
ionized under cool plasma conditions. Using hot plasma conditions in this work,
these poorly ionized elements – together with others such as B, Zn, As, Cd, Ir, Pt,
and Au – were all measured at low ppt levels.

141

The BECs and 3σ DLs for all 49 elements in the 5% HNO3 blank are shown in
Figure 2. The BECs for most elements were below 1 ng/L (ppt) in solution.
This value is equivalent to <1 μg/kg (ppb) relative to the solid Cu, taking the 1000x
dilution into account. This sensitivity indicates that the 8900 ICP-QQQ method
is suitable for ultratrace analysis of these impurity elements in high-purity Cu.
Low ppt BECs were also achieved for alkali elements, Li, Na, and K, under the hot
plasma conditions used. BECs at the 10s to 100s ppt-level were achieved for themost challenging elements: S (84 ppt) and Si (231 ppt).
7 ➝ 7 Li [H 2] ISTD: 9 ➝ 9 Be
x10 -123 ➝ 23 Na [H2] ISTD: 45 ➝ 61 Sc [H 2]y = 0.0019* x + 2.3713E-004
R = 0.9998
DL = 0.519 ppt
BEC = 0.1222 ppt

x10 -239 ➝ 39 K [H 2] ISTD: 45 ➝ 61 Sc
x10 -2y = 4.1225E-004* x + 0.0025
R = 0.9990
DL = 3.983 ppt
BEC = 6.142 ppt

y = 4.3486E-004* x + 0.0024
R = 0.9984
DL = 2.808 ppt
BEC = 5.435 ppt

2

1

Ratio

4

Ratio

Ratio

4

2

2

0

0
50.0

50.0

100.0

50.0

Conc (ppt)

Conc (ppt)

28 ➝ 28 Si [H 2] ISTD: 9 ➝ 9 Be
1.5

100.0

31 ➝ 47 P [H2] ISTD: 9 ➝ 9 Be
x10 -2y = 0.0017* x + 0.3930
R = 0.9990
DL = 72.11 ppt
BEC = 231.2 ppt

4

100.0
Conc (ppt)

32 ➝ 48 S [H 2] ISTD: 9 ➝ 9 Be

y = 2.8307E-004* x + 0.0020
R = 0.9992
DL = 5.621 ppt
BEC = 7.174 ppt

x10 -1y = 5.3432E-004* x + 0.0449
R = 0.9995
DL = 19.49 ppt
BEC = 84.1 ppt

3

Ratio

Ratio

Ratio

1

2

0.5

1

0

0
200.0

400.0
Conc (ppt)

50.0

100.0
Conc (ppt)

Figure 1. Calibrations for easily-ionized elements Li, Na, and K, and challenging elements Si, P, and S.

142

2

200.0

400.0
Conc (ppt)

Concentration (ng/L, ppt)

1000

100

10

1

0.1

BEC

U

Th

Bi

Pb

Tl

Au

Pt

Ir

Re

W

Ta

Hf

Ba

Cs

Te

Sb

Sn

Cd

Ag

Pd

Rh

Ru

Nb

Mo

Zr

Sr

Rb

Se

As

Ge

Ga

Zn

Ni

Co

Fe

Mn

Cr

V

Ti

Ca

K

S

Si

P

Al

Mg

Na

Li

B

0.01

DL

Figure 2. BECs and 3σ DLs for 49 elements in 5% HNO3 blank. The BEC and DL for Rb, Pd, Sb, Re, Ir, and Bi could not be calculated, as the measured
counts were zero in all replicates of the blank.

Determination of impurities in 0.1% 9N high purity copper
The 8900 ICP-QQQ method was used to determine the concentration of
49 elements in the 0.1% high purity copper solutions. ISTD correction wasapplied to correct for signal differences between the synthetic standards(with no Cu matrix) and the 0.1% Cu samples. Signal differences were all lessthan 30% between the non-matrix and Cu-matrix samples, demonstrating therobustness of the hot plasma conditions used.
All elements measured—apart from Si, S, and Te—were <10 ppt in the digest, asshown in Figure 3. Most elements were measured at 1 ppt or below, which isequivalent to <1 g/kg (ppb) in the solid metal. The mixed O2 + H2 reaction cell gas
removed the significant spectral interferences caused by ArCu+ on Ru+, Rh+,and Pd+ (see Table 2). Removing the interferences allowed the determination ofthese elements at single- or sub-ppt levels (equivalent to single- or sub-ppb in thesolid metal).

Concentration (ng/L, ppt)

100

10

1

0.1

U

Th

Bi

Pb

Tl

Au

Pt

Ir

Re

W

Ta

Hf

Ba

Cs

Te

Sb

Sn

Cd

Ag

Pd

Rh

Ru

Mo

Nb

Zr

Sr

Rb

Se

As

Ge

Ga

Zn

Ni

Co

Fe

Mn

Cr

V

Ti

Ca

K

S

P

Si

Al

Na

Mg

B

Li

0.01

Concentration in 0.1% Cu solution

Figure 3. Measured concentrations of 49 elements in 0.1% 9N Cu sample (error bars = standard deviation for three samples). The values shown in ng/L(ppt) in solution) are equivalent to the values in μg/kg (ppb) in the original solid metal. The concentration reported for Re was 0.000 ppt. SDs were zerofor Rh, Pd, Ta, Re, and Tl.

143

Spike recovery
120

Spike recovery (%) in 0.1% Cu solution

100

80

60

40

20

U

Th

Bi

Pb

Tl

Au

Pt

Ir

Re

W

Ta

Hf

Ba

Cs

Te

Sb

Sn

Cd

Ag

Pd

Rh

Ru

Nb

Mo

Zr

Sr

Rb

Se

As

Ge

Ga

Zn

Ni

Co

Fe

Cr

Mn

V

Ti

Ca

K

S

P

Si

Al

Na

Mg

B

Li

0

Figure 4. Spike recovery test at 50 ppt (200 ppt for S, P, and Si) in 0.1% Cu solution. Most elements were within 90–110% recovery. The red lines
indicate upper and lower limits of 85 to 115% recovery.

To validate the method, a spike recovery test was carried out for all 49 impurity
elements. A 0.1% 9N copper blank solution was spiked at 50 ppt (200 ppt for Si, P,
and S). The recoveries were within 84-112% for all 49 elements, with most being
within 90-110%, as shown in Figure 4.

Conclusion
Ultratrace level impurities can be analyzed quickly and accurately in high purity
copper metal digests using the Agilent 8900 ICP-QQQ. The optional m-lensensures that the background signals for the alkali elements are minimized under
hot plasma conditions. Using MS/MS mode with a mixed cell gas (O2 + H2),
the method delivered the following performance benefits:– Low ppt level BECs were achieved for most impurities, including the alkali
elements, using matrix-tolerant hot plasma conditions.
– Low-level BECs at the 10s to 100s ppt-level were obtained for sulfur andsilicon—the most challenging elements to measure using ICP-MS.
– No matrix matching for Cu matrix was required, as ISTDs corrected for
matrix differences between the standards (in 5% HNO3) and the samples(in 0.1% Cu).
– Using the fast and simple method with a single, mixed cell gas mode,a total of 49 elements were determined at ultralow levels in 0.1% high purity
Cu sample.

References
1.	Larry Zhao, All About Interconnects, Semiconductor Engineering, 2017,
accessed October 2018, https://semiengineering.com/all-about-interconnects/
2.	Katherine Bourzac, Making Wiring that Doesn't Trip Up Computer Chips, MIT
Technology Review, 2012, accessed October 2018, https://www.
technologyreview.com/s/428466/making-wiring-that-doesnt-trip-up-computerchips/

144

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Determination of Sulfur, Phosphorus, and Manganesein High Purity Iron
Authors

Introduction

Yasuyuki Shikamori andKazumi Nakano
Agilent Technologies, Japan

ICP-MS is the analytical technique of choice for the analysis of trace elements iniron and steel. However, the sensitivity and interference removal performance of
quadrupole ICP-MS (ICP-QMS) is not sufficient for the determination of difficult
analytes such as phosphorus (P) and sulfur (S) at the low levels required.
Furthermore, the determination of manganese (Mn) in an iron matrix is extremely
challenging for ICP-QMS due to overlap (or tailing) from the very intense 54Fe and56
Fe peaks that occur either side of the single isotope of manganese at m/z 55.

Keywords
phosphorus, sulfur, manganese,
iron, steel, JSS 001-6, JSS 003-6,
abundance sensitivity, oxygenmass-shift

The Agilent 8800 Triple Quadrupole ICP-MS (ICP‑QQQ) provides more effective
and reliable removal of polyatomic interferences, such as 14N16OH on 31P and16
O2 on 32S, using controlled chemical reaction in the CRC. This note describes
the performance of the 8800 ICP‑QQQ operating in MS/MS mode, for thedetermination of the trace elements S, P and Mn in two high purity iron CRMs
(JSS 001-6 and 003-6).

Experimental
Instrumentation: Agilent 8800 #100.
Plasma condition: Preset plasma/HMI-mid.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -175 V.
CRC and acquisition conditions:– MS/MS O2 mass-shift method to remove the 14N16OH+ and 16O2+
interferences on 31P+ and 32S+ respectively: O2 gas at 0.3 mL/min,
Octopole bias = -5 V and KED = -7 V.
– MS/MS He on-mass mode to measure 55Mn+:
He gas at 5.0 mL/min, Octopole bias = -18 V and KED = 4 V.
All other parameters were optimized by Autotune in the MassHunter software.
Figure 1 shows the mechanism used on the 8800 ICP-QQQ to avoid the 14N16OH+
and 16O2+ interferences on 31P+ and 32S+ by mass-shift mode (Q1≠Q2) using O2
reaction gas.
Reaction gas

Q1 (m/z = 31, 32)+ 16 (= 16O)

O2

ORS

Q1 (m/z = 47, 48)

P , S+
14 16
N OH +, 16O 2+

P16O +S16O +

31 + 32

31

32

N16OH +, 16O 2+

14

Figure 1. Mechanism of MS/MS mass-shift mode (Q2 = Q1+16) using O2 reaction gas for themeasurement of P as 31P16O + and S as 32S16O + at m/z 47 and 48 respectively.

145

Sample preparation: Two Steel CRMs, JSS-001 and JSS-003 were purchasedfrom The Japan Iron and Steel Federation (Tokyo, Japan). 0.1 g of each SteelCRM was digested in a mixture of 1 mL HCl and 2 mL HNO3 and diluted to
100 mL with UPW. No further chemical matrix separation, e.g., solvent extraction,ion exchange, etc. was applied. The digested CRM samples containing 0.1%(1000 ppm) Fe were analyzed directly on the ICP-QQQ using the robust plasma
conditions provided by Agilent’s HMI aerosol dilution system.

Results and discussion
BEC and DL of P and S
The calibration plots shown in Figure 2 demonstrate that the 8800 ICP-QQQ with
MS/MS mass-shift mode can successfully perform the trace level (single ppb)
quantitation of P and S in 0.1% Fe solutions. The BEC and DL achieved for P were0.14 ppb and 0.05 ppb respectively, and the BEC and DL for S were 6.45 ppb and0.75 ppb respectively.
P ➝ 31P16O /[O2 mass-shift]S ➝ 32S16O /[O2 mass-shift]31

x10 -132

y = 0.0035 * x + 4.8781E-004
R = 1.0000
DL = 0.05287 ppb
BEC = 0.1405 ppb

x10 -12

y = 0.0031 * x + 0.0197
R = 1.0000
DL = 0.7469 ppb
BEC = 6.445 ppb

2

Ratio

DL 0.75 µg/L
BEC 6.4 µg/L

Ratio

DL 0.05 µg/L
BEC 0.14 µg/L

1

1

0

0
20.0

40.0
Conc (ppb)

60.0

20.0

40.0

60.0

Conc (ppb)

Figure 2. Calibration curve for P (left) and S (right) in 0.1% Fe matrix, obtained using O2 mass-shiftmode under robust plasma conditions.

146

Trace Mn analysis in Fe matrix
The abundance sensitivity (AS, a measure of peak separation) of ICP-QQQ in
MS/MS mode is the product of the Q1 AS x Q2 AS. This means the AS of the8800 ICP-QQQ is theoretically about 2x that achievable on ICP‑QMS, and the
ICP-QQQ is therefore able to successfully separate the 55Mn peak from the very
intense overlaps from 54Fe and 56Fe in a high iron matrix. This is demonstrated in
Figure 3 which shows the spectra of 10 ppb Mn in a 0.1% Fe matrix sample
solution measured in Single Quad mode (left) and MS/MS mode on the ICP-QQQ(right). Helium was used as the cell gas in both cases to remove 54FeH+ and
ArNH+ interferences by KED.
ICP-QMS

ICP-QQQ

Fe

Fe

Mn
1000000000

Mn
1000000000

Fe

100000000

10000000

1000000

1000000

100000

Mn

CPS

CPS

Fe

100000000

10000000

10000

100000

1000

1000

100

100

10

10

50

55

Mn

10000

60

50

55

m/z

60

m/z

Figure 3. Spectra of 10 ppb Mn in a 0.1% Fe matrix sample solution obtained in Single Quad mode (left) and ICP-QQQ in MS/MS mode (right).

Determination of P, S and Mn in high purity iron CRMs
Trace elements including P, S and Mn were determined by ICP-QQQ in high purity
iron CRMs: JSS 001-6 and 003-6, using O2 mass-shift mode (for P and S) andHe mode (for Mn). As summarized in Table 1, excellent agreement was obtained
between the measured (found) and certified values for all three elements,
indicating the effective interference removal offered by the 8800 ICP‑QQQ in
MS/MS mode. Excellent spike recovery at the 50 ppb level was also confirmedwith JSS 003.
Table 1. Analytical results for P, S and Mn in two high purity iron CRMs.
JSS 001-6

JSS 003-6

Element Q1

Q2

ORS

Certified Uncertainty Found
Certified Uncertainty Found
50 ppbvalue[mg/kg] value[mg/kg] spike[mg/kg][mg/kg]recovery
%

P

31

47

O2

0.5*

S

32

48

O2

1.5

Mn

55

55

He

0.03*

0.3

0.458

3.5

0.7

3.170

103

1.512

1.3

0.5

1.287

92

0.036

3.2

0.2

3.432

101

147

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The Benefits of Improved Abundance Sensitivity with
MS/MS for Trace Elemental Analysis of High Purity Metals
AuthorIntroduction

Fred Fryer
Agilent Technologies, Australia

The use of a quadrupole mass filter for the separation of compounds in mass
spectrometry is well established. Initially used for organic mass spectrometry
and residual gas analysis, the quadrupole spectrometer was adopted for theearliest ICP-MS systems, and has remained the default choice throughout thehistory of ICP-MS. However, the performance characteristics of the quadrupole
mass filter do impose several limitations on quadrupole ICP-MS (ICP-QMS).

Keywords
quadrupole, resolution, hyperbolic,abundance sensitivity, copper, highpurity zinc

The resolution (R) of a mass filter (meaning its ability to separate adjacentmasses) is defined as M/ΔM, the mass of the target peak/the mass difference
to nearest adjacent peak that can be distinguished (separated). However,for practical specifications, the resolution is often simply quoted as the widthof the peak at a given peak height. The quadrupole mass filter used in an
ICP‑QMS instrument is typically operated with a nominal peak width of about
0.75 u at 10% peak height, illustrated in Figure 1.
Peak height

Peak width (u)at 50% peak height(typically 0.5-0.6)

Peak width (u)at 10% peak height(typically 0.65-0.75)
M-1

M

M+1

Figure 1. Illustration of resolution calculation for a mass spectrometer.

For two peaks within the normal signal range of the instrument, this allows thecomplete, baseline separation of masses 1 u apart, within the elemental
mass range from Li (7 u) to U (238 u) and beyond. Higher resolution of
0.4 u peak width is possible by adjusting the quadrupole voltages, but the signal
is reduced (less ion transmission) due to rejection of a higher proportionof the ions that are nominally “on-mass”. Typically, the signal loss at higher
resolution is around 10-50%, depending on the design and operating
characteristics of the quadrupole.
Both the efficiency of transmission of ions at the set-mass (i.e., the sensitivity)
and the rejection of ions at other masses (i.e., the resolution of adjacent peaks)
are affected by the shape of the field within the quadrupole, and the frequencyof the alternating RF fields.

148

A hyperbolic field (generated by rods with a hyperbolic profile) alternating at highfrequency gives more effective filtering of the ion beam than a lower frequency
field generated by round quadrupole rods. The practical benefit of hyperbolic rods
and high frequency RF voltage is therefore better ion transmission at higher
resolution. Some of the many real-world applications where the combination ofhigh sensitivity and good peak separation is required for adjacent low/highconcentration elements measured by ICP-MS are shown in Table 1.
Table 1. Elements that require improved separation of adjacent peaks for low level analysis.
Low concentration

High signal

Example matrix
Soil, plants

31

P

16

O2, 32S

55

Mn

56

Fe, Ar O

Iron and steel, soil

63

Cu, Cu64

Zn, ZnMetal refining

11

B

12

C

Soils, solvents, petrochem

13

C

14

N

Laser imaging

65

40

66

16

Due to the ion transmission characteristics of a quadrupole, the peak that is
generated from the ion signals at each mass forms a non-symmetric Gaussian
distribution with a negative skew; i.e., the peak has a longer tail on the leadingedge (low mass side) than the trailing edge (high mass side). These “tails” mayextend significantly beyond the limits of the nominal 0.75 u peak width, but since
they are at intensities far below 10% of the peak height, they cannot be measured
using the simple resolution figure quoted above. The contribution that a peak at
mass M makes to its neighbors at M-1 u and M+1 u can be quantified, however,and this figure is referred to as the abundance sensitivity (AS) of the quadrupole,
illustrated in Figure 2.

Abundance sensitivity
is the ratio of peak height
M to M-1 and M+1

10% peak height

Poor abundance
sensitivity.
The peak tails intoneighboring peaks.
Good abundance
sensitivity. No contribution
to neighboring peaks
M-1

M

Figure 2. Illustration of abundance sensitivity calculation for a mass spectrometer.

149

For a good quadrupole mass spectrometer in ICP-QMS, the AS would typically beof the order of 10-7, meaning that for an on-mass signal of 107 counts, there is acontribution of one count at the adjacent mass (M+/-1 u).
In applications where the trace analyte must be separated from a very intense
matrix peak at the adjacent M+1 mass, such as the examples shown in Table 1,
the matrix peak may be at an intensity greater than 109 or 1010, and the AS of aquadrupole mass spectrometer is insufficient for accurate trace measurement ofan adjacent overlapped analyte at low/sub ppb levels.
The problem of adjacent mass overlaps now has an elegant solution in the
Agilent 8800 Triple Quadrupole ICP-MS (ICP-QQQ). The 8800 ICP-QQQ uses atandem mass spectrometer configuration with two quadrupole mass filters (Q1and Q2) separated by a collision/reaction cell. In MS/MS mode, both quadrupoles
are operated as unit mass filters, so the overall AS of the instrument is the
product of the Q1 AS x the Q2 AS. With two research-grade, high frequency,
hyperbolic quadrupoles, each operating with AS of 10-7, the combined AS of the8800 ICP-QQQ is theoretically 10-14, although this cannot be verified
experimentally as the magnitude of the signal difference exceeds the dynamic
range of the detector.

Experimental
Trace copper in high purity zinc
Major uses of Zn include galvanized coating to protect steel, die castings, andsolder. Impurities in the metal cause Zn plating to lift, die casts to crack, or solder
to ‘de-wet’, hence high purity zinc (>99.995 % ) is a preferred commodity.
Common impurities are Cu, Au and Sb, but may also include Cd, Al, Fe, Ag, Bi, As,
In, Ni, P, and S.
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/Low matrix.
Ion lens tune: Auto tune was used for optimization.
CRC conditions: Helium cell gas at 4.8 mL/min with KED of 4 V.

Results and discussion
Analysis was performed on high purity Zn, dissolved to give a 0.1% (1000 mg/L)
Zn solution in a final acid concentration of 2% HNO3. The sensitivity of the 8800
ICP-QQQ was reduced to bring the signal for the major Zn isotopes (64, 66) within
the detector’s upper limit of dynamic range (~ 1010 cps). The intense Zn signals
were measured automatically in analog detector mode, while the Cu isotopes
were measured in pulse mode. It can clearly be seen in Figure 3 that the intense
Zn peaks at m/z 64 and 66 made no contribution to the signal at the two adjacent
trace Cu isotopes at m/z 63 and 65. The Cu isotope ratio matched the theoreticalabundances (63Cu/65Cu natural ratio of 69.17/30.83), at 1 µg/L concentration.
If there was a contribution from an adjacent Zn mass, then the isotope ratio
would be biased.

150

From the 63Cu calibration (Figure 4), the BEC and DL measured for Cu in the 0.1%
Zn matrix were 1.7 ppb and 0.01 ppb respectively, indicating a low and stablebackground signal. The sensitivity of Cu was 7700 cps/ppb in 1000 µg/L Zn,
under the “de-tuned” conditions used to bring the Zn peaks within the detector
range. This represents about a 2x reduction in the signal that would be obtained
under normal tuning conditions for this type of matrix, if measurement of thematrix element peaks was not required.
1.E+10
1.E+09
1.E+081.E+07Signal CPS

1.E+06
1.E+05
1.E+04
1.E+03
1.E+02
1.E+01
1.E+00
60/60

61/61

62/62

63/63

64/64

65/65

66/66

67/67

68/68

69/69

70/70

Mass pair (Q1/Q2)

Figure 3. 1000 mg/L Zn spiked with 1 ug/L Cu. (1 ppb: 63/total = 0.667, 65/total = 0.333,
no mass bias correction performed. If there was some contribution from Zn it would influencem/z 63 differently from m/z 65, because of the different abundance of the Zn isotopes).

Figure 4. Standard addition calibration of 63Cu in 1000 mg/L Zn.

151

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Ultratrace Copper Analysis in a Semiconductor Grade
Organometallic Titanium Complex
Authors

Introduction

Akio Hashizume, Toshiya Shingen,
ADEKA Corporation, Japan

Most quadrupole ICP-MS (ICP-QMS) instruments use CRC technology to resolve
spectroscopic interferences. Helium collision mode is widely accepted due to its
versatility and ease of use for multi-element analysis of complex and variablesamples. While the performance achievable with He mode meets therequirements for most applications, there are some applications, for example
impurity analysis of semiconductor materials, that require improved interference
removal capability. For these applications, a reactive cell gas (reaction mode) may
be used, but the use of highly reactive cell gases in quadrupole ICP-MS is prone to
unexpected interferences and overlaps, especially when the matrix is complex, orother analytes are present at varying concentrations. The new Agilent 8800 Triple
Quadrupole ICP-MS (ICP‑QQQ) eliminates the variability associated with reactive
cell gases in ICP-QMS, by using the first quadrupole (Q1) to control the ions thatenter the CRC. This ensures that the reactions are predictable and the product ion
spectrum is simple and consistent.

Katsuo Mizobuchi,
Agilent Technologies, Japan

Keywords
semiconductor, organometallic,copper, titanium, ammonia mass-shift

This report describes the measurement of trace Cu in a semiconductor grade
organometallic Ti complex used in advanced semiconductor processing. It is achallenging application for quadrupole ICP-MS since both isotopes of copper,
63
Cu and 65Cu, suffer interference from TiO and TiOH ions, and the use of reactive
cell gases to avoid the overlap leads to a very complex product ion spectrum,
particularly for organic samples. We demonstrate that the Agilent 8800 ICP-QQQ,
operating in MS/MS mass-shift mode using ammonia as a reaction gas, was able
to separate Cu+ from the Ti-based interferences and measure Cu at low ppt levels
in a matrix of 500 ppm Ti. Results were also acquired using MS/MS He collisionmode, for comparison.

Experimental
Instrumentation: Agilent 8800 #200 with narrow injector (id = 1.5 mm) torch(G3280-80080) used for organic solvent analysis. A low flow PFA nebulizer(G3285-80002) was used in self-aspiration mode. An option gas flow of 20% O2balanced in Ar was added to the carrier gas via the standard option-gas line toprevent carbon build up on the interface cones.
Operating conditions: Table 1 summarizes plasma, ion lens and cell tuning
conditions.
Acquisition conditions: MS/MS mode was used; cell gas was either NH3 or He.
Sample and sample preparation: Semiconductor grade organometallic Ti
complex (ADEKA Corp., Japan) was diluted with high purity IPA (Tokuyama Corp.,
Japan) to 500 ppm Ti solution. A spiked standard was prepared from the multielement standard, xstc-331, purchased from SPEX CertiPrep Ltd. (UK).

152

Table 1. Experimental conditions.
Units
Cell conditions

Plasma conditions

Ion lens

Cell gas

He collision cell modeNH3 reaction cell modeHe

NH3 (10% NH3 in He)

Cell gas flow rate

mL/min8.0

6.5

Octopole bias

V

-18

-18

KED

V

4

-10

Cell exit

V

-100

-70

Deflect

V

-3

-12

Plate

V

-70

-60

RF

W

1600

SD

mm

12.0

Carrier gas

L/min

0.70

Make-up gas

L/min

0.20

Opt gas flow rate

L/min

0.20

Extract 1

V-60

Extract 2V-10

Results and discussion
He collision mode
The He cell gas flow rate was optimized for the lowest BEC of Cu in a 500 ppm Ti
solution. As the BEC for 63Cu was lower than the BEC for 65Cu due to the higher
abundance of the 63 isotope and the more significant interference from TiO+ at
m/z 65, Cu was determined on-mass at m/z 63. In MS/MS mode, this is achievedby the acquisition conditions: Q1 = 63; Q2 = 63 (63, 63).
Two solutions were analyzed: 500 ppm Ti solution and 500 ppm Ti + 1 ppb Cu
spike. Figure 1 (left) shows the signal at m/z 63 obtained from the analysis of thetwo solutions, plotted as a function of He flow rate. The BEC calculated fromthese signals is also given in the figure. It shows that the lowest Cu BEC in He
mode was 46 ppt, achieved at a flow rate of 8.0 mL/min He.
NH3 reaction cell mode
Cu+ reacts efficiently with NH3 to form NH3 cluster ions with the general form
Cu(NH3)n+. TiO+ does not follow the same reaction pathway as Cu+, so the Cu
product ion can be measured free from Ti overlap. Based on a preliminary study,
one of the intense product ions, Cu (NH3)2+, was selected to measure Cu
separated from the original TiO+ interference. A mass pair of Q1 = 63, Q2 = 97
was used with NH3 as the reaction gas. Figure 1 (right) shows the result. A BEC of
11 ppt for Cu in 500 ppm Ti solution was achieved in NH3 mode (10% NH3/He
mixed gas), at a flow rate of 6.5 mL/min NH3.

153

Conclusion
Table 2 summarizes the analytical performance achieved by the 8800 ICP-QQQ
operating in MS/MS mode with He collision and NH3 reaction gas. As can be seen,
NH3 reaction mode is more effective than He collision mode for the removal of the
TiO+ interference on Cu. The BEC obtained for Cu in a Ti matrix by NH3 reaction
mode is four times lower than He mode, with seven times higher sensitivity.
Table 2. Summary of Cu measurement in Ti matrix.
Flow rate (mL/min)

BEC (ppt) of Cu in 500 ppm Ti

Sensitivity (cps/ppb)

He collision mode

8.0

45.5

810

NH3 reaction mode

6.5

10.9

5900

1.E+081.E+07

1.E+08SIGNAL of 500 ppm Ti

BEC of Cu

1.E+05

1.E+07
1.E+06

1.E+04

1.E+05

1.E+03

1.E+04

1.E+02

1.E+03

1.E+01
1.E+00
0.0

2.0

4.0

6.0

He flow rate (mL/min)

8.0

10.0

1.E+06
SIGNAL of mass pair = (63, 97)

SIGNAL of 500 ppm Ti + 1 ppb Cu

BEC of Cu in 500 ppm Ti (ppt)

SIGNAL of mass pair of (63, 63) cps

1.E+06

SIGNALof 500ppm
Ti Ti
SIGNALof 500ppm
SIGNALof 500ppm
1 ppb
SIGNALof 500ppm
Ti +Ti1+ppb
Cu Cu
BEC
of Cu
BEC
of Cu

1.E+05

1.E+07
1.E+06

1.E+04

1.E+05

1.E+03

1.E+04

1.E+02

1.E+03

1.E+02

1.E+01

1.E+02

1.E+01

1.E+00
0.0

2.0

4.0

6.0

8.0

BEC of Cu in 500 ppm Ti (ppt)

1.E+07

1.E+01
10.0

NH 3 flow rate (mL/min)Figure 1. (Left) Cu signal (mass pair 63, 63) vs. He cell gas flow rate, for 500 ppm Ti matrix unspiked and with 1 ppb Cu spike, and calculated BEC.
(Right) Cu signal (mass pair 63, 97) vs NH3 cell gas flow rate, for 500 ppm Ti matrix unspiked and with 1 ppb Cu spike, and calculated BEC.

154

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Analysis of 10 nm Gold Nanoparticles using theHigh Sensitivity of the Agilent 8900 ICP-QQQ
Authors

Introduction

Susana Nunez and Heidi Goenaga
Infante, LGC Limited, UK
Michiko Yamanaka, Takayuki Itagaki,
and Steve Wilbur, Agilent Technologies

The measurement of nanoparticles (NPs) is of public and scientific interest.
More information is needed to understand the fate of NPs in the environment andthe potential toxic effects once absorbed into the body. Gold (Au) NPs have abroad range of uses in medical, industrial, and technology applications. Au is arelatively easy element to measure by ICP-MS, as it is not affected by common
spectral interferences. However, the detection of very small particles (<20 nm)
remains challenging for ICP-MS, due to the low signal generated from suchparticles. The Agilent 8900 ICP-QQQ has a low background (<0.2 cps) andsensitivity up to Gcps/ppm, making it suited to small particle detection.

Keywords
nanoparticles, single nanoparticle
analysis, TRA, dwell time, gold
nanoparticles

Experimental
Instrumentation: Agilent 8900 Advanced Applications configuration ICP-QQQ
with 1-mm i.d. injector torch and standard sample introduction system.
Method: All aspects of method setup and data analysis were carried out using
the fully integrated Single Nanoparticle Application Module option for ICP-MS
MassHunter. The “Batch at a Glance” data table shown in Figure 1 summarizes
the sample results for an entire batch. Detailed graphical results are displayed foreach selected sample, allowing results to be viewed and compared, or method
settings to be optimized if necessary. Reference [1] gives details of the particle
size calculation used in the module.

Figure 1. Data analysis view of the Single Nanoparticle Application software module.

155

Tuning conditions: For highest sensitivity, 197Au was measured in single quadmode with no cell gas.
Plasma parameters: RF power =1550 W, sampling depth = 7.0 mm, and carriergas flow rate = 0.78 L/min.
Data acquisition: TRA analysis with a dwell time of 0.1 ms. Data acquisition timewas 60 s.
Reference materials and sample preparation:
Three Au NP reference materials (RMs) were used in the study: NIST 8011 with anominal diameter of 10 nm (8.9 ± 0.1 nm determined by Transmission Electron
Microscopy (TEM)); NIST 8012 with a nominal diameter of 30 nm (27.6 ± 2.1 nm
determined by TEM); and NIST 8013 with a nominal diameter of 60 nm (56.0 ± 0.5
nm determined by TEM). All final solutions containing Au nanoparticles or ionic
Au standards were prepared in 0.01% L-cysteine for stabilization.

Results and discussion
Analysis of Au NP samples
Solutions containing gold NPs with particle sizes of 10 nm, 30 nm, and 60 nm
were prepared at concentrations of 0.25 ng/L, 5 ng/L and 50 ng/L, respectively.
The solutions were measured using fast TRA acquisition. Figure 2 shows themeasured raw signal event frequency and the calculated size distribution for asolution containing 10 nm particles. From the results, the practical detection limitof the particle diameter was estimated to be around 30,000 cps (equivalent to~6.5 nm) and the background equivalent diameter (BED) was 3 nm.
The 30 nm and 60 nm particles were also measured, and the results are
summarized in Table 1. The results for the median, mode, and mean particle sizes
for all three standards agreed well with the reference sizes obtained by TEM.
Background level (3cts / 0.1ms = 30000 cps)

Frequency

Normalized Frequency

10 nm particles

40

20

0
10000

1000001000000

10000000

100

50

0

100000000

0

10

20

Number of ions detected in single event (cps)

30

40

50

60

70

80

Calculated diameter of particle (nm)Figure 2. Raw signal event frequency (left) and calculated size distribution of 10 nm particles (right).
Table 1. Measured particle size for Au NPs in three NIST RMs.
Nominalsize (nm)156

Particle size (nm)by TEM

Measured particle size ( n = 10 )MedianMode

Meansize (nm) RSD (%)

size (nm) RSD (%)

size (nm) RSD (%)

10

8.9

± 0.1

9.0

3.3

10

0.0

9.2

3.3

30

27.6

± 2.1

26.9

0.3

28

0.0

27.0

0.3

60

56.0

± 0.5

56.1

0.3

56

1.8

57.2

0.4

Conclusion
The low background and high sensitivity of the Agilent 8900 ICP-QQQ make itsuitable for single particle analysis of solutions containing the smallest-sized
nanoparticles. The size and composition of gold NP solutions were characterizedfrom 10 nm up to 60 nm, with good accuracy. The practical detection limit of theparticle diameter was estimated to be 6.5 nm and the BED was 3 nm.

Reference
1.	H. E. Pace, N. J. Rogers, C. Jarolimek, V.A. Coleman, C.P. Higgins, and J. F.
Ranville, Anal. Chem., 2011, 83, 9361-9369

More information
Analysis of 10 nm gold nanoparticles using the high sensitivity of the Agilent
8900 ICP-QQQ, Agilent publication, 5991-6944EN

157

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High Sensitivity Analysis of SiO2 Nanoparticles using theAgilent 8900 ICP-QQQ
Authors

Introduction

Michiko Yamanaka, Takayuki Itagaki,
and Steve Wilbur,
Agilent Technologies

ICP-MS is a well-established technique for measuring the elemental content ofmaterials. With the recent development of Single Particle ICP-MS (spICP-MS)
acquisition mode, ICP-MS can also be used to characterize the nanoparticle (NP)content of a sample.

Keywords
nanoparticles, single nanoparticle
analysis, TRA, dwell time, silicon
dioxide NPs

Silicon dioxide (SiO2) NPs are used for many applications including paints,
coatings, adhesives, food additives, polishing micro-electronic devices etc.
Given their wide spread use, there is a clear requirement for SiO2 NPs to bemonitored. Si measurement by ICP-MS is not easy since the major isotope of Si,
28
Si (92.23% abundance), is interfered by the background polyatomic ions CO+
and N2+. The interferences can be addressed using reaction chemistry in thecollision/reaction cell of an ICP-MS. However, for controlled and consistent
reaction processes, a tandem mass spectrometer instrument such as theAgilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) is required.

Experimental
Instrumentation: Agilent 8900 Advanced Applications configuration ICP-QQQ
fitted with a 1 mm i.d. injector torch and standard sample introduction system.
Method: All aspects of the method setup and data analysis were carried out
using the fully integrated Single Nanoparticle Application Module option of the
ICP-MS MassHunter software. The “Batch at a Glance” data table summarizes the
sample results for an entire batch. The detailed graphical results are displayed foreach selected sample, allowing results to be viewed and compared, or method
settings to be optimized if necessary. References [1 and 2] provide details of theparticle size calculation used in the module.
Tuning conditions: H2 on-mass mode was used to remove potential interferences
by CO+ and N2+ on 28Si+. H2 cell gas flow = 3 mL/min.
Plasma parameters: RF power =1550 W, sampling depth of 7.0 mm and carriergas flow rate of 0.76 L/min.
Data acquisition: TRA analysis with dwell time of 0.1 ms.

Frequency

300
Background noise

200

50nm particle

100
0
10000

1000001000000

Signal in single event (cps)Normalized Frequency

Reference materials and sample preparation: SiO2 NP reference materials (RMs)with nominal diameters of 50 nm, 60 nm, 100 nm, and 200 nm were bought fromnanoComposix (San Diego, USA). They were diluted to a particle concentration of
between 40 and 1000 ng/L with de-ionized (DI) water and sonicated for 5 min toensure sample homogeneity. A Si ionic standard of 5 μg/L was prepared with DI
water and used to measure the elemental response factor.
100

50

0
0

50

100

Calculated diameter of particle (nm)Figure 1. Raw signal event frequency (left) and calculated size distribution of 50 nm particles (right).
158

Results and discussion
Analysis of SiO2 NPs in UPW
The frequency distribution plots of the signals obtained from 50 nm SiO2 NPs areshown in Figure 1. The particle signals were clearly distinguished from thebackground (dissolved, ionic component). From the results, we can estimate thatthe practical detection limit for the particle diameter was below 50 nm and thebackground equivalent diameter (BED) was 22 nm.
The results for the size analysis of different SiO2 NP solutions are summarized inTable 1. The results for median, mode, and mean particle sizes agreed well withthe reference sizes obtained by TEM.
Table 1. Measured particle size for SiO2 NPs in four RMs.
Nominalsize (nm)Particle size (nm) Prepared particle
by TEM
concentration (ng/L)

Measured particle size ( n = 10 )MedianMode

Meansize (nm)size (nm)size (nm)5046.3 ± 3.1

40

49

50

50

60

57.8 ± 3.5

40

61

62

62

100

97.0 ± 4.8

100

99

100

102

200

198.5 ± 10

1000

200

204

200

Analysis of SiO2 NPs in a high-level carbon matrix

Normalized Frequency

Real samples such as biological samples, food matrices, pharmaceuticalingredients, and organic solvents contain carbon matrices that give rise to a
12 16 +C O polyatomic ion interference on 28Si+. Figure 2 shows the particle size
distribution for a mixed solution of the 100 and 200 nm SiO2 measured in asample containing 1% ethanol. Despite the high concentration of carbon,
the size distribution for each group of particle sizes was consistent with theresults obtained by TEM. The 8900 ICP-QQQ in MS/MS mode with hydrogencell gas was able to eliminate the 12C16O+ interference effectively.
100

50

0
50

100

150

200

250

Calculated diameter of particle (nm)Figure 2. Size distribution result of 100 and 200 nm SiO2 NPs in 1% ethanol.

159

Conclusion
SiO2 NPs can be determined and characterized successfully using the Agilent
8900 ICP-QQQ operating in MS/MS mode with H2 cell gas. Even in the presenceof a high level of carbon matrix. The Single Nanoparticle Application Module for
ICP-MS MassHunter was used to calculate the particle sizes. The spICP-QQQ
method provides fast analysis times, excellent detection limits for particle sizeand concentration, and accurate results for SiO2 particles less than 100 nm.

References
1.	H. E. Pace, N. J. Rogers, C. Jarolimek, V.A. Coleman, C.P. Higgins, and J. F.
Ranville, Anal. Chem., 2011, 83, 9361-9369
2.	M. Yamanaka, T. Itagaki and S. Wilbur, Agilent publication, 2016, 5991-6596EN

More information
High sensitivity analysis of SiO2 nanoparticles using the Agilent 8900 ICP-QQQ in
MS/MS mode, Agilent publication 5991-6596EN

160

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Accurate determination of TiO2 nanoparticles incomplex matrices using the Agilent 8900 ICP-QQQ
Authors

Introduction

Michiko Yamanaka
Agilent Technologies, Japan

Titanium dioxide (TiO2) nanoparticles (NPs) are widely used in paints, foodcolorants, cosmetics, pharmaceuticals, and many other applications. Due to theirhigh refractive index, TiO2 NPs are common ingredients in sun protection
products used to guard against UV exposure. However, the fate of NPs in theenvironment and the potential for toxic effects once absorbed into the bodyremain largely unknown. Many researchers have investigated different
methodologies to measure TiO2 NPs in cosmetic or food samples [1, 2, 3, 4].

Steve Wilbur
Agilent Technologies, USA

TiO2 NPs have three principal levels of structure, beginning with nanoscale
crystallites. These crystals fuse to form ‘hard’ nanoscale aggregates, which inturn associate to form microscale agglomerates [5]. When aqueous dispersionsof TiO2 NPs are prepared, the particle sizes observed are the aggregation or
agglomeration sizes, which are usually different from (larger than) the primary(crystal) particle sizes [5, 6]. Typically, the primary size is measured bytransmission electron microscopy (TEM) or X-ray diffraction (XRD), and thedispersion size is measured by laser diffraction spectrometry (LDS) or dynamic
light scattering (DLS).
The relatively recent development of Single Particle ICP-MS (spICP-MS) now
provides a powerful tool to characterize the NP content of dispersed samples.
spICP-MS is used to measure the target element signals generated fromindividual NPs in the solution analyzed. This approach allows the simultaneous
determination of the number, concentration, and size of particles present,
as well as the dissolved element concentration.
In practice, however, there are some challenges for the measurement of TiO2
NPs using conventional single quadrupole ICP-MS (ICP-QMS). Many real samples
may contain P, S, Ca, Si and C, and all these elements cause interferences thathinder the measurement of Ti. Also, the most abundant isotope of Ti, 48Ti (73.7%
abundance), suffers an isobaric interference from 48Ca; therefore, the lessinterfered isotopes 47Ti or 49Ti are typically measured. However, the less abundantisotopes provide lower sensitivity, which limits the detection of smaller-sized
TiO2 NPs by ICP-QMS.
The Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) can operate in MS/MS
mode to resolve the spectral interferences on Ti, including the isobaric
interference from 48Ca on 48Ti. The 8900 ICP-QQQ is a tandem mass
spectrometer, meaning that it has an additional mass spectrometer with unit (1 u)
resolution, positioned before the collision/reaction cell. This extra mass filter
selects the ions that can enter the cell, providing control of the reaction chemistrywhen reactive cell gases are used. ICP-QQQ with MS/MS provides an elegant andeffective approach for solving the most challenging spectral overlaps [7].

161In this study, TiO2 NPs in sunscreen were measured in spICP-MS mode using theAgilent 8900 ICP-QQQ in MS/MS mode. The optional Single Nanoparticle
Application Module software for ICP-MS MassHunter was used for method setup
and data processing.
Current regulations
The methodologies used to evaluate the properties of nanomaterials are not yet
considered to be finalized and approved, which may be impeding the introductionof specific regulations relating to NPs. In June 2014, the USA Food and Drug
Administration (FDA) issued guidance on the safety assessment of
nanomaterials in cosmetic products [8]. As part of the FDA, the Center for Drug
Evaluation and Research (CDER) is responsible for ensuring the safety of titanium
dioxide (and zinc oxide) nanomaterials for use in over-the-counter (OTC)sunscreen products.
Currently, the European Union Scientific Committee on Consumer Safety (SCCS)
considers that it is safe to use TiO2 NPs as a UV filter at a concentration up to
25% in sunscreens. Manufacturers must respect this limit according to European
legislation (annex VI list of UV filters) of the EU regulation on cosmetic products;
regulation EC 1223/2009 [9]. The regulation was amended in 2016 to state that in
the case of combined use of titanium dioxide and titanium dioxide (nano), thesum shall not exceed 25% [10].
In 2016, following a request from the European Commission to the European
Food Safety Authority (EFSA), the Scientific Panel on Food Additives and Nutrient
Sources added to Food (ANS) considered the safety of titanium dioxide (TiO2,
E 171) when used as a food additive [11]. The Panel will establish a health-based
guidance value for acceptable daily intake (ADI) once more data is available on
the reproductive toxicity of E 171.

Experimental
Reference materials and calibration solutions
The TiO2 standard reference material (SRM) NIST 1898 Titanium Dioxide(Maryland, US) was used. The SRM contains crystal or primary sized particles<50 nm, but the size of particles dispersed in the aqueous phase range from 71 to
112 nm due to nanoscale aggregation [5]. The SRM was diluted with de-ionizedwater to a particle concentration that was calculated to give 500 – 2000 particle
counts per minute, and sonicated to ensure sample homogeneity. A 1 ppb Ti ionicstandard prepared in 1 % nitric acid was used to measure the elemental response
factor for Ti. A gold NP RM with a nominal particle size of 60 nm (NIST 8013 Gold
Nanoparticles) was used to measure the nebulization efficiency of the ICP-QQQ.
Sunscreen samples
Sunscreen products were bought in a local store in Tokyo, Japan. The samples
were diluted with de-ionized water plus 0.1 % Triton™ X-100. The results obtained
from an initial screening analysis using the spICP-MS method, showed thesize-range of TiO2 particles present in the different sunscreen samples varied.
One of the samples contained particles <30 nm, while another product contained
particles sized 30 to 200 nm. A sunscreen that contained TiO2 NPs sized 30 to
100 nm was selected for further investigation. The selected sunscreen was
prepared in various diluent matrices: de‑ionized water; tap water; and a “matrix
162

mixture” containing 100 ppm of P and S, 50 ppm of Ca and Si, and 0.1 % ofethanol. The matrix mixture was used to check the impact of matrix-based
interferences on the measurement of Ti.
Instrumentation
An Agilent 8900 Advanced Applications configuration ICP-QQQ was usedthroughout. The instrument was equipped with the standard glass concentric
nebulizer and quartz spray chamber, optional quartz torch with 1.0 mm i.d.
injector, and standard nickel sampling and skimmer cones. Samples wereintroduced directly into the ICP-QQQ using the standard peristaltic pump and1.02 mm i.d. pump tubing. Analyses were performed in fast Time Resolved
Analysis (fast TRA) mode, using a dwell time of 0.1 ms (100 μs) per point,with no settling time between measurements. The major titanium isotope, 48Ti,
was measured in MS/MS mass-shift mode, using a mixed cell gas containing
oxygen and hydrogen to resolve all the polyatomic and isobaric interferences.
Q1 was set to m/z 48 (the mass of the precursor 48Ti ion) and Q2 was set tom/z 64 (the mass of the target product ion 48Ti16O). O2 and H2 cell gases wereused to promote the formation of the TiO+ product ion, avoiding the on-massinterference from 48Ca and matrix-based polyatomic ions that overlap 48Ti.
The operating conditions of the Agilent 8900 ICP-QQQ are detailed in Table 1.
Table 1. ICP-QQQ operating conditions.
Parameter

Value

RF power

1550 W

Sampling depth

8.0 mmCarrier gas

0.70 L/min

Sample uptake rate

0.35 L/min

Spray chamber temp.

2 °C

Dwell time

0.1 msSettling time

None

Acquisition mode

MS/MS (Q1: m/z 48, Q2: m/z 64)

Oxygen flow rate

0.15 mL/min (10% of full scale)Hydrogen flow rate

7.0 mL/min

Axial Acceleration

1.0 V

Octopole bias voltage-6 V

Energy discrimination-15 V

The Single Nanoparticle Application Module of the ICP-MS MassHunter software
was used for method setup and data analysis. Sample results for an entire batchare summarized in the interactive ‘Batch at a Glance’ table. Detailed graphicalresults are displayed for selected samples, permitting visual confirmation andoptimization of parameters if needed.

163

Results and discussion
Optimization of cell gas conditions using ionic Ti solution
Before measurement of the NPs, cell gas conditions were investigated. Ti reacts
readily with oxygen, so can be measured as TiO+ in oxygen mass-shift mode.
The first quadrupole (Q1) was set to pass only m/z 48, to allow 48Ti+ (and any
on-mass interferences) to enter the cell. The second quadrupole (Q2), which islocated after the collision/reaction cell, was set to m/z 64 to pass the target
product ion (48Ti16O+) to the detector. Any potential native ion overlaps at m/z 64(e.g. 64Zn and 64Ni) are rejected by Q1. Most of the primary interferences at
m/z 48, such as 32S16O+, 30Si18O+, 31P16OH+, 12C18O2+, can be avoided by measuring
Ti as TiO+ in oxygen cell gas mode. However, some of the 48Ca ions also reactwith oxygen to form 48CaO+, which interferes with the 48TiO+ product ions at
m/z 64. Adding hydrogen gas can eliminate the Ca interference by converting
CaO+ to CaOH+. TiO+ does not react in the same way with H2 cell gas, so remains
as the TiO+ product ion at m/z 64. Inter-isotope overlaps (such as 46Ti18O and46
Ca18O) can affect the 48Ti16O measurement at m/z 64 when a single quadrupole
or bandpass MS system is used. With MS/MS, however, these overlaps are
avoided as the precursor ions (46Ti and 46Ca) are rejected by Q1 and so do notenter the cell to react.
Table 2 shows the quantitative results for Ti (measured as 48Ti+ in no gas modeand 48TiO+ in O2/H2 mode) in various matrices. The quantitative results obtained in
no gas mode show a large positive error due to the interferences on 48Ti.
In contrast, O2/H2 cell gas mode effectively reduces the interferences including
the potential CaO+ product ion overlap formed from 48Ca. This method enables
the TiO+ product ion from the most abundant isotope of Ti (mass 48; 73.7%
relative abundance) to be measured, providing the sensitivity required for
detection of small particles.
Table 2. Interference check results for 48Ti in various matrices, with and without cell gas.
Cell gas mode

Sensitivity(cps/ppb)

Apparent concentration of Ti, measured as 48Ti+ or 48TiO+ (ppb)
100 ppm P

100 ppm S

50 ppm Ca

50 ppm Si

0.1% ethanol

Matrix mixture*

No gas155,000

1.7

6.0

225

0.39

0.14

261

O2 + H2

79,000

0.010

0.001

0.18

0.054

0.001

0.23

*Includes all the matrices (100 ppm of P and S, 50 ppm of Ca and Si, and 0.1% ethanol).

Measurement of a TiO2 NP reference material
NIST 1898 TiO2 NP reference material was measured by ICP-QQQ in MS/MS
mass-shift mode with O2/H2 reaction gas. The time resolved signal chart for NIST
1898 (Figure 1) shows clear NP peaks with a wide variation in intensity (peakheights). In single particle ICP-MS, the peak height for each particle signal “plume”
is representative of the particle mass (size). Figure 2 shows the signal frequency
distribution for NIST 1898 (upper), and the calculated particle size distribution(lower). The mean size of 71 nm agrees well with the results by LDS (71 ± 4 nm),
X-Ray Disc Centrifugation (77 ± 7 nm), and DLS (112 ± 4 nm) according to the
NIST certificate [5]. Note that DLS measures the hydrodynamic particle size,
which includes the layer where the particle surface interacts with the solvent.
Consequently, DLS has been reported to give particle sizes that are larger thanthe value measured by other techniques [12].
164

x107

Response (cps)

3

2

1

0
20.0

40.0
Time (sec)Figure 1. Time resolved signal for NIST 1898 TiO2 NP reference material. The blue line represents
a baseline automatically set by the MassHunter software function.

Frequency

6

4

2

0
10000

1000001000000
10000000
Signal (CPS)

100000000

Normalized

100

50

0
100

200
Particle size

Figure 2. Signal frequency distribution (upper) and particle size distribution (lower) for NIST 1898
TiO2 NP reference material.

Analysis of TiO2 NPs in sunscreens
TiO2 NPs were measured in a commercial sunscreen prepared (dispersed) inseveral different solutions and the results are presented in Figure 3. Figure 3-A
shows the TiO2 signal distribution and Figure 3-B shows the particle size
distribution for the sunscreen dispersed in de-ionized water (plus Triton X-100).
The mean particle size of TiO2 was calculated as 77 nm. The same sunscreen
was dispersed in tap water (Figures 3-C and 3-D), and a synthetic matrix mixture
comprising 100 ppm of P and S, 50 ppm of Ca and Si, 0.1 % of ethanol (Figures
3-E and 3-F). These results show signal distributions that are almost the same as
the ones obtained for the sunscreen dispersed in de-ionized water. The mean
particle sizes (79 nm for tap water and 84 nm for the matrix mixture) are similar.
The particle size detection limit (the threshold between the baseline noise andparticle signals) was about 30 nm for the dispersed sunscreens in all thematrices. The synthetic high matrix (Figure 3-E and 3-F) did not affect the size-DLor the accuracy of the particle size measurement.
The results show that TiO2 NPs <100 nm diameter can easily be measured using
the MS/MS capability of the 8900 ICP-QQQ, even in a high concentration matrix.
165

A

B 100

Normalized

Frequency

10

5

0
10000

0
1000001000000 10000000 100000000 1000000000
Signal (CPS)

100

200

300

200

300

200

300

Particle size

D 100

Normalized

Frequency

C 15

10

5

0
10000

50

0
1000001000000
10000000 100000000 1000000000
Signal (CPS)

E 15

100
Particle size

F 100

10

Normalized

Frequency

50

5

50

0

0
10000

1000001000000
10000000 100000000 1000000000
Signal (CPS)

100
Particle size

Figure 3. TiO2 NP measurement of commercial sunscreen using ICP-QQQ. Signal distribution A) and particle distribution B) of sunscreen dispersed inde-ionized water. Signal distribution C) and particle distribution D) of sunscreen dispersed in tap water. Signal distribution E) and particle distributionF) of sunscreen dispersed in the matrix mixture.

Conclusion
The Agilent 8900 ICP-QQQ operating in MS/MS mode with O2/H2 cell gas wasused for the successful determination and characterization of TiO2 nanoparticles
in various sample matrices. MS/MS mass-shift mode effectively resolved thepolyatomic and isobaric ions that interfere with the measurement of Ti at its mostabundant isotope. This unique MS/MS capability provided a particle size
detection limit of ~30 nm.
Overall, the method delivered low background signals and excellent sensitivity,
even in the presence of a high level of P, S, Ca, Si, and C matrix.

166References
1.	V. Nischwitz and H. Goenaga-Infante, J. Anal. At. Spectrom., 2012, 27(7),1084–1092.
2.	C. Contado and A. Pagnoni, Anal. Methods, 2010, 2, 1112–1124.
3.	I. López-Heras, Y. Madrid, C. Cámara, Talanta, 2014, 124, 71–78.
4.	P. Lu, S. Huang, Y. Chen, L. Chiueh and D. Y. Shih, J. Food and Drug Anal., 2015,
23, 587–594.
5.	Standard Reference Material 1898 (Titanium Dioxide Nanomaterial)
Certificate of Analysis, 2012.
6.	Z. Magdolenova, D. Bilaničová, G. Pojana, L. M. Fjellsbø, A. Hudecova, K.
Hasplova, A. Marcomini and M. Dusinska, J. Environ. Monit., 2012, 14,455–464.
7.	G. Woods and E. McCurdy, Spectroscopy, 2015, 30 (11), 18–25.
8.	Guidance for Industry: Safety of Nanomaterials in Cosmetic Products, U.S.
Department of Health and Human Services Food and Drug Administration
Center for Food Safety and Applied Nutrition, June 2014, https://www.fda.gov/
Cosmetics/GuidanceRegulation/GuidanceDocuments/ucm300886.
htm#introduction (accessed July, 2017).
9.	Regulation (EC) No 1223/2009 of the European Parliament and of the Councilof 30 November 2009 on cosmetic products, http://eur-lex.europa.eu/
legal-content/EN/ALL/?uri=CELEX%3A32009R1223 (accessed July, 2017).
10.	Commission Regulation (EU) 2016/1143 of 13 July 2016 amending Annex VI
to Regulation (EC) No 1223/2009 of the European Parliament and of theCouncil on cosmetic products, http://eur-lex.europa.eu/legal-content/EN/
TXT/?uri=CELEX:32016R1143 (accessed July, 2017).
11.	Re-evaluation of titanium dioxide (E 171) as a food additive, EFSA Journal
2016; 14 (9):4545, www.efsa.europa.eu/efsajournal, (accessed July 2017).
12.	A. Dhawan and V. Sharma, Anal. Bioanal. Chem., 2010, 398 (2), 589–605.

167

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Environmental
Title

168

Page

Routine soil analysis using the Agilent 8800 ICP-QQQ

169

The accurate measurement of selenium in reference materials using online
isotope dilution

172

ICP-QQQ with oxygen reaction mode for accurate trace-level arsenic
analysis in complex samples

176

Avoidance of spectral overlaps on reaction product ions with O2 cell gas:comparison of quadrupole ICP-MS and ICP-QQQ

181

Removal of complex spectral interferences on noble metal isotopes

184

Analysis of platinum group elements (PGEs), silver, and gold in roadsidedust using triple quadrupole ICP-MS

190

Direct analysis of ultratrace rare earth elements in environmental waters
by ICP-QQQ

199

Solving doubly charged ion interferences using an Agilent 8900 ICP-QQQ

205

Removal of REE++ interference on arsenic and selenium

211

Removal of molybdenum oxide interference on cadmium

215

Rapid analysis of radium-226 in water samples by ICP-QQQ

218

Feasibility study of fluorine detection by ICP-QQQ

222

HPLC-ICP-MS/MS: fluorine speciation analysis

225

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Routine Soil Analysis using the Agilent 8800 ICP-QQQ
AuthorIntroduction

Kazuhiro Sakai
Agilent Technologies, Japan

Quadrupole ICP-MS is widely used in inorganic testing laboratories, due to its
high sensitivity, low detection limits, wide dynamic range, and high speed
multi-element analysis. The technique is well suited to the analysis of elemental
contaminants present in soil and sediment samples. Helium (He) collision cell
technology can be used successfully to remove many common matrix-basedpolyatomic interferences. He mode is less effective for the removal ofinterferences caused by doubly charged ions though. For example, interferenceson arsenic (As) and selenium (Se) by doubly charged ions of rare earth elements(REEs). Typically, the REE content of environmental samples is low. However,
all interferences, including the doubly charged ions of REEs on As and Se, can beremoved using oxygen mass-shift mode of Agilent’s ICP-QQQ. This approachprovides a high level of confidence in the analysis of unknown samples.
Agilent’s ICP-QQQ instruments also offer the same robustness and matrix
tolerance of Agilent’s single-quadrupole ICP-MS systems.

Keywords
soil, sediment, routine analysis, As, Se,
HMI, matrix tolerance, robustness

This study demonstrates the robustness of the Agilent 8800 ICP-QQQ for routine
soil analysis.

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/HMI-4. The ICP-MS MassHunter software
automatically sets robust plasma tuning conditions that are suitable for soil/
sediment analysis.
Method: the method was based on a preset method for soil (EPA 6020). It was
modified to include O2 mass-shift mode for sulfur (S), As, and Se. All otherelements were measured in He mode. After the calibration standards and initial
QC samples had been analyzed, 13 sample blocks were analyzed. Each block
consisted of 10 samples (two each of Soil A, Soil B, Estuarine Sediment, River
Sediment A, River Sediment B). A Periodic Block consisting of Continuing
Calibration Blank (CCB) and Continuing Calibration Verification (CCV) samples
was automatically inserted into the sequence after each set of 10 samples.
Samples: Five soil and sediment CRMs bought from High-Purity Standards Inc.
(Charleston, SC, USA) were analyzed in this study. These included CRM River
Sediment A, CRM River Sediment B, CRM Estuarine Sediment, CRM Soil A, andCRM Soil B.

169

Results and discussion
The total number of analyses of calibration standards, QC samples, and soil
samples was 177 over ~12 hours. The internal standard (ISTD) stability plot,shown in Figure 1, met EPA 6020 requirements of between 70 and 120% of thevalue of the initial calibration standard.
The accuracy of the method was evaluated by analyzing the soil and sediment
CRMs as unknown samples. Each CRM was measured 26 times in the batch.
The mean concentrations and relative standard deviations (%RSD) were
calculated and compared to the certified value, as shown in Table 1. The mean
concentration for all elements was in good agreement with the certified value,with most RSDs well below 5% over the 12-hour analysis.
140

ISTD Recovery (%)

120
100
80
60
40
20
std 5

rince

ES

std 1

Soil-ACCV 13

ES

Soil-ACCV 12ES

CCV 11

ES

Soil-A

Soil-ACCV 10ES

Soil-A

CCV 9

ES

CCV 8

ES

Soil-A

CCV 7

ES

Soil-A

Soil-A

CCV 6

ES

Soil-A

CCV 5

ES

CCV 4

ES

Soil-A

CCV 3

ES

Soil-A

Soil-A

CCV 2

ES

CCV 1

ICV

Soil-A

std 4

Cal blank0

Samples
6 Li (ISTD) [He]45 Sc (ISTD) [He]74 -> 90 Ge (ISTD) [02]74 Ge (ISTD) [He]115 In (ISTD) [He]89 Y (ISTD) [He]175 Lu (ISTD) [He]193 Ir (ISTD) [He]Figure 1. ISTD signal stability plot over 12 hours.

Conclusion
The Agilent 8800 ICP-QQQ with HMI offers the robustness and matrix tolerance
required for the routine analysis of the widest range of trace and major elements
in high matrix samples, such as soil and sediments. Doubly charged REE
interferences that can affect arsenic and selenium measurement at trace levels
were avoided using MS/MS mass-shift mode with O2 cell gas. Most otherelements were measured in He mode, proven to remove common matrix-basedpolyatomic interferences in complex and variable matrices. Not all soils,
sediments, and food products contain significant concentrations of REEs.
However, the presence of REEs in samples that are analyzed using single
quadrupole ICP-MS can lead to false positive results for As and Se. The use of the
ICP-QQQ with MS/MS improves confidence in the results for these two importantelements. Furthermore, method development is simplified with the use of preset
methods and autotuning, ensuring reproducible performance from day-to-day andirrespective of operator experience.

More information
Routine soil analysis using an Agilent 8800 ICP-QQQ, Agilent publication
5991-6409EN

170

Table 1. Mean recovery % of three soil/sediment CRMs.
Element

Integration
time (s)

MDL
(ppb)

River Sediment A

Be

3

0.06

< MDL

23

Na

0.1

0.98

5191

2.6

24

Mg

0.1

0.73

7292

27

Al

0.1

1.00

25862

31

P

1

3.20

32

S

1

39

K

44

51

Estuarine Sediment A

Soil ARSD (%)

Mean
recovery
(%)

7292

2.6

104

106

7341

2.6

105

2.7

101

51034

2.5

102

2.4

104

1042

2.0

104

20678

2.3

103

97

33670

1.8

96

2.9

103

10.4

3.4

104

83

3.0

104

< MDL

101

399

2.9

100

10.9

3.0

109

2.7

100

35335

3.3

101

20215

2.2

101

11

2.9

106

10.8

2.8

108

0.33

3.1

0.049

52

2.8

103

30.7

3.2

102

30.2

2.6

101

0.3

0.021

102

2.9

102

20.2

3.1

101

30.2

2.4

101

Zn

0.3

0.063

1499

2.5

100

151

2.9

101

101

2.3

101

75

As

1

0.024

60

3.6

100

10.5

3.6

105

20.4

3.0

102

78

Se

3

0.049

2.0

3.6

101

4.9

3.0

99

1.0

6.2

99

95

Mo

0.3

0.022

0.19

10.5

< MDL

107

Ag

0.3

0.015

0.15

9.0

0.015

16.4

0.038

17.3

111

Cd

3

0.012

10.3

2.0

103

0.11

4.5

0.37

2.9

125

121

Sb

0.3

0.011

50.8

2.1

102

0.58

4.4

3.2

3.5

106

135

Ba

0.3

0.055

50.9

2.1

102

1.5

5.4

513

2.6

103

201

Hg

1

0.003

< MDL

205

Tl

0.3

0.008

0.97

2.0

208

Pb

0.3

0.009

719

232

Th

0.3

0.007

238

U

0.3

0.09

Mean
conc.
(ppb)

RSD (%)

Mean
recovery
(%)

Mean
conc.
(ppb)

2.1

5.5

106

< MDL

104

20862

2.4

104

2.6

104

10553

2.7

2.4

103

70884

< MDL

520

4.10

< MDL

< MDL

0.1

7.50

15623

2.2

104

15568

2.7

104

Ca

0.1

2.70

28860

2.1

96

7760

3.2

V

0.3

0.021

26

2.6

105

103

52

Cr

0.3

0.04

29792

2.7

99

55

Mn

0.3

0.062

809

2.2

56

Fe

0.1

0.45

120085

59

Co

0.3

0.017

60

Ni

0.3

63

Cu

66

9

Mean
conc.
(ppb)

RSD (%)

Mean
recovery
(%)

< MDL

< MDL

< MDL

0.018

97

< MDL

< MDL

2.1

103

30.7

2.6

102

41

2.4

101

2.1

3.1

106

10.4

2.5

104

10

2.2

103

1.0

2.4

104

< MDL

1.0

2.5

102

171

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The Accurate Measurement of Selenium in Reference
Materials using Online Isotope Dilution
AuthorIntroduction

Naoki Sugiyama
Agilent Technologies, Japan

Selenium (Se) is an important element in environmental and agricultural
studies. It is an essential trace nutrient but is toxic in excess. ICP-MS is theanalytical method of choice for both total and speciated Se measurements,
but Se is a difficult element to quantify accurately at trace levels by ICP-MS
for several reasons:

Keywords
selenium, environmental, agricultural,
online isotope dilution analysis, OIDA,
oxygen mass-shift– The signal for Se is low, since it is poorly ionized in
the plasma due to its high Ionization Potential (IP) of 9.75 eV.
– Because Se is poorly ionized, it suffers signal suppression in high matrix
samples — an issue that is further compounded by the lack of a suitableinternal standard element with a similar mass and IP.
– All the analytically useful Se isotopes suffer from multiple spectralinterferences, as summarized in Table 1.
– The resolution required to separate all of the spectral interferences is beyond
the capabilities of sector-type high resolution (HR-)ICP-MS.
The Agilent 8800 ICP-QQQ in MS/MS mode is able to remove the complex
spectral interferences from all the Se isotopes shown in Table 1, allowing the useof Isotope Dilution (ID) analysis, which requires at least two interference-freeisotopes. ID is the most accurate quantification technique as it is based on direct
measurement of isotopic abundances in each sample, rather than a relative
measurement of analyte response compared to a standard. As a result, it offers
better traceability and improved correction of non-spectroscopic interferences
encountered in high matrix sample analysis. This note describes the applicationof the Agilent 8800 ICP-QQQ using ID for the accurate quantification of Se in arange of certified reference materials (CRMs).
Table 1. Spectral interferences on Se isotopes.
Se isotope
Mass

Abundance %

77

7.63

Interference
Isobaric

Argide39

Oxides

K38Ar+

61
59

78

23.77

78

Kr+

40

Ca38Ar+62

Ni16O+,
Co18O+
Ni16O+

Hydride
76
76
77

GeH+,
SeH+
SeH+

Chloride
40
40
41

Ar37Cl+,
Ca37Cl+K37Cl+

Doublycharged
154
154
156
156

80

82

49.61

8.73

80

82

Kr+

Kr

+

40

42

Ca40Ar+

Ca Ar
40

+

64

Ni16O+,

64

Zn16O+,

32

S216O+,

32

S16O3+

66

Zn16O+

79

BrH+

45

Sc35Cl+

160
160

81

BrH+

45

Sc37Cl+

164
164

172

Dimer

Sm++,
Gd++
Gd++,
Dy++
Gd++,
Dy++,

Dy++,
Er++

38
39
40
40

Ar40Ar+,
K39K+
Ar40Ar+,
Ca40Ca+Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/General purpose.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V,
Extract 2 = -180 V.
CRC conditions: O2 gas at 0.4 mL/min plus H2 gas at
2.0 mL/min, Octopole bias = -18 V and KED = -6 V.
Acquisition parameters: MS/MS O2 mass-shift method. The reaction of Se+ with
O2 to form SeO+ is endothermic (ΔHr = 0.71 eV) , but the reaction is efficiently
promoted using high collision energy using a low octopole bias voltage setting [1].
Preliminary studies have shown that low BEC for Se isotopes can be achieved via
the addition of a small amount of H2 in MS/MS O2 mass-shift method.
Method: Online isotope dilution analysis (OIDA) [2] was used. OIDA is a usefuldevelopment of traditional isotope dilution, as it removes the time consuming
step of spiking enriched-isotope standards into each individual sample. A 82Se
enriched standard purchased from Oak Ridge National Laboratory (USA) was
prepared at the appropriate concentration and added via the standard online ISTD
mixing kit to the samples. Product ions derived from the 16O-atom additiontransition were measured for the three most analytically useful isotopes of Se.
On the 8800 ICP-QQQ, this is simply achieved by defining the acquisition methodwith Q1/Q2 settings: Q1=78/Q2=94, Q1=80/Q2=96 and Q1=82/Q2=98 for the Se
isotopes at m/z 78, 80 and 82 respectively.
It should be noted that the use of MS/MS (where Q1 acts as a 1 u mass filter) is
essential for this measurement, as it ensures that only one Se isotope enters thecell for any given mass pair measurement, and only the 16O atom addition ismeasured because the mass difference between Q1 and Q2 is 16 u. This ensuresthat there is no overlap due to the precursor ions from different Se+ isotopes
giving SeO+ product ions at the same mass, such as the 80Se18O+ product ion
overlap on 82Se16O+, both of which appear at m/z 98. ICP-QQQ in MS/MS mode
thereby removes one of the critical limitations of reaction chemistry with
ICP-QMS, where all the sample ions enter the cell together so no specific reaction
transition can be defined. Each Se isotope mass pair was measured with an
integration time of 1 s and three replicates.
Sample preparation: The CRMs were microwave digested using a MilestoneETHOS closed vessel microwave digestion system (Milestone, Sorisole, Italy) andfollowing the manufacturer’s recommended procedures. The final dilution factorof the samples varied from 250 to 500x.

173

Results and discussion
Study of cell gases for spectroscopic interference removal
Figure 1 shows the result of a preliminary study of the effects of the choice ofcell gas on interference removal. The findings of the study showed that O2/H2
mass-shift (Figure 1) enables the measurement of 78Se, 80Se and 82Se relatively
free from interferences in the range of synthetic matrices tested.
5000
4500
4000

BEC ppt

3500
3000
2500
2000
1500
1000

Se

77

Se

78

O 2+H 2

Ca200ppm
0.5%HCI

1ppmREE

Br500ppb

1% HNO 3

1ppmREE

1% HNO 3

Br500ppb

NH 3+H 2

Ca200ppm
0.5%HCIH 2 MS/MS

Ca200ppm
0.5%HCI82

1ppmREE

Se80

Br500ppb

1% HNO 3

He MS/MS

Ca200ppm
0.5%HCI

1ppmREE

Br500ppb

0

1% HNO 3

500

Se

Figure 1. Preliminary study of the effectiveness of different cell gases for interference removal.
Four synthetic matrices likely to give rise to interferences on the Se isotopes were measured using
each of the 4 different cell gas modes.

Measurement of Se in CRMs
The concentration of Se was determined in 12 different CRMs using the OIDA
method. The CRMs were obtained from NIST (Gaithersburg MD, USA), GSJ
Geochemical Reference Samples (Tokyo, Japan), Japan Society for Analytical
Chemistry (Tokyo, Japan), and National Institute of Metrology (Beijing, China).
The matrices included environmental waters (NIST 1643e and JASC 0302-3 River
Water), rock (JB-3 basalt), sedimentary rock (JSI-1 and NIST 1646a Estuarine
Sediment), soil (JSAC0411 Volcanic Ash Soil), biological samples (NIST 1566a
Oyster Tissue, NIST 2976 Mussel Tissue), and plant materials (NIST 1575a Pine
Needles, NIST 1515 Apple Leaves, NIST1573a Tomato Leaves).
Figure 2 shows the Se results for each CRM expressed as % recovery relative
to the certified value. The measured results for Se were in good agreement with
the CRM values (90%-112%), using two Se isotope pairs: 78/82 and 80/82.
This demonstrates the effectiveness of the Agilent 8800 ICP-QQQ in MS/MS
mode for the removal of multiple interferences on 78Se, 80Se and 82Se.

174

140%
120%

Recovery %

100%
80%
60%
40%
20%
0

Se
&
Se

Se 78Se&&
Se 82Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se 80Se&&
Se 82Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

Se
&
Se

78

80

80

78

80

78

80

78

78

80

78

80

78

80

78

80

78

80

78

80

82

82

82

82

82

82

82

82

82

82

82

82

82

82

82

82

82

82

82

82

NIST
1643e

JSAC
0302-3
river
water

JB-3
BasaltJSI-1
sedimentary rock

NIST
1566a
oysterNIST
2976
musselJSAC
0411
volcanic
ashes

NIST
1646a
estuarine
sediment

NIST
1575a
pine
needles

NIST
1515
apple
leavesNIST
1573a
tomatoleavesFigure 2. Result of Se quantification using OIDA in various CRMs.

References
Agilent 8800 Triple Quadrupole ICP-MS: Understanding oxygen reaction mode in
ICP‑MS/MS, 2012, Agilent technical overview, 5991‑1708EN
On-line isotope dilution analysis with the 7700 Series ICP-MS: Analysis of traceelements in high matrix samples, Giuseppe Centineo, Jose Angel Rodriguez
Castrillon and Esther Munoz Agudo, 2011, Agilent application note, 5990-9171EN

More information
The accurate measurement of selenium in twelve diverse reference materials
using on-line isotope dilution with the 8800 Triple Quadrupole ICP-MS in MS/MS
mode, Agilent publication 5991-0259EN

175

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ICP-QQQ with Oxygen Reaction Mode for Accurate
Trace-Level Arsenic Analysis in Complex Samples
Authors

Introduction

Ed McCurdy and Glenn Woods
Agilent Technologies (UK) Ltd.

Arsenic (As), with its high first ionization potential and single isotope at mass 75,
is one of the most difficult elements to measure accurately by ICP-MS,
particularly in complex matrices. The polyatomic interferences from ArCl+ and
CaCl+ that overlap As+ at mass 75 can be removed effectively using quadrupole
ICP-MS (ICP‑QMS) in helium collision mode, but collision mode cannot resolve
the doubly-charged ion interferences from 150Nd++ and 150Sm++. A quadrupole
mass spectrometer separates ions based on their mass to charge ratio (m/z),
so doubly-charged ions appear at half their true mass; 150Nd++ and 150Sm++
therefore give an apparent overlap on As at mass 75.

Keywords
arsenic, zirconium, doubly-charged ion
interferences, oxygen mass-shift

Oxygen reaction mode (O2 mode) offers a solution to these doubly-charged ion
overlaps, since As can be converted to a reaction product ion 75As16O+, measured
at m/z 91, where it is separated from the doubly charged Nd and Sm, which do
not form such product ions. However, the new mass of the AsO+ product ion is
also overlapped by an isotope of zirconium (91Zr+). The presence of Zr in a sample
may therefore cause an error in the results for As measured as AsO+ using O2
reaction mode on ICP-QMS.
ICP-QQQ solves this problem, as MS/MS mode allows all masses apart fromm/z 75 (including the 91Zr+ ions) to be rejected by the first quadrupole (Q1),
ensuring that the AsO+ product ions can be measured free from overlap.
ICP-QQQ with MS/MS therefore allows the accurate determination of As incomplex samples that contain any combination of Cl, Ca, Nd, Sm and Zr.

176

Experimental
Reagents and sample preparation: All of the sample matrices used for thiswork were prepared using single-element stock solutions (Spex CertiPrep,
Claritas grade). The acid matrix and elemental standard concentrations areshown in the caption for each spectrum and are representative of the acid matrix(dilute HNO3/HCl) and matrix levels commonly found in ICP-MS samples.
The sample matrices investigated were:– Dilute nitric acid (1% HNO3)– Dilute hydrochloric acid (5% HCl)
– Calcium (100 ppm)
– Neodymium and samarium (1 ppm each element)– Zirconium (0.5 ppm)
Instrumentation: Agilent 8800 #100.
Plasma conditions and ion lens tune: Preset plasma/General purpose, Softextraction tune: Extract 1 = 0 V, Extract 2 = -170 V.
Acquisition conditions: Four operational modes were used, to investigate thedifferent interference removal performance provided by the different cell modes:– Single Quad (SQ); no gas– Single Quad (SQ); collision mode (using helium (He) cell gas at a flow rate of
4 mL/min)– Single Quad (SQ); reaction mode (using oxygen (O2) cell gas at a flow rate of
0.2 mL/min).
– MS/MS; reaction mode (using O2 cell gas at a flow rate of 0.2 mL/min)
KED bias voltage was +5 V in no gas and He mode, and -8 V in O2 mode.
The three “Single Quad” modes represent the performance available onconventional ICP-QMS operating in collision or reaction mode. MS/MS mode isunique to the tandem mass spectrometer configuration of the 8800 ICP-QQQ.

177

Results and discussion
Figures 1a, 1b and 1c illustrate how Single Quad mode with He cell gas is
effective at removing the common ArCl+ and CaCl+ polyatomic interferences on
As+ at m/z 75, but is ineffective against the Nd++/Sm++ interferences.
x105

A

001SMPL.d003SMPL.d004SMPL.d

CaCI

CPS

As (1 ppb) in:
5% HCI
5% HCI + 100 ppm Ca
5As(1 ppb)

ArCI

CI2

0
70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

Q2
x104

B

001SMPL.d003SMPL.d004SMPL.d

1.5

CPS

As (1 ppb) in:
5% HCI
5% HCI + 100 ppm Ca
1As(1 ppb)

0.5

0
70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

Q2
x104

C

001SMPL.d003SMPL.d004SMPL.d

1.5011SMPL.d

CPS

Nd++ andSm++1

As (1 ppb) in:
5% HCI
5% HCI + 100 ppm Ca
1 ppm Nd/Sm

As(1 ppb)

0.5

0
70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

Q2

Figure 1. a) As+ (m/z 75) in no gas mode, showing polyatomic interferences from ArCl+ and CaCl+;b) ArCl+ and CaCl+ polyatomics are removed in He collision mode; c) He collision mode fails to
remove Nd++ and Sm++ interferences at m/z 75.

178

Figures 2a and 2b show how Single Quad mode with O2 reaction gas successfully
avoids the doubly-charged Nd and Sm interferences by mass-shifting the As to
the new AsO+ product ion mass at m/z 91; but O2 reaction mode on ICP-QMS
cannot remove the 91Zr+ overlap on the AsO+ product ion.
x104

A001SMPL.d003SMPL.d

4004SMPL.d
011SMPL.d

As (as AsO+)(1 ppb)Trace Sr contaminationfrom 100 ppm Ca

CPS

As (1 ppb) in:
5% HCI
5% HCI + 100 ppm Ca
1 ppm Nd/Sm

2

0
84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

Q2
x104

B

001SMPL.d003SMPL.d004SMPL.d4

0.5 ppm Zr

011SMPL.d008SMPL.d

As (as AsO+)(1 ppb)Sr contaminationfrom 100 ppm Ca

CPS

As (1 ppb) in:
5% HCI
5% HCI + 100 ppm Ca
1 ppm Nd/Sm
0.5 ppm Zr

2

0
84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

Q2

Figure 2. a) Nd++ and Sm++ interferences at m/z 75 are avoided in SQ O2 reaction mode,by measuring As as the AsO + product ion at m/z 91; b) SQ O2 reaction mode fails to remove91
Zr+ overlap on the AsO + product ion.

179

Figure 3 shows that the 8800 ICP-QQQ in MS/MS mode with O2 reaction gas
provides reliable and consistent measurement of As (as AsO+) in all matrices.
All the original polyatomic and doubly-charged interferences at m/z 75 areavoided by mass-shifting the As to m/z 91; and in MS/MS mode the 91Zr+ ion isremoved by Q1, so the potential overlap on the AsO+ product ion at m/z 91 isalso removed.
x104001SMPL.d003SMPL.d

4004SMPL.d
011SMPL.d008SMPL.d
As (1 ppb) in:
5% HCI
5% HCI + 100 ppm Ca
1 ppm Nd/Sm
0.5 ppm Zr

CPS

As (as AsO+)(1 ppb)
2

0
84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

Q2

Figure 3. MS/MS mass-shift with O2 reaction mode provides consistent, interference-freemeasurement of As as AsO in all the matrices.

Conclusion
With the combination of O2 reaction mode and MS/MS operation, the 8800
ICP-QQQ provides a reliable approach to the accurate measurement of As incomplex samples. All the polyatomic and doubly-charged interferences that
affect As measurement at its native mass (m/z 75) are avoided by using O2 mode
to mass-shift the As to its AsO+ product ion, measured at m/z 91. Furthermore,
MS/MS mode on the 8800 ICP-QQQ also eliminates potential native ion overlaps
at m/z 91, as they are rejected by Q1 that is set to m/z 75 when measuring As.

180

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Avoidance of Spectral Overlaps on Reaction Product
Ions with O2 Cell Gas: Comparison of Quadrupole ICP-MSand ICP-QQQ
AuthorIntroduction

Ed McCurdy
Agilent Technologies (UK) Ltd.

The 8800 ICP-QQQ opens up many new analytical possibilities and novel
methodologies for interference removal based on reaction chemistry. The major
benefit provided by the 8800 ICP-QQQ is its unique tandem mass spectrometer
configuration, which permits operation in MS/MS mode. In MS/MS, the first
quadrupole (Q1) operates as a 1 u mass filter, providing precise selection of theions that can enter the reaction cell, and therefore control of the reaction processes
that occur. This level of reaction process control is fundamentally different to theoperation of conventional quadrupole ICP-MS (ICP-QMS) when using these same
reaction chemistries, as ICP-QMS has no way to reject ions before they enter thecell, and so cannot select which ions are involved in the reactions.

Keywords
titanium, reaction chemistry, oxygenmass-shift

This difference is apparent in many reaction chemistries, including both on-massmeasurements (where the interfering ions are reactive and are moved away fromthe analyte ions, which are then measured at the natural mass), and mass-shiftmethods (where the analyte ions are reactive and are moved to a new product ion
mass that is free from the original overlap). Overlaps on analyte product ionscommonly occur in ICP-QMS and can give severe errors in results, especially incases where the sample matrix or co-existing analyte levels vary from sample
to sample.
In this note, we compare the performance of ICP-QMS (the 8800 ICP-QQQ
operated in Single Quad mode with Q1 as a bandpass filter) and ICP-QQQ (the8800 ICP-QQQ operated in MS/MS mode) for the measurement of titanium (Ti)
as TiO+ product ions, using oxygen reaction mode (O2 mode).
The native ion overlaps that could affect the measurement of TiO+ product ionswith oxygen reaction gas are shown in Table 1. It should be noted that thesenative ion overlaps cannot be rejected by the cell bandpass settings of aconventional quadrupole ICP-MS, because they occur at the same mass as theanalyte product ion being measured.
Table 1. Potential native ion overlaps on TiO + product ions in O2 reaction mode.
Precursor ion (Q1) Product ion (Q2)

Potential overlaps from other analytes

Ti

TiO

Ni

Cu

Zn

46

62

62

Ni

–

–

47

63

–

63

48

64

–

–

49

65

–

65

50

66

–

–

Cu

–
64

Cu

Zn

–
66

Zn

181

Experimental
For the spectral comparison, scan data were collected for the mass range fromm/z 60 to 69, covering the TiO+ product ions formed from Ti in O2 reaction mode.
Instrumentation: Agilent 8800 #100.
Plasma conditions and ion lens tune: Preset plasma/General purpose,
Soft extraction tune: Extract 1 = 0 V, Extract 2 = -180 V.
CRC conditions: Cell gas = O2 gas at 0.3 mL/min, Octopole bias = -5 V, KED = -7 V.
Acquisition parameters: Scan range = m/z 60 to 69; points per peak = 20;
integration time per mass = 1 sec.

Results and discussion
The comparative results for TiO+ measured in Single Quad (SQ) mode andMS/MS mode are shown in the overlaid spectra in Figures 1 and 2. In both cases,
the TiO+ ions at mass 62, 63, 64, 65 and 66 (from the 5 isotopes of Ti at 46, 47,
48, 49 and 50, respectively) are shown, measured using the same O2 reaction
mode conditions for both modes. The four solutions measured for the overlaid
spectra are:
– 1 ppb Ti in 1% HNO3
– 1 ppb Ti + 10 ppb Ni in 1% HNO3
– 1 ppb Ti + 10 ppb Cu in 1% HNO3
– 1 ppb Ti + 10 ppb Zn in 1% HNO3
The overlaid spectra in Single Quad mode, shown in Figure 1, show that the peaks
for the five TiO+ isotopes match the theoretical isotopic template in the 1 ppb Ti
sample. However, in the other samples containing the elements Ni, Cu and Zn,
all of the TiO+ product ions suffer significant overlap from the native Ni (m/z 62),Cu (m/z 63 and 65) and Zn (m/z 64 and 66) ions. Unexpected or variable levels ofthese common elements would lead to an error in the reported results for Ti
measured as TiO+ using quadrupole ICP-MS in O2 reaction mode.
x105

Ti isotopic pattern
1 ppb Ti

Single quad mode

1 ppb Ti + 10 ppb Ni
1 ppb Ti + 10 ppb Cu

CPS

1 ppb Ti + 10 ppb Zn

0.5

TiO

0
60

61

62

63

64

65

66

67

68

Mass

Figure 1. Overlaid spectra for TiO + product ions in variable samples measured using SQ mode(see text for sample composition).

182

69

In contrast, the overlaid spectra for MS/MS mode, shown in Figure 2,
demonstrate consistent measurement of all five TiO+ product ions in all four
solutions. The presence of the other elements Ni, Cu and Zn has no impact on the
TiO+ peaks and all five TiO+ product ion isotopes could be used to give reliable
results for Ti in these variable samples. This illustrates how MS/MS mode on the8800 ICP-QQQ can simplify method development, because consistent cellconditions, acquisition parameters and isotope selection can be used for a rangeof variable sample types. A further benefit is that interferences are removed fromall isotopes under the same cell conditions, so secondary (or qualifier) isotopes
become available for data confirmation or isotope analysis.
x105

Ti isotopic pattern
1 ppb Ti

MS/MS mode

1 ppb Ti + 10 ppb Ni
1 ppb Ti + 10 ppb Cu

CPS

1 ppb Ti + 10 ppb Zn

0.5

TiO

0
60

61

62

63

64

65

66

67

68

69

Mass

Figure 2. Overlaid spectra for TiO + product ions in variable samples measured using MS/MS mode(see text for sample composition).

Conclusion
The comparative spectra presented in this note illustrate the improved accuracy
and consistency delivered by ICP-QQQ operating in MS/MS mode, compared toa conventional quadrupole ICP-MS using a reaction cell with bandpass filter.
By rejecting non-target native ions that would occur at the same mass as analyte
product ions, potential interferences can be eliminated by MS/MS. This allows
simpler, more consistent method development, as well as improving accuracy
for interfered elements in complex and variable samples.

183

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Removal of Complex Spectral Interferences on
Noble Metal Isotopes
AuthorIntroduction

Naoki Sugiyama
Agilent Technologies, Japan

The precise determination of the noble metals, comprising the Platinum Group
Elements (PGEs: Ru, Rh, Pd, Os, Ir and Pt), Au and Ag, is of great interest in areas
such as ore exploration and geochemical studies, and these metals are
increasingly used for industrial applications including advanced materials andalloys, medical devices, and catalysts for pharmaceutical manufacturing.
Environmental monitoring is also required as some of these elements are used in
automobile catalytic converters. ICP-MS is widely used for these applications due
to its high sensitivity and multi-element capability. However, the analysis ischallenging because the metal concentrations are often low and they are subject
to severe spectral overlaps.

Keywords
Platinum Group Elements, gold, silver,ore exploration, geochemical,
environmental, catalytic converter,
ammonia

Table 1 summarizes the interferences and abundance (%) of each isotope of theelements (the isotopes highlighted in yellow represent the recommended isotope
for determination by ICP-MS). Several methods have been developed to resolve
the interferences, such as mathematical correction, matrix removal and highresolution magnetic sector (HR-)ICP-MS. However, the mass resolution required
to separate some of the interferences is beyond the capability of current
commercial HR‑ICP‑MS. For example, separation of 103Rh+ from 87Sr16O+, 105Pd+
from 89Y16O+, and 109Ag+ from 93Nb16O+ requires mass resolution (M/ΔM) of
102900, 27600 and 31500, respectively; commercial HR-ICP-MS instruments arelimited to a maximum resolution of 10,000. To remove the multiple, complex
interferences on noble elements, the Agilent 8800 ICP-QQQ was used in MS/MS
mode, using ammonia as the reaction gas.

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/Low matrix.
Ion lens tune: Soft extraction tune: Extract 1 = -3 V, Extract 2 = -200 V.
CRC conditions: NH3 (10% NH3 in He) was used as CRC gas in MS/MS mode.
Following a preliminary optimization study, three different NH3 gas flow rates(low (L), medium (M) and high (H)) were used. Cell conditions are given in Table 2.
No gas mode was also applied for comparison purposes.

184

Table 1. Abundance (%) of each isotope of noble metals and the interference on each isotope.
mElement

96
Ru

97

5.54

98

99

100

101

102

1.87

12.76

12.6

17.06

31.55

Rh

103

104

105

106

22.33

27.33

1.02

11.14

Zr, Nb,
Mo

Mo
MoH

SeO,
BrOH

Mo
MoH

Cd

SrO

SrO,
RbO

SrO

YO,
SrOH

YOH,
ZrO

ZrO

ZrO,
MoO

Argide

NiAr

NiAr

NiAr

NiAr

CuAr

ZnAr

CuAr

ZnAr

ZnAr

ZnAr

Others

CuCl

ZnCl

CuCl

ZnCl

CuCl,
ZnCl

ZnCl,
Pb++

ZnCl

ZnCl

186

187

188

189

190

191

192

193

194

195

196

1.59

1.96

13.24

16.15

26.26

32.97

33.83

25.24

185

0.02

Ir
0.014

197

198

0.782

7.163
100

W

W

MH

Re

Hg

Hg

WH

MO, MOH

Argide

ZrO,
MoO

62.7

Au
Atomic

NbO

40.78
37.3

Pt

Interference

Cd

MoH
RbO

184

11.72

Cd

SrO

Os

110

48.16

SeO

m
Element

26.46
51.84

MH
MO, MOH

109

8.62

Ag
Atomic

108

100

Pd

Interference

107

NdAr

NdAr

YbO

YbO

YbO

YbO

YbO

LuO

YbO,
LuD,
HfO

HfO

HfO

HfO

HfO

TaO,
HfOH

Wo,
TaOH

NdAr

SmAr

SmAr,
NdAr

SmAr

SmAr,
NdAr

EuAr

SmAr

EuAr

SmAr,
GdAr

GdAr

GdAr

GdAr

GdAr

Others185

Table 2. CRC conditions.
No gas

NH3-L

NH3-M

NH3-H

Cell gas

na

NH3

NH3

NH3

Gas flow rate (mL/min)

na

2.0

3.0

5.0

Octopole bias (V)

-8

-5

-10

-12

KED (V)+5-8

Cell exit (V)Deflect lens (V)-90
20

Plate lens (V)

10

6

2

-110

MethodThe BECs of the noble metals were determined in a series of synthetic-matrix
samples, using an external calibration method. Indium (In) internal standard(ISTD) was mixed online with the sample via the standard ISTD mixing
T-connector. An integration time of 1 s per isotope was used with 3 replicates(7 replicates for blank).
Samples and sample preparation
Standards and matrix samples were prepared from single element stock
solutions purchased from Kanto Chemical Co., Inc. (Saitama, Japan) and a REE
mixture standard, XSTC-1 purchased from Spex certiPrep. All solutions werediluted into a final acid mix of 1% HNO3 and 3% HCl.

Results and discussion
Matrix interference study
Tables 3 and 4 summarize the results of the spectral interference study obtainedby analyzing individual synthetic matrix blank solutions. Table 3 shows theobserved interferences, expressed as BEC (ppb), in each matrix blank measured
using no gas mode. As expected from Table 1, the synthetic matrices caused
significantly elevated BECs (>> 1 ppb) on all the primary and secondary isotopesof all the analytes except for Ru; Rh suffered a relatively minor increase in BEC of~0.5 ppb in the 10 ppm Pb/1 ppm Hg matrix.
Table 4 shows the results obtained using NH3 reaction mode. The optimum gas
flow rate for NH3 for each element was investigated and three gas flow rates(Low: 2.0, Medium: 3.0, and High: 5.0 mL/min) were used. The best isotope andmethod is highlighted in bold in the Table. It can clearly be seen that NH3 reaction
mode effectively removes the interferences on all the analytes, giving BECs of<< 0.1 ppb for the preferred isotope/cell mode in all the matrices. The mechanism
for the removal of each interference using the MS/MS capability of the 8800
ICP-QQQ is as follows:– Ru: slight interferences from Zn and Mo were resolved using on-mass methodwith NH3-M.
– Rh: Pb++ interference was resolved using on-mass method with NH3-M.
– Pd: significant interferences from SrOH+ and YO+ were seen on 105Pd, the onlyisotope free from atomic isobar. On-mass method with NH3-H removed theinterferences.
– Ag: significant ZrO+ interference on both 107Ag and 109Ag was resolved using
on-mass method with NH3-H.
186

– Os: YbO+ interference was observed on both 188Os+ and 189Os+. Since Os+sensitivity in NH3 mode is low, but Os+ forms a product ion of OsNH+, NH3-L
with mass-shift gave the best result.
– Ir: LuO+ and HfO+ interfere with 191Ir+ and 193Ir+ respectively. NH3-M with
mass-shift method worked for 191Ir+ as Ir+ forms a product ion of IrNH+.
– Pt: 195Pt+ suffers a significant interference from HfO+. While the overlap is lesssignificant on 198Pt+, 198Pt+ suffers an atomic isobar interference from 198Hg+.
However, Hg+ is effectively neutralized by NH3 so 198Pt+ can be measured freefrom interference.
– Au: significant interferences by TaO+ and HfOH+ are resolved by mass-shiftmethod with NH3-M. Au+ forms a product ion of Au(NH3)2+.
Table 3. Summary of spectral interferences in no gas mode, showing analyte BECs (ppb) in each matrix blank. Matrix overlaps that made a significant
contribution to the analyte BECs are indicated in red (BEC > 10 ppb) and orange (BEC > 1 ppb).
Ru

Rh

Pd

Ag

Os

101

103

105

107

109

188

189

Isotope99

NH3 flow rate mL/min

NA

Methodon-mass

on-mass

on-mass

on-mass

on-mass

on-mass

on-mass

on-mass

Mass pair

99-99

101-101103-103105-105

107-107

109-109

188-188

189-189

10 ppm Cu Zn

0.058

0.041

0.138

0.328

0.064

0.061

0.000

0.000

10 ppm Sr Rb

0.000

0.034

0.150

4.39

0.005

0.001

0.000

0.000

10 ppm Ni

0.007

0.019

0.000

0.022

0.012

0.016

0.000

0.000

10 ppm Mo

0.059

0.018

0.000

0.004

0.000

0.018

0.000

0.000

10 ppm Pb, 1 ppm Hg

0.000

0.000

0.472

0.002

0.033

0.034

0.000

0.000

10 ppm Zr Nb

0.000

0.000

0.000

0.022

21.9

1.59

0.000

0.000

10 ppm REE

0.004

0.000

0.009

165

0.147

0.005

2.78

2.99

10 ppm Ta

0.008

0.000

0.000

0.004

0.003

0.000

0.000

0.000

10 ppm Hf

0.000

0.000

0.000

0.004

0.312

0.026

0.000

0.000

10 ppm W

0.000

0.000

0.000

0.003

0.001

0.001

0.000

0.000

Ir
Isotope

191

NH3 flow rate mL/min

NA

Method

Pt

Au

193

195

198

197

on-mass

on-mass

on-mass

on-mass

on-mass

Mass pair

191-191

193-193

195-195

198-198

197-197

10 ppm Cu Zn

0.003

0.002

0.000

0.279

0.001

10 ppm Sr Rb

0.002

0.000

0.001

0.310

0.004

10 ppm Ni

0.009

0.004

0.002

0.444

0.011

10 ppm Mo

0.000

0.000

0.000

0.295

0.000

10 ppm Pb, 1 ppm Hg

0.002

0.002

0.000

1293

0.000

10 ppm Zr Nb

0.002

0.775

1.98

3.17

0.417

10 ppm REE

123

0.712

0.788

2.17

0.138

10 ppm Ta

0.000

0.000

0.244

114

284

10 ppm Hf

0.071

28.1

70.9

2.34

14.1

10 ppm W

0.001

0.000

0.000

19.6

0.002
187

Table 4. Summary of spectral interferences in MS/MS NH3 reaction cell mode, showing analyte BECs (ppb) in each matrix blank. Matrix overlaps thatmade a significant contribution to the analyte BECs are indicated in red (> 10 ppb) and orange (> 1 ppb).
t

Ru

Rh

Pd

Ag

Isotope

99

103

105

107

NH3 flow rate mL/min

3.0

3.0

5.0

5.0

Methodon-mass

on-mass

on-mass

on-mass

on-mass

on-mass

on-mass

mass-shift on-mass

mass-shift

Mass pair

99-99

101-101103-103105-105

107-107

109-109

188-188188-203

189-189

189-204

10 ppm Cu Zn

0.000

0.000

0.000

0.001

0.061

0.057

0.000

0.000

0.001

0.002

10 ppm Sr Rb

0.000

0.005

0.016

0.033

0.000

0.000

0.000

0.000

0.002

0.000

10 ppm Ni

0.000

0.000

0.000

0.000

0.010

0.009

0.000

0.000

0.000

0.000

10 ppm Mo

0.005

0.001

0.000

0.000

0.001

0.000

0.000

0.000

0.001

0.000

10 ppm Pb, 1 ppm Hg

0.000

0.000

0.000

0.001

0.033

0.035

0.000

0.000

0.001

0.000

10 ppm Zr Nb

0.000

0.000

0.000

0.000

0.003

0.000

0.000

0.000

0.002

0.001

10 ppm REE

0.000

0.000

0.000

0.014

0.004

0.004

2.79

0.003

5.85

0.010

101

Os
109

188

189

2.0

10 ppm Ta

0.000

0.000

0.000

0.000

0.000

0.000

0.000

0.001

0.003

0.000

10 ppm Hf

0.000

0.000

0.000

0.000

0.000

0.000

0.000

0.001

0.058

0.000

10 ppm W

0.000

0.000

0.000

0.001

0.001

0.001

0.000

0.000

0.000

0.000

Ir

Pt

Isotope

191

NH3 flow rate mL/min

3.0

Methodon-mass

mass-shift on-mass

mass-shift on-mass

mass-shift on-mass

mass-shift on-mass

mass-shift

Mass pair

191-191

191-206

193-193193-208

195-195

195-229

198-198

198-232

197-197

197-231

10 ppm Cu Zn

0.004

0.000

0.003

0.004

0.003

0.000

0.002

0.000

0.000

0.000

10 ppm Sr Rb

0.002

0.000

0.001

0.001

0.000

0.000

0.000

0.000

0.000

0.000

10 ppm Ni

0.004

0.000

0.001

0.004

0.000

0.000

0.000

0.002

0.000

0.000

10 ppm Mo

0.000

0.000

0.000

0.000

0.000

0.000

0.003

0.000

0.000

0.000

10 ppm Pb, 1 ppm Hg

0.002

0.001

0.000

0.000

0.000

0.000

0.005

0.001

0.000

0.000

10 ppm Zr Nb

0.017

0.000

0.679

0.066

0.031

0.009

0.003

0.001

0.000

0.000

10 ppm REE

44.3

0.019

1.56

0.019

0.031

0.002

0.000

0.000

0.044

0.003

10 ppm Ta

0.000

0.000

0.000

0.000

0.004

0.000

0.261

0.009

4.11

0.046

10 ppm Hf

0.690

0.095

21.4

2.40

0.904

0.115

0.141

0.070

0.070

0.003

10 ppm W

0.001

0.000

0.000

0.000

0.001

0.000

0.479

0.000

0.001

0.000

188

193

Au

195

198

197

5.0

3.0

3.0

Analysis of complex synthetic matrix sample using optimized NH3 reaction mode
A complex synthetic matrix sample containing 10 ppm each of Cu, Zn, Sr, Rb,
Ni, Mo, Pb, Zr, Nb, REEs, Ta, Hf, W and 1 ppm Hg was prepared, and this matrix
was spiked with 1 ppb each of Ru, Rh, Pd, Ag, Os, Ir, Pt and Au as analytes.
The concentration of the noble metals was determined in two modes: No gas
mode and NH3 reaction cell mode, and the spike recovery results are displayedin Figure 1 for each mode. The results demonstrate that MS/MS mode with NH3
reaction cell gas successfully removes multiple interferences on all the noble
metals, providing accurate results for these analytes even in a complex andchallenging matrix.

Determined conc. (ppb)

1.0E+02

1.0E+01

1.0E+00

1.0E-01
Ru

99

No gas mode

Ru

101

Rh

103

Pd

105

Ag

107

Ag

109

Os

188

Os

189

Ir

191

Pt

198

Au

197

NH3 reaction cell

Figure 1. Result of synthetic matrix sample test. 1 ppb noble metals were measured in a multi-matrix sample containing 10 ppm of each Cu, Zn, Sr, Rb,
Ni, Mo, Pb, Zr, Nb, REEs, Ta, Hf, W and 1 ppm Hg.

189

> Return to table of contents> Search entire document

Analysis of Platinum Group Elements (PGEs), Silver, andGold in Roadside Dust using Triple Quadrupole ICP-MS
Authors
Dominique Demare andLiliane Jean-Soro,
Université Gustave Eiffel (IFSTTAR),
Nantes, France
Alain Desprez,
Agilent Technologies Ltd, France
Glenn Woods and Ed McCurdy,
Agilent Technologies LDA (UK) Ltd

Accurate, interference-free measurement of sub-ppb levels of
the PGEs using the Agilent 8900 ICP-QQQ
Introduction
There is increasing interest in monitoring the noble metals­—that is the Platinum
Group Elements (PGEs), Ru, Rh, Pd, Os, Ir, and Pt, together with Ag and Au—
in the environment. The levels of these elements have increased due todeposition arising from automobile catalytic converters (1, 2). Precious
metals are also used in healthcare and pharmaceuticals and in advanced
technologies such as industrial catalysts, fuel cells, and electrodes, capacitors,
and magnetic storage for consumer electronics. Production, use, and disposalof these products leads to wider release of the PGEs into the environment,
which increases the need for routine monitoring of the metals in environmental
samples. ICP-MS is widely used for analysis of trace levels of metals andmetalloids, due to the technique’s high sensitivity and multi-element capability.
However, determination of the PGEs in samples such as soil and roadside dust
is challenging for conventional single quadrupole ICP-MS because of the low
concentration of the elements. Also, there is the potential for intense spectral
overlaps from several common matrix elements, as shown in Table 1.
Many different approaches have been employed in an attempt to avoid, correct,
or resolve matrix-based spectral overlaps in ICP-MS, including mathematicalcorrection, matrix removal, and magnetic sector High-Resolution (HR)-ICP-MS.
However, mathematical corrections are often unreliable, and matrix elimination istime-consuming, expensive, and prone to errors and contamination. HR-ICP-MS
seems an attractive option, as it should give certainty that the analyte has been
resolved from the overlapping ion on the mass scale. But many common spectralinterferences require mass resolution far beyond the capability of commercial
HR-ICP-MS instruments. For example, resolving 103Rh+ from 87Sr16O+ requires
mass resolution (M/ΔM) of 102,900; resolving 105Pd+ from 89Y16O+, requires
resolution of 27,600; and resolving 109Ag+ from 93Nb16O+ requires resolution of
31,500. Current HR-ICP-MS instruments have a maximum mass resolution of
10,000, so are unable to separate any of these spectral overlaps.
The most widely used approach to resolve the common polyatomic ion overlapsthat occur in quadrupole ICP-MS is to use a Collision/Reaction Cell (CRC)
pressurized with helium (He) cell gas. He mode enables selective attenuationof polyatomic ions using a process called kinetic energy discrimination (KED).
However, some of the matrix-based interferences on the trace PGEs are at
too high intensity to be completely removed using He KED mode. Also, someinterferences, such as 206Pb++ on Rh at mass 103, are caused by spectral overlapsthat are not polyatomic ions, so He mode cannot remove them effectively.

190

Table 1. Noble metal isotopic abundances (%) and potential spectral interferences on each isotope. Preferred isotopes for ICP-MS analysis arehighlighted in yellow, secondary isotopes may be useful for data confirmation.
Mass

Analyte Isotope Abundance (%)
Ru

96

Rh

Pd

Potential Spectral Interferences
Ag

Isobaric

5.54

Zr, Nb, Mo

98

1.87

Mo

99

12.76

100

12.6

101

17.06

102

31.55

HydrideOxide/
Hydroxide

Argide

Other

NiAr

CuCl

SeO, BrOH
MoH

SeO

MoH
Mo
MoH

SrO

NiAr

CuCl

RbO

NiAr

ZnCl

SrO

NiAr

CuCl, ZnCl

SrO, RbO

CuAr

ZnCl, Pb++

11.14

SrO

ZnAr

ZnCl, Pb++

105

22.33

YO, SrOH

CuAr

ZnCl

106

27.33

Cd

YOH, ZrO

ZnAr

ZrO

ZnAr

Cd

ZrO, MoO

ZnAr

Cd

ZrO, MoO

103
104

1.02

ZnCl

100
8.62

107

51.84

108

26.46

109

48.16

110

11.72
Os

Ir

Pt

NbO

Au

184

0.02

186

1.59

W

187

1.96

Re

188
189
190

26.26

193

NdAr

YbO

SmAr

13.24

YbO

SmAr, NdAr

16.15

YbO

SmAr

0.014

YbO

SmAr, NdAr

LuO

EuAr

0.782

YbO, LuO, HfO

SmAr

37.3
40.78
62.7

194

32.97

195

33.83

196

25.24

197
198

NdAr
YbO

191
192

W

Hg
100

7.163

Hg

WH

HfO

EuAr

HfO

SmAr, GdAr

HfO

GdAr

HfO

GdAr

TaO, HfOH

GdAr

WO, TaOH

GdAr

In this work, an alternative approach to He KED was investigated, using an
Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) to resolve the multiple,
matrix-based interferences that affect analysis of the PGEs (1). The 8900
ICP-QQQ is a tandem mass spectrometer with two high performance, hyperbolic,quadrupole mass filters, one before (Q1) and one after (Q2) the ORS 4 CRC.
The tandem (MS/MS) configuration gives the possibility to use the additional
quadrupole—Q1, before the CRC—to select the ions that can enter the cell.
This allows the ion/molecule reaction chemistry to be precisely controlled, evenwhen highly reactive cell gases such as ammonia (NH3) are used in the CRC.
Reaction chemistry processes happen much faster than He KED, so can provide
more effective separation of trace analytes that are overlapped by intense
spectral interferences.

191

The 8900 ICP-QQQ includes UHMI (Ultra High Matrix Introduction) aerosol
dilution technology, which increases plasma robustness and allows samples
with higher Total Dissolved Solids (TDS) to be analyzed routinely. The 8900 withUHMI improves trace level analysis, as samples can be analyzed with minimal
dilution, which reduces the risk of errors and contamination from the dilution
step. Use of a more robust (hotter) plasma also increases ionization, improving
sensitivity for poorly ionized noble metals such as Ir, Pt, and Au.
A series of synthetic matrix element mixes and a certified reference material(CRM) of road dust were used to evaluate the effectiveness and accuracy of the8900 ICP-MS/MS method.
This work was performed in collaboration with the Université Gustave Eiffel,
formerly IFSTTAR, Institut Français des Sciences et Technologies desTransports, de l’Aménagement et des Réseaux (the French Institute of Scienceand Technology for Transport, Development and Networks).

Experimental
Instrumentation
An Agilent 8800 ICP-QQQ was used for initial measurements, with later work
being performed using an Agilent 8900 ICP-QQQ model. Both instruments wereoperated in the standard configuration, which includes Ni interface cones andstandard “x” type ion lens. The standard sample introduction system was used,consisting of a MicroMist nebulizer, Peltier-cooled quartz double-pass Scott-type
spray chamber, and quartz torch with 2.5 mm injector. Preset plasma condition
UHMI-4 (aerosol dilution factor of approximately 4) was selected for the analysis.
The interference removal capability of NH3 reaction gas in MS/MS mode(both quadrupoles functioning as true mass filters) was assessed. Results
acquired with NH3 in MS/MS mode were compared to the data collected withno cell gas and in He KED mode, as typically used on single quadrupole ICP-MS.
Three different NH3 gas flow rates (Low (NH3-L), Medium (NH3-M), and High
(NH3-H)) were used. The NH3 cell modes used a cell gas of 10% NH3 in He buffergas, which controls the in-cell formation of unwanted reaction gas product ions.
Details of all the cell gas modes and other acquisition conditions are given in
Table 2.
Table 2. Agilent 8900 ICP-QQQ acquisition and CRC conditions.
No Gas

He

NH3-L

NH3-M

NH3-H

Acquisition Mode

SQ

SQ

MS/MS

MS/MS

MS/MS

Cell Gas

N/A

He

NH3

NH3

NH3

Gas Flow (mL/min)

N/A

5.0

2.0

3.0

5.0

Octopole Bias (V)

–8

–18

–5

–10

–12

KED (V)+5–8

Cell Exit (V)

192

–90

Deflect Lens (V)

20

0

10

6

2

Integration Time/Mass (s)

0.2

0.3

1

1

1

Method
The Background Equivalent Concentrations (BECs) of the PGEs were quantified
in a series of synthetic interference solutions containing several potentiallyinterfering matrix elements, either individually or in various combinations.
The BECs for the PGEs were calibrated against simple, synthetic, non-matrixmatched calibration standards.
Spike recoveries were measured for a spike containing 1 μg/L (ppb) of each of
the PGEs, Ag, and Au in the highest, most complex synthetic matrix (all individual
matrix components in one solution). To check the accuracy of the method for real
sample analysis, the PGEs were also quantified in a digested CRM (BCR 723 Road
Dust, IRMM, Geel, Belgium). The CRM has certified values for Rh, Pd, and Pt.
Data was acquired for all three cell gas modes during one visit to the sample
vial, and three replicate measurements were acquired for each sample. The nogas and He mode conditions used Single Quad (SQ) mode (Q1 not operating as
a mass filter) to replicate the interference removal performance achievable withsingle quadrupole ICP-MS. The NH3 cell gas conditions used MS/MS mode witheither on-mass measurement of the analyte ion, or mass-shift measurement
where an analyte reaction product ion is measured. The indium (In) internal
standard (ISTD) was added to the sample solutions online via the standard ISTD
mixing T-connector.

Standards and sample preparation
Standards and interference matrices—most elements at 10 mg/L (ppm)—were
prepared from single element 1000 or 10,000 mg/L stock solutions. The single
and multiple matrix element mixes analyzed are shown in Table 3. All synthetic
solutions were acidified to 4% HNO3 and 12% HCl. This matrix is typical of the
final acid concentration resulting from digestion of soil, dust, and mineral ore
samples using aqua regia (a 1:3 mix of concentrated HNO3/HCl).
The acid concentration in the synthetic samples matched the acid mix in thedigested CRM. The CRM was prepared by mineralization of 0.5084 g of BCR 723
in 2 mL of concentrated HNO3 and 6 mL of concentrated HCl. The volume wasthen brought up to 50 mL by addition of ultrapure water, giving a final matrix
containing approximately 1% TDS in 16% aqua regia.

Results and discussion
Interference removal in complex synthetic matrices
The BEC results obtained in the study of matrix-based spectral interferencesin the synthetic matrix solutions are shown in Table 3. The BECs for the PGEs
in each of the matrix solutions are compared for no gas, He, and the optimum
NH3 mode (low, medium, or high NH3 flow). The colored cells in Table 3 indicate
the level of contribution that the matrix interferences made to the PGE BEC.
For example, a matrix interference contribution causing a BEC of between 0.1
ppb and 1 ppb is indicated by the yellow shading. As can be seen from Table 3,
Ru did not suffer significant interference in any of the synthetic matrices, evenwhen measured in no gas mode. However, the other PGEs all suffered moderateor severe interference (up to 996 ppb BEC) in no gas mode. Interference
contributions were higher than 10 ppb for Pd, Ag, Ir, Pt, and Au. The BECs for Rh
and Os were lower, but still in the 100s of ng/L (ppt) or low ppb range.
193

The He mode data in Table 3 was evaluated to assess the relative performanceof the standard single quadrupole ICP-MS approach to controlling polyatomic
ions. Compared to no gas mode, He KED mode gave lower BECs for many of
the PGEs, some improved by several orders of magnitude. But He mode was notable to completely resolve all the overlaps to a low enough level for trace analysisof all the PGEs. In He mode, the contribution of the spectral interferences fromsome of the matrix combinations was still in the ppb range for Pd, Ag, and Os
and above 10 ppb for Ir, Pt, and Au.
By contrast, the optimum NH3 mode significantly reduced the interference
contributions on the PGEs in all the matrix solutions, including the most complex
interference mix. BECs were lower than single or low 10s ppt for all the PGEs
except Ir and Pt-195. The BECs for Ir and Pt in NH3 mode remained a little higher
at 0.1 to 0.2 ppb. But these BECs are still around 100x lower than was achieved in
He mode and up to 1000x lower than in no gas mode. The improved interference
removal capability provided by NH3 in MS/MS mode allows the reliable
quantitation of PGEs at ultra-trace levels in a complex environmental matrix
such as roadside dust.

Spike recoveries, detection limits (DLs) and BECs in a complex matrix mix
To evaluate more specifically the accuracy of the ICP-MS/MS method, a 1 μg/L(ppb) PGE spike was measured in the highest and most complex synthetic
interference solution. The mix contained 10 ppm of all interfering elements(listed in Table 3) except for Hg, which was present at 1 ppm. The PGE spike
concentrations were quantified in no gas, He, and the optimum NH3 cell gas
mode. As shown in Figure 1, the PGE spike concentrations measured in nogas mode were strongly affected by spectral overlaps formed from the matrix
elements. The matrix interferences in He mode were lower, but several of themeasured results were still far above the true spike concentrations. The NH3mode results are all free from significant overlap, with measured PGE spike
concentrations close to the true value of 1 ppb.

Figure 1. Reported concentrations of the PGEs spiked at 1 ppb in the most complex mixed matrix,
measured in three different gas modes.

Table 4 shows the DL and BEC for each PGE in the optimum NH3 cell gas mode.
The DLs were calculated from three times the standard deviation of a low standard(10 ppt) divided by the slope of the calibration. The BECs were calculated from theblank intensity divided by the sensitivity. The DLs and BECs for the PGEs measured
in NH3 mode were all in the low or sub-ppt range despite the reduction in sensitivity
that occurs due to the use of aerosol dilution with UHMI. The low DLs and BECs
indicate that the 8900 ICP-QQQ can achieve excellent detection capability, evenwhen combined with the very robust plasma conditions needed for routine analysis
of high matrix sample digests.
194

Table 3. PGE Background Equivalent Concentrations (BECs) in μg/L (ppb) due to matrix-based spectral overlaps measured in no gas, He, and NH3 cellgas modes. Significant matrix interferences are indicated by colored cells: Yellow (BEC >0.1 ppb), orange (BEC >1 ppb), and red (BEC >10 ppb). MS/MS
mode with NH3 cell gas resolves interferences on all analytes. Note, some PGEs have two usable isotopes.
No cell gas, SQ mode BEC results (μg/L)
Element

Rhodium

Palladium

Isotope99

Ruthenium
101

103

105

107

Silver109

188

Osmium189

Iridium
191

195

Platinum
198

Gold
197

10 ppm Cu Zn

0.035

0.028

0.036

0.069

0.014

0.004

0.001

0.002

0.005

0.000

0.000

0.002

10 ppm Sr Rb

0.001

0.021

0.096

2.957

0.004

0.001

0.001

0.001

0.002

0.000

0.000

0.002

10 ppm Ni

0.001

0.004

0.002

0.020

0.007

0.008

0.001

0.003

0.005

0.000

0.000

0.001

10 ppm Mo

0.016

0.005

0.001

0.006

0.001

0.006

0.004

0.005

0.001

0.000

0.000

0.001

10 ppm Pb, 1 ppm Hg

0.000

0.000

0.254

0.004

0.002

0.004

0.011

0.012

0.006

0.000

666.9240.001

10 ppm Zr Nb

0.000

0.000

0.001

0.829

10.43634.858

0.018

0.018

0.004

0.005

5.270

0.127

10 ppm REE, Sc, Y

0.012

0.030

0.014

78.040

0.098

0.008

3.793

2.229

45.307

1.004

4.540

0.390

10 ppm Ta

0.000

0.001

0.000

0.004

0.001

0.001

0.001

0.001

0.001

0.090

45.38662.76010 ppm Hf

0.000

0.000

0.000

0.001

0.001

0.002

0.001

0.016

0.325

29.337

1.062

5.095

10 ppm W

0.001

0.000

0.000

0.001

0.000

0.002

0.004

0.001

0.001

0.005

104.2370.614

10 ppm all, 1 ppm Hg

0.081

0.078

0.347

75.3429.210

30.395

3.314

1.936

43.25631.971996.057

81.912

He cell gas, SQ mode BEC results (μg/L)
Element

Rhodium

Palladium

Isotope99

Ruthenium
101

103

105

107

Silver109

188

Osmium189

Iridium
191

195

Platinum
198

Gold
197

10 ppm Cu Zn

0.001

0.001

0.001

0.001

0.005

0.004

0.004

0.002

0.005

0.001

0.000

0.002

10 ppm Sr Rb

0.000

0.001

0.002

0.058

0.001

0.001

0.003

0.002

0.001

0.001

0.000

0.001

10 ppm Ni

0.001

0.000

0.000

0.004

0.005

0.007

0.004

0.003

0.004

0.000

0.000

0.000

10 ppm Mo

0.005

0.001

0.000

0.001

0.000

0.001

0.008

0.005

0.001

0.000

0.000

0.001

10 ppm Pb, 1 ppm Hg

0.000

0.000

0.468

0.001

0.004

0.003

0.016

0.013

0.007

0.000

602.0630.000

10 ppm Zr Nb

0.000

0.000

0.000

0.038

0.479

0.155

0.023

0.019

0.002

0.004

3.969

0.041

10 ppm REE, Sc, Y

0.000

0.001

0.010

2.692

0.010

0.005

0.543

0.366

11.157

0.064

1.578

0.020

10 ppm Ta

0.002

0.000

0.000

0.002

0.001

0.000

0.002

0.002

0.001

0.055

16.10225.002

10 ppm Hf

0.000

0.000

0.000

0.001

0.001

0.000

0.004

0.006

0.082

8.937

0.627

1.122

10 ppm W

0.001

0.000

0.000

0.000

0.001

0.001

0.007

0.003

0.001

0.002

36.586

0.199

10 ppm all, 1 ppm Hg

0.016

0.003

0.399

2.748

0.510

0.169

0.489

0.320

11.1589.264

669.89427.554NH3 cell gas, MS/MS mode BEC results (μg/L)
Element

Rhodium

Palladium

Isotope99

Ruthenium
101

103

105

107

Silver109

188

Osmium189

Iridium
191

195

Platinum
198

Gold
197

NH3 flow rate (mL/min)

3.0

3.0

3.0

5.0

5.0

5.0

2.0

2.0

3.0

5.0

5.0

5.0

MS/MS mode

On-mass

On-mass

On-mass

On-mass

On-mass

On-mass Mass-shift Mass-shift Mass-shift Mass-shift Mass-shift Mass-shift

Mass Pair (Q1 - Q2)

99 - 99

101 - 101

103 - 103

105 - 105107 - 107109 - 109

188 - 203

189 - 204

191 - 206

195 - 229

198 - 232

197 - 231

10 ppm Cu Zn

0.002

0.001

0.000

0.000

0.004

0.004

0.002

0.004

0.003

0.000

0.000

0.001

10 ppm Sr Rb

0.000

0.003

0.009

0.012

0.000

0.001

0.002

0.003

0.003

0.000

0.000

0.000

10 ppm Ni

0.001

0.001

0.000

0.003

0.005

0.008

0.004

0.003

0.005

0.000

0.000

0.000

10 ppm Mo

0.001

0.001

0.000

0.001

0.000

0.001

0.004

0.008

0.003

0.001

0.003

0.000

10 ppm Pb, 1 ppm Hg

0.000

0.000

0.000

0.001

0.002

0.003

0.010

0.011

0.010

0.000

0.004

0.001

10 ppm Zr Nb

0.000

0.000

0.000

0.002

0.004

0.006

0.020

0.018

0.005

0.001

0.002

0.000

10 ppm REE, Sc, Y

0.000

0.001

0.009

0.017

0.002

0.006

0.050

0.046

0.105

0.008

0.031

0.001

10 ppm Ta

0.000

0.000

0.000

0.000

0.000

0.002

0.004

0.007

0.003

0.001

0.000

0.000

10 ppm Hf

0.001

0.000

0.000

0.000

0.000

0.001

0.007

0.009

0.036

0.113

0.003

0.000

10 ppm W

0.000

0.000

0.000

0.000

0.000

0.002

0.009

0.007

0.006

0.000

0.000

0.000

10 ppm all, 1 ppm Hg

0.002

0.004

0.020

0.044

0.022

0.023

0.030

0.017

0.183

0.137

0.023

0.002

195

The low DLs and BEC are partly due to the optimized configuration of the 8900
ICP-QQQ, which gives extremely low background signals. For example, 0 cps
were measured in the calibration blank for Os, Ir, and Au in NH3 mode. A second
factor is the highly selective reaction chemistry in the CRC when the 8900 is
operated in MS/MS mode with NH3 cell gas. The MS/MS configuration uses Q1
to select the specific mass of ions that are allowed to enter the CRC and react.
Q1 ensures that only the selected analyte ions and on-mass interfering ions enter
the CRC, so the reactions are controlled and predictable, leading to very effective
resolution of the interfering ions. No new potentially overlapping product ions canform from ions at other masses, because all other masses are excluded from the
CRC when Q1 is operating as a true mass filter.
Table 4 also shows the percent recoveries for the 1 ppb PGE spike in the highest,
most complex mixed matrix solution. All recoveries in NH3 mode were within 10%of the target value, with the exception of Os, which suffers from chemical instability
in the presence of HNO3. Osmium stability can be improved by reducing the HNO3
concentration in the solutions and increasing the HCl concentration.
Table 4. PGE DLs, BECs, and recoveries of a 1 ppb spike in a complex synthetic interference matrix.
Element

Mass Pair(Q1 - Q2)

DL
(ng/L)

BEC(ng/L)

1 ppb Spike
Recovery(%)

Ru

99 - 99

1.691

1.123

104

Ru

101 - 101

0.67

0.129

101

Rh

103 - 103

0.653

0.126

101

Pd

105 - 105

5.541

2.133

108

Ag

107 - 107

3.78

5.288

106

Ag

109 - 109

0.849

0.327

107

Os

188 - 203

6.245

3.704

81

Os

189 - 204

6.558

3.571

78

Ir

191 - 206

8.566

5.882

103

Pt

195 - 229

6.247

1.202

102

Pt

198 - 232

2.232

0.918

109

Au

197 - 231

7.592

4.348

91

Recovery of PGEs in CRM BCR 723 Road Dust
The aqua regia digestion of CRM BCR 723 Road Dust was analyzed to evaluate
the accuracy of the ICP-MS/MS method for quantitative analysis of the PGEs in a
representative complex sample matrix. BCR 723 Road Dust has certified values
for Rh, Pd, and Pt, and the recoveries for these elements in NH3 mode on the8900 ICP-QQQ are shown in Figure 2.
For all three certified elements, the values measured using the 8900 ICP-QQQ
in NH3 mode were in good agreement with the certified values. For Rh and Pt,
the 8900 mean measured concentrations were almost identical to the certified
mean values, and the measured precision (n=3) was less than 2% RSD. For Pd,
the 8900 result was a little higher than the certified mean value, but still within
the 95% confidence limits. The Pd result measured by the 8900 method is close
to the limit of quantification (LOQ), as indicated by the relatively high RSD of 7%.
However, note that the uncertainly of the certified value is also high at 31% (6.1 ±1.9 μg/kg), due to the low concentration of the element. The certified value for Pd
is also based on results from only 8 of the 20 labs that participated in the CRM
certification exercise, further illustrating the difficulty of measuring this element
at the low levels present in BCR 723.
196

Conclusion
A method has been developed for the routine analysis of the PGEs and othernoble metals in high and complex matrices using the Agilent 8900 ICP-QQQ in
MS/MS mode with NH3 cell gas. Using the UHMI aerosol dilution system, the
ICP-MS was able to tolerate the high levels of TDS (~10 g/L, 1%) in an aqua regia
digest of a Road Dust CRM sample. UHMI enables high matrix sample digests
such as soil, roadside dust, and mining samples to be analyzed with minimal
dilution, avoiding potential problems of dilution errors or contamination fromthe diluent.
The 8900 ICP-QQQ method used MS/MS mode with NH3 cell gas to resolve
matrix-based interferences on the noble metals. The ability of ICP-MS/MS to
resolve severe spectral interferences on the PGEs was shown by the low BECs
obtained in a range of complex synthetic matrices. The method was further
validated by demonstrating accurate spike recovery of the PGEs in the mostcomplex matrix mix and accurate recovery of the certified elements in a Road
Dust CRM sample. Potential matrix-based spectral interferences that cannot
be addressed either by He KED mode on single quadrupole ICP-MS or by High
Resolution ICP-MS were resolved successfully using the ICP-MS/MS methodwith NH3 cell gas.
The 8900 ICP-QQQ offers a unique combination of exceptional matrix tolerance
due to the robust UHMI plasma conditions, together with the low backgroundand effective control of NH3 reactions due to the MS/MS configuration. This
combination allowed the development of a method that enables the accurate,interference-free measurement of sub-ppb levels of the PGEs with goodprecision in complex sample matrices.
The method is suitable for routine environmental monitoring of trace PGEs,
as well as other applications such as mineral prospecting, extraction, andprocessing/reprocessing of the PGEs.

Figure 2. Agilent 8900 ICP-MS/MS measured results compared to certified mean values anduncertainly ranges (95% confidence limits) for Rh, Pd, and Pt in CRM BCR 723 Road Dust.

197

References

198

1.

M. Omrani, M. Goriaux, Y. Liu, S. Martinet, L. Jean-Soro, V. Ruban, Environ.
Pollut., 257 (2020) 113477

2.

M. Omrani, M. Goriaux, L. Jean-Soro, V. Ruban, Environ. Sci. Pollut. Res. 28(2021) 33231–33240

3.

Handbook of ICP-QQQ Applications using the Agilent 8800 and 8900,
4th Edition, Agilent publication 5991-2802EN, 2020

> Return to table of contents> Search entire document

Direct Analysis of Ultratrace Rare Earth Elements
in Environmental Waters by ICP-QQQ
AuthorNaoki Sugiyama,
Agilent Technologies Inc.

Measure emerging pollutants in river water using theAgilent 8900 ICP-QQQ in MS/MS mass-shift mode
Introduction
The Rare Earth Elements (REEs)—also known as the lanthanides—range fromlanthanum to lutetium. Scandium and yttrium are also commonly considered to
be REEs. REEs are used in a wide range of applications from the glass industry,
phosphors, permanent magnets, and lasers to clean energy, defense
technologies, and batteries (1–3). With their increasing importance in high techapplications, there is growing concern about the migration of REEs into theenvironment during mining, processing, use, discarding, or recycling. Moreevidence is required to understand the effects of REEs on the environment,
ecosystems, and from dietary intake. Depending on the findings that emerge
from the research, regulations may be introduced to limit the disposal of REEs
into water courses. In support of both research and routine monitoring purposes,
quick, reliable, and sensitive analytical methods are needed to measure theseemerging pollutants at low concentrations in a range of sample-types.
While ICP‑MS is suited to the measurement of REEs at trace levels, the direct
measurement of REEs in waste and natural waters remains challenging for two
main reasons. Typically, the natural background concentration of the REEs isvery low in environmental waters, often at or below the detection capabilities of
conventional single quadrupole ICP-MS. Also, the analysis may be hindered byspectral interferences such as BaO+ on Eu+, BaH+ on La+, or low mass REE-oxideions overlapping high mass REEs. A chelating resin can be used topreconcentrate the REEs and separate them from Ba, which is usually present at
a much higher concentration. But this approach must be optimized for eachsample matrix, requiring time, skill, and resources that may not be available inroutine labs.
Triple quadrupole ICP-MS (ICP-QQQ) is a simpler, faster, direct method for the
analysis of REEs in environmental waters at the ultratrace level. Compared tosingle quadrupole ICP-MS, ICP-QQQ offers greater sensitivity and advanced
interference removal using controlled reaction chemistry in the collision/reaction
cell (CRC). Agilent ICP-QQQ instruments feature two quadrupoles (Q1 and Q2),
one either side of the CRC, enabling double mass selection (MS/MS). Q1 rejects
all nontarget ions before they enter the cell, allowing only analyte ions andon-mass interference ions to pass to the cell. These ions can then be separatedusing predictable, consistent, and reproducible reaction chemistry (4). Q2 thenensures that only the analyte ions (on mass mode) or analyte-product ions(mass-shift mode) pass to the detector, free of interferences.
In this study, an Agilent 8900 ICP-QQQ was used for the direct analysis of REEs inwater that was collected at four different points along a Japanese river. Using an
MS/MS mass-shift method with nitrous oxide (N2O) as a reaction cell gas, anyinterferences were resolved quickly and effectively.
199

Experimental
Instrumentation
An Agilent 8900 ICP-QQQ (model #100 for advanced applications) was used inthis study. The instrument was fitted with a quartz double-pass spray chamber,quartz torch with 2.5 mm id injector, and Ni interface cones. Sample delivery wasvia a peristaltic pump and PFA microflow nebulizer (G3139-65100 nebulizer) witha small dead volume. The samples were clean, natural waters, so `low-matrix'
preset plasma conditions were selected in the Agilent ICP-MS MassHunter
software. The preset plasma setting automatically optimizes the plasma
conditions for the routine analysis of samples with total dissolved solids < 0.1%.
Selection of reactive cell gas
Oxygen (O2) and N2O were investigated as reaction cell gases to remove spectralinterferences on REEs using a MS/MS mass-shift method. The potential spectralinterferences include BaO+ on Eu+, BaH+ on La+, or low mass REE-oxide ions onhigh mass REE ions.
Since the O atom transfer reaction of REE+ with N2O (REE+ + N2O —> REEO+ + N2)
is exothermic for all REEs, good sensitivity was expected with N2O. As shown in
Figure 1, comparable or greater sensitivity was achieved for all REEs using N2O
compared to O2 cell gas. Based on these results, N2O was used as the reaction
cell gas in this study.

Figure 1. Comparison of the sensitivity of ICP-QQQ MS/MS mass-shift method with O2 andN2O cell gas.

All 8900 ICP-QQQ operating and tuning conditions are summarized in Table 1.
Table 1. ICP-QQQ tuning and operating conditions.

200

Parameter

Setting

RF Power (W)1550

Sampling Depth (mm)8.0

Nebulizer Gas Flow Rate (mL/min)

1.05

Makeup Gas Flow Rate (mL/min)

0.0

Extraction 1 Lens (V)–5.0

Extraction 2 Lens (V)–200

Omega Lens (V)7.0

Omega Bias Lens (V)–110

Octopole Bias (V)–3.0

Cell Gas Flow Rate (% of full scale)

20

Axial Acceleration (V)1.0

Method detection limits (MDLs)
MDLs for the REEs were calculated from three times the standard deviationof nine replicate measurements of a low-level standard (0.3 ppt each REE in
1% HNO3). The results are summarized in Table 2. All the MDLs are sub ppt,
confirming the suitability of the method for the determination of REEs atbackground levels in environmental waters.
Certified reference material analysis
A river water certified reference material (CRM), SLRS-6 (NRC-CNRC, Ottawa,
Canada) was analyzed using the ICP-QQQ in MS/MS mode with N2O. All REEs
were measured as oxide ions, with a mass-shift of 16 u, as indicated in the
Q1/Q2 settings provided in Table 2.
There is good agreement between the CRM reported values (5) and measured
concentrations for all elements except for Sc (Table 2). To investigate thediscrepancy, Sc was analyzed in the CRM using no gas and helium (He) collision(kinetic energy discrimination) mode. The measured concentrations were 367
and 33.3 ppt, respectively. No detailed information is given for the reported value
for Sc on the CRM certificate. Since the reported concentration (333.0 ppt)
agrees with the measured value obtained in no gas mode (367 ppt), the author
suspects the CRM reported value provided for Sc is not correct. Because theCRM contains Si at the ppm level, a spectral interference on Sc+ by SiO+ or SiOH+
may account for the high reported value.
Using the ICP-QQQ method, any Si-based interferences on Sc+ would be avoided.
In MS/MS mode, Q1 operates as a single (1 u) mass filter so that only ions withthe targeted m/z enter the CRC and react with the cell gas. Q1 rejects all othermasses (including Si ions), avoiding any subsequent interferences by SiO+ or
SiOH+ on Sc+.
River water analysis
River water samples were collected at four points (A to D) of the Tama River,Japan. Two of the samples were collected at wastewater treatment plant(WWTP) discharge points (C and D), as shown in Figure 2. Three samples werecollected from each sampling point, then filtered through a 0.45 μm filter, andacidified to 1% HNO3.
Table 2. MDLs and SLRS-6 river water CRM reported values (5) and ICP-QQQ measured results.
Element

Q1/Q2

Integration
Time (s)

MDL
(ppt)

SLRS-6
Reported (ppt)

SLRS-6This Study (ppt)

Sc

45/61

1.0

0.127

333.0

16.3

Y

89/105

1.0

0.053

128.0

125.7

La

139/155

1.0

0.062

248.3

241.3

Ce

140/156

1.0

0.061

292.7

288.5

Pr

141/157

1.0

0.057

59.1

57.3

Nd

146/162

3.0

0.066

227.8

221.3

Sm

147/163

3.0

0.096

39.5

37.8

Eu

153/169

1.0

0.082

7.26

6.50

Gd

157/173

3.0

0.078

31.6

29.9

Tb

159/175

1.0

0.059

4.07

3.75

Dy

163/179

3.0

0.073

21.9

21.1

Ho

165/181

1.0

0.100

4.30

4.14

Er

166/182

1.0

0.092

12.4

11.7

Tm

169/185

1.0

0.079

1.79

1.63

Yb

172/188

3.0

0.096

11.2

10.7

Lu

175/191

1.0

0.052

1.91

1.74
201

UpstreamA
Hamura intake-weir
Akikawa river
Hachioji WWTP
Haijima intake-weir

Asakawa river

Tamagawa Jyouryu WWTP

Ogurigawa river
Minami Tama WWTP

B
C

Daimaru intake-weirDNogawa river

Kita Tama 2 WWTP

Hirasegawa river
Intake-weirTodoroki WWTP

To Tokyo Bay

Water flow

Figure 2. Tama River water flow balance and sample collection points A to D. The water flowbalance is based on data provided by the Japanese Ministry of Land, Infrastructure, Transport,
and Tourism, 1999.

Results and discussion
Each water sample was analyzed in triplicate using the 8900 ICP-QQQ method,
and the average REE concentration for each site is shown in Figure 3 (left). The
REEs are a chemically similar group of elements, so tend to behave consistently.
However, in most natural materials, the REEs alternate between high and low
concentrations, giving a saw-tooth profile which makes it difficult to see
anomalies. For this reason, geochemists often normalize REE data by dividing theconcentration of each REE measured in the sample by that element’s value in areference material. In this case, the reference material used was Post-Archean
Australian Shales (PAAS) (6), as shown in Figure 3 (right).
Apart from gadolinium (Gd), the normalized REE results for waters from different
points on the river gave consistent, smooth profiles, despite the low
concentrations. Gd was consistent with the other REEs in the river water collected
at the upstream location (Mitake). But there was a spike in the Gd concentrationin the samples taken at the other three sites. The results indicate contamination
by Gd compounds, which were not removed by WWTP and so were discharged
into the river. A possible source is widely used Gd-based magnetic resonanceimaging (MRI) contrast agents.
The plots in Figure 3 also suggest that the light REEs were depleted in the WWTP
effluents, but the higher mass REEs were somewhat enriched. There is also asuggestion that Ce might be anomalously high in the water from the Kita Tama
WWTP, as this element lies above the smooth line formed by the other light REEs.
These patterns may indicate other sources of REE contamination from local
industry, although most REE concentrations apart from Gd were at the single ppt
level or below.
202

1000
1000

1.E-03
1.E-03
MitakeMitakeFuchuuFuchuuMitakeMitakeFuchuuFuchuuMinamiMinami
Tama
Tama
wwtp
wwtp

KitaKita
Tama
Tama
wwtp
wwtp

MinamiMinami
Tama
Tama
wwtp
wwtp

KitaKita
Tama
Tama
wwtp
wwtp

1.E-04
1.E-04
PAAS normalized REE conc.
PAAS normalized REE conc.

REE conc. (ppt)
REE conc. (ppt)10010010 10

1.E-05
1.E-05

1 1

1.E-06
1.E-06

0.10.10.01
0.01

1.E-07
1.E-07La LaCe CePr PrNdNdSmSmEu EuGd GdTb TbDy DyHo HoEr ErTmTmYb YbLu Lu

1.E-08
1.E-08La LaCe CePr PrNdNdSmSmEu EuGd GdTb TbDy DyHo HoEr ErTmTmYb YbLu Lu

Figure 3. Concentrations of REEs in Tama River water samples by ICP-QQQ. Left: Average of three samples from each site with error bars
showing two times the standard deviation. Right: Same REE results normalized to PAAS values.

Conclusion
The study demonstrates the suitability of the Agilent 8900 ICP-QQQ with
MS/MS mode for the direct measurement of 16 REEs in river water. All potential
polyatomic interferences arising from Ba oxide or low mass REE-based hydride,oxide, and hydroxide polyatomic interferences were resolved using the N2O
mass-shift method.
Sub ppt MDLs were achieved for all the REEs using the MS/MS method.
The high sensitivity and low background provided by the 8900 are needed for thedetermination of emerging pollutants in environmental samples, which are
typically present at ultratrace concentrations.
The results from the analysis of the Japanese river water samples collected at
different points along the river highlighted an interesting finding for Gd. While all
the other REEs were measured below 50 ppt in all samples, there was a spike in
the Gd concentration in samples collected at or near to wastewater discharge
points. Gd MRI reagents may be the source of the contamination.

203

References

204

1.

US Geological Survey Mineral Resources Program
The Rare-Earth Elements—Vital to Modern Technologies and Lifestyles,
Fact Sheet 2014–3078, November 2014

2.

Naoki Sugiyama and Glenn Woods, Direct measurement of trace rare earth
elements (REEs) in high-purity REE oxide using the Agilent 8800 Triple
Quadrupole ICP-MS with MS/MS mode, Agilent publication, 5991-0892EN

3.

Juane Song, Xiang-Cheng Zeng, Dong Yan, and Wei-ming Wu, Routine
determination of trace rare earth elements in high purity Nd2O3 using theAgilent 8800 ICP-QQQ, Agilent publication, 5991-5400EN

4.

Reaction data for 70 elements using O2, NH3 and H2 with the Agilent 8800
Triple Quadrupole ICP-MS, Agilent publication, 5991-4585EN

5.

Delphine Yeghicheyan et al, A New Interlaboratory Characterisation of Silicon,
Rare Earth Elements and Twenty-Two Other Trace Element Concentrationsin the Natural River Water Certified Reference Material SLRS-6 (NRC-CNRC),
Geostandards and Geoanalytical Research, Vol. 43 issue 3, 2019, 475–4

6.

W.B Nance and S.R Taylor, Rare earth element patterns and crustal
evolution—I. Australian post-Archean sedimentary rocks, Geochimica et
Cosmochimica Acta, Vol. 40, issue 12, 1976, 1539-1551

> Return to table of contents> Search entire document

Solving Doubly Charged Ion Interferences using
an Agilent 8900 ICP-QQQ
AuthorNaoki Sugiyama,
Agilent Technologies Inc.

Improved data quality using MS/MS oxygen mass-shift method
to resolve common M++ ion interferences
Introduction
Most ICP-MS instruments use collision/reaction cell (CRC) technology to control
spectral interferences, greatly improving data accuracy for many elements inroutine applications. Helium collision cell mode (He mode) is the most widelyused CRC technique for the trace element analysis of many commonly analyzed
samples. It is especially effective at resolving spectral interferences that arise
from overlapping matrix or plasma-based ions such as metal oxide ions or argide
ions. He mode uses Kinetic Energy Discrimination (KED) to reduce thetransmission of all common matrix-based polyatomic interferences under asingle set of cell conditions.
A different approach is needed to remove doubly charged ion interferences (M++)
though, since He mode enhances the interference. While M++ interferences are
not as common as polyatomic ion interferences in most general applications, it isuseful for analysts to be aware of the potential for their formation. It is also usefulfor analysts to have a method to correct for M++ interferences should they arise.
A quadrupole mass spectrometer separates ions based on their mass-to-charge
ratio (m/z), so M++ ions appear at half their true mass, overlapping any singly
charged analyte ions with the same m/z. M++ interferences can be corrected using
mathematical interference correction equations. This approach is often used tocompensate for doubly charged ion interferences from rare earth elements (REE++)
on arsenic (As) and selenium (Se). But accurate results can only be obtainedusing correction equations when the interference and analyte signal are of thesame order of magnitude. Otherwise, the correction provides an inaccurate value.
With the development of samples with more complex matrices, there is anincreasing need for more reliable, reproducible, and higher-quality data.
Triple quadrupole ICP-MS (ICP-QQQ) with its double mass selection (MS/MS)
can remove M++ interferences using controlled reaction chemistry in the CRC.
ICP-MS/MS methods enable reactive cell gases such as hydrogen, oxygen, andammonia to be used effectively (1, 2).
In this study, an ICP-MS/MS reaction cell method using O2 was used to remove M++
interferences on various analytes. Many elemental ions react with O2 to form anoxide ion while the M++ interference remains unreactive or is much less reactive.
This allows the element of interest to be quantified by measuring the oxide ion at +16 u, away from the spectral interference (1, 2). This “mass-shift” methodology wasused to remove doubly charged ion interferences on Ca, Sc, Zn, As, and Se.

205Experimental
Instrumentation
An Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ #100 for Advanced
applications) was used. The instrument was fitted with the standard sample
introduction system comprising a glass concentric nebulizer, quartz double-pass
spray chamber, quartz torch with 2.5 mm id injector, and Ni interface cones.
The ICP-QQQ was operated in single quadrupole (SQ) no gas mode, in SQ He
mode, and with O2 cell gas in MS/MS mass-shift mode. The 8900 is fitted with afour cell gas channels, allowing different cell gases to be used in the same
method if needed. Robust “general purpose” plasma conditions were set
automatically using the ICP-MS MassHunter software. The main operating
conditions and tuning parameters are shown in Table 1.

Calibration standards and sample preparation
Calibration standards were prepared from Agilent Environmental Calibration
Standards (p/n 5183-4688) via sequential dilution using de-ionized water. Fe, Sc,
and Sr calibration standards were prepared separately from single elements
standards (Kanto Chemical Co Inc., Japan). A Rare Earth Element (REE) mixed
solution was bought from SPEX CertiPrep Inc. National Institute of Standards andTechnology (NIST) 1640a Trace Elements in Natural Water Standard Reference
Material (Gaithersburg MD, USA) was used to evaluate the method. The SRM wasalso spiked with 1 ppm of each of Sr, Zr, Ba, Sm, Gd, Nd, and Dy to simulate amore challenging sample matrix for the evaluation. Also, since no Sc is present in
NIST 1640a, a 10 ppb spike was added to the SRM to represent the analyte.
Table 1. ICP-QQQ operating conditions and tuning parameters.

Acquisition mode

No GasHe

O2Single quad

Single quadMS/MS

RF power (W)1550

Sampling depth (mm)10Nebulizer gas flow rate (mL/min)

1.05

Make up gas flow rate

0.0

Octopole bias (V)

–8

–18

Axial acceleration (V)KED (V)

5–8

Cell gas flow rate (mL/min)-

4.5

0.6 (40% full scale)

Deflection lens (V)

20

4

2

Shaded parameters are predefined by selecting general-purpose plasma settings.

206

–10

2

Results and discussion
Attenuation of doubly charged ion interferences
To study the effectiveness of the method for the removal of M++ interferences,
Sr++ interference on Ca+, Zr++ on Sc, Ba++ on Zn+, and REE++ interferences on As+
and Se+ were investigated. The background equivalent concentrations (BECs) of
Ca, Sc, and Zn were determined in a solution containing 10 ppm of Sr, Zr, and Ba.
As and Se were measured in a solution containing 10 ppm each of 16 REEs.
The results, which were obtained using no gas mode, He mode, and O2 mass-shiftmode, are shown in Figure 1. The graphs show that the lowest BECs for all
elements were obtained using O2 mass-shift mode. The higher results obtained in
no gas mode highlight the effect of the doubly charged ion spectral interferencesthat arise from the matrix elements on all five analytes. The results also show that
He mode is ineffective for the removal of M++ ion interferences, even enhancing theinterference slightly compared to no gas mode.
Natural water SRM analysis
Matrix spiked and unspiked samples of the NIST 1640a natural water SRM wereanalyzed using ICP-QQQ. All elements were measured in He mode. For comparison
purposes, the five analyte elements (Ca, Sc, Zn, As, and Se) that potentially suffer
M++ interferences arising from the Sr, Zr, Ba, Sm, Gd, Nd, and Dy matrix spikes werealso measured in MS/MS mass-shift mode with O2 cell gas. Quantitative results are
given in Tables 2 and 3.
As can be seen in Table 2, He mode provided accurate results for all elements inthe non-matrix spiked SRM sample. All isotopes were within ±10% of the certified
values apart from 43Ca (111%), which suffered interference from a Sr++ overlap(the SRM contains 126 ppb Sr).
There was a large deviation from the certified concentrations for some isotopesof Ca, Sc, Zn, As, and Se in the 1 ppm matrix spiked SRM due to M++ ion
interferences, as indicated by the shaded cells in Table 2.

207

Figure 1. BEC results of the matrix spectroscopic interference study.

208

Table 2. Analytical results for NIST 1640a Trace Elements in Natural Water SRM with and without
matrix element spikes. All data was acquired using the 8900 ICP-QQQ operating in He mode.
SRM
1640a
Element

Integration
Time (s)MDL** n=9(µg/L)SRM
1640a

SRM 1640a+ 1 ppm Matrix

Certified(µg/L)

Average
n=3(µg/L)

Recovery(%)

Average
n=3(µg/L)

Recovery
(%)

3.026

3.15

104

3.15

104

Be

0.5

0.06

23

Na

0.5

0.54

3137

3195

102

3200

102

24

Mg

0.5

0.35

1058.6

1056

100

1028

97

27

Al

0.5

0.07

53.0

54.2

102

52.0

98

39

K

0.5

2.8

579.9

595

103

568

98

42

Ca

0.5

58

5615

5598

100

5376

96

43

Ca

0.5

5.8

5615

6257

111

11120

198

44

Ca

0.5

1.0

5615

5767

103

9085

162

45

Sc

0.5

0.02

10*

10.6

106

13.7

137

51

V

0.5

0.01

15.05

14.9

99

14.3

95

52

Cr

0.5

0.01

40.54

40.4

100

38.9

96

53

Cr

0.5

0.02

40.54

41.3

102

39.8

98

55

Mn

0.5

0.01

40.39

39.9

99

38.1

94

56

Fe

0.5

0.03

36.8

34.7

94

33.4

91

59

Co

0.5

0.01

20.24

20.9

103

20.2

100

60

Ni

0.5

0.02

25.32

26.3

104

25.4

101

66

Zn

1.0

0.01

55.64

55.6

100

54.0

97

68

Zn

1.0

0.01

55.64

59.3

107

107

192

75

As

1.0

0.02

8.075

8.1

100

40.9

506

78

Se

1.0

0.14

20.13

19.7

98

320

1588

80

Se

1.0

8.6

20.13

19.3

96

165

819

88

Sr

0.5

0.01

126

127.1

101

1130.2

100

95

9

Mo

0.5

0.01

45.6

44.8

98

43.3

95

107

Ag

0.5

0.01

8.081

8.47

105

8.52

105

111

Cd

0.5

0.01

3.992

4.03

101

4.01

101

121

Sb

0.5

0.01

5.105

4.99

98

4.77

93

137

Ba

0.5

0.02

205

Tl

0.5

0.00

1.619

1.51

93

1.47

91

208

Pb

0.5

0.01

12.101

11.5

95

11.1

92

238

U

0.5

0.00

25.35

27.1

107

26.5

104

151.8

151

100

1165

101

*SRM was spiked with 10 ppb Sc analyte** MDL was calculated as 3 sigma of quantified value of 9 replicates of the solution which contains 1/10 of the concentration of
the lowest level of calibration standards ; 1 ppb for Na. Mg, Ca, K and 0.1 ppb for other elements.

209

In contrast to the He mode data, accurate results were obtained for Ca, Sc, Zn,
As, and Se in both the matrix spiked and matrix unspiked SRM using O2 massshift mode (Table 3). The results demonstrate the effective interference removal
capability of O2 reaction cell mode to handle M++ ion overlaps.
Table 3. Analytical results for NIST 1640a Trace Elements in Natural Water SRM with andwithout matrix element spikes. All data was acquired using the 8900 ICP-QQQ operating in
MS/MS mass-shift mode with O2 cell gas.
SRM
1640a

SRM
1640a

SRM 1640a+ 1 ppm Matrix

Element

Integration
Time (s)MDL** n=9(µg/L)

Certified(µg/L)

Average
n=3(µg/L)

Recovery(%)

Average
n=3(µg/L)

Recovery
(%)

42

Ca

0.5

2.48

5615

5671.21015739.5

102

43

Ca

0.5

9.72

5615

5731.71025839.4

104

44

Ca

0.5

1.36

5615

5721.51025774.5

103

45

Sc

0.5

0.001

10*

10.4

104

10.5

105

66

Zn

1.0

0.09

55.64

54.2

97

52.8

95

68

Zn

1.0

0.07

55.64

54.9

99

53.9

97

75

As

1.0

0.01

8.075

8.4

104

8.6

106

78

Se

1.0

0.05

20.13

20.4

101

20.7

103

80

Se

1.0

0.03

20.13

20.4

101

20.8

103

*SRM was spiked with 10 ppb Sc analyte** MDL was calculated as 3 sigma of quantified value of 9 replicates of the solution which contains 1/10 of the concentration of
the lowest level of calibration standards ; 1 ppb for Na. Mg, Ca, K and 0.1 ppb for other elements.

Conclusion
The Agilent 8900 ICP-QQQ operating in MS/MS mode with O2 cell gas is highly
effective for the removal of doubly charged ion interferences on different
isotopes.
A natural water SRM was spiked with Sr, Zr, Ba, and REEs to cause M++
interferences on Ca, Sc, Zn, As, and Se. Accurate results were obtained for all
elements in the SRM apart from Ca, Sc, Zn, As, and Se using helium mode.
Although He mode is a proven approach used to reduce common polyatomic
interferences in ICP-MS, it isn’t effective for the removal of M++ interferences –as confirmed by the results in this study. However, M++ interferences weresuccessfully resolved using a MS/MS mass-shift method with O2 cell gas,
providing accurate results for Ca, Sc, Zn, As, and Se.
Agilent ICP-QQQ instruments combine the versatile, almost universal He mode
(using KED) with controlled reactive cell gas modes (using MS/MS).
This combination of methods enables ICP-QQQ to generate the most accurate
results for environmental and food sample analysis, without sacrificing
instrument ease-of-use. It also allows the analytical results to be checked acrossmultiple isotopes, providing extra confidence in the final data.

References

210

1.

Reaction data for 70 elements using O2, NH3 andH2 with the Agilent 8800 Triple Quadrupole ICP-MS, Agilent publication,
5991-4585EN

2.

Agilent 8800 Triple Quadrupole ICP-MS: Understanding oxygen reaction
mode in ICP-MS/MS, Agilent publication, 5991-1708EN

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Removal of REE++ Interference on Arsenic
and Selenium
Authors

Introduction

Kazumi Nakano andYasuyuki Shikamori
Agilent Technologies, Japan

Trace analysis of arsenic (As) and selenium (Se) in environmental and foodsamples is of a great interest, since both elements can be toxic even at quite lowlevels. It is difficult to quantify As and Se accurately at trace levels in somematrices by quadrupole ICP-MS as all the analytically useful isotopes can sufferfrom multiple spectral interferences, as summarized in Table 1. This application
investigates ICP-QQQ in MS/MS reaction mode to remove interferences on As
and Se, with an emphasis on the removal of the doubly-charged ions arising fromRare Earth Elements (REE++). While the concentration of REEs in environmental
and food samples is usually low, some plants will accumulate REEs from the soil,
and a high concentration will lead to false positive results for As and Se.

Keywords
Rare Earth Elements, REE, arsenic,
selenium, environmental, food, CRMs,
oxygen mass-shift

Table 1. Spectroscopic interferences on As and Se isotopes.
As and Se isotope

Interference

Element

Mass

Abundance %Doubly charged

As

75

100

150
150

Se

77

7.63

154
154

78

23.77

156
156

80

49.61

160
160

82

8.73

164
164

Matrix

Sm ,
Nd++

40

Sm++,
Gd++

40

Gd++,
Dy++

41

Gd++,
Gd++,

45

Dy++,
Er++

45

++

40

40

Dimer

Ar Cl ,Ca37Cl+37+

Ar37Cl+,
Ca37Cl+K37Cl+

38
39

Sc35Cl+40
40

Ar40Ar+,
K39K+
Ar40Ar+,
Ca40Ca+

Sc37Cl+Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/Low matrix.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -180 V.
CRC conditions: O2 gas flow rate of 0.2 mL/min, Octopole bias = -8 V and KED =-6 V.
Acquisition parameters: MS/MS O2 mass-shift method to measure As+ (as AsO+)
and Se+ (as SeO+), as illustrated in Figure 1. Unlike conventional quadrupole
ICP-MS, the 8800 ICP-QQQ mass-shift method can be applied to complex matrix
samples that may contain Zr and/or Mo. The MS/MS configuration prevents
undesired ions such as 91Zr+ and 94Mo+ from overlapping the MO+ product ions,as they are rejected by Q1.

211

O2

Q1 (m/z = 75)

ORS

As +
150
Nd2+, 150Sm 2+,
151
Eu 2+, 40Ar35Cl+,40
Ca 35Cl+, 91Zr+
75

Q1 (m/z = 75)
75

As +

Zr+

75

150

91

AsO +

75

As16O +

78

Se16O +

Nd2+, 150Sm 2+, 151Eu 2+, 40Ar35Cl+, 40Ca 35Cl+

O2

Q1 (m/z = 78)
Se +156
Gd2+, 156Dy2+,
139
LaOH 2+,
140
CeO 2+, 38Ar40Ar+,
74
Mo +
78

ORS

Q1 (m/z = 94)
78

Mo +

74

Se +

78

SeO +

Gd2+, 156Dy2+, 139LaOH 2+, 140CeO 2+, 38Ar40Ar+

156

Figure 1. ICP-QQQ MS/MS O2 mass-shift method for measuring 75As (top) and 78Se (bottom).

Samples and sample preparation: SPEX XSTC-1 (a mixture of 10 ppm each ofCe, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Sm, Sc, Tb, Tm, Yb and Y) purchased from
SPEX CertiPrep Ltd. (UK) was used. Four certified reference materials (CRMs):
NIST 1515 Apple Leaves, NIST 1573a Tomato Leaves, NIST 1575a Pine Needles
and NMIJ 7531a Brown Rice, were used for the method validation. It should be
noted that NIST 1515 contains 3 mg/kg Sm and Gd, and 0.2 mg/kg Eu.
NIST 1573a contains 0.19 mg/kg Sm, 0.17 mg/kg Gd, 5% Ca and 2.7% K,
a combination of matrix elements that might be expected to cause severeinterferences on As and Se. All CRMs were microwave-digested in HNO3 and H2O2,
diluted and analyzed.

Results and discussion
Effectiveness of O2 mass-shift method for removing REE++ interferences
To investigate the effectiveness of interference removal modes on the 8800
ICP-QQQ, As and Se were measured in a mixed REE solution containing
1 ppm each of Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Sm, Sc, Tb, Tm, Yb and Y.
Three different 8800 ICP-QQQ cell modes were used:– Single Quad (SQ); no gas– Single Quad (SQ); reaction mode using hydrogen (H2) cell gas– MS/MS; reaction mode using O2 cell gas with + 16 u mass-shift“Single Quad” represents the performance of conventional ICP-QMS while MS/MS
mode is unique to ICP-QQQ.

212

Figure 2 shows the BECs of As and Se in each of the measurement modes. The
results in Figure 2 illustrate the excellent interference removal performance of theO2 mass-shift method for the detection of As and Se in a matrix containing REEs.
100
10

1

0.1

0.01
0.001

No gas(Single Quad)As

H 2 on-mass(Single Quad)O 2 mass-shift method(Single Quad)

Se

Figure 2. BEC of As and Se in 1ppm REE mixed solution with three measurement modes:
no gas, H2 on-mass and O2 mass-shift mode.

Figure 3 shows the product ion scan spectra obtained using O2 mass-shift mode
for a solution containing 1 ppm REEs without (left) and with (right) a 1 ppb As
spike. As illustrated in the schematic, Q1 was fixed at m/z = 75 and Q2 wasscanned across the selected mass range to monitor all existing and cell-formed
ions derived from precursor ions at m/z 75. Figure 3 (left) shows the product ionsfrom m/z 75 in the blank REE matrix; the signal at Q2 m/z = 75 (mass of As) isdue to REE++. The absence of a signal at m/z = 91 (the mass of AsO+) in the blank
REE matrix, indicates that the REEs do not react with O2 in the cell to give rise to
product ions (such as REEO2++) that overlap AsO+ at m/z 91. Consequently, As canbe successfully measured as AsO+ at m/z = 91 as shown in Figure 3 (right).
O2

O2

Q1 (75)REE

Q1 (scan)Q1 (75)
75

+

x104
1.5

Signal intensity

x104

Signal intensity

Q1 (scan)As ,REE 2+

2+

0.5

1

REE 2+

0.5

As
60

70

75

80

91

100

110
Q2

60

70

75

80

91

100

110
Q2

Figure 3. Product ion scan spectrum of O2 mass-shift method. (Left) 1 ppm mixed-REE solution and (right) 1 ppm mixed-REE plus 1 ppb As spike.

213

Method validation with CRMs
The ICP-QQQ method was applied to the measurement of As and Se in four
CRMs. Table 2 summarizes the results. The measured concentrations of As and
Se in the CRMs were all in good agreement with the certified values.
Table 2. Results of the determination of As and Se in four CRMs using MS/MS O2 mass-shift modeon the 8800 ICP-QQQ.
As (as AsO+ at m/z 91)
Certified
mg/kg

214

Found average Recovery
mg/kg%

Se (as SeO+ at m/z 94)
Certified
mg/kg

Found average Recovery
mg/kg%

NIST1515
Apple Leaves

0.038±0.007 0.037

97

0.050±0.009 0.050

100

NIST1575a
Pine Needles

0.039±0.002 0.038

97

0.099±0.004 0.099

100

NIST1573a
Tomato Leaves

0.112±0.004 0.113

101

0.054±0.003 0.058

107

NMIJ 7531a
Brown Rice

0.280±0.009 0.258

92

NA

NA

0.032

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Removal of Molybdenum Oxide Interference
on Cadmium
Authors

Introduction

Michiko Yamanaka
Agilent Technologies, Japan

Cadmium (Cd) is a well-known toxic element along with As, Hg and Pb.
The maximum contamination level of these elements in food, pharmaceuticals,
drinking water, wastewater and other matrices is strictly controlled under national
and international legislation. Out of the eight natural isotopes of Cd, only 111Cd is
free from direct overlap by an atomic isobar (an isotope of a different element at
the same mass as the Cd isotope), and even 111Cd is potentially subject tospectroscopic interference by 95MoO+. Fortunately, the concentration of Mo is low
in most samples, and quadrupole ICP-MS (ICP‑QMS) operating in helium collisionmode can remove the interference, allowing the accurate measurement of Cd.
However, there are some cases where the Mo concentration is high and a betterinterference removal technique is required in order to accurately determine Cd.
This paper describes the application of MS/MS H2 reaction mode on the Agilent
8800 ICP-QQQ for the determination of trace Cd in the presence of a highconcentration of Mo.

Keywords
cadmium, molybdenum oxide,
environmental, food, CRMs, hydrogenon-mass

Experimental
Instrumentation: Agilent 8800 #100. Indium (In) was introduced as the internal
standard using the on-line ISTD kit.
Plasma conditions and ion lens tune: RF power = 1550 W; sampling depth =8.0 mm; carrier gas = 1.01 L/min; make-up gas/dilution gas =0.0 L/min; Soft extraction tune: Extract 1 = 0 V, Extract 2 = -165 V, Omega bias =-100 V, Omega = 11.4 V.
CRC conditions: H2 flow rate 9.0 mL/min,
Octopole bias = -22 V, KED = +5 V.
Acquisition parameters: MS/MS H2 on-mass method i.e. 111Cd was measured at
m/z 111 using quadrupole settings of (Q1 = 111, Q2 = 111).

215

Results and discussion
Optimization of H2 flow rate
Figure 1 (left) shows the signal at m/z 111 for a 10 ppm Mo solution and a 10
ppm Mo + 1 ppm Cd solution, plotted as a function of H2 flow rate. Figure 1 (right)
shows the calculated BEC of Cd in the presence of 10 ppm Mo. The optimum cellgas flow rate of 9.0 mL/min was used for subsequent experiments.
In order to test the effectiveness of MS/MS mode with H2 cell gas in comparison
to no gas mode, a spike recovery test of 1 ppb Cd in a series of Mo matrix
solutions ranging from 0.1 to 100 ppm was conducted. Figure 2 summarizes theresults. In no gas mode, the error in quantification of the 1 ppb Cd spikedramatically increases with the concentration of Mo; in contrast, H2 reaction
mode delivers a consistent and accurate result for Cd even in the presence of
100 ppm Mo.

10000

10000

10000

1000
100
10

0

2

1000

100

100

10

Mo 10 ppm
Mo 10 ppm+Cd 1 ppb

1

1000

1

4
6
H 2 flow rate (mL/Min)

8

10

10

Cd BEC in 10 ppm Mo
Cd sensitivity

0

2

4
6
H 2 flow rate (mL/Min)

1
8

10

Figure 1. (Left): Signal for m/z 111 with 10 ppm Mo and 10 ppm Mo + 1 ppb Cd, plotted as afunction of H2 flow rate. (Right): Estimated Cd BEC in the presence of 10 ppm Mo as a function ofH2 flow rate.

Determined Cd conc. (ppb)

100

10

1

0.1

0.1 ppm Mo+ 1 ppb Cd
No gas1 ppm Mo+ 1 ppb Cd

10 ppm Mo+ 1 ppb Cd

50 ppm Mo+ 1 ppb Cd

100 ppm Mo+ 1 ppb Cd

H2

Figure 2. 1 ppb Cd spike recovery in a series of Mo matrix solutions using no gas mode andMS/MS H2 mode.

216

Cd sensitivity cps (ppb)

100000CD BEC (ppt)

100000SIGNAL cps

100000Method validation: Analysis of Cd in CRMs
The concentration of Cd was determined in four different CRMs: NIST 1515 Apple
Leaves, NIST 1573a Tomato Leaves, NIST 1575a Pine Needles and NMIJ 7531a
Brown Rice Flour (National Metrology Institute of Japan). Each sample was
microwave digested following the manufacturer’s recommended procedures,
then diluted and analyzed by ICP-QQQ; the final dilution factor was around100–200. For each CRM, the digested sample was analyzed using the developed
method. A second sample of each CRM was prepared and analyzed after the
addition of a 10 ppm Mo spike. As summarized in Table 1, good recoveries wereobtained for all four references materials both for the unspiked samples and the
duplicates with the high added Mo concentration, demonstrating the validity ofthe method for real sample analysis.
Table 1. Measurement of Cd in four CRMs using the 8800 ICP-QQQ in MS/MS mode with
H2 reaction gas.
CRMs

Without Mo addition

With 10 ppm Mo addition

Certified
mg/kg

Determined
mg/kg

Recovery%

Determined
mg/kg

Recovery%

NIST1515
Apple Leaves

0.014

0.013

93

0.016

100

NIST1573a
Tomato Leaves

1.52

1.496

98

1.475

100

NIST1575a
Pine Needles

0.223

0.220

99

0.224

107

NMIJ 7531a
Brown Rice Flour

0.308

0.298

97

0.293

NA

217

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Rapid Analysis of Radium-226 in Water Samples
by ICP-QQQ
Authors

Introduction

Ben Russell1, Elsje May van Es1,2,
Glenn Woods3, David Read1,2

Radium-226 is a radionuclide that occurs naturally as part of the uranium-238
decay series. 226Ra decays with a half-life of 1,600 years to radon-222 with theemission of alpha and gamma radiation. The element is known for its historical
use in the luminescent paint used in clocks, watches, and other instruments.
These uses led to severe health problems for the so-called Radium Girls who
painted the watch and clock dials. 226Ra has a long half-life compared to theother Ra isotopes and is considered a significant contributor to occupational
radiological dose with regards to industrial sources of naturally occurring
radioactive materials (NORM).

1. National Physical Laboratory,
Teddington, UK
2. Chemistry Department, University ofSurrey, Guildford, Surrey, UK
3. Agilent Technologies UK Limited,
Lakeside, Stockport, UK

Ra occurs naturally in waters through interaction with uranium-bearing minerals[1]. It is also present as a result of waste from the industrial exploitation of mineral
resources (including uranium mining and processing sites, and produced waters
following hydraulic fracturing). Radium waste producers are required to comply
with stringent limits when discharging to watercourses. Analytical methods must
therefore be capable of detecting 226Ra at values ranging from 0.01 Bq/L to 1 Bq/L
(equivalent to 0.3 – 30 pg/L (ppq) or 0.0003 – 0.03 ppt) [2,3,4].
226

Ra analysis is typically performed by alpha spectrometry, which requires
time-consuming and labor-intensive separation before measurement, followed bycount times of several days per sample to reach the target detection limits.

226

This study outlines a new method developed by the National Physical Laboratory(NPL) Nuclear Metrology Group for the rapid analysis of 226Ra in water samples.
The new method uses a preconcentration step prior to measurement of 226Ra
using triple quadrupole ICP-MS (ICP-QQQ)[5]. The procedural time is significantly
reduced compared to decay counting techniques, and 226Ra is measurable atconcentrations required to meet the regulatory detection limits.

Experimental
Sample preparation
Radium-226 calibration standards were prepared from an in-house standard
solution in a dedicated facility used for the preparation of aqueous radioactive
sources for decay counting or mass spectrometry measurement. The calibration
standards were diluted in 2% (v/v) HNO3.
Groundwater samples were also investigated to assess the impact of a more
complex sample matrix. Samples were evaporated to dryness and redissolved in
2% (v/v) HNO3. The solutions were then spiked with 226Ra over a concentration
range of 0.03 – 30 ppt to represent the concentrations expected following
preconcentration.
High volume water samples (1 L) were spiked over the same concentration range
as the groundwater samples to represent samples close to, and higher than, theregulatory discharge limits. Samples were acidified to pH 2 and passed through achromatographic column to trap 226Ra [6]. The 226Ra was then eluted, evaporated to218incipient dryness and then made up in 5 mL 2% HNO3, representing a concentration
factor of ~200. Unspiked water samples were run through the same
preconcentration procedure, and then measured to establish the elemental
composition and confirm no contribution of polyatomic interferences to thebackground at m/z = 226. Matrix matched calibration standards were prepared byspiking water samples following preconcentration, which also enabled the recovery
to be calculated (≥ 70% over the concentration range studied).
Instrumentation
An Agilent 8800 Triple Quadrupole ICP-MS (ICP-QQQ) was used throughout.
The standard sample introduction system was used, comprising a quartz torchwith 2.5 mm i.d. injector, a quartz spray chamber, glass concentric nebulizer,
and nickel-tipped interface cones. The instrument operating conditions are
summarized in Table 1.
Table 1. ICP-QQQ operating conditions; low matrix tuning is appropriate for samples where most of
the matrix has been removed during analyte preconcentration.
SettingParameter
Scan mode

Single Quad
Low matrix (optimized
for high sensitivity)

Plasma conditions
RF power (W)

HMI
1550

Carrier gas (L/min)

1.07

0.60

Dilution gas (L/min)

0

0.35

Extract 1

0.0

Extract 2-200.0Omega Bias (V)-100.0Omega lens (V)

13.6

Octopole bias (V)-8.0

He cell gas (mL/min)

0 – 1.0

0.5 – 1.0

Results and discussion
Sensitivity of ICP-QQQ for 226Ra
The half-life of 226Ra is relatively short with regards to ICP-MS measurements(1 Bq/kg is equivalent to 27.3 ppq, compared to long-lived 238U (half-life 4.5×109
years), where 1 Bq/kg is equivalent to 8.0×107 ppq). In practice, this means thatcalibration should be performed using standards prepared for the radioisotope ofinterest, rather than calibrating using a long-lived or stable isotope as an analog.
The instrument detection limits (IDLs) for several operating conditions (Q1 modes
and cell gas flows), were calculated from a calibration curve prepared by spiking
2% (v/v) HNO3 with 226Ra at concentrations of 0.01–30 ppt (Table 2).
Table 2. Limit of detection for different instrument conditions and cell gas flow rates.
Instrument mode

Single Quad

MS/MS

He flow rate (mL/min)

0.0

0.5

1.0

0.0

0.5

1.0

Limit of detection (ppt)

0.08

0.10

0.02

0.04

0.04

0.07

219

The IDLs in Table 2 are close to the higher end of the regulatory limits quoted(0.03 ppt), and orders of magnitude higher than the lowest values (0.3 ppq).
Measurement of 226Ra at environmentally relevant levels therefore requires aneffective preconcentration step prior to ICP-QQQ analysis, to rival the detection
limits of traditional alpha spectrometry measurement.
Interference removal by ICP-QQQ
Multiple potential interferences from polyatomic ions including 88Sr138Ba+,
Sr139La+, 86Sr140Ce+, 208Pb18O+, 186W40Ar+, and 97Mo129Xe+ can potentially affect
ICP-MS measurement of 226Ra. Multiple separation stages prior to sample
introduction are often required to remove the interferences. As an alternative
approach, helium (He) collision mode was investigated for the removal ofpolyatomic interferences, initially by introducing up to 100 ppm Sr + Ba, Sr + La,
Ce, W, and Pb standards. The background at m/z = 226 was 0 cps in single quadmode when using 0.5–1.0 mL/min He cell gas, confirming the ability of He mode
to attenuate all the polyatomic ions. Given that the on-mass polyatomic
interferences are formed during sample introduction and not in the collision/
reaction cell (CRC), MS/MS was not required, so the instrument was operated insingle quad mode throughout.
87

Groundwater samples from different locations in North West England were thenanalyzed to determine the impact of a more complex sample matrix on
instrument performance. The samples were spiked with 226Ra and measured atvarying He gas flow rates together with unspiked samples and blank solutions.
Bismuth-209 was used as an internal standard. The impact of matrix suppression
was overcome using robust plasma conditions and aerosol dilution with theHigh Matrix Introduction (HMI) system of the 8800. HMI allows higher matrix
levels to be analyzed directly without requiring chemical separation prior tomeasurement, further reducing the total procedural time. The reduction insensitivity when operating with 0.5 mL/min He cell gas was offset by the lower
background, giving comparable or improved background equivalentconcentrations (BECs) at m/z = 226 compared to no gas mode (Table 3).
The sensitivity at 0.5 mL/min He cell gas is illustrated in the calibration plotshown in Figure 1.
Table 3. BECs of 226Ra using no gas and He gas mode.
He flow rate (mL/min)

220

BEC (ppt)
Sample 1

Sample 2

Sample 3

0

0.015

0.017

0.00850.5

0.00830.00890.00921.0

0.011

0.0092

0.013

8000

y = 279.61x + 9E-13
R2 = 1

7000
Counts per second

6000
5000
4000
3000
2000
1000
0
0

5

10

15
20
Concentration (ppt)

25

30

Figure 1. Calibration plot for 226Ra standards in single quad mode with 0.5 mL/min He.

Measurement of high volume water samples
In water samples, 226Ra was detected down to 0.03 ppt (1 Bq/L), which is equivalent
to 5 mBq/L in the original sample, assuming a preconcentration factor of 200.
The RSD was <10% at concentrations above 1.4 ppt (50 Bq/L), equivalent to
250 mBq/L in the original sample. The results demonstrate that ICP-QQQ combinedwith preconcentration from high volume water samples is capable of measuring
226
Ra at concentrations relevant to regulatory discharge limits. Improved accuracy
at the lower limits is potentially achievable through higher preconcentration factors.

Conclusion
A method is presented that demonstrates the capabilities of ICP-QQQ for themeasurement of the naturally occurring radionuclide 226Ra. The use of He collision
gas effectively removes potential polyatomic interferences, while operating with
HMI reduces the impact of matrix suppression. When combined withpreconcentration using chromatographic separation techniques, the detection
limits achievable are applicable to the regulatory limits for water. The measurement
time of several minutes per sample represents a significant improvementcompared to several days using traditional alpha spectrometry. The increase insample throughput is potentially beneficial for routine monitoring of water supplies,
as well as routine environmental monitoring at nuclear and industrial sites.

References
1.	P.L. Smedley, A survey of the inorganic chemistry of bottled mineral watersfrom the British Isles. Applied Geochem. 2010, 25, 1872–1888
2.	Environmental Permitting Guidance: Radioactive Substances Regulation,
Environment Agency, London, 2010,
3.	Guidelines for Drinking-water Quality (Fourth Edition), World HealthOrganisation, 2011, ISBN 978 92 4 154815 1
4.	National Primary Drinking Water Regulations; Radionuclides; Final Rule (PartII), 40 CFR Parts 9, 141, and 142, Environment Protection Agency, 2011
5.	E.M. van Es, B.C. Russell, P. Ivanov, D. Read, Development of a method for rapid
analysis of Ra-226 in groundwater and discharge water samples by ICP-QQQMS. App. Rad. & Isotopes, 126, 2017, 31-34
6.	E.M. van Es, B.C. Russell, P. Ivanov, M. Garcia Miranda, D. Read, The behaviourof 226Ra in high volume environmental water samples on TK100 resin. J.
Radioanal. Nucl. Chem., 2017, 312: 10
221

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Feasibility Study of Fluorine Detection by ICP-QQQ
AuthorIntroduction

Noriyuki Yamada
Agilent Technologies, Japan

Fluorine (19F) cannot be directly detected by conventional quadrupole ICP-MS(ICP-QMS) because of severe water-derived interferences at m/z 19 from 1H316O+
and 1H18O+, and extremely low sensitivity due to the fact that it is very difficult toconvert fluorine atoms to the positive ions that are measured in ICP-MS.
The interference problem can be resolved by high resolution ICP-MS, but thesensitivity issue remains a challenge because almost no F atoms are ionized in
an argon plasma due to F having an ionization potential (17.423 eV) that is higher
than that of Ar (15.760 eV).

Keywords
fluorine-containing polyatomic ions,barium, oxygen on-mass, ammonia
mass-shift

However, fluorine-containing polyatomic ions (XF+) can be formed in the plasma
and they may be used to determine fluorine. Candidate ions are those with ahigh bond-dissociation energy for the X+-F bond and low ionization potential of
X or XF. Since oxygen is present in the plasma (from the water matrix or from air
entrainment), the formation of XO+ or XO often competes against that of XF+.
Therefore, a low bond-dissociation energy for X+-O and X-O bonds (low affinity of
X+ and X for O) is also desirable for the efficient formation of XF+. Barium wasselected as "X" for this feasibility study, based on its thermochemical properties(Table 1).
Table 1. Gas phase thermochemical properties of elements having an affinity for fluorine*.
Element X

D0(X+-F)IP (X)

D0(X-F)IP (XF)

D0(X+-O)

D0(X-O)

C

7.77

11.27

5.60

9.11

8.35

11.15

Al

3.16

5.99

6.99

9.73

1.81

5.31

Si

7.01

8.15

5.69

7.54

4.99

11.49

Ba

6.39

5.21

5.98

4.70

5.60

5.80

La

6.83

5.61

6.86

5.56

8.73

8.50

Eu

6.05

5.67

5.59

5.90

4.00

5.90

*Unit: eV. D0(A-F) is the bond-dissociation energy for A-F bond (affinity of A for F) and IP(B) is the ionization potential of B.

Experimental
Instrumentation: Agilent 8800 #200 with a Micromist nebulizer.
Plasma conditions and ion lens tune: RF power = 1500 W; Sampling depth = 8mm; Carrier gas flow rate = 1.00 L/min; sample uptake rate 0.33 mL/min; 100
ppm Ba uptake rate = 0.03 mL/min; Make-up gas flow rate = 0.32 L/min; Extract 1= -150 V, Extract 2 = -4 V.
CRC conditions: O2 gas at 1 mL/min (100%), Octopole bias = -60 V, Energy
discrimination = -10 V in O2 mode; 10% NH3/90% He flow rate 8.5 mL/min (85%),
Octopole bias = -20 V, Energy discrimination = -10 V in NH3 mode.

222

Acquisition parameters: MS/MS O2 on-mass and MS/MS NH3 mass-shift.
Integration time per mass for BaF and BaF(NH3)3 = 1 sec; integration time permass for BaF(NH3)4 = 10 sec.
In order to produce BaF+ in the plasma, Ba solution was mixed online with fluorine
standards per a fixed mixing ratio of 1:10. The mixing occurred just before thenebulizer. BaF+ was efficiently formed under general plasma conditions with the
BaO+/Ba+ ratio at about 11%. Under hotter plasma conditions, the formation of
BaF+ decreases because it tends to break apart. Under cooler plasma conditions,the formation of BaF+ also decreases because of the formation of BaO+ or,
possibly, BaO. The signal intensity of BaF+ was proportional to the concentrationof Ba, which was fixed at about 10 ppm (after mixing).
Interference removal using MS/MS mode
Ba19F+ (m/z=157) suffers an interference from 138Ba18O1H+. O2 and NH3 were
tested as reaction gases to reduce the interference. It was found that O2 reacts
with BaOH+ more efficiently than it reacts with BaF+ in high energy reaction mode
(octopole bias < -50 V). Therefore, using MS/MS mode, a mass pair (Q1  Q2) =(157  157) was selected to detect BaF+ in O2 mode. With Q1 set to 157 u, 138Ba+
was prevented from entering the cell and forming new interferences throughunwanted reactions.
138

NH3 was found to react with BaF+ at a high NH3 flow rate to form BaF(NH3)n+,where n = 2, 3, 4. The most abundant complex ion was BaF(NH3)3+ at m/z = 208,
but BaF(NH3)4+ at m/z = 225 was preferable in terms of signal to background ratioor BEC. Mass pairs (Q1  Q2) = (157 208) and (157  225) were selected in
NH3 mode.

Results and discussion
Figures 1 and 2 show calibration curves up to 2 mg/L (ppm) for fluorine indeionized water. The lowest detection limit (27 ppb) was obtained in O2 mode.
The lowest BEC (87 ppb) was obtained by measuring BaF(NH3)4+ in NH3 mode.
Table 2 shows the BEC and DL results for F obtained from this study incomparison with the literature values.
157  157 [O2]x104157  225 [NH 3]

y = 4073.8021 * x + 918.4170
R = 0.9999
DL = 0.02673 ppm
BEC = 0.2254 ppm

x102

y = 67.1020 * x + 5.8500
R = 0.9999
DL = 0.0307 ppm
BEC = 0.08718 ppm

CPS

CPS

1

1
0.5

0

0
1.0

2.0
Conc (ppm)

Figure 1. Calibration curve for F measured as
BaF+ in O2 mode.

1.0

2.0
Conc (ppm)

Figure 2. Calibration curve for F measured as
BaF(NH3) 4+ in NH3 mode.

223

Table 2. Analytical performance for fluorine detection by ICP-MS.
Analyte ion

Sensitivity[cps/ppm]

BEC [ppm]

DL [ppm]

Technique, referenceF-

60,000NA

0.11

Negative ion mode ICP-MS, Appl.
Spectrosc, 42, 425 (1988)

F+

3,000

NA

0.023

He-ICP-MS, Japan analyst 52(4),275-278, 2003

0.00330.0001IC-ICP-MS (indirect determination),
Analyst. 1999 Jan;124(1):27-31

26

2.05

5.07

HR-ICP-MS, J. Anal. At. Spectrom, 18,1443, 2003

4,073

0.23

0.027

ICP-QQQ, O2 mode, this work

BaF(NH3)3

929

0.17

0.043

ICP-QQQ, NH3 mode, this work

BaF(NH3)4+

67

0.087

0.031

ICP-QQQ, NH3 mode, this work

Al+ (AlF2+ complex) NA
F+
BaF+
+

Conclusion
Based on this preliminary study, it is clear that the controlled reaction chemistrythat is possible with MS/MS mode on the 8800 ICP-QQQ can provide a novel
approach to the measurement of F by ICP-MS. In addition to demonstrating
detection limits that are comparable with published data measured using
conventional quadrupole ICP-MS or high-resolution ICP-MS, the 8800 ICP-QQQ
also allows unprecedented flexibility to monitor specific reaction transitions,making it invaluable for method development.

224

> Return to table of contents> Search entire document

HPLC-ICP-MS/MS: Fluorine Speciation Analysis
Authors

Introduction

Nor Laili Azua Jamari, Jan Frederik
Dohmann, Andrea Raab, Eva M. Krupp,
and Jörg Feldmann
Trace Element Speciation Laboratory(TESLA), University of Aberdeen,
Scotland, UK

Fluorine is often used in the form of organofluorine compounds in applications
such as pharmaceuticals, agrochemicals, and materials. This usage has resulted
in the accumulation of large quantities of unknown organofluorine compounds
in the environment [1, 2]. Fluorine is a difficult element to determine by ICP-MS.
Its high ionization potential (17.423 eV) results in a low yield of F+ ions in theplasma, leading to low sensitivity.

Keywords
BaF+, fluorine speciation analysis,
fluoride, fluoroacetate, trifluoroacetate,
HPLC-ICP-QQQ

Fluorine can be determined, however, by mixing barium and fluorine solutions
and measuring the polyatomic ion BaF+ by triple quadrupole ICP-MS (ICP-QQQ)[3]. Because 138Ba is the most abundant isotope, the highest sensitivity would beachieved for 138Ba19F+ at m/z 157. Mechanisms for the formation of BaF+ are
shown in equations 1 and 2.
(1)

138

Ba+ + 19F0  138Ba19F+		

(2)

138

Ba++ + 19F- 138Ba19F+		

While this approach resolves the low ionization yield issue for F, the formationof potential interfering ions at m/z 157 from 138Ba18O1H+, 138Ba16O1H3+, and138
Ba17O2H+ also needs to be considered. These interferences can be reduced byoperating the ICP-QQQ in MS/MS mode, using oxygen as the reaction gas.
This approach was used for development of an online HPLC-ICP-QQQ speciation
method for the determination of F.

Experimental
Instrumentation: Agilent 8800 ICP-QQQ with Micromist nebulizer and s-lens.
Operating conditions: Table 1 summarizes the plasma, ion lens, and cell tuning
conditions.
Acquisition parameters: MS/MS mode with O2 on-mass. Integration time perm/z for BaF+ = 1 sec.
HPLC system: Agilent 1290 with Metrosep A Supp 5 (150 mm x 4.0 mm)
separation column and Metrosep RP Guard/3.5 column. Buffer = 3.2 mM sodium
carbonate and 1.0 mM sodium bicarbonate (pH 10); flow rate = isocratic 0.7 mL/
min of 70% buffer solution; sample injection = 100 µL.
A transfer capillary was used to connect the chromatographic column to thenebulizer of the ICP-QQQ system via a T-pin, which allowed the mixing of Ba withF solution. The parameters were optimized in a previous study [4].

225

Table 1. ICP-QQQ operating conditions.
Parameter

Unit

Value

RF power

W

1500

Sampling depth

mm

8.0

Carrier gas flow rate

L/min

1.00

Make-up gas flow rate

L/min

0.36

Extract 1

V-150.0Extract 2

V

5.0

DeflectV-48.0

Oxygen flow rate

mL/min0.75

Octopole Bias

V

-60.0

Octopole RF

V

200

Energy discrimination

V

-10.0

Wait time offset

msec

2

Sample uptake rate

mL/min0.33

32 mg/L Ba uptake rate

mL/min0.22

Plasma

LensesCell

Results and discussion
Figures 1 and 2 show the chromatograms and calibration curves for fluorine
speciation analysis of three different fluorine compounds: fluoride, fluoroacetate(FAA), and trifluoroacetate (TFA). All compounds were baseline separated within
10 minutes. The sensitivity of F is similar for each sample, indicating the method
is compound independent and fluorine specific.
The limits of detection (LOD) of the HPLC-ICP-QQQ method were 0.012 mg/L,
0.073 mg/L, and 0.12 mg/L for fluoride, FAA, and TFA, respectively. Table 2 shows
the LOD results for F from this study compared to data reported in the literature.
12000

Trifluoroacetate

8000
6000
4000
2000

Fluoroacetate
Trifluoroacetate

20000
15000
10000
5000

0

0
0

2

4

6

8

10

Time (min)Figure 1. HPLC-ICP-QQQ chromatogram offluoride, fluoroacetate, and trifluoroacetate atdifferent F concentrations: 0.1, 0.25, 0.5, 1.0,
2.5, and 5.0 mg/L (as indicated by red to green
colored lines).

226

Fluoride

25000
Peak area

Intensity (cps)30000

Fluoroacetate

Fluoride

10000

0

2

4

6

F concentration (mg/L)

Figure 2. HPLC-ICP-QQQ calibration curves offluorine compounds: fluoride, fluoroacetate,
and trifluoroacetate.

Table 2. Limit of detection (LOD) of F analysis obtained by different methods.
LOD (mg/L)

Reference

IC-ICP-MS
Al+(indirect determination) (AlF+ complex)

0.0001Analyst, 1999, 124, 27–31

HR-ICP-MSF+

5.1

J. Anal. At. Spectrom., 2003, 18,
1443–1451

ETV-ICP-MS

F+

3.2

J. Anal. At. Spectrom., 2001, 16,
539–541

ICP-MS/MS

BaF+

0.027

Agilent, 2015, 5991-2802EN

0.043

J. Anal., At. Spectrom., 2017, 32,
942-950

BaF+ for fluoride

0.012

This work

BaF+ for fluoroacetate

0.073This work

BaF+ for trifluoroacetate

0.12This work

MethodHPLC-ICP-MS/MS

Analyte ion

Conclusion
For the first time, coupling an HPLC directly to an ICP-QQQ enabled thespeciation analysis of fluorine-containing compounds through the formation of
the polyatomic ion BaF+ [4]. The method was not only able to detect fluorine
specifically but also has a comparable low LOD, which opens up possibilities for
future non-targeted fluorine speciation analysis in environmental samples.

References
1.	L. Ahrens, Polyfluoroalkyl compounds in the aquatic environment: A review of
their occurrence and fate. J. Environ. Monit., 2011,13, 20–31.
2.	A. Harsanyi, G. Sandford, Organofluorine chemistry: applications, sources, andsustainability. Green Chem., 2015, 17: 2081–2086.
3.	N. Yamada, Feasibility study of fluorine detection by ICP-QQQ, Agilent
Applications Handbook, 2015, 5991-2802EN.
4.	N. L. A. Jamari, J. F. Dohmann, A. Raab, E. M. Krupp, J. Feldmann, Novel
non-target analysis of fluorine compounds using ICP-MS/MS and HPLC-ICPMS/MS. J. Anal., At. Spectrom., 2017, 32, 942-950.

227

> Return to table of contents> Search entire document

Foods and Consumer Products
Title

Page

Elemental analysis
Benefits of the Agilent 8900 ICP-QQQ with MS/MS operation for routine
food analysis

229

Routine elemental analysis of dietary supplements using an Agilent 8900
ICP-QQQ

241

Accurate and sensitive analysis of arsenic and selenium in foods using
ICP-QQQ to remove doubly-charged REE interferences

250

Analysis of TiO2 nanoparticles in foods and personal care products bysingle particle ICP-QQQ

254

Accurate analysis of trace mercury in cosmetics using the Agilent 8900
ICP-QQQ

263

Sulfur isotope fractionation analysis in mineral waters using an Agilent 8900
ICP-QQQ

269

Speciation

228

Fast analysis of arsenic species in infant rice cereals using LC-ICP-QQQ

275

High throughput determination of inorganic arsenic in rice using hydride
generation-ICP-QQQ

282

Fast determination of inorganic arsenic (iAs) in food and animal feed by
HPLC-ICP-MS

286

Multielement analysis and selenium speciation in cattle and fish feedusing LC-ICP-QQQ

295

Arsenic speciation analysis in apple juice using HPLC-ICP-MS with theAgilent 8800 ICP-QQQ

304

Speciated arsenic analysis in wine using HPLC-ICP-QQQ

312

Fast analysis of arsenic species in wines using LC-ICP-QQQ

319

Simultaneous iodine and bromine speciation analysis of infant formulaby HPLC-ICP-MS

326

Determination of pesticides using phosphorus and sulfur detection by
GC-ICP-QQQ

333

> Return to table of contents> Search entire document

Benefits of the Agilent 8900 ICP-QQQ with MS/MS
operation for routine food analysis
Authors

Introduction

Kazuhiro Sakai,Agilent Technologies, Japan

Growing awareness of and concern about the issue of food safety is reflected in
the tightening of regulations governing toxic elements and compounds in food.
Many toxic elements such as As, Hg, Cd, Pb etc. are routinely monitored toensure food safety, while minerals that are beneficial/essential to human healthsuch as Se, Na, Mg, K, Ca, etc., are also measured. As a fast, high throughput,
multi-element technique, with a wide dynamic range and high sensitivity, ICP-MS
is increasingly used for routine food analysis. Recent improvements in matrix
tolerance with Agilent’s High Matrix Introduction (HMI/UHMI) technology is afurther benefit for the application as food matrices are varied and can becomplex. UHMI uses aerosol dilution to reduce the sample matrix load on theplasma, allowing matrix levels up to several percent total dissolved solids (TDS)
to be analyzed routinely. This is much higher than the limit of 0.2% (2000 ppm)
which has traditionally applied to samples intended for ICP-MS analysis.
Control of polyatomic ion interferences in quadrupole ICP-MS has also improved
significantly with the development of collision/reaction cells (CRCs), which use
kinetic energy discrimination (KED) to attenuate polyatomic ions in helium (He)collision mode. Agilent’s octopole-based CRC, the ORS4, is routinely used tosuppress a wide range of matrix-based polyatomic ion interferences under one
set of cell conditions [1]. Hence, reliable and accurate quantification of all requiredelements at regulated levels in a variety of sample matrices is now possible using
conventional quadrupole ICP-MS (ICP-QMS).
However, some food-analysis applications require greater sensitivity for specificelements, while some complex sample matrices may cause spectralinterferences that remain a challenge for ICP-QMS. For example, doubly charged
ions of some rare earth elements (REEs) appear at the same mass as key
analytes, hindering accurate low-level measurement of arsenic (As) and selenium(Se) in some sample types [2, 3].
Improved interference removal with ICP-QQQ
The Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) has a unique tandem
MS configuration, comprising two scanning quadrupole mass analyzers eitherside of an octopole-based ORS4 collision reaction cell. As a result, the 8900
ICP-QQQ is able to utilize reactive cell gases and ion/molecule reaction chemistry
in combination with MS/MS mode to resolve difficult spectral interferences [4].
The superior interference removal offered by reaction chemistry with MS/MS led
to the previous generation Agilent 8800 ICP-QQQ being widely accepted inindustry and research labs in fields such as semiconductor device and high purity
chemical/material manufacturing, life-science, geoscience, radionuclides andmany others [5-8]. MS/MS mode is also beneficial for the analysis of certain
elements which are subject to problematic interferences in routine applications,such as the analysis of food samples, soils, waste water and groundwater.

229

Since the matrix tolerance and robustness of the Agilent 8900 ICP-QQQ is
comparable to Agilent’s market-leading single quadrupole ICP-MS systems,
the 8900 ICP-QQQ can be used to analyze these high-matrix samples routinely.
Solving problems associated with As and Se analysis
Arsenic is a well-known toxic element, while Se is an essential element that canbe toxic in excess. Consequently, many countries regulate the permitted
concentrations of As and Se in food, animal feed, drinking water, surface waterand soils. However, As and Se can suffer spectral interferences from polyatomic
ions including ArCl+, CaCl+, ArAr+, S2O+, SO3+, GeH+, and BrH+. These interferences
can be reduced using ICP-QMS operating in helium (He) cell mode, allowing
the accurate and precise measurement of As and Se at the concentration levels
required to meet typical regulatory demands.
However, He mode is not effective against doubly-charged ion overlaps.
The lanthanides or rare earth elements (REE) can form doubly charged ions
(REE++) which overlap As and Se. These doubly-charged overlaps can be avoidedusing mass-shift mode with O2 as the reaction cell gas. In this mode, the analytes
are measured as reaction product ions 75As16O+ and 78Se16O+, mass-shifted tom/z 91 and 94 respectively, where they are free from the original REE++ overlaps.
This reaction chemistry can be used in the CRC of an ICP-QMS, but existing ionsfrom the plasma may overlap the newly-formed product ions; e.g. 91Zr+ on
75
As16O+, and 94Mo+ on 78Se16O+. To ensure controlled and consistent reaction
chemistry, MS/MS mode on an ICP-QQQ is required, where the first quadrupole(Q1) operates as a mass filter set to the appropriate As+ or Se+ precursor ion
mass. Q1 rejects all other masses, thereby removing the existing Zr+ and Mo+ ionsand preventing them from overlapping the new analyte product ions.
Typically, the REE content of food and other natural samples is low, but crops
grown in REE-enriched soils can take up high concentrations of these elements.
The use of MS/MS mode with O2 reaction cell gas avoids the potential risk ofreporting incorrect results for As and Se in the case of an unexpectedly high levelof REEs.
In this study, the Agilent 8900 ICP-QQQ was evaluated as a routine tool for the
analysis of 30 elements, including As and Se, in food sample digests.

Experimental
Certified Reference Materials (CRMs)
Five food CRMs purchased from National Institute of Standards and Technology(NIST) and High-Purity Standards Inc. (Charleston, SC, USA) were analyzed in thisstudy. The CRMs used were NIST 1567b Wheat Flour, NIST 1568b Rice Flour,
NIST 1515 Apple Leaves, NIST 1573a Tomato Leaves and High Purity Standards
Mixed Food Diet Solution.
Sample preparation
Due to the requirement to measure several volatile elements, including Hg, closed
vessel microwave digestion using a Milestone ETHOS 1 Advanced Microwave
Digestion System was used to digest the food CRMs. Sample weights ofapproximately 1.0 g for each of the flour CRMs (NIST 1567b, NIST 1568b) and
0.5 g for each of the other sample types (NIST 1515, NIST 1573a) were accurately
weighed into closed microwave vessels. 6 mL of HNO3 and 1 mL of HCl230

(electronics (EL) grade acids, Kanto Chemicals) were added to the microwave
vessels. After 15 minutes held at room temperature, microwave heating wasapplied, using the heating program shown in Table 1. All CRMs were completely
dissolved, resulting in clear solutions which were diluted to a final volume of
100 mL with ultrapure water (Merck, Darmstadt, Germany).
Table 1. Microwave digestion heating programs for four CRM food samples.
Power (W)

Temp (°C)

Ramp (min)Hold (min)

500

70

2

3

1000

140

5

5

100

200

5

15

Ventilation30

It is well known that carbon present in the sample solution enhances the ICP-MS
signal of some elements, notably As, Se and P, although the precise mechanismof the enhancement is not clearly understood [9, 10]. With the high digestion
temperature used in this work (200 °C), the carbon matrix was effectively
decomposed during digestion. If any residual carbon did remain its effect could
be mitigated by adding 2% butan-1-ol online with the internal standard solution.
Instrumentation
An Agilent 8900 ICP-QQQ (Standard configuration) with the standard sample
introduction system consisting of a glass concentric nebulizer, quartz spraychamber, and Ni interface cones was used. UHMI technology is included on the8900 ICP-QQQ Standard configuration, allowing matrices as high as 25% NaClsolution to be analyzed [11]. The plasma conditions were selected according to
the sample type and expected matrix level using the “Preset plasma” function of
the MassHunter software.
Acquisition conditions
For the multi-element analysis of the food samples, a multi-tune method wasused so all elements could be acquired in the optimum cell gas mode. Multi-tune
permits samples to be automatically analyzed using the optimum tune and cellconditions for each analyte element. He mode was used for all elements except
P, S, As and Se which were determined in mass-shift mode using O2 cell gas.
The method was based on an appropriate preset method for food samples, which
was modified to include O2 cell gas mode. Preset plasma condition “UHMI-4” wasselected, where the number 4 represents the approximate aerosol dilution factor.
The UHMI setting automatically applies the predefined and calibrated parameters
for RF power, sampling depth, carrier gas flow rate and dilution gas flow rate,
giving precise and reproducible plasma conditions for the target sample types.
The lens voltages were auto-tuned for maximum sensitivity. Table 2 summarizes
the instrument operating parameters.

231

Table 2. Agilent 8900 ICP-QQQ operating conditions.
SettingParameter
Cell mode

He modeO2 modeScan type

Single Quad

MS/MS

Plasma conditions

UHMI-4

RF power (W)1600

Sampling depth (mm)10

Carrier gas flow rate (L/min)

0.77

Dilution gas flow rate (L/min)

0.15

Extract 1 (V)0Extract 2 (V)-250

Omega Bias (V)-140

Omega lens (V)8.8

Cell gas flow (mL/min)

5.5

0.3 (20% of full scale)

KED (V)

5-7

Bold parameters are predefined by selecting preset plasma condition UHMI-4.

Calibration standards and internal standards
Calibration standards were prepared from an Agilent multi-element environmental
calibration standard (p/n 5183-4688) which contains 1000 ppm each of Fe, K, Ca,
Na, Mg and 10 ppm each of Ag, Al, As, Ba, Be, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, Sb,
Se, Th, Tl, U, V, and Zn. Standards for B, Rb, Sr, Sn and Hg were prepared from1000 ppm Atomic-Absorption grade single element standards from Kanto
Chemicals (Tokyo, Japan). S and P were prepared from 10,000 ppm Spex single
element standards (SPEX CertiPrep, NJ, USA). The internal standard (ISTD)
solution was prepared from an Agilent internal standard stock solution for
ICP-MS systems (p/n 5188-6525) containing 6-Li, Sc, Ge, Rh, In, Tb, Lu, and Bi.
Ir was added from an Atomic-Absorption grade single element standard
purchased from Kanto Chemicals. The ISTD was added to the sample using thestandard online ISTD kit.
Calibration standards were prepared in 6% HNO3 and 1% HCl to match the acidcontent of the sample solutions. The ISTDs were prepared in 1% HNO3 and 0.5%
HCl. The calibration ranges were as follows: major elements: 0-100 ppm, traceelements: 0-500 ppb, B: 0-200 ppb, Hg: 0-1 ppb and Sn: 0-2 ppb.

232

24 Mg [He] ISTD: 45 Sc [He]
x102

Ratio

2

y = 0.0020* x + 0.0018
R = 1.0000
DL = 0.1235
BEC = 0.8964

1

0
50000

Conc

10000078 ➝ 94 Se [O2] ISTD: 74 ➝ 90 Ge [O2]

Ratio

1

y = 0.0017* x + 5.7410E-005
R = 1.0000
DL = 0.05063
BEC = 0.03399

0.5

0
200.0

400.0
Conc

600.0

Figure 1. Representative calibration curves for a major element (Mg) and a trace element (Se).

Sequence of calibrants, samples, and QC solutions
The sequence consisted of an initial multi-level calibration, covering the typicalrange for the target analytes, followed by a QC block containing an Initial
Calibration Blank (ICB) check and Initial Calibration Verification (ICV) solution.
After calibration and initial QC check, twelve sample blocks were analyzed per theflow chart shown in Figure 2; each block consisted of 2 preparation blanks and
10 samples (2 each of Wheat Flour, Rice Flour, Apple Leaves, Tomato Leaves andMixed Food Diet). A Periodic Block consisting of Continuing Calibration Blank(CCB) and Continuing Calibration Verification (CCV) samples was automaticallyinserted into the sequence after each sample block.
Initial Calibration
0.05-500ppb for trace elements
5-100,000 ppb for major elements
2-200 ppb for B
0.05-5 ppb for Sn
0.01-1 ppb for Hg

Initial QC
ICV, ICB

Samples

Periodic QC

preparation blank n=1
preparation blank n=2
NIST 1567b Wheat Flour n=1
NIST 1567b Wheat Flour n=2
NIST 1568b Rice Flour n=1
NIST 1568b Rice Flour n=2
NIST 1515 Apple Leaves n=1
NIST 1515 Apple Leaves n=2
NIST 1573a Tomato Leaves n=1
NIST 1573a Tomato Leaves n=2
Mixed Food Diet n=1
Mixed Food Diet n=2

Run after 12 samples(2 preparation blanks
and 10 samples)
CCV, CCB

Figure 2. Sequence of calibrants, samples, and QC solutions analyzed in a single 15-hoursequence. Sample Block was repeated continuously with automatic insertion of Periodic QC Blockafter each Sample Block.

233

The total number of analyses of calibration standards, QC samples and fooddigest samples was 183 over ~15 hours. The sample-to-sample run time wasabout 5 minutes, which included a 10 s probe rinse and 60 s sample introduction
system rinse at 0.3 rps peristaltic pump rate. Table 3 shows the detection limits(DL) obtained using this method.
Table 3. Method detection limits.

234

Element

Scan Mode

B

Single Quad

Q1

Q2

Dl (ppb)

110.3653Na

Single Quad

23

0.1945Mg

Single Quad24

0.1235Al

Single Quad

27

0.1847

P

MS/MS

31

47

0.0919

S

MS/MS

32

48

0.4367K

Single Quad

39

7.0656Ca

Single Quad

44

8.7579V

Single Quad

51

0.0079Cr

Single Quad

52

0.0880Mn

Single Quad

55

0.0099Fe

Single Quad

56

0.1595

Co

Single Quad

59

0.0009Ni

Single Quad

60

0.0484

Cu

Single Quad

63

0.0102

Zn

Single Quad

66

0.0308As

Single Quad75

0.0044

As

MS/MS

Se

Single Quad

Se

MS/MS

75

78

91

0.0040780.3158940.0506Rb

Single Quad

85

0.0115

Sr

Single Quad

88

0.0006

Mo

Single Quad

95

0.0090Ag

Single Quad

107

0.0063

Cd

Single Quad111

0.0018Sn

Single Quad

118

0.0074Sb

Single Quad

121

0.0026Ba

Single Quad

138

0.0008Hg

Single Quad

202

0.0005Tl

Single Quad

205

0.0104Pb

Single Quad

208

0.0016

Th

Single Quad

232

0.0018U

Single Quad

238

0.0009

140

120

ISTD Recovery (%)

100

80

60

40

20

0:00
0:16
0:32
0:48
1:04
1:20
1:36
1:52
2:08
2:24
2:40
2:56
3:12
3:28
3:44
4:00
4:16
4:32
4:48
5:04
5:20
5:36
5:51
6:07
6:23
6:39
6:55
7:11
7:27
7:43
7:59
8:15
8:31
8:47
9:03
9:19
9:35
9:51
10:07
10:23
10:39
10:54
11:10
11:26
11:42
11:58
12:14
12:30
12:46
13:02
13:18
13:34
13:50
14:06
14:22
14:38
14:54
15:10
15:26
15:42

0

45 Sc (ISTD) [He]45 ➝ 61 Sc (ISTD) [O 2]74 Ge (ISTD) [He]74 ➝ 90 Ge (ISTD) [O 2]

103 Rh (ISTD) [He]115 In (ISTD) [He]193 Ir (ISTD) [He]209 Bi (ISTD) [He]Figure 3. ISTD signal stability for the sequence of 183 samples analyzed over 15 hours.

Results and discussion
ISTD and CCV stability
Figure 3 shows the ISTD signal stability for the sequence of 183 samples
analyzed over 15 hours. The ISTD recoveries for all samples were well within±20 % of the value in the initial calibration standard. These ISTD recoveries arecomparable to the results obtained routinely using ICP-QMS, demonstrating theequivalent robustness of the 8900 ICP-QQQ.
The midpoint of the calibration standards was used as the CCV solution. CCV
recovery over the 15-hour analysis was stable and within ±10% for all elements,
as shown in Figure 4, again demonstrating that the 8900 ICP-QQQ has the highmatrix tolerance required for routine food digest analysis.
CRM recovery results
The accuracy of the method was evaluated by analyzing the five food CRMs as
unknown samples. Each CRM was measured 24 times in the batch. The mean
concentration and relative standard deviation (%RSD) were calculated for eachelement and compared to the certified value, as shown in Tables 4 to 8. Using thepreferred measurement mode, the results for all elements were in good
agreement with the certified and reference values. Results are shown for both He
mode and O2 mass-shift mode for As and Se, to compare the results for samples
where a sample might contain an unexpected high level of REEs. NIST 1515
Apple Leaves CRM contains low μg/kg concentrations of As and Se (Table 6) andhigh concentrations of REEs. Reference (non-certified) values for Nd, Sm, and Gd
are 17, 3, and 3 mg/kg, respectively. In the case of Apple Leaves and, to a lesser
extent, Tomato Leaves, more accurate recovery was obtained for As and Se using
O2 mass-shift mode, illustrating the potential error that can be caused by the
relatively high level of REE in these two reference materials.

235

150
140
130

CCV Recovery (%)

120
110
100
90
80
70
60
50
ICV

CCV-1

CCV-2

CCV-3

CCV-4

CCV-5

CCV-6

CCV-7

CCV-8

CCV-9

CCV-10

CCV-11

11 B [He]23 Na [He]24 Mg [He]27 Al [He]31 ➝ 47 P [O 2]32 ➝ 48 S [O 2]

39 K [He]44 Ca [He]51 V [He]52 Cr [He]55 Mn [He]56 Fe [He]59 Co [He]60 Ni [He]63 Cu [He]66 Zn [He]75 As [He]75 ➝ 91 As [O 2]78 Se [He]78 ➝ 94 Se [O 2]

85 Rb [He]88 Sr [He]95 Mo [He]107 Ag [He]111 Cd [He]118 Sn [He]121 Sb [He]138 Ba [He]202 Hg [He]205 Tl [He]209 Pb [He]232 Th [He]238 U [He]CCV-12

Figure 4. CCV recovery for all elements over the 15-hour analysis.
Table 4. Results for NIST 1567b Wheat Flour, n = 24.
Element

Measured Solution
Concentration (μg/L)

RSD (%)

Calculated Sample
Concentration (mg/kg)

Certified Concentration(mg/kg)Recovery
(%)

23 Na

65.2

2.3

6.50

±

0.15

6.71

±

0.21

24 Mg

3842

1.6

383

±

6

398

±

12

96

27 Al

39

2.8

3.9

±

0.1

4.4

±

1.2

88

31 -> 47 P

12936

2.0

1291

±

26

1333

±

36

97

32 -> 48 S

15496

2.2

1546

±

34

1645

±

25

94

39 K

12700

2.3

1267

±

29

1325

±

20

96

44 Ca

1871

1.8

186.7

±

3.4

191.4

±

3.3

51 V

0.10

8.1

0.010

±

0.001

0.01*

97

98
100

55 Mn

86

1.7

8.54

±

0.14

9.00

±

0.78

95

56 Fe

142

1.6

14.20

±

0.22

14.11

±

0.33

101

63 Cu

19

1.6

1.94

±

0.03

2.03

±

0.14

96
96

66 Zn

112

1.9

11.17

±

0.21

11.61

±

0.26

75 As

0.047

16.5

0.0046±0.001

0.0048±0.000397

75 -> 91 As

0.049

19.4

0.0049±0.001

0.0048±0.0003

101

78 Se

11.5

4.2

1.15

±

0.05

1.14

±

0.10

101

78 -> 94 Se

11.8

1.9

1.17

±

0.02

1.14

±

0.10

103
97

85 Rb

6.54

1.8

0.652

±

0.012

0.671

±

0.012

95 Mo

4.60

2.1

0.459

±

0.009

0.464

±

0.034

99

111 Cd

0.239

5.7

0.0238±0.00140.0254±0.000994

118 Sn0.035512.8

0.0035±0.00050.003*

202 Hg0.006611.3

0.0007±0.00010.0005*

208 Pb

0.09374.4

0.0094±0.0004* Reference value

236

0.0104±118
131
0.002490

Table 5. Results for NIST 1568b Rice Flour, n = 24.
Element

Measured Solution
Concentration (μg/L)

RSD (%)

Calculated Sample
Concentration (mg/kg)

Certified Concentration(mg/kg)Recovery
(%)

23 Na

65.6

3.2

6.54

±

0.28

6.74

±

0.19

24 Mg

5454

1.5

543

±

8

559

±

10

97
97

27 Al

40.3

3.3

4.01

±

0.13

4.21

±

0.34

95

31 -> 47 P

15162

2.8

1510

±

43

1530

±

40

99

32 -> 48 S

11369

2.5

1133

±

28

1200

±

10

94

39 K

12371

2.0

1233

±

24

1282

±

11

96

44 Ca

1158

2.1

115.3

±

2.5

118.4

±

3.1

97

51 V

182.3

1.0

18.2

±

0.2

19.2

±

1.8

95

55 Mn

75.4

1.0

7.51

±

0.08

7.42

±

0.44

101

56 Fe

0.173

1.7

0.0173±0.00030.0177±0.0005*

98

63 Cu

22.7

1.0

2.26

±

0.02

2.35

±

0.16

96

66 Zn

191.7

1.4

19.10

±

0.26

19.42

±

0.26

98

75 As

2.97

1.4

0.296

±

0.004

0.285

±

0.014

104

75 -> 91 As

3.01

1.7

0.300

±

0.005

0.285

±

0.014

105

78 Se

3.4

8.9

0.341

±

0.030

0.365

±

0.029

93

78 -> 94 Se

3.5

3.8

0.352

±

0.013

0.365

±

0.029

96

85 Rb

61.1

1.1

6.088

±

0.069

6.198

±

0.026

98

95 Mo

13.96

1.2

1.391

±

0.017

1.451

±

0.048

96

111 Cd0.201

4.9

0.0201±0.00100.0224±0.001390

118 Sn0.060

7.4

0.0060±0.00040.005±

0.001*

121

202 Hg0.05292.1

0.0053±0.00010.0059±0.000489

208 Pb0.068

3.0

0.0068±0.00020.008±

0.003*

85* Reference value

Table 6. Results for NIST 1515 Apple Leaves, n = 24.
Element

Measured Solution
Concentration (μg/L)

RSD (%)

Calculated Sample
Concentration (mg/kg)

Certified Concentration(mg/kg)Recovery
(%)

11 B

141

2.9

28

±

0.8

27

±

2

104

23 Na

196

1.6

39.1

±

0.6

24.4

±

1.2

160*1

24 Mg

14083

1.3

2812

±

36

2710

±

80

104

27 Al

1458

1.6

291

±

5

286

±

9

102

31 -> 47 P

8088

2.2

1615

±

35

1590*

32 -> 48 S

9211

1.4

1839

±

26

1800*

39 K

80429

2.2

16057

±

361

16100

±

200

44 Ca

74060

1.2

14786

±

172

15260

±

1500

97

51 V

1.20

2.8

0.24

±

0.01

0.26

±

0.03

92

52 Cr

1.3

1.4

0.25

±

0.00

0.3*
54

102
102
100

85

55 Mn

265

1.0

53

±

1

56 Fe

379

0.8

76

±

1

±

3

59 Co

0.44

1.5

0.088

±

0.001

60 Ni

4.4

1.7

0.88

±

0.02

0.91

±

0.12

97

63 Cu

28.2

1.0

5.62

±

0.06

5.64

±

0.24

100

66 Zn

60.3

0.9

12.0

±

0.1

12.5

±

0.3

96

75 As

2.0

1.2

0.395

±

0.005

0.038

±

0.007

1040

80*

98
95

0.09*

98

75 -> 91 As

0.2

3.7

0.036

±

0.001

0.038

±

0.007

94

78 Se

13.43

5.8

2.7

±

0.2

0.050

±

0.009

5364

78 -> 94 Se

0.271

13.8

0.054

±

0.008

0.050

±

0.009

108

85 Rb

46.3

0.9

9.2

±

0.1

88 Sr

123.0

1.0

25

±

0

9*
25

±

103
2

98

237

Element

Measured Solution
Concentration (μg/L)

RSD (%)

Calculated Sample
Concentration (mg/kg)

Certified Concentration(mg/kg)

95 Mo

0.44

5.3

0.088

±

0.005

111 Cd

0.06

7.0

0.013

±

0.001

0.014*

121 Sb

0.06

4.6

0.011

±

0.001

0.013*

138 Ba

245

1.9

49

±

1

49

±

2

100

202 Hg

0.21

2.0

0.041

±

0.001

0.044

±

0.004

93

208 Pb

2.3

1.3

0.452

±

0.006

0.470

±

0.024

96

232 Th

0.14

2.2

0.028

±

0.001

0.03*

93

238 U

0.034

3.7

0.0068±0.00030.006*

113

0.094

±

Recovery
(%)

0.013

94
91
85

*Reference value.
Bold values for As and Se were obtained in single quad mode with He cell gas. The accurate results obtained using MS/MS mode with O2 mass-shift are shown in thelines below.
*1 The measured Na result was high compared to the reference value; the same result was obtained from a repeated analysis of the same solution, so a spike recovery
test was performed for confirmation. The spike recovery result was good (recovery: 99%), suggesting that the original sample had suffered Na contamination.

Table 7. Results for NIST 1573a Tomato Leaves, n = 24.
Element

Measured Solution
Concentration (μg/L)

RSD (%)

Calculated Sample
Concentration (mg/kg)

Certified Concentration(mg/kg)Recovery
(%)

11 B

167

1.9

33.3

±

0.6

33.3

±

0.7

10

23 Na

613

2.5

122

±

3

136

±

4

90

24 Mg

57311

2.0

11412

±

225

27 Al

2573

2.4

512

±

12

598

±

12

86

31 -> 47 P

10928

2.7

2176

±

59

2160

±

40

101

32 -> 48 S

48387

1.4

9635

±

131

39 K

134250

2.2

26732

±

591

27000

±

500

99

44 Ca

243939

1.4

48574

±

671

50500

±

900

96

51 V

4.0

2.2

0.792

±

0.017

0.835

±

0.010

95

52 Cr

9.3

1.6

1.85

±

0.03

1.99

±

0.06

93

55 Mn

1236.5

1.5

246

±

4

246

±

8

100

56 Fe

1843.3

1.7

367

±

6

368

±

7

100

59 Co

2.8

1.4

0.55

±

0.01

0.57

±

0.02

96

60 Ni

7.9

1.9

1.56

±

0.03

1.59

±

0.07

98

12000*

95

9600*

100

63 Cu

23.7

1.5

4.71

±

0.07

4.70

±

0.14

100

66 Zn

149.4

1.5

29.8

±

0.5

30.9

±

0.7

96
126

75 As

0.7

2.3

0.141

±

0.003

0.112

±

0.004

75 -> 91 As

0.6

1.7

0.112

±

0.002

0.112

±

0.004

100

78 Se

1.03

15.6

0.205

±

0.032

0.054

±

0.003

380

78 -> 94 Se

0.31

11.2

0.061

±

0.007

0.054

±

0.003

113

85 Rb

69.7

1.2

13.88

±

0.16

14.89

±

0.27

93

88 Sr

421.0

1.3

84

±

1

85*

95 Mo

2.1

2.8

0.42

±

0.01

0.46*

99
91

107 Ag

0.09

9.1

0.018

±

0.002

0.017*

104

111 Cd

7.4

1.4

1.47

±

0.02

1.52

±

0.04

97

121 Sb

0.28

3.4

0.055

±

0.002

0.063

±

0.006

88

138 Ba

302.8

2.1

60.3

±

1.3

202 Hg

0.15

2.4

0.030

±

0.001

232 Th

0.52

2.1

0.104

±

0.002

0.12*

87

238 U

0.14

2.3

0.029

±

0.001

0.035*

81

63*
0.034

±

96
0.004

88

* Reference value
Bold values for As and Se were obtained in single quad mode with He cell gas. The accurate results obtained using MS/MS mode with O2 mass-shift are shown in thelines below.

238

Table 8. Results for the High Purity Standard Mixed Food Diet Solution, n = 24.
Element

Measured Solution
Concentration (μg/L)

RSD (%)

Calculated Sample
Concentration (mg/kg)

Certified Concentration(mg/kg)Recovery
(%)

23 Na

15808

2.9

61.8

±

1.8

60.0

±

0.6

105

24 Mg

3300

2.3

12.9

±

0.3

12.0

±

0.1

108

27 Al

26

4.5

0.100

±

0.005

0.100

±

0.002

100

31 -> 47 P

15543

3.3

60.8

±

2.0

60.0

±

0.6

101

39 K

41898

2.2

164

±

4

160

±

2

102

44 Ca

9800

2.7

38.3

±

1.0

40.0

±

0.4

52 Cr

0.55

10.4

0.0021±0.0002

55 Mn

49.2

1.7

0.192

±

0.003

0.200

±

0.004

96

56 Fe

204.5

1.8

0.80

±

0.01

0.80

±

0.01

100

59 Co

0.2

2.4

0.0008±0.0000

60 Ni

5.1

2.5

0.020

±

0.001

0.020

±

0.001

99

63 Cu

15.3

1.7

0.060

±

0.001

0.060

±

0.006

100

66 Zn

74.5

2.0

0.29

±

0.01

0.30

±

0.01

97

75 As

5.1

2.0

0.020

±

0.000

0.020

±

0.001

99

75 -> 91 As

5.2

2.6

0.020

±

0.001

0.020

±

0.001

102

78 Se

1.26

14.8

0.0049±0.00070.005*

99

78 -> 94 Se

1.31

6.6

0.0051±0.00030.005*

102

95 Mo

1.5

3.1

0.0059±0.0002111 Cd2.0

2.1

0.0078±0.00020.002*

0.0008*98

0.006*
0.0080

±

96
107

98
0.000898* Reference value
Bold values for As and Se were obtained in single quad mode with He cell gas. The accurate results obtained using MS/MS mode with O2 mass-shift are shown in thelines below.

Conclusion
The Agilent 8900 Standard configuration ICP-QQQ with UHMI offers therobustness and matrix tolerance required for the routine analysis of the widest
range of trace and major elements in high matrix samples, such as food digest
samples. Doubly-charged REE interferences that can affect the accurate
measurement of arsenic and selenium at trace levels were avoided using O2 cellgas with MS/MS mass-shift mode. Most other elements were measured in He
mode; a field-proven method that is widely used to remove common matrixbased polyatomic interferences in complex and variable matrices.
While not all food products, soils and sediments contain significant
concentrations of REEs, the use of ICP-QQQ with MS/MS improves the accuracy
and confidence in the results for As and Se measured in food and environmental
samples that often contain complex, variable, high TDS matrices.
Method development was greatly simplified with the use of Pre-set Methods andauto tuning, which ensures reproducible performance irrespective of operator
experience.

239

References
1. Ed McCurdy and Glenn Woods, J. Anal. At. Spectrom., 2004, 19, 607-615
2. Brian P Jackson et al, J. Anal. At. Spectrom., 2015, 30, 1179-1183
3. Kazuhiro Sakai, Agilent Application Note, 2015, 5991-6409EN
4.	Agilent 8800 ICP-QQQ Application Handbook, Second Edition, 2015,
5991-2802EN
5.	Lieve Balcaen et al, Anal. Chim. Acta, 2014, 809, 1-8
6.	S.D. Fernandez et al, Geochem Geophy Geosy, 2015, 16, 2005 - 2014
7.	Takeshi Ohno and Yasuyuki Muramatsu, J. Anal. At. Spectrom., 2014, 29,
347-351
8.	Clarice D. B. Amaral et al, Anal. Methods, 2015, 7, 1215-1220.
9.	Erik H. Larsen, Stefan Sturup, J. Anal. At. Spectrom., 1994, 9, 1099-1105
10.	Maurizio Pettine, Barbara Casentini, Domenico Mastroianni, Silvio Capri, Anal.
Chim. Acta, 2007, 599, 2, 191-198
11.	Wim Proper, Ed McCurdy and Junichi Takahashi, Agilent Application Note,2014, 5991-4257EN

240

> Return to table of contents> Search entire document

Routine Elemental Analysis of Dietary Supplements
using an Agilent 8900 ICP-QQQ
Authors
Kazuhiro Sakai,Agilent Technologies Inc.

Effective removal of doubly charged and oxide ion interferences
ensures accurate measurement of As and Cd
Introduction
Global consumer demand for dietary supplements is expected to increasesteadily over the next few years (1). Dietary supplements contain ingredientssuch as nutrients, vitamins, and minerals that may be lacking in the consumer’s
normal diet. Supplements are marketed as supporting a balanced diet as part ofa healthy lifestyle, and therefore differ from drugs that are intended to treat or
prevent an illness. Supplements may be consumed in forms such as tablets,
capsules, softgels, gelcaps, powders, and liquids (2). In the European Union,
the term food supplement is usually applied to products that are called dietary
supplements in the US (3).
As with any food product, dietary supplements may be subject to contamination.
For example, trace metals can be introduced from raw materials, during
manufacturing/processing, or from packaging materials. Therefore, theresponsibility for a product’s quality and safety lies mainly with manufacturers
and distributors. In the European Union, manufacturers must adhere to
regulations on labeling, contents, claims, and dosage recommendations (3).
The U.S. Food and Drug Administration (FDA) also requires accurate labelingaccording to current Good Manufacturing Practice (cGMP) and labeling
regulations (2). Since any unsafe or mislabeled products can be taken off themarket, manufacturers are increasingly testing their products for potential
contaminants including trace elements.
To assist manufacturers with quality assuring their products, the United States
Pharmacopeia (USP) issued General Chapter <2232>, which deals with theregulation of Elemental Contaminants in Dietary Supplements (4). While <2332>
is intended for products labeled as conforming to USP or National Formulary (NF)
standards, it contains useful guidance for analysts.
In this study, triple quadrupole ICP-MS (ICP-QQQ) was used for the routine
analysis of the four most toxic elements—arsenic, cadmium, lead, and mercury—in dietary supplements.

241Improved interference removal with ICP-QQQ
The Agilent 8900 ICP-QQQ features a unique tandem MS configuration,
comprising a scanning quadrupole mass analyzer either side of an octopolebased collision/reaction cell (CRC). This configuration enables the 8900 ICP-QQQ
to use MS/MS mode to resolve difficult spectral interferences using reactive cellgases in a wide range of sample types (5 to 9). MS/MS mode is also beneficial forthe more difficult elements and problematic interferences sometimes
encountered in routine applications, such as the analysis of food samples, soils,
wastewater, and groundwater (5).
Solving doubly charged and oxide interferences
Due to their toxicity, many countries regulate the permitted concentrations ofAs and Cd in drinking water, surface water, soils, foodstuffs, and drugs. The onlyisotope of As (m/z 75) can suffer spectral interferences from polyatomic ions
including ArCl+ and CaCl+. These interferences can be reduced using single
quadrupole ICP-QMS operating in helium collision mode (He mode), allowing theaccurate measurement of As at the concentration levels required to meet typicalregulatory demands. While He mode can be considered a universal cell gas for
reducing polyatomic interferences using kinetic energy discrimination (KED),
KED is not effective against doubly charged (M++) ion overlaps. The lanthanides
or rare earth elements (REE) can form doubly charged ions (REE++) which
overlap As (and Se) (10, 11). Also, KED does not eliminate oxide interferences well(5). For example, 59Co16O+ interference on 75As+, 95Mo16O+ on 111Cd+, and 98Mo16O+
on 114Cd+. Vitamin B 12 is rich in Co as cyanocobalamin, and multimineral
supplements are rich in Mo, included as an essential nutrient (12).
ICP-QQQ has been shown to be effective for the removal of M++ and oxideinterferences on various analytes using a reactive cell gas (11). Many elemental
ions react with O2 to form an oxide ion, while the M++ interference remains
unreactive or is much less reactive. This allows the element of interest to bequantified by measuring the oxide ion at + 16 u, free from the spectralinterference.
CoO+ does not react with O2, while As+ reacts with O2 to form AsO, allowing AsO
and Co to be separated. MoO+ reacts with O2 to form MoO2+, while Cd+ does notreact with O2, allowing MoO and Cd to be separated. To test the method, 1 ppb As
was determined in a series of solutions containing 0 to 100 ppm Co, and 1 ppb
Cd was determined in solutions containing 0 to 10 ppm Mo. All solutions wereanalyzed in He mode (to represent conventional ICP-QMS) and MS/MS modeusing O2 cell gas (only available with ICP-QQQ).
As shown in Figure 1, He mode is suitable for the analysis of As and Cd inmatrices that contain Co and Mo at low ppm concentrations. However, poor
recoveries were achieved for As in the presence of 100 ppm Co and Cd in a
10 ppm Mo matrix. In contrast, ICP-QQQ operating in MS/MS mode with O2 cellgas avoided the oxide ion interferences on As and Cd, respectively, at all matrix
concentrations. The method allows consistent, low-level determination of As,
measured as 75AsO+ at m/z 91, and 111Cd+ at m/z 111.

242

Figure 1. Left: Recoveries of 1 ppb As spikes in a series of Co matrix solutions. Right: Recoveries of 1 ppb Cd spikes in a series of Mo matrix solutions.
He mode results (blue bars) and MS/MS O2 mode results (green bars).

Experimental
Standard reference materials
Three National Institute of Standards and Technology (NIST) standard referencematerials (SRMs) were analyzed in this study, including 1515 Apple Leaves,
1573a Tomato Leaves, and 3280 Multivitamin/Multielement tablets (Gaithersburg
MD, USA). The Apple Leaves SRM contains low μg/kg levels of As in the presenceof mg/kg levels of REEs.
Samples and sample preparation
Three vitamin supplements and two multimineral supplements were bought in a
local store in Tokyo, Japan. All SRMs and samples were prepared using a single
microwave digestion method. A subsample of 0.20 g was accurately weighed andplaced in a PTFE microwave vessel and 6.0 mL of 61% Electronic grade nitric acidand 1.0 mL of 36% Electronic grade hydrochloric acid (Kanto Chemical Co., Inc,
Japan) were added. The samples were left for 20 minutes before being placed
into a microwave (Mars 6, CEM) and digested using the program given in Table 1.
The fully digested samples were then diluted to 50 mL with de-ionized water(DIW). The final digests of the multimineral supplements were further diluted
two-fold with acid diluent (total of 12.0 mL HNO3, 2 mL HCl, and 86 mL DIW) tomatch the acid concentration of the other samples.
Although vitamins are water soluble, they were acid-digested because thecarbon concentration was expected to be high. Carbon present in the sample
solution enhances the ICP-MS signal of some elements, notably As, Se, and P,
although the precise mechanism of the enhancement is not clearly understood(13, 14). With the high temperature used in this work (210 °C), the carbon in thesamples converts to CO2 through acid digestion, so the carbon concentration in
the sample solution decreases. If any residual carbon did remain, its effectcould be mitigated by adding 2% butan-1-ol online with the internal standard(ISTD) solution.

243

Table 1. Microwave digestion program.
Temperature (°C)

Ramp Time (min)Hold Time (min)

210

15

15

Ventilation

30

Calibration standards and internal standards
Calibration standards for As, Cd, Hg, and Pb were prepared from 1000 ppm
single element standards (Kanto Chemicals, Tokyo, Japan). The ISTD solution
containing Ge, In, Tl, and Bi was also prepared from single element standard(Kanto Chemicals). Calibration standards and ISTDs were prepared to match theacid content of the sample solutions. The ISTD was added to the sample using
the standard online ISTD kit.
Instrumentation
An Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ, Standard configuration)with UHMI technology was used. The ICP-QQQ was fitted with the standard
sample introduction system consisting of a glass concentric nebulizer, quartz
spray chamber, and Ni interface cones. The plasma conditions were selectedaccording to the sample type and expected matrix level using the “preset plasma”
function of the Agilent ICP-MS MassHunter software. UHMI allows matrices ashigh as 25% NaCl solution to be analyzed (15).
Acquisition conditions
The method was based on an appropriate preset method for food samples, which
was modified to include O2 cell gas mode. Preset plasma conditions “HMI-4” wereselected, where the number 4 represents the approximate aerosol dilution factor.
The HMI setting automatically applies the predefined and calibrated parameters
for RF power, sampling depth, nebulizer gas flow rate, and dilution gas flow rate.
Automating these settings speeds up and simplifies instrument set up as well as
ensuring precise and reproducible plasma conditions for the target sample types.
The lens voltages were autotuned for maximum sensitivity. Table 2 summarizes
the instrument operating parameters.
Table 2. ICP-QQQ operating conditions.
Parameter

Setting

Cell mode

He modeO2 modeScan type

Single Quad

MS/MS

Plasma conditions

HMI-4

RF power (W)1600

Sampling depth (mm)10Nebulizer gas flow rate (L/min)

0.82

Dilution gas flow rate (L/min)

0.15

Extract 1 (V)0Extract 2 (V)-250

Omega bias (V)-130

Omega lens (V)8.6

Cell gas flow (mL/min)

5.5

0.45
30% of full scale

Energy Discrimination (V)5-7

Shaded parameters are predefined by selecting HMI-4 preset plasma conditions.

244

Results and discussion
Calibration curves for As and Cd acquired in He mode and MS/MS mode with O2
cell gas are shown in Figure 2.

Figure 2. Calibration curves for As (top) and Cd (bottom).

All analytes were measured in He mode, and As and Cd were also analyzed in
MS/MS O2 mode. Three sigma method detection limits (MDLs) and 10 sigma
Limit of Quantitation (MLOQs) were calculated from 10 measurements of the
preparation blank (Table 3).
SRM recovery
The accuracy of the method was evaluated by analyzing the three SRMs as
unknown samples. Each SRM was measured nine times in the batch. The mean
concentrations and relative standard deviation (%RSD) were calculated andcompared to the certified value, as shown in Tables 4 to 6. The results for all
elements were in good agreement with the certified and reference values.
The results for the Apple Leaves SRM and, to a lesser extent Tomato Leaves,show that more accurate recoveries were obtained for As using O2 mass shiftmode compared to He mode. The results illustrate the potential error that can becaused by the relatively high level of REEs in these two reference materials.
Quantitative analysis of bought products and spike recoveries
The 8900 ICP-QQQ was used to analyze three vitamin supplements (Samples 1 to3) and two multimineral supplements (Samples 4 and 5). The quantitative results
and spike recovery results are shown in Tables 7 and 8, respectively. The spikes
were added to the microwave vessels before microwave digestion. The spikerecoveries for all elements were ±10% of the expected values.
Table 4. Results for NIST 1515 Apple Leaves. The shaded value for As was
obtained in single quad mode with He cell gas. The unshaded (accurate) result
was obtained using MS/MS mass-shift mode with O2.

245

Table 3. Method Detection Limits and Method Limits of Quantification.
Analyte

Q1

Q2

Cell
Mode

Integration
Time (sec)ISTD

In Solution
Prep Blank (n=10)

In Sample
Multimineral

In Sample
Other Samples

MDL
µg/L

MLOQ
µg/L

MDL
µg/g

MLOQ
µg/g

MDL
µg/g

MLOQ
µg/g

75

He

1

72

Ge

0.00670.022

0.00330.011

0.00170.0055

91

O2

1

72

Ge

0.00150.00500.00080.00250.00040.0013

111

He

1

115

In

0.00190.00620.00090.00310.00050.0016

111

O2

1

115

In

0.00050.00180.00030.00090.00010.0004

Hg

202

He

3

205

Tl

0.00040.00140.00020.00070.00010.0004

Pb

208

He

1

209

Bi

0.00270.00890.00130.00440.00070.0022

As
As

75

Cd
Cd

111

Table 4. Results for NIST 1515 Apple Leaves. The shaded value for As was obtained in single quadmode with He cell gas. The unshaded (accurate) result was obtained using MS/MS mass-shift modewith O2.
Q1

As

Q2

Cell
Mode

Measured
Solution
Concentration(μg/L)

RSD %
(n=9)

Calculated
SampleConcentration(mg/kg)

75

He

1.6

1.1

0.406 ± 0.004

CertifiedConcentration(mg/kg)0.038 ± 0.007

Recovery (%)

1069

91

O2

0.14

2.1

0.035 ± 0.001

111

He

0.057

13

0.014 ± 0.002

111

O2

0.059

4.3

0.015 ± 0.001

Hg

202

He

0.18

4.6

0.045 ± 0.002

0.044 ± 0.004

102

Pb

208

He

2.0

2.4

0.49 ± 0.012

0.47 ± 0.024

104

As

75

Cd
Cd

111

0.014 *

91
102
105

*Reference value

Table 5. Results for NIST 1573a Tomato Leaves. The shaded value for As was obtained insingle quad mode with He cell gas. The unshaded (accurate) result was obtained using MS/MS
mass-shift mode with O2.
Q1

Q2

Cell
Mode

75

He

0.56

6.7

0.139 ± 0.009

91

O2

0.45

2.6

0.113 ± 0.001

111

He

6.1

7.8

1.53 ± 0.12

111

O2

6.4

6.7

1.60 ± 0.11

Hg

202

He

0.12

8.2

0.031 ± 0.003

0.034 ± 0.004

91

Pb

208

He

2.6

9.1

0.64 ± 0.058––

CertifiedConcentration(mg/kg)Recovery (%)

As
As

75

Cd
Cd

111

Measured
Solution
Concentration(μg/L)

RSD %
(n=9)

Calculated
SampleConcentration(mg/kg)

CertifiedConcentration(mg/kg)0.112 ± 0.004

1.52 ± 0.04

Recovery (%)

124
101
101
105

Table 6. Results for NIST 3280 Multivitamin/Multielement Tablets.
Q1

As

Cell
Mode

Measured
Solution
Concentration(μg/L)

RSD %
(n=9)

Calculated
SampleConcentration(mg/kg)

75

He

0.25

2.7

0.127 ± 0.003

0.132 ± 0.044

96

91

O2

0.24

2.2

0.119 ± 0.003

111

He

0.17

4.4

0.0851 ± 0.0037

111

O2

0.16

6.5

0.0802 ± 0.0052

0.08015 ±
0.00086

100

Hg

202

He

< 0.0004–< 0.0002

–

–

Pb

208

He

0.53

4.1

0.266 ± 0.011

0.2727 ± 0.0024

97

As

75

Cd
Cd

246

Q2

111

90
106

Table 7. Quantitative results for vitamin supplements.
Sample 1
Q1

Sample 2

Sample 3

Q2

Cell Unspiked Spiked
Spike
Calculated Unspiked Spiked
Spike
Calculated Unspiked Spiked
Spike
Calculated
SampleSampleSampleMode (μg/L)(μg/L) Recovery(μg/L)(μg/L) Recovery(μg/L)(μg/L) Recovery(%)
Concentration(%)
Concentration(%)
Concentration(μg/g)(μg/g)(μg/g)

75

He

0.035

1.10

106

0.0086<0.00671.10

110<0.0017

0.024

1.08

105

0.006

91

O2

0.038

1.08

104

0.0093<0.00151.04

104<0.0004

0.021

1.07

105

0.005

111

He

0.013

1.05

103

0.0031<0.00191.02

102<0.0005<0.00191.01

101<0.0005

111

O2

0.014

1.10

109

0.00340.00081.07

1060.00020.00091.05

1050.0002

Hg

202

He

<0.0004

0.098

98<0.0001<0.0004

0.098

98<0.0001<0.0004

0.098

98<0.0001

Pb

208

He

0.029

1.07

104

0.0069

0.011

1.04

103

0.0026

0.007

1.03

102

0.0018

As
As

75

Cd
Cd

111

Table 8. Quantitative results for multimineral supplements.
Sample 4

Sample 5

Q1

Q2

Cell Unspiked Spiked
Spike
Calculated
Unspiked Spiked
Spike
Calculated
SampleSampleMode (μg/L)(μg/L) Recovery(μg/L)(μg/L) Recovery(%)
Concentration(%)
Concentration(μg/g)(μg/g)

75

He

0.38

1.37

100

0.18

0.47

1.46

99

0.23

75

91

O2

0.33

1.35

102

0.16

0.45

1.38

92

0.23

111

He

0.21

1.17

97

0.10

0.29

1.21

92

0.14

111

O2

0.21

1.21

101

0.10

0.29

1.26

97

0.14

Hg

202

He

0.00190.098

970.00090.00150.094

920.0007

Pb

208

He

0.29

1.29

100

0.14

0.12

1.06

94

0.060

As
As
Cd
Cd

111

Correction techniques using single quadrupole ICP-MS
All five samples could be measured in He mode using a single quadrupole
ICP-QMS. However, if the ratio of Co/As and/or Mo/Cd is high, there would beinterference from 59Co16O+ on 75As+ and 95Mo16O+ on 111Cd+. Because it is difficult
for the analyst to be aware of oxide interferences, the Quick Scan function can beused to identify all elements present in the sample. As shown in Figure 3, by
checking the Quick Scan data, potential interferences can be identified, such as
CoO+ based on the high concentration of Co in one of the samples.
Once any potential interferences have been identified using Quick Scan,interference correction equations can be applied to compensate for doubly
charged and oxide interferences.
Alternatively, it is possible to perform routine analysis without prior knowledge ofpotential interferences using an 8900 ICP-QQQ operating in MS/MS mode.

247

Figure 3. ICP-MS MassHunter Quick Scan qualitative results showing a high concentration of Co in one of the samples.

Conclusion
The Agilent 8900 ICP-QQQ with UHMI effectively removes challenging spectralinterferences making it suitable for the routine analysis of the trace elements inhigh matrix samples such as multimineral supplements.
Doubly charged REE interferences that can affect As measurement at tracelevels were avoided using O2 cell gas and MS/MS mass-shift mode, as shownby the recoveries for the Apple Leaves SRM. Also, oxide interferences that canaffect As and Cd measurement at trace levels were avoided using the same MS/
MS method. Excellent recoveries were achieved for Hg and Pb using He mode –a proven technique for the removal of common matrix-based polyatomic
interferences in complex and variable matrices. Therefore, it is possible toperform routine analysis of all elements without prior knowledge of potential
interferences using an 8900 ICP-QQQ operating in He mode and MS/MS mode.
For laboratories without access to ICP-QQQ, only ICP-QMS, the Quick Scanfunction of ICP-MS MassHunter can be used to identify potential interferencesfrom M++ and oxide ion interferences. These interferences can then be correctedusing interference correction equations.

248

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249

> Return to table of contents> Search entire document

Accurate and Sensitive Analysis of Arsenic and Selenium
in Foods using ICP-QQQ to Remove Doubly-Charged
REE Interferences
Authors

Introduction

Brian Jackson, Dartmouth College,
Hanover, New Hampshire, USA

Concern about the impact on public health from potentially toxic elements andcompounds present in everyday foodstuffs has led to new legislative guidance[1, 2]. The inorganic forms of arsenic (As) are known to be toxic and carcinogenic
to humans, and food and drinks are a potential source of exposure [3]. Selenium(Se) is an essential micro-nutrient that can be deficient in the diet as Se-poor soils
yield Se-poor food crops. Accurate quantification of Se in food is necessary toassess nutrient status.

Amir Liba, Jenny Nelson,
Agilent Technologies, USA

Keywords
arsenic, selenium, rare earth elements,
environmental, agricultural, humanhealth, NIST 1547 Peach Leaves, NIST
1515 Apple Leaves, oxygen mass-shift

As and Se can be difficult to quantify accurately at trace levels by conventional
quadrupole ICP-MS (ICP-QMS), as all the analytically useful isotopes can sufferfrom multiple spectral interferences, as shown in Table 1. Potential interferenceson As and Se include the doubly-charged ions of the Rare Earth Elements (REE++)
and matrix and plasma-born polyatomic ions. The quadrupole mass
spectrometer separates ions based on mass to charge ratio (m/z), so the REE++
ions appear at half their true mass, overlapping the singly-charged analyte ions ofAs and Se. Typically the REE content in food samples is low, but crops grown in
REE-enriched soils may take up higher concentrations of these elements [4, 5]
leading to false positive results for As and Se. In this study, we evaluated thecapability of the Agilent 8800 ICP-QQQ in MS/MS reaction mode to remove
interferences, including REE++, on As and Se.
Table 1. Spectroscopic interferences on As and Se isotopes.
As and Se isotope

Interference

Element

Mass

Abundance %Doubly charged

As

75

100

150
150

Se

77

7.63

154
154

78

23.77

156
156

80

49.61

160
160

82

8.73

164
164

250

Matrix

Dimer

Sm++,
Nd++

40

Sm++,
Gd++

40

Gd++,
Dy++

41

Gd++,
Dy++,

32

40

32

40

Dy++,
Er++

45

40

40

Ar35Cl+,Ca35Cl+Ar35Cl+,Ca35Cl+K37Cl+

38
39

S216O+,
S16O3+,40
Ca40Ar+,45
Sc35Cl+
Sc37Cl+Ar40Ar+,
K39K+
Ar40Ar+,
Ca40Ca+Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/General purpose.
Acquisition parameters: MS/MS mass-shift mode using O2/H2 at a gas flow of 0.6
mL/min and 1.0 mL/min respectively. As was measured as the reaction product ion
AsO+ at m/z 91, and Se was measured as SeO+ at m/z 96.
Reagents: Two National Institute of Standards and Technology (NIST) standard
reference materials (SRMs), NIST 1547 Peach Leaves and NIST 1515 Apple
Leaves, were studied. These SRMs contain low µg/kg levels of As and Se in thepresence of mg/kg levels of REEs.
Sample prep: All samples were acid digested using a closed vessel microwave
digestion system. The SRMs were prepared in triplicate. First, 0.25 g sample wasdigested in 2.5 mL of 9:1 HNO3:HCl acid mix, and the digest was then diluted to a
final weight of 25 g with ultra-pure water. 5% butanol was added to the internal
standard mixture to equalize the organic plasma load between samples andstandards. NIST 1547 and 1515 contain low µg/kg concentrations of As and Se(Table 2) and high concentrations of REEs. Reference (non-certified) values for Nd,
Sm and Gd are 7, 1, and 1 mg/kg in NIST 1547, and 17, 3, and 3 mg/kg in NIST
1515, respectively.

Results and discussion
Both SRM digests were analyzed using the 8800 ICP-QQQ with O2/H2 as thereaction gas (Table 2). A previous study showed that the presence of H2 in thecell further improved Se detection capability [6]. The measured values for As and
Se in NIST 1547 and 1515 were well within the certified range for both SRMs,
demonstrating the successful elimination of the REE++ interferences in O2/H2
MS/MS mode on the 8800. These results were obtained without the need forcorrection equations (i.e. uncorrected).
Table 2. Analysis of As and Se in NIST 1547 and 1515 in He mode and H2 mode using ICP-QMS (bothuncorrected and corrected data is given) and by ICP-QQQ in MS/MS mode. All concentrations are in
mg/kg, and are averages of 3 replicate sample digests expressed as mean ± standard deviation.
ICP-QMS He mode
SRM

Certified

Uncorrected

Corrected

ICP-QMS H2 mode
Uncorrected

Corrected

ICP-QQQ O2/
H2 mass-shift
Uncorrected

As (mg/kg)
NIST 1547

0.060±0.018 0.170±0.016

0.068±0.003* 0.113±0.004

0.079±0.004* 0.065±0.002*

NIST 1515

0.038±0.007 0.250±0.016

0.026±0.021* 0.126±0.005

0.047±0.004* 0.032±0.002*

NIST 1547

0.120±0.009 0.394±0.04

0.113±0.02*

0.119±0.009*

0.119±0.009* 0.127±0.006*

NIST 1515

0.050±0.009 0.808±0.04

0.013±0.04*

0.050±0.003*

0.050±0.003* 0.047±0.006*

Se (mg/kg)*95% confidence interval overlaps with the certified range

251

Results obtained using ICP-QMS are included for comparison purposes.
"Corrected" refers to the use of correction equations. ICP-QMS operating in helium
mode is suitable for the analysis of As and Se in general routine sample types
that might contain a small amount of REEs, and H2 mode has been shown to beeffective at reducing doubly charged species. Compared to these conventional
methods, ICP-QQQ had 10-fold lower detection limits, which makes it particularly
suited to low level determination of As and Se in complex sample matrices.
ICP-QMS can also use O2 mass-shift mode but, with ICP-QMS, all matrix andanalyte ions enter the cell, so the analyte reaction product ions measured(75As16O+ at m/z 91, and 78Se16O+ at m/z 94), could suffer overlap from existing
analyte or matrix ions at the product ion mass (e.g. 91/94Zr+ and 94Mo+). To confirm
that the ICP-QQQ MS/MS method can be applied to samples that contain highconcentrations of Zr and Mo, an aliquot of NIST 1547 was spiked with 1 mg/L
(1000 ppm) Zr and Mo, and the results are shown in Table 3. The measured
values for As (as AsO+) and Se (as SeO+) in the spiked sample are the same as forthe unspiked samples, demonstrating that MS/MS mode is effective at rejecting
existing overlapping ions present at the mass of the cell-formed analyte productions. This capability is unique to the tandem mass spectrometer configuration of
the 8800 ICP-QQQ, where the ions that enter the cell are controlled by anadditional mass filter, Q1, positioned in front of the collision/reaction cell.
Table 3. ICP-QQQ measured results for As and Se in NIST 1547 unspiked and spiked with 1 mg/L
Zr and Mo. No correction equations were applied.
ICP-QQQ O2/H2 mass-shift
SRM NIST 1547

Certified

Unspiked (n=3)

Spiked with 1 mg/L Zr & Mo (n=1)

As (mg/kg)

0.060±0.018

0.065±0.002

0.063

Se (mg/kg)

0.120±0.009

0.127±0.006

0.13Conclusion
The Agilent 8800 ICP-QQQ with MS/MS capability has been shown to be theoptimum method to successfully measure trace levels of As and Se in thepresence of high concentration of REEs in NIST 1547 Peach Leaves and NIST
1515 Apple Leaves. All REE doubly-charged and matrix-based polyatomic
interferences that affect As and Se measurement at m/z 75 and m/z 78 areavoided using O2/H2 cell gas and MS/MS mass-shift mode. Arsenic is shifted toits product ion AsO+ which is measured at m/z 91, and Se is shifted to SeO+,
measured at m/z 94. Importantly, MS/MS mode also eliminates potential ion
overlaps at m/z 91 and m/z 94 from 91/94Zr+ and 94Mo+, as these ions are rejectedby Q1. The extent and concentration of REEs in food products is not well studied.
However, monitoring for the presence of Nd++, Sm++, and Gd++ at m/z 150 and
156 during an analysis would identify samples where doubly charged REE
formation might be problematic.

252

More information
For a full account of this application see publication: Advantages of reaction cell
ICP-MS on doubly charged interferences for arsenic and selenium analysis infoods, Brian P. Jackson, Amir Liba and Jenny Nelson, J. Anal. At. Spectrom., 2015,
Advance Article. DOI: 10.1039/C4JA00310A.

Acknowledgements
Brian Jackson acknowledges the support of NIEHS P42 ES007373, NIEHS P01
ES022832, EPA RD83544201 for the work presented herein.

References
1.	U.S.FDA. 2013. Guidance for Industry. Arsenic in apple juice: Action level.
2.	COMMISSION CA. 2014. Report of the eighth session of the codex committee
on contaminants in foods. CL2014/11-CF. Geneva, Switzerland.
3.	Agency for Toxic Substances and Disease Registry (ATSDR), 2007,
Toxicological Profile for Arsenic, U.S. Department of Health and Human
Services, Public Health Service
4.	Sucharova J. 2011. Optimisation of drc icp-ms for determining selenium inplants. J. Anal. At. Spectrom., 2011,26, 1756-1762
5.	Wang R-Y, Hsu Y-L, Chang L-F, Jiang S-J. 2007. Speciation analysis of arsenic
and selenium compounds in environmental and biological samples by ion
chromatography-inductively coupled plasma dynamic reaction cell mass
spectrometer. Anal Chim Acta 2007; 590: 23
6.	Sugiyama N. The accurate measurement of selenium in twelve diverse
reference materials using on-line isotope dilution with the 8800 Triple
Quadrupole ICP-MS in MS/MS mode, Agilent publication 2012, 5991-0259EN

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> Return to table of contents> Search entire document

Analysis of TiO2 Nanoparticles in Foods andPersonal Care Products by Single Particle ICP-QQQ
Authors
Janja Vidmar1
Katrin Loeschner1Raquel Larios2
National Food Institute, Technical
University of Denmark (DTU Food),
Denmark2
Agilent Technologies, Spain
1

Using the 8900 ICP-QQQ in MS/MS mass-shift mode to resolve
48
Ca+ isobaric interference on 48Ti+
Introduction
Titanium dioxide (TiO2) is classified as a food additive within the European Union(E171) and in the USA (INS171), where it is widely used as whitening andbrightening agent. In the EU, E171 can be used in several food categories withno maximum upper limit (quantum satis) (1). E171 mainly consists of larger
TiO2 particles, but it also contains a fraction of nanoparticles (NPs), which aredefined as particles with one or more dimensions less than 100 nm (2). TiO2 isalso used in food contact materials, cosmetics, and personal care products,
such as toothpaste.
With increasing production and use of TiO2 based additives, there is concern
among regulatory authorities and consumers about the potential impact ofhuman exposure to TiO2 NPs. Several toxicological studies on TiO2 NPs have been
carried out (3–5), but no general agreement on the effects of TiO2 NPs on
biological systems has been reached. The European Food Safety Authority (EFSA)
has released several scientific opinions (6, 7). EFSA concluded that the use of
TiO2 as a food additive does not raise a genotoxic concern and established a No
Observed Adverse Effect Levels (NOAEL) of 2.250 mg/TiO2 kg/bw per day.
However, when the French food safety agency, ANSES, reviewed recent studies
on TiO2, they found a lack of conclusive results on the safety of the E171 additive.
Following the appraisal, the French government announced that the sale of foodproducts containing TiO2 (E171) will be banned from January 1, 2020 (8). EFSA
recently released a scientific opinion stating the need for further research on theparticle size distribution of E171 in food (9).
European regulations state that all ingredients present in the form of engineered
nanomaterials shall be clearly indicated in the list of ingredients. The names ofsuch ingredients shall be followed by the word ‘nano’ in brackets (10). In 2011,
the European Commission published a recommendation for the definition of ananomaterial suggesting that for regulatory purposes, the size distribution andnumber concentration of nanomaterials should be known (11). To keep pace withevolving regulations, effective analytical methods are needed for thecharacterization of TiO2 NPs in a range of sample types.
ICP-MS is a powerful tool for the characterization of NPs, providing composition
information that complements established techniques such as transmission andscanning electron microscopy (TEM/SEM), and dynamic light scattering (DLS).
When used in single particle (sp) mode, spICP-MS provides simultaneous
determination of the particle number and size distribution (assuming sphericalparticles). In addition, spICP-MS provides the concentrations of both the particles
and the dissolved content of the element or elements of interest. The ease-of-use
of modern ICP-MS instruments makes it the technique of choice for regulatory
purposes, while its flexibility ensures that the same instrument can be used for
multi-element analysis and speciation studies.

254

Titanium is a challenging element to measure by conventional single quadrupole
ICP-QMS. The isobaric interference on the most abundant isotope, 48Ti, by 48Ca
cannot be mass resolved by ICP-QMS. At its highest resolution setting, High
Resolution (HR) ICP-MS can theoretically resolve 48Ca from 48Ti, as the required
resolution (M/∆M) is 10,458. However, 48Ca is present at high concentrations inmany food samples, such as milk, making separation of the adjacent peaks moredifficult. Also, the combination of low sensitivity at high resolution, and peaktailing due to the poor abundance sensitivity of HR-ICP-MS means that thismeasurement is often not practical. Other elements such as sulfur, phosphorus,
silicon, and carbon, which are also present in many foods at significant
concentrations, form polyatomic interferences that hinder the accurate
measurement of 48Ti. Typically, the less interfered isotopes 47Ti or 49Ti aremeasured by ICP-QMS. However, these less abundant isotopes provide lower
sensitivity, which limits the detection of smaller-sized TiO2 NPs by ICP-QMS,
leading to biased size distribution results.
The Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) can operate in MS/MS
mode with reactive cell gases to resolve the spectral interferences on 48Ti,
including the isobaric interference from 48Ca. The first quadrupole, Q1,
positioned before the collision/reaction cell (CRC), operates as a unit mass filter,allowing only the ions with target m/z to enter the cell and rejecting all ions ofdifferent masses. Analyte-ion selection by Q1 enables excellent control of thereaction chemistry in the cell. Also, the low background, high sensitivity, andvery short dwell times (100 μs) of the 8900 enable the ICP-QQQ to detect
small-sized particles.
In this study, TiO2 NPs present in different food samples and toothpaste werecharacterized by spICP-MS using an Agilent 8900 ICP-QQQ. The results show thebenefits of triple quadrupole (MS/MS mode) technology with O2/H2 cell gases toresolve polyatomic and isobaric interferences on 48Ti.

Experimental
Standards and reference materials (RM)
NIST 8012 gold NPs RM (Gaithersburg, MD, USA) and ionic gold standards(PlasmaCAL standard, SCP Science, Baie D'Urfé, QC, Canada) were used.
The gold NP RM, with a known average particle diameter of 27.6 nm asdetermined by TEM, and the ionic gold standard were analyzed to calculate thenebulization efficiency.
To determine the response factor for titanium, ionic titanium standard(PlasmaCAL standard, SCP Science) was used. Solutions of 5 to 200 ng Ti/mL in
100 times diluted milk (for milk samples) or 0.1% nitric acid (for TiO2 NPs in waterand food samples) were analyzed.

255

Anatase and rutile are two naturally occurring mineral forms of TiO2. Two TiO2
nanomaterials with different size distributions were used to spike milk samples
and check the performance of the method. The nanomaterials included a TiO2
representative test material, JRCNM 10200a (referred to as JRC NPs), from the
Joint Research Centre´s Nanomaterial Repository. The JRC NPs material
contains primary particles of 115 nm and consists of anatase. NIST 1898 TiO2
NPs SRM (referred to as NIST NPs) was also used. The NIST NPs SRM has a
primary size < 50 nm and consists of 76% anatase and 24% rutile.
Samples and sample preparation
The concentrations of Ca, S, and P in cow’s milk are in the range of 1070–1330µg/mL, 320 µg/mL, and 630-1020 µg/mL,respectively (12). A matrix mimicking adiluted (100 times) milk matrix was prepared by diluting ionic Ca, S, and P
standards (PlasmaCAL standards, SCP Science) in water. The final
concentrations were 10 µg/mL for Ca, 3 µg/mL for S, and 10 µg/mL for P(individually and as a mix). In addition, 10 ng/mL of ionic Ti was spiked into the
100-fold diluted simulated milk matrix, and in 0.1% nitric acid (HNO3).
Different food samples were bought from local stores in Denmark. The foods
included skimmed milk with 0.1% fat content, salad dressing, and cakedecorations (edible gold stars). A commercial toothpaste from a Dutch
supermarket, which was extensively studied in the EU FP7 Project “NanoDefine”(13), was also analyzed. Details of the sample preparation for each sample typewere as follows:– Milk spiked with TiO2 NPs: Stock suspensions of 1 mg TiO2/mL were prepared.
After appropriate dilution, TiO2 was spiked into undiluted skimmed milk at 200
and 400 ng TiO2/mL for JRC NPs, and 15 and 30 ng TiO2/mL for NIST NPs.
– Toothpaste: The sample preparation protocol was adopted from Correia
et al. (14). 100 mg of toothpaste was dispersed in 10 mL of ultrapure water(UPW) by vortexing. The solution was further diluted 10 times in 0.1%
sodium dodecyl sulfate (SDS, Sigma-Aldrich, St. Louis, MO, USA), followedby vortexing.
– Salad dressing: 100 mg of salad dressing was dispersed in 5 mL of 0.1%
SDS placed in a high intensity cup horn (Branson Digital Sonifier SFX 550).
The solution was further diluted 10 times in 0.1% SDS, followed by vortexing.
– Cake decorations: One golden star was added to 5 mL of UPW and dissolved,
with assistance from a high intensity cup horn. The solution was further
diluted 10 times in UPW, followed by vortexing.
– Before analysis, all samples were diluted with UPW (milk 100x, toothpaste
2500x, salad dressing 500x, and cake decoration 250x).

256

Instrumentation
An Agilent 8900 ICP-QQQ (#100, Advanced Applications configuration) was usedwith an SPS 4 autosampler. The instrument was equipped with a MicroMist
concentric nebulizer, Scott type double-pass quartz spray chamber, a quartz torchwith a small internal diameter (1.0 mm) injector, and standard nickel cones.
Samples were introduced directly into the ICP-QQQ via the standard peristaltic
pump and tubing. The operating conditions of the Agilent 8900 ICP-QQQ aredetailed in Table 1.
Table 1. ICP-MS operating conditions.
Parameter

Value

RF Power (W)1550

Sampling Depth (mm)8Nebulizer Gas (L/min)

0.70

Sample Inlet Flow (mL/min)~ 0.35

Spray Chamber Temperature (°C)

2

Dwell Time (ms)

0.1

Settling Time (ms)0Acquisition Mode

MS/MS (Q1: m/z 48, Q2: m/z 64)

Gas Flow Rates (mL/min)

O2: 0.15 (10% of full scale)H2: 7.0

Axial Acceleration (V)1.0

Octopole Bias Voltage (V)–6.0

Energy Discrimination (V)–15.0

Acquisition Time (s)60Data was acquired for 60 s with a dwell time of 0.1 ms for each sample.
The major titanium isotope, 48Ti, was measured in MS/MS mass-shift mode,using a mixed cell gas containing oxygen and hydrogen. The method was used toresolve all the isobaric interferences—mainly arising from 48Ca—and the matrixbased polyatomic interferences, such as those derived from C, S, and P. Q1 was
set to m/z 48 (the mass of the precursor 48Ti ion) and Q2 was set to m/z 64 (themass of the target product ion 48Ti16O). O2 promoted the formation of the 48Ti16O+
product ion, and H2 helped with the formation of 48Ca16O1H+, avoiding interferenceon 48Ti16O+ by 48Ca16O+ (Figure 1). The instrument operating parameters were also
used in a previous study (15). After each run, the sample introduction system wasrinsed using UPW, diluted acids, and Triton X-100.

Figure 1. Determination of 48Ti+ as 48Ti16O+ product ion using the 8900 ICP-QQQ operating in MS/MS mass-shift mode with O2/H2 as the reaction
cell gases.

257

The Single Nanoparticle Application Module of the Agilent ICP-MS MassHunter
software was used for method setup and data analysis. Analysis was performedin peak integration mode. The particle baseline was determined automatically by
the software. The particle detection threshold was adjusted manually, and thesame value was used for samples of the same type. The application of the same
threshold ensured that a direct comparison of particle mass concentrations andmedian particle diameters between samples was possible. A particle density of
3.9 g/cm³ and an analyte mass fraction (the value of molecular mass divided byanalyte mass) of 1.67 was used for the calculations. The sample inlet flow wasdetermined gravimetrically.

Results and discussion
Interference check in relevant matrices containing ionic Ti
To check the effectiveness of the MS/MS mass-shift mode to remove potential
interferences on Ti, solutions containing single interfering elements and a mixture
simulating 100 times diluted milk were analyzed (Table 2). The apparent Ti
concentration was measured in all the solutions, as 48TiO+ in MS/MS mode with
O2/H2, and as 48Ti+ without any reaction gas (in Single Quad and MS/MS modes).
The results in no gas mode (SQ and MS/MS) show a large positive error in all
matrices containing interfering elements, with the most pronounced errors in thepresence of Ca. In contrast, O2/H2 in MS/MS mode effectively reduced allinterferences, allowing the accurate measurement of Ti, even in the presence of Ca
and in the simulated milk matrix. The highest Ti sensitivity and the lowest detection
limit (DL) were also achieved in O2/H2 MS/MS mode. The results suggest that the8900 ICP-QQQ operating in MS/MS mass-shift mode with O2/H2 would detect
smaller sized particles compared to the two no gas modes.
Analysis of TiO2 NPs spiked into milk samples
TiO2 has been considered as a whitener for low-fat milk (16), although its addition
to milk is currently not permitted in Europe. To check the effectiveness of the method
to accurately measure TiO2 NPs of different size distributions and concentrations,two different TiO2 NPs (JRC and NIST) were spiked into the milk samples.
JRC NPs, which contain larger sized particles with a broader size distribution than
NIST NPs, resemble E171, which consists primarily of anatase. The fraction of NPs
in E171 ranges between 17 and 36% and the mean diameters of the primaryparticles range between 115 to 145 nm (17).
Table 2. Interference check results for 48Ti in various matrices, with and without cell gas.
MatrixCa
10 µg/mLS
3 µg/mL

Cell ModeP
10 µg/mLMix
Ca+S+P

10 ng/mL
Ti in Mix
Ca+S+P

10 ng/mL
Ti in 0.1%
HNO3
Sensitivity1(cps/ ng/mL)

Apparent Ti Measured Concentration, ng/mL

DL2(ng/mL)No gas MS/MS

35.6

0.395

0.264

36.3

41.7

9.58

207,044

4.1

No gas SQ

35.0

0.341

0.224

34.2

45.8

11.1

294,872

8.2

O2/H2 MS/MS

0.017

0.004

0.012

0.031

10.0

10.2

399,949

0.0075

1. Based on calibration curve of six ionic standards from 0.1 to 50 ng/mL ionic Ti in 0.1% HNO3
2. DL calculated as three times the standard deviation of four blanks (mix Ca + S + P)

258

Figure 2 shows the comparison of the measurement of the same TiO2 NPs
spiked at the same concentration into diluted milk or UPW and analyzed in MS/
MS mode with O2/H2 reaction gas. The particle size distributions were similar in
UPW and in the milk matrix for both particle types. In water and the milk-matrix,
the mean particle diameters were 226 ± 7 and 223 ± 2 nm (JRC NPs), and 78 ± 1
and 72 ± 2 nm (NIST NPs), respectively. The similarity of the results shows thatinterferences from Ca, S, or P in the milk matrix were resolved.
The particle size data agreed with existing data for the two particle types.
According to the certificate of analysis for the NIST NPs, the stable nanoscalespecies is a monomodal aggregate of fused crystallites with a modal size of
70 nm. The JRC NPs are similar to NM-100 (18), which contain primary particles
ranging from 20 up to 300 nm and aggregates ranging from 30 up to 700 nm.
The mean diameter obtained by TEM was 190 nm (18).
ultrapure water
100-times diluted milk

80
60
40
20
0

0

100

200

300

400

500

Figure1002 (left)

Normalized frequency (%)

Normalized frequency (%)

100

600

Particle size (nm)ultrapure water
100-times diluted milk

Figure 2 (right)

80
60
40
20
0

0

100

200

300

1
Particle
size (nm)2

Figure 2. Particle size distributions for 4 ng/mL JRC NPs (left) and 0.15 ng/mL NIST NPs (right) in
UPW and 100 times diluted milk measured in MS/MS mass-shift mode.

Similar particle size results were obtained by comparing the two spiked levels forboth NP types (Table 3). The average mass recoveries, which were in the range of
71 to 85%, were considered satisfactory.
Table 3. spICP-MS results for measuring JRC and NIST NPs in 100 times diluted milk at two
different concentration levels (n=3 for each spike level).
JRC NPs
2 ng/mL

JRC NPs
4 ng/mL

NIST NPs
0.15 ng/mL

NIST NPs
0.30 ng/mL

Number of Detected
Particles (particles/min)

917 ± 135

1624 ± 113

1648 ± 199

2988 ± 90

Particle Number Conc
(E+07 particles/L)

4.40 ± 0.55

7.80 ± 0.54

7.60 ± 0.92

13.80 ± 0.42

Particle Mass Conc(ng/mL)1.55 ± 0.26

2.91 ± 0.11

0.13 ± 0.01

0.25 ± 0.02

Mass Recovery (%)

76 ± 1371 ± 685 ± 781 ± 4

Median Particle Size (nm)204 ± 3210 ± 260 ± 262 ± 1

Mean Particle Size (nm)216 ± 0223 ± 272 ± 274 ± 0Effects of interferences on measurement of 47Ti and 48Ti in no gas mode
To show the interference removal benefits of MS/MS mass-shift mode compared
to SQ or MS/MS in no gas mode, 47Ti and 48Ti were measured without cell gas in
the same spiked diluted milk samples. NIST NPs were not detectable due to thehigh background on 47Ti and 48Ti. The larger JRC NPs were detectable (Figure 3),
but the minimum detectable size increased from 40 nm (MS/MS mass-shiftmode) to 213 nm (47Ti) and 160 nm (48Ti) in no gas mode. There was also an
increase in the median diameters from 210 nm (MS/MS mass-shift mode) to
292 nm, and 210 nm (MS/MS mass-shift mode) to 260 nm, respectively.

259

The high (ionic) background on 48Ti could be attributed to the isobaric
interference of 48Ca, as shown in Table 2. For 47Ti, a high particle background wasobserved in both the spiked and non-spiked milk matrix. As no particles weredetected in the non-spiked milk sample in MS/MS mass-shift mode, it could beconcluded that these were not Ti-containing particles, but likely caused bypolyatomic interferences.
m/z 47 (No gas)
m/z 48 --> 64 (O2/H 2)

80
60
40
20
0

0

100

200

300

400

500

Figure1003 (left)

Normalized frequency (%)

Normalized frequency (%)

100

80
60
40
20
0

600

Figure 3 (right)

m/z 48 (No gas)
m/z 48è--> 64 (O2/H2)0100

Particle size (nm)

200

300

400

500

600

Particle size (nm)Figure 3. Particle size distributions for 4 ng/mL JRC NPs in 100 times diluted milk determinedby analyzing 47 Ti in no gas mode (left) and 48Ti in no gas mode (right). For comparison purposes,
the size distribution obtained in MS/MS mode with O2 /H2 gas is shown in grey in both graphs.

Analysis of TiO2 NPs in toothpaste, salad dressing, and cake decorations
Other products that include TiO2 in the list of ingredients were analyzed.
Toothpaste, salad dressing, and a cake decoration (edible golden star) wereselected as examples. The particle size distribution results, which are presented
in Figure 4, show that each of the samples contains TiO2 NPs with different size
ranges. The cake decoration contained the smallest sized NPs (median size of 54nm), while the salad dressing contained the largest particles (median size of 334nm). The particle sizes determined in toothpaste (median size 155 nm) agreed
with previously published results (14). The fraction of particles < 100 nm was 22,
3, and 70% for toothpaste, salad dressing, and the cake decoration, respectively.
The average TiO2 mass concentrations were in the mg/g sample range.
80
60
40
20
0

0

100

200

300

Particle size (nm)

400

500

Salad dressing

80
60
40
20
0

0

200

400

600

5
Particle
size (nm)800

Figure1004

Normalized frequency (%)

Figure1004

Toothpaste

Normalized frequency (%)

Normalized frequency (%)

100

Cake decoration

Figure 4

80
60
40
20
0

0

100

200

300

6
Particle
size (nm)

400

500
7

Figure 4. Particle size distributions for TiO2 NPs in toothpaste (left), salad dressing (middle),
and a cake decoration (right).

Conclusion
A single particle ICP-MS method was developed for the determination andcharacterization of TiO2 NPs in foods and personal care products. An Agilent
8900 ICP-QQQ was used in the study, since its high sensitivity and short dwell
times provide fast analysis times and excellent detection limits for thedetermination of small-sized particles. Also, the advanced interference-removal
capabilities of ICP-QQQ using MS/MS allowed the analysis of the most abundanttitanium isotope, 48Ti, enabling the accurate analysis of small-sized TiO2 NPs.
Operating the ICP-QQQ in MS/MS mode with O2/H2 cell gas, isobaric (48Ca) andpolyatomic interferences on 48Ti were successfully resolved in matrices
containing high concentrations of P, S, and Ca. By measuring 48Ti rather
than the less abundant Ti isotopes, a particle size detection limit of 30 nm wasachieved for TiO2 NPs.
260

The method was used for the characterization of TiO2 NPs in foods that are
known to contain the food additive E171, including toothpaste, salad dressing,and a cake decoration. spICP-MS can be used to indicate the elemental
composition and size of particles in a sample, complementing the information on
particle size and shape provided by electron microscopy.
Having access to reliable analytical methods for the characterization of NPs isimportant, as France will ban the sale of food products containing E171 fromJanuary 1, 2020. EFSA has also identified the need for further research on theparticle size distribution of TiO2 NPs in food.

Acknowledgments
We thank Luisa Hässmann for her contribution to the experimental work andMichiko Yamanaka (Agilent) for her technical support.

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Regulation (EC) No 1333/2008 of the European Parliament and of theCouncil of 16, December 2008 on food additives, Official Journal of theEuropean Union, 2008, L354, 16–33

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Y. Yang, K. Doudrick, X. Bi, K. Hristovski, P. Herckes,
P. Westerhoff, R. Kaegi, Characterization of food-grade titanium dioxide:
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S. Bettini, E. Boutet-Robinet, C. Cartier, C. Coméra, E. Gaultier, J. Dupuy, N.
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E. Houdeau, Food-grade TiO2 impairs intestinal and systemic immune
homeostasis, initiates preneoplastic lesions and promotes aberrant crypt
development in the rat colon. Sci Rep, 2017, 7: 40373

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Z. Chen, Y. Wang, T. Ba, Y. Li, J. Pu, T. Chen, Y. Song, Y. Gu, Q. Qian, J. Yang,
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R. Liu, X. Zhang, Y. Pu, L. Yin, Y. Li, Small-sized TiO2 nanoparticles mediate
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Nanotechnol, 2010, 10, 5161–5169

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Re-evaluation of titanium dioxide (E 171) as a food additive, EFSA Journal,
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Evaluation of four new studies on the potential toxicity of titanium dioxideused as a food additive (E 171), EFSA Journal, 2018; 16 (7): 5366

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Accurate Analysis of Trace Mercury in Cosmetics
using the Agilent 8900 ICP-QQQ
Authors
Xin-mei Wang and Ke Wang1.
Xiang-cheng Zeng, Donna Hsu,
and Juan-e Song2.
1 Shanghai Institute for Food andDrug Control, China
2 Agilent Technologies Co. Ltd,
China

Effective removal of tungsten-based interferences onfive Hg isotopes using MS/MS
Introduction
Many mercury (Hg) compounds are toxic, causing symptoms ranging from skinirritation, headaches, and tremors, through to nervous system damage, renal
failure, and heart disease (1). Because Hg compounds are easily absorbed
through the skin, their use in cosmetics is controlled. For example, the US Foodand Drug Administration (FDA) does not allow Hg in cosmetics, except under
specific conditions where there are no other safe and effective preservatives
available (2). Increasingly, however, Hg has been found in cosmetic products suchas skin creams, soap, and lotions sold as “anti-aging” or “skin lightening”.
Mercury is a challenging element to determine at low levels by ICP-MS. It has ahigh first ionization potential (10.44 eV), so is relatively poorly ionized in theplasma, leading to low sensitivity. Also, Hg has seven naturally occurring isotopes,
each with relatively low % abundance, further reducing sensitivity. Many forms of
Hg are also volatile, and the element’s chemistry means that it can be difficult tostabilize in solution. To address these issues, analysts must control the acid mix
used for sample preservation and rinse solutions, to avoid problems with poor
linearity and long washout times. Despite these difficulties, ICP-MS can still be
used successfully to perform trace-level analysis of Hg, if appropriate sample
stabilization—for example with the addition of HCl—is used.
Trace-level mercury analysis is even more difficult in samples—including somecosmetics—that contain a high concentration of tungsten (W). The W matrix
forms polyatomic ions WO+ and WOH+ that overlap all the Hg isotopes, making
Hg measurement even more challenging. For example, the most abundant Hg
isotopes, 200Hg and 202Hg, suffer interferences from 184W16O+ and 186W16O+,
respectively. Collision/reaction cells (CRCs) are used successfully to control
many common polyatomic interferences in conventional single quadrupole
ICP-MS (ICP-QMS). However, even with CRC operation, ICP-QMS cannot reduce
the WO+ and WOH+ interferences sufficiently to allow the accurate determinationof Hg at trace levels in samples that contain a high level of W.
The superior interference removal capability of triple quadrupole ICP-MS(ICP-QQQ) was investigated for this application. ICP-QQQ has dramatically
improved the performance of reaction cell methods by using two mass-selection
steps (MS/MS), one before and one after the CRC. In MS/MS, reaction chemistry
in the CRC is controlled and consistent because only the target analyte massenters the CRC. This capability offers a much more predictable and reliableapproach to resolving interferences on a wide range of elements, particularly incomplex and variable samples (3–5).
In this study, an Agilent 8900 ICP-QQQ was used for the measurement of Hg in atungsten-rich cosmetic sample.
263

Experimental
Standards and samples
Mercury standards were prepared in 0.5 % high purity hydrochloric acid (TAMAPure-AA-100, Kanagawa, Japan).
A tungsten-rich cosmetic toning lotion was bought from a local store in Shanghai.
The liquid sample was weighed to the nearest 0.100 g, and then diluted 100-foldwith de-ionized water acidified with 0.5 % HCl to ensure Hg stability. The sample
was shaken for a couple of minutes to ensure it was fully homogenized.
The concentration of W in the original cosmetic sample was about 4000 mg/kg(ppm), as determined by ICP-QQQ in a diluted sample. Therefore, the W matrix inthe sample as analyzed was about 40 mg/L (ppm) after the 100x dilution.
Instrumentation
An Agilent 8900 Standard configuration ICP-QQQ was used. The instrument
was fitted with the standard sample introduction system comprising a glass
concentric nebulizer, quartz double-pass spray chamber, quartz torch with
2.5 mm id injector, and Ni interface cones. The ICP-QQQ was operated in
no gas mode, with He cell gas, and with O2 cell gas in both single quad (SQ) andMS/MS modes. The main operating conditions are shown in Table 1.
Table 1. 8900 ICP-QQQ operating conditions.
Parameter

No gasHe

Acquisition mode

O2

Single Quad

MS/MS

RF power (W)1550

Sampling depth (mm)8.0

Carrier gas flow rate (L/min)

0.8

Make-up gas flow rate (L/min)

0.4

Spray chamber temp. (°C)

2

He cell gas flow rate (mL/min)O2–

O2 cell gas flow rate (mL/min)

5.0

–

–

0.9

Results and discussion
As the most abundant isotope, 202Hg is selected as the preferred isotope for
ICP-MS measurements. However, some analysts select 201Hg instead (or aswell), as the 201 isotope has proportionally lower W-based interference. The Hgcalibration was prepared in a matrix of dilute (0.5 to 1.0%)
HCl to ensure that the Hg remained stable in solution as a Cl-complex.
The calibration plots for 201Hg and 202Hg are shown in Figure 1. The figures ofmerit—linearity, detection limit (DL), and background equivalent concentration(BEC)—taken from the 202Hg calibration are presented in Table 2.
Table 2. DL, BEC, and R value of the calibration curve of 202Hg in dilute HCl determined in four
different cell modes.
8900 calibration performance figures of merit for 202Hg

264

No gasHe

O2 Single Quad

O2 MS/MS

R

0.997

0.999

0.999

0.999

DL (μg/L)

0.002

0.001

0.002

0.002

BEC (μg/L)

0.011

0.008

0.003

0.003

201 ➝ 201 Hg [O2-MSMS] ISTD:209 ➝ 209 Bi [O…

202 ➝ 202 Hg [O2-MSMS] ISTD:209 ➝ 209 Bi [O…
x10 -3y = 6.7542E-004* x +3.100E-006
R = 0.9997
DL = 0.00297 ppb
BEC = 0.004708 ppb

2

y = 0.0015* x +5.6900E-006
R = 0.9996
DL = 0.002602 ppb
BEC = 0.003678 ppb

0.5
Ratio

Ratio

x10 -3

0

1

0
0.5

1.0
Conc (ppb)

0.5

1.0
Conc (ppb)

Figure 1. Calibration plots for 201Hg and 202Hg, demonstrating good sensitivity and linearity due toeffective stabilization of Hg by the addition of HCl.

ICP-MS/MS reaction mechanism used to resolve W-based interferences on Hg
The general reaction mechanism using MS/MS mode with O2 cell gas to resolve
the WO+ and WOH+ interferences on Hg is shown in Figure 2. Since 200Hg suffers
the most serious polyatomic ion overlaps, the reaction mechanism is illustratedusing the example of the 184W16O+ overlap on 200Hg+. Q1 is set to m/z 200,
so 200Hg+ and WO+ ions at m/z 200 pass through Q1 and enter the CRC.
WO+ reacts with the O2 cell gas to form WO2+ and WO3+, shifting to higher masses.
The 200Hg+ ions do not react with the O2 cell gas and so remain at m/z 200.
By setting Q2 to m/z 200, 200Hg+ ions pass to the detector free of interference.
The same reaction mechanism is effective at resolving the WOH+ interferences,
as WOH+ also reacts with the O2 cell gas to form higher-order product ions.
Multiple isotope analysis study
To investigate the effectiveness of interference removal in the different cell gas
modes, a 1 μg/L (ppb) Hg spike was added to the diluted W-rich cosmetic lotion
sample. The five most abundant Hg isotopes were measured in the four different
cell gas modes, and the isotopic ratios calculated. Comparing the measured
isotope ratios with the theoretical natural ratios gives an excellent indication of
the effectiveness of the interference-removal on each isotope. This capability isimportant for many ICP-MS applications, where the results calculated from asecond isotope can be used to confirm the concentration reported using the
primary or preferred isotope. Performing “confirmatory measurements” isrecommended or required in several regulated methods across theenvironmental, food, and pharmaceutical industries. This approach is analogous
to the use of “qualifier ions” in organic mass spectrometry.
The isotope ratios for several Hg isotope pairs measured in the W-rich cosmetic
sample using the four cell gas modes are presented in Table 3. These results
show that MS/MS mode with O2 cell gas gives measured Hg ratios that are
virtually identical to the theoretical natural ratios. O2 in MS/MS mode is much
more effective than the other modes for the removal of the tungsten oxide andhydroxide polyatomic interferences. The effective removal of the WOH+ overlap
on 201Hg is illustrated by the accurate ratios obtained for the 200Hg/201Hg ratio in
MS/MS mode using O2 cell gas.
265

Figure 2. Reaction mechanism in MS/MS mode with O2 cell gas for removal of WO + overlap to allow on-mass detection of Hg in a tungsten matrix.
The same mechanism is also effective at resolving WOH+ overlaps.
Table 3. Hg isotope ratios in tungsten-rich sample measured in different cell modes.
Hg ratioNatural value

8900 measured results
No gasHe

O2 Single Quad

O2 MS/MS

198/199

0.591

1.738

1.769

1.435

0.598

198/200

0.432

0.831

0.823

0.739

0.43

200/201

1.75

49.4

61.4

7.75

1.76

201/202

0.441

0.022

0.017

0.126

0.445

As a further illustration of the ability of MS/MS to resolve interferences on
multiple Hg isotopes, a scan spectrum comparison was made using on-massmeasurement (Q1 = Q2). The mass range of the Hg isotopes was acquired for a
simple Hg standard (1 μg/L) and a solution containing the same concentration of
Hg spiked into a high W matrix (10 mg/L). The overlaid spectra are shown in
Figure 3, together with the template indicating the natural abundance of the Hg
isotopes. The spectra show that the measured isotopic abundances match thenatural Hg isotope pattern in both samples. This confirms the ability of MS/MS
mode with O2 cell gas to remove the W-based overlaps caused by the high W
matrix in the second sample.
x103

008SMPL.d009SMPL.d

CPS

6

4

2

0
198➞198

199➞199200➞200201➞201202➞202

Mass pairFigure 3. Hg isotopes with W matrix (blue shading) and without W matrix (gray shading),
confirming accurate Hg isotope abundances and effective removal of W-based interferenceson all Hg isotopes by ICP-QQQ with MS/MS.

Hg in tungsten-rich samples
Hg was measured in a tungsten-rich cosmetic sample using four different cellgas modes. The five most abundant isotopes of Hg (198, 199, 200, 201, and 202)
were used for quantitation, giving five independently calibrated results for total
Hg. The results for Hg in the original cosmetic sample, corrected for the 100
times dilution, are shown in Table 4.

266

Table 4. Apparent Hg concentration (μg/kg) in tungsten-rich cosmetic sample, quantitatedindependently using five isotopes. The data shows errors due to the contribution from WO+ and
WOH+ overlaps in no gas, He, and O2 (SQ) cell modes.
8900 measured results
Cell mode

198

199

200

201

202

No gas

267000872000126400

4770

98700

He

173200

57700

90700

2460

66500

O2 Single Quad

772

249

399

2.8

288

O2 MS/MS

2.1

1.8

2.4

1.5

1.7

Matrix-based interferences affect different isotopes of an analyte to different
degrees, so giving different errors in the quantitative results calculated fromeach isotope.
Comparing the elemental concentrations calculated from the different isotopesof an element can therefore be used to identify whether the reported
concentrations were affected by interferences. The reported Hg concentrationsin MS/MS mode with O2 (~2 μg/kg in the original sample, or 0.02 μg/L in the
100x diluted solution) are much lower than the results reported using the othercell modes. Also, the good agreement between the results obtained for the fiveisotopes in O2 (MS/MS) mode shows that this mode can simultaneously remove
polyatomic interferences from all five Hg isotopes. These results contrast withthe other modes, where incomplete removal of interferences from most of theisotopes led to erroneously high values and large differences between the results
calculated using the different isotopes. The reported concentration of 2.8 μg/kg
obtained for 201Hg using O2 cell gas in single-quad mode shows that the WOH+
interference could be reduced reasonably effectively. However, the other isotopes
gave variable results in O2(SQ) mode, so the 201Hg result could not be verified bycomparing it with a second, qualifier isotope. The data in Table 4 shows that,even when a suitable reaction gas is identified, MS/MS is essential for full controlof the reaction chemistry.
Spike recovery test
A spike recovery test was carried out to further evaluate the interference removal
capability and matrix tolerance of the method. Since 200Hg suffers the mostserious polyatomic ion overlaps, it was selected as the target mass for the spikerecovery test.
A 30 ppt spike of Hg was added to the diluted cosmetic lotion sample. The spikerecovery in O2 (MS/MS) mode was 104%, confirming the interference removal
capability and matrix tolerance of the method (Table 5).
Table 5. 30 ppt Hg spike recovery results in different cell gas modes.
Mode

Sample (μg/L)

Spike recovery (%)

200 HgNo gas SQ

1364

6635

200 Hg

He SQ

906

879

200 Hg

O2 SQ

3.99

216

200 Hg

O2 MS/MS

0.024

104

267

Conclusion
The Agilent 8900 ICP-QQQ operating in MS/MS mode with O2 cell gas is highly
effective for the removal of tungsten oxide/hydroxide polyatomic interferences on
the five major Hg isotopes.
– Hg was measured accurately and consistently at trace levels in the presenceof W using an MS/MS on-mass method with O2 reaction cell gas.
– Compared to conventional single quadrupole ICP-MS, ICP-MS/MS reduced
interferences by more than two orders of magnitude.
– The ICP-MS/MS method easily meets the requirements of trace level Hganalysis in tungsten-rich cosmetic samples.

References
1.	G. Genchi, M. S. Sinicropi, A. Carocci, G. Lauria, and A. Catalano, Mercury
Exposure and Heart Diseases, Int. J. Environ. Res. Public Health, 2017, 14(1),74, https://doi.org/10.3390/ijerph14010074
2.	Federal Food, Drug, and Cosmetic Act (FD&C Act), Cosmetics and U.S. Law,
accessed October 2018, https://www.fda.gov/Cosmetics/GuidanceRegulation/
LawsRegulations/ucm2005209.htm
3.	E. Bolea-Fernandez, L. Balcaen, M. Resano, and F. Vanhaecke, Overcoming
spectral overlap via inductively coupled plasma-tandem mass spectrometry(ICPMS/MS). A tutorial review, J Anal. At. Spectrom., 2017, 32, 1660-1679
4.	L. Fu, S. Shi, and X. Chen, Accurate quantification of toxic elements in medicine
food homologous plants using ICP-MS/MS, Food Chemistry, 245, 2018,692-697
5.	L. Whitty-Léveillé, K. Turgeon, C. Bazin, and D. Larivière, A comparative studyof sample dissolution techniques and plasma-based instruments for the
precise and accurate quantification of REEs in mineral matrices, Anal Chim
Acta, 961, 2017, 33–41

268

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Sulfur isotope fractionation analysis in mineral waters
using an Agilent 8900 ICP-QQQ
Authors

Introduction

Naoki Sugiyama
Agilent Technologies, Tokyo, Japan

Stable isotope geochemistry is a branch of geology that investigates the age ofnatural materials, their origin and the processes they have undergone sinceformation [1]. Stable isotope analysis is also used in biogeochemical studies tomonitor element cycling in ecosystems [2] and to identify geographical/regional
differences for food provenance and archaeology. Of the elements of interest in
stable isotope studies (hydrogen, carbon, nitrogen, oxygen and sulfur), only sulfur
is accessible using aqueous solution analysis by ICP-MS, and even sulfur isdifficult to measure by conventional quadrupole ICP-MS.
The relative abundance of the two major stable isotopes of sulfur, 32S (94.99%
abundance) and 34S (4.25%), varies significantly in nature, so the 34S/32S ratio canbe used to characterize a sample. In sulfur stable isotope analysis, the variationin the 34S/32S isotope ratio is calculated and reported as a deviation or delta (δ) in
34
S abundance relative to a standard material, the troilite (iron sulfide) mineralfrom the Canyon Diablo meteorite, referred to as δVCDT (Vienna Canyon Diablo
Troilite). Natural variations in 34S abundance, expressed in parts per thousand or“per mil” (‰), can be of the order of -50‰ to +40‰ (and occasionally muchgreater), due to redox reaction. Examples of some values for natural S isotope
fractionation are given in Table 1 [3].
Table 1. Sulfur isotope distribution in nature.
SourceIgneous rocks
Sedimentary rocks
Seawater SO4

δ34S (‰) relative to VCDT
0
-40 to +40+21

Atmospheric SO4-30 to +30

Surface water/groundwater SO4-22 to +135

Soil (organic sulfur)-30 to +30

Vegetation (organic sulfur)-34 to +32

Animals (organic sulfur)-10 to +22

Fossil fuels (organic sulfur)-11 to +28

Sulfur isotope ratio (IR) analysis has been mostly done by gas phase isotope
ratio mass spectrometry (IRMS) but recent developments in ICP-MS technology
have vastly improved its ability to measure sulfur accurately at low levels. In thiswork, we investigated the performance of a new, high sensitivity ICP-MS
instrument, the Agilent 8900 Triple Quadrupole ICP‑MS (ICP-QQQ), for low level
S IR analysis of mineral waters. Spectral interferences on S arising from O2+ canbe removed by operating the ICP-QQQ in MS/MS mode, allowing both sulfur
isotopes to be measured and potentially offering a faster and simpler S isotope
analysis technique.

269

Experimental
Sulfur IR analysis method: mass-bias correction, matrix effects andbackground control
For accurate and precise IR analysis by ICP-MS, the instrumental mass bias
must be corrected, and the effect of the sample matrix must be controlled.
As is typical for isotope ratio analysis by ICP-MS, instrumental mass-bias wascorrected using sample-standard bracketing. A standard solution of known S
isotope composition was measured before and after each sample, and the sample
IR was corrected by the average IR of the two standard measurements. A 0.5 ppm
solution of IAEA-S-1 was used as the mass bias correction standard [4].
The sample matrix can also affect the relative transmission of different mass ionsin ICP-MS, and consequently the mass bias and the measured IR. To overcome thiseffect, a chelation technique can be used to remove the sample matrix before
analysis [5]. Alternatively, the variation in sample matrix composition can be
reduced by diluting all samples and standards in a consistent matrix. In this work,
the mass bias standard and samples were diluted using a solution which contained
50 ppm calcium (Ca) and 100 ppm sodium chloride (NaCl). Use of this diluent
reduced the matrix variation that could otherwise have caused fluctuations in themass bias. The S concentration in the matrix blank was around 0.7 ppb which was
low enough not to affect the accuracy of the IR analysis.
Sample dilution in a consistent matrix avoided the necessity for time consuming
matrix removal. The matrix dilution approach was made possible by the highsensitivity and low S background of the 8900 ICP‑QQQ. Sulfur is ubiquitous inlaboratory consumables, supplies, and many of the materials used in instrumentcomponents, typically leading to a high elemental background signal. To minimize
the contribution from the ICP-MS hardware, key components of the argon gas
flow path of the 8900 #100 (Advanced Applications configuration) ICP-QQQ havebeen replaced using more inert materials. This has successfully reduced thebackground signal for S (and Si), allowing a detection limit specification of< 50 ppt for S, Si (and P) to be quoted1. In a recent study, S was measured with asensitivity of 104 cps/ppb using the 8900 #100 ICP-QQQ to achieve a backgroundequivalent concentration (BEC) of less than 100 ppt S in ultrapure water [6].
Instrumentation
An Agilent 8900 ICP-QQQ (#100, Advanced Applications configuration) equippedwith the standard Ni cones and x-lens was used. The standard glass concentric
nebulizer was replaced with a PFA nebulizer, run using self-aspiration for better
signal precision.
The two most abundant isotopes of S, 34S and 32S, were measured using theAgilent 8900 #100 in MS/MS mass-shift mode with O2 cell gas [6]. The polyatomic
interference from 16O2+ on the primary isotope of S, 32S+ at m/z 32, and from 16O18O+
on the minor 34S isotope at m/z 34 were avoided by shifting S+ to a new mass.
S+ reacts readily with O2 cell gas to form the product ion SO+, while the O2+
interference does not react in the same way with the O2 cell gas. Consequently, theSO+ product ions can be measured free of interference at M + 16 u (m/z 48 for the
primary 32S16O+ isotope product ion and m/z 50 for 34S16O+). Tuning conditions andmethod parameters are summarized in Table 2.
270

1. This specification is verified on every Agilent 8900 Advanced Applications and Semiconductor
configuration instrument during factory testingTable 2. Agilent 8900 ICP-QQQ tuning and method conditions.

PlasmaLens

Cell

Data Acquisition

Tuning parameterValue

RF power (W)1550

Sampling depth (mm)8.0

Nebulizer gas flow rate (L/min)

0.90

Make up gas flow rate (L/min)

0.30

Extract 1 (V)-80

Extract 2 (V)-150

Omega (V)

10.0

Omega bias (V)-120

Octp Bias (V)-5.0

Axial Acceleration (V)2.0

KED (V)-8.0

Cell gas

OxygenCell gas flow rate (mL/min)

0.45

Method parameter

Value

Integration time (s)1 and 5 for 32S and 34S

Number of sweeps

1000

Number of replicates

10

Rinse

1% HNO3 rinse (s)20

50 ppm Ca/100 ppm NaCl rinse (s)30Peripump

Uptake time (s)30Stabilization time (s)30The high sensitivity and low background of 32S and 34S can be clearly seen in
Figure 1, which shows a spectrum of sulfur obtained using the MS/MS method.
x105

003SMPL.d001SMPL.d

CPS

1.5

1.0

0.5

0
32 ➝ 48

33 ➝ 49
34 ➝ 50
Mass pair36 ➝ 52

Figure 1. MS/MS spectrum of 10 ppb sulfur solution (grey) and blank (blue).

271

Sample and sample preparation
Sulfur isotope certified reference materials (CRMs) IAEA-S-1 (34δVCDT = -0.3‰)
and IAEA-S-2 (34δVCDT = +22.7 ‰) were purchased from National Institute ofStandards and Technology (NIST), Gaithersburg, MD, USA. Each CRM was gently
dissolved in diluted nitric acid and diluted to the appropriate concentration.
A matrix blank was prepared with 50 ppm Ca (SPEX Certiprep, US) and 100 ppm
NaCl (Wako Pure Chemical Industries Ltd, Japan) in 1% nitric acid (Tamapure
100: Tama Chemicals Co. Ltd, Japan). This solution was also used to dilute thestandards and samples.
The seawater and mineral water samples were diluted between 10 and 2000
times to give a S concentration in the range 0.2 to 0.8 ppm. Concentration
matching contributed to accurate isotope ratio analysis because, at these levels,
32
S is measured in analogue mode and 34S in pulse counting mode. Concentration
matching also removes any potential errors caused by detector dead time(the instrument default dead time was 36.3 ns for mass 32).

Results and discussion
Synthetic sample analysis
Sulfur isotope CRMs IAEA-S-1 and IAEA-S-2 and two mixes of the two CRMs wereprepared to give four samples with theoretical 34δVCDT values of -0.3, 5.4, 11.2 and22.6. Each blend was prepared at a S concentration of 0.5 ppm. The S IRs were
measured six times (standard corrected as described previously).
Figure 2 shows the raw IR data for the IAEA-S-1 mass bias standard and thecorrected IR data for the CRM blend samples. The average 34δ values and errors(two times the standard deviation) were determined for the four CRM mixes,
and these measured values were plotted against the theoretical values for each
mixed standard. The results can be seen in Figure 3, demonstrating the good
linearity obtained.

28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
-2

0.04940.04920.04880.0486
0.04840.04820.048034

δ sampleIR stdFigure 2. Raw IR analysis of bracketing mass bias standard IAEA-S-1 (triangles) and corrected
S IRs of six separate measurements of each of four isotope CRM blends (points).

272

IR std

0.0490S1S S -1
2 3.1
S1S S -1
2 3.1
S1S S -1
2 3.1
S1S S -1
2 3.1
S1S S -1
2 3.1
S1S S -1
2 3.1
S1S S -1
2 2.
2
S1S S -1
2 2.
2
S1S S -1
2 2.
2
S1S S -1
2 2.
2
S1S S -1
2 2.
2
S1S S -1
2 2.
2
S -1
S -2
S -1
S -2
S -1
S -2
S -1
S -2
S -1
S -2
S -1
S -2
S -1
S -1
S -1
S -1
S -1
S -1
S -1
S -1
S -1
S -1
S -1
S -1

34

δ (corrected)

Synthetic sample (34δ=5.4, 11.2, 22.6 and -0.3)

Synthetic samples IR analysis
25.0

20.0

Experimental 34δ (‰)

15.0

10.0

5.0

0.0
-5.0

0.0

5.0

-5.0

10.0

15.0

20.0

25.0

Theoretical 34δ (‰)

Figure 3. Average of Sulfur IR analysis of the four IAEA CRM blends.

Water sample analysis
Three different brands of mineral water were purchased at a local store in Tokyo,
Japan. The mineral water samples were prepared for analysis, together withsamples of; JSAC 0301, a Japanese river water CRM (from the Japan Society for
Analytical Chemistry); a spring water collected from the IKAHO hot spring in thenorth of Japan; a NASS 5 seawater CRM (National Research Council, Canada);
and Tamapure-AA 100 high purity sulfuric acid (Tama Chemicals Co., Ltd.).
Before the IR measurements were undertaken, the sulfur concentration of eachsample was checked to determine the appropriate dilution factor. The dilution
factors applied to the samples are given in Table 3. Each sample was measured
10 times and the average and the standard deviation were calculated. Figure 4
shows the average IR and the error (as two times standard deviation) of the IR.
Table 3. Dilution factors.
SampleMineral water A

Dilution factor
10

Mineral water B

10

Mineral water C

1000

JSAC 0301: Japanese river water CRM

10

IKAHO hot spring water

1000

NASS 5

2000

High purity sulfuric acid

50000

273

Measured 34δ (Error bar shows 2x SD [n = 10])
25.0
20.0

10.0

34

δ‰

15.0

5.0
0.0
-5.0

-1.2
H 2SO4

9.0

13.9

5.0

12.9

17.9

21.5

JSAC0301

IKAHO

Mineralwater A

Mineralwater B

Mineralwater CNASS 5Figure 4. Measured sulfur IR for sulfuric acid, river water CRM, spring water, 3 commercial mineralwaters (brands A, B and C) and seawater CRM.

The results show a clear difference in the S IRs for all of the samples, including
between the 3 brands of mineral water. The 34δ value of +21.5‰ determined in theseawater reference material agrees well with the global average oceanic seawater
value of +21‰ for seawater sulfate (see Table 1 and reference 3).
The new, fast ICP-QQQ method for sulfur isotope analysis could be useful in
identifying the natural characteristics of a water-source, monitoring seasonal andbiogeochemical variations, and also for determining the impact of man-madesources of sulfur on the environment.

Conclusion
The Agilent 8900 Advanced Applications configuration ICP-QQQ is ideally suited to34
S/32S isotope ratio analysis, which can provide valuable information for sample
characterization in natural systems or to monitor anthropogenic impact. The 8900
ICP-QQQ provides a low background and high sensitivity for sulfur, which enabled amethod to be developed that simply required the sample to be diluted with thematrix blank before analysis. Sample/standard bracketing was used to correct for
any instrumental mass-bias or drift.
By operating the 8900 ICP-QQQ in MS/MS mode with O2 cell gas, problematic
spectral interferences due to O2+ overlaps on 32S+ and 34S+ were successfully
avoided. The S IR analysis method was applied to various samples including threemineral waters, a river CRM, a seawater CRM, a hot spring water, and high purity
sulfuric acid. The precision of the IRs achieved was excellent at 1-1.5 ‰(as two times the standard deviation).

References
1.	J. Ryu, R.A. Zierenberg, R.A. Dahlgren et al, 2006, Chemical Geology
229 : 257-272 [2]2.	R. Tostevin, A. V. Turchyn, J. Farquhar, D. T. Johnston, D. L. Eldridge, J. K. B. Bishop
and M. McIlvin, 2014, Earth and Planetary Science Letters, 396, 14-21.
3.	T.B. Coplen et. Al., 2002, Pure and Applied Chemistry, 74 (10), 1987-2017.
4.	National Institute of Standards and Technology certificate sheet for Reference
Material 8554 - IAEA-S-1 (Sulfur Isotopes in Silver Sulfide), https://www-s.nist.gov/
srmors/view_msds.cfm?srm=8554
5.	X. K. Zhu, A Makishima, Y. Guo et al, Int. J. Mass Spectrom., 2002, 220, 21-29
6.	K. Nakano, Ultra-low level determination of phosphorus, sulfur, silicon and chlorine
using the Agilent 8900 ICP-QQQ, Agilent publication, 2016, 5991-6852EN
274

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Fast Analysis of Arsenic Species in Infant Rice Cereals
using LC-ICP-QQQ
Authors

Introduction

Courtney K. Tanabe1-2, Susan E.
Ebeler1-2, Jenny Nelson1-3

Arsenic contamination of food can be harmful to human health. To assess
the risk, several speciation methods have been developed to separate thetoxic inorganic forms of As (iAs)—a class 1 carcinogen—from less toxic or
non-toxic forms.

1. Food Safety and Measurement
Facility, University of California, Davis,
USA
2. Department of Viticulture andEnology, University of California, Davis,
USA
3. Agilent Technologies, Inc., USA

In a previous study (1), a speciation method specified in US FDA EAM: Section
4.11 (2) was used to separate four arsenic species in 31 baby rice cereals.
The arsenic species included the inorganic forms; As(III) (arsenite) and As(V)(arsenate), and two organic forms; monomethylarsonic acid (MMA), anddimethylarsinic acid (DMA). The four species were separated using isocraticanion-exchange HPLC, and ICP-MS was used to detect arsenic-containing
chromatographic peaks.
This study aimed to develop a rapid and reliable screening method for inorganic
arsenic (iAs) analysis, to assist the food industry in meeting existing and future
regulations. As shown in Table 1, the FDA has proposed an action limit of 100 ppb
for iAs in infant rice cereals. This limit is in line with the European Union’s limit forrice used for the production of food for infants and young children.
Table 1. Example regulatory maximum concentrations governing iAs in rice and rice-based products.
Regulating body

Action or Maximum
Concentration for iAs (ppb)

Rice Type or Rice Product100 (proposed)

Infant rice cereals

Codex Alimentarius
Commission (4, 5)

200

Polished (white) rice350

Husked (brown) rice

European Union (6)200Polished rice

US FDA (3)China (7)250

Parboiled and husked rice

300

Rice waffles, wafers, crackers, and cakes

100

Rice used for the production of food for
infants and young children

150

Rice grains

The methodology described in this application note is based on a previous
method developed by Jackson (8), where As species were determined using
HPLC coupled to a triple quadrupole ICP-MS (ICP-QQQ). HPLC-ICP-QQQ was also
used in this study, but instead of analyzing the iAs species separately, As(III) was
intentionally oxidized to As(V) with hydrogen peroxide before analysis (9, 10).
By converting As(III) and analyzing all inorganic species as As(V), this method
was able to separate MMA and DMA from iAs (as As(V)) in less than 2 minutes.
The analysis time is 10 times faster than the current FDA methods used for As
speciation (2). The same fast HPLC-ICP-QQQ approach has also been applied to
As speciation in wine (11).

275

Oxygen was used as a reaction gas in the collision/reaction cell (CRC) of the
ICP-QQQ to resolve the Cl-based spectral interferences on As-75 for total As
measurements. For the speciation measurements, the potential Cl-based
interferences are resolved chromatographically, so ICP-QQQ with MS/MS is notessential. While this analysis could be done on a single quadrupole ICP-MS suchas the Agilent 7800 or 7900 ICP-MS, ICP-QQQ offers higher sensitivity and lower
detection limits where both As speciation and total As analysis is required.
Results are presented that demonstrate the accuracy and reproducibility of the
new method. The method was further validated by analyzing four rice standard
and certified reference materials.

Experimental
Standards
The As(III) and As(V) standards were bought from Spex Certiprep (Metuchen, NJ,
USA). The MMA and DMA standards were bought from Chem Service (WestChester, PA, USA). An arsenobetaine (AB) standard was also purchased fromChem Service to be used as a flow injection marker (internal standard) for
post-column injection. Calibration standards were prepared at 0.1, 0.5, 1.0, 5.0, 10,
and 20 μg/L (ppb) for each of DMA, MMA, and total iAs (sum of As(III) and As(V)).
Standard/certified reference materials
Four SRM/CRMs were used as quality control materials for the As speciation
measurements and total As measurements (without HPLC separation). The SRM
used was the National Institute of Standards and Technology (NIST) 1568a Rice
Flour. The three CRMs were the National Metrology Institute of Japan (NMIJ)
7503a White Rice Flour, the NMIJ 7532a Brown Rice Flour, and the Joint
Research Centre (JRC) ERM-BC211 - Arsenic in Rice.
Samples and sample preparation
Six baby rice cereals were purchased from a local store in Berkeley, CA, USA.
Each cereal was produced by a different manufacturer.
Arsenic was extracted from the rice matrix according to FDA method EAM 4.11
(2). Infant rice cereal (1 g) was weighed into a centrifuge tube and 10 mL of
0.28 mol/L HNO3 was added. The capped tube was placed in a preheated block
digestion system at 95 °C for 90 minutes. The mixture was then diluted with
6.6 mL H2O, centrifuged, and filtered. Equal 0.5 mL portions of rice extract, H2O2,
and mobile phase were pipetted into a 2 mL plastic HPLC vial as the test solution.
Each sample was prepared in duplicate.
Instrumentation
An Agilent 1260 HPLC fitted with a Hamilton PRP-X100 5 μm 50 x 2.1 mm
column was coupled to an Agilent 8800* Triple Quadrupole ICP-MS (ICP-QQQ).
The mobile phase was 40 mM ammonium carbonate ((NH4)2CO3, trace metal
grade 99.999%, Sigma Aldrich) with 3% v/v methanol (Optima LC/MS grade,
Fisher Chemical) adjusted to a pH of 9.0 with ammonium hydroxide (Optima
Grade, Fisher Scientific). The ICP-QQQ was equipped with a standard sample
introduction system comprising a glass concentric nebulizer, quartz spraychamber, quartz torch with 2.5 mm i.d. injector, and nickel-tipped interface
cones. Peak integration was carried out according to FDA EAM §4.10 (12) and4.11.15 (2). The instrument operating conditions are summarized in Table 2.
276

Table 2. HPLC-ICP-QQQ operating conditions.
ICP-QQQ
Forward power

1550 W

Sampling depth

8.0 mmSpray chamber temp.

2 °C

Carrier gas

0.95 L/min

Make-up gas

0.20 L/min

Extract 1

0V

Octopole bias

-5.0 V

Energy discrimination-7 V

O2 cell gas flow rate

0.31 mL/min

Scan mode

MS/MS

Q1/Q2 mass

75/91 u

HPLC
Mobile phase flow

0.5 mL/min

Injection volume

5 μL

Sample temperature

4 °C

ISTD injection volume

5 μL

Results and discussion
Development of a fast method
The focus of the method was to reduce the analysis time per sample comparedto the current FDA method for As speciation. In common with Jackson’s method(8), a small injection volume, short ion-exchange column, high mobile phase linear
velocity, and oxygen cell gas mode were used.
Figure 1 shows overlaid chromatograms for a representative calibration set of
0.5, 1.0, 5.0, and 20 μg/kg standards. All As species are baseline separated inless than two minutes. Simply by oxidizing As(III) to As(V) and analyzing all iAs
in the form of As(V), the analysis time was reduced significantly compared toapproximately 20 minutes for the current FDA regulatory method (2).
x104
40.5 ppb
1.0 ppb
5.0 ppb
20.0 ppb

2

0
0.5

1.0

1.5

Figure 1. Overlay of the 0.5, 1.0, 5.0, and 20.0 µg/kg As species calibration standards.
An AB internal standard (flow injection marker; fourth peak) was added post column
via an external switching valve.

277

Linear calibrations
The calibration curves for DMA, MMA, and iAs showed good linearity (Figure 2).
All As concentrations in the rice samples were within the linear range except
iAs, which was measured at a maximum concentration of 150% of the highest
calibration standard.
75 ➝ 91 DMA

75 ➝ 91 MMA

x105

x105
2

Count

Count

2

1

0

1

0
10.0

20.0

10.0

Conc (ug/g)

20.0Conc (ug/g)

75 ➝ 91 iAs
x105

Count

2

1

0
10.0

20.0
Conc (ug/g)

Figure 2. Calibration curves for DMA, MMA, and total iAs (sum of converted As(III) and As(V)).

Detection limits
The limits of detection (LOD) and limits of quantitation (LOQ) given in Table 3 arebased on repeated measurements of the 0.05 μg/kg (ppb) mixed standard, n=15.
Table 3. LOD (3 sigma), LOQ (30 sigma), and estimated LOQ in rice for each As species.
LOD, μg/kg

LOQ, μg/kg

Estimated wine LOQ, (50 x dilution) μg/kg

DMA

0.018

0.175

8.8

MMA

0.026

0.258

12.9

iAs

0.022

0.221

11.0

Reproduced by permission of The Royal Society of Chemistry. P. J. Gray et al, J. Anal. At. Spectrom., 2017, 32,
1031 Analyis of rice RMs

Arsenic species were determined in four rice reference materials using the new
HPLC-ICP-QQQ method. The total As concentration in each sample was also
determined by direct ICP-QQQ analysis (no HPLC separation). Table 4 lists thereference and measured concentrations for DMA, MMA, iAs, and total As.
Only one of the reference materials—NIST 1568b—had a reference value for
MMA. The HPLC-ICP-QQQ measured concentrations were compared to thereference values, where available. Species recoveries ranged from 93 to 123%of their certified values when concentrations were above the LOQ. The recoveries
for total As were also acceptable, ranging from 92 to 112%.

278

Table 4. Quantitative results for As species and total As in rice reference materials.
DMA (mg/kg)
Rice RM

Reference

MMA (mg/kg)

Measured

Reference

Measured

11.6 ± 3.5

iAs (mg/kg)

Total As (mg/kg)

Reference

Measured

Reference

Measured

NIST 1568b

180 ± 12195 ± 4 (109%)14.9 ± 0.9 (128%)92 ± 10105 ± 1 (114%)285 ± 14315 ± 3 (110%)NMIJ 7503a

13.3 ± 0.9

15.4 ± 0.1 (116%) None reported<LOD

84.1 ± 3a

79 ± 4 (94%)

98 ± 794 ± 4 (96%)

NMIJ 7532a

18.6 ± 0.8

18.7 ± 1.3 (101%) None reported

2.2 ± 1.9298 ± 8277 ± 12 (93%)

320 ± 10297 ± 12 (93%)

ERM BC-211

119 ± 13146 ± 3 (123%)

19.9 ± 0.6

124 ± 11124 ± 2 (100%)260 ±13290 ± 5 (112%)

None reported

a. NMIJ 7503a iAs uncertainty estimated as the square root of the sum of squares of the AsIII and AsV uncertainties.
Reproduced with permission of The Royal Society of Chemistry. P. J. Gray et al, J. Anal. At. Spectrom., 2017, 32, 1031.

To check the quality of the data, z-scores were also calculated. Z-scores are thenumber of standard deviations from the mean, with values between –3 and +3
being sufficient for regulatory purposes. The percent recovery for DMA in ERM
BC211 RM was biased high, but the z-score was 2.1. The recovery for MMA in
NIST 1568b RM was 128% but the reference concentration was below themethod’s LOQ. The z-score was 0.94.
Quantitative results in infant rice products
Six baby rice cereal samples were measured in duplicate using the HPLC-ICPQQQ speciation method. Table 5 lists the measured concentrations for DMA andiAs; MMA was only present above the LOQ (0.026 ppb) in two of the rice samples(E and F). There was no significant difference between the two duplicates run foreach cereal sample, showing the reproducibility of the method.
The concentration of iAs in four of the six rice samples was below the US FDA’s
proposed action limit and the EU’s maximum limit of 100 ppb for iAs in infant ricecereals. Samples C and D exceeded the regulatory limit.
Table 5. Quantitative results in μg/kg (ppb) for As species in six infant rice market basket samples
measured in duplicate.
Sample Name

DMA

MMA

iAs

Baby rice cereal A_1

11.4

N/D

63.3

Baby rice cereal A_2

11.2

N/D

62.3

Baby rice cereal B_1

12.5

N/D

53.6

Baby rice cereal B_2

14.9

N/D

56.4

Baby rice cereal C_1

33.9

N/D

106.4

Baby rice cereal C_2

36.0

N/D

113.5

Baby rice cereal D_1

15.4

N/D

102.6

Baby rice cereal D_2

15.1

N/D

103.6

Baby rice cereal E_1

41.9

2.2

87.9

Baby rice cereal E_2

39.0

2.3

89.4

Baby rice cereal F_1

46.4

8.7

89.4

Baby rice cereal F_2

46.7

9.0

90.4

Proposed US FDA limitof 100 ppb for iAs
Pass

Pass

Fail

Fail

Pass

Pass

N/D = Not detected279

Conclusion
A fast and fit-for-purpose HPLC-ICP-QQQ method is described for themeasurement of inorganic As and two organic As species in baby rice cereal.
A full speciation analysis can be completed in under two minutes.
– By oxidizing As(III) to As(V) with H2O2 during sample preparation, total iAs
was determined as As(V).
– The narrow bore column and 0.5 mL/min HPLC flow rate provided excellent
sensitivity, which allowed low volume injections to be used.
– Sample run times were 10x faster than the current FDA 4.11 method for thedetermination of As in rice.
– The HPLC-ICP-QQQ method delivered improved sensitivity, limits of detection
and limits of quantification compared to the FDA 4.11 method.
The reproducibility of the method was demonstrated by the good agreement
between the quantitative results for duplicate measurements of six rice cereal
samples. The results showed that two of the samples contained iAs above
100 ppb.
This method provides valuable information for the safety of rice and rice-based
infant cereals, as well as allowing food producers to meet regulatory
requirements.

References
1.	Rima Juskelis, Wanxing Li, Jenny Nelson, and Jack C. Cappozzo, Arsenic
Speciation in Rice Cereals for Infants, J. Agric. Food Chem., 2013, 61, 45,
10670-10676
2.	K. M. Kubachka, N. V. Shockey, T. A. Hanley, S. D. Conklin and D. T. Heitkemper,
Arsenic Speciation in Rice and Rice Products Using High Performance Liquid
Chromatography - Inductively Coupled Plasma-Mass Spectrometric
Determination draft 1.1, Nov 2012, accessed May 2018, https://www.fda.gov/
downloads/Food/FoodScienceResearch/LaboratoryMethods/UCM479987.
pdf
3.	Codex Alimentarius Commission, Report from the Thirty-Seventh Session,
Geneva, Switzerland, 2014
4.	Codex Alimentarius Commission, Report from the Thirty-Ninth Session,
Rome, Italy, 2016
5.	European Union Commission, 2015, Regulation (EC) No. 1881/2006
6.	Y. G. Zhu, G. X. Sun, M. Lei, M. Teng, Y. X. Liu, N. C. Chen, L. H. Wang, A. M.
Carey, C. Deacon, A. Raab, A. A. Meharg and P. N. Williams, High Percentage
Inorganic Arsenic Content of Mining Impacted and Nonimpacted Chinese
Rice, Environ. Sci. Technol., 2008, 42, 5008–5013
7.	B. Sadee, M. E. Foulkes, S. J. Hill, Coupled techniques for arsenic speciation
in food and drinking water: a review, J. Anal. At. Spectrom, 2015, 30, 102–118
8.	B. P. Jackson, Fast ion chromatography-ICP-QQQ for arsenic speciation,
J. Anal. At. Spectrom., 2015, 30, 1405–1407

280

9.	S. Musil, Á. H. Pétursdóttir, A. Raab, H. Gunnlaugsdóttir, E. Krupp, J. Feldmann,Speciation without chromatography using selective hydride generation:
inorganic arsenic in rice and samples of marine origin, Anal. Chem., 2014, 86(2), 993–999
10.	H. R. Hansen, A. Raab, A. H. Price, G. Duan, Y. Zhu, G. J. Norton, J. Feldmann,
A. A. Meharg, Identification of tetramethylarsonium in rice grains with elevatedarsenic content, J. Environ. Monit., 2011,13, 32–34
11.	C. K. Tanabe, H. Hopfer, S. E. Ebeler, J. Nelson, Fast Analysis of Arsenic
Species in Wines using LC-ICP-QQQ, Agilent publication, 2017, 5991-8454EN
12.	S. D. Conklin, K. Kubachka, N. Shockey, Elemental Analysis Manual for Foodand Related Products, §4.10 HPLC-ICP-MS As Species in Fruit Juice (Ver. 1;
2013), accessed May 2018, http://www.fda.gov/EAM

More information
For a full account of this study, see Patrick J. Gray, Courtney K. Tanabe, Susan E.
Ebeler, and Jenny Nelson, A fast and fit-for-purpose arsenic speciation method
for wine and rice, J. Anal. At. Spectrom., 2017, 32, 1031–1034; DOI: 10.1039/
C7JA00041C

Acknowledgement
The Food Safety and Measurement Facility is supported by donations and gifts
from Agilent Technologies, Gerstel US, and Constellation Brands.

281

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High Throughput Determination of Inorganic Arsenic in
Rice using Hydride Generation-ICP-QQQ
Authors

IntroductionÁsta H. Pétursdóttir, Stanislav Musil,
Nils Friedrich, Eva M. Krupp and Jörg
Feldmann. University of Aberdeen,
Scotland, UK

The concentration of potentially toxic chemicals such as arsenic in rice is closely
monitored to ensure food safety. However, the toxicity of arsenic depends on thechemical form or “species” of the element that is present rather than total
concentration. Inorganic arsenic (iAs) species, arsenite (As(III)) and arsenate(As(V)), are known to be carcinogenic and highly toxic, whereas the common
organoarsenic species monomethylarsonic acid (MMA) and dimethylarsinic acid
(DMA) are less toxic [1].

Helga Gunnlaugsdóttir Matis,
Environment and Genetics
Department, Reykjavik, Iceland

Keywords
arsenic, arsenite, arsenate, IMEP-7 rice,
NIST 1568a Rice Flour, oxygenmass-shift

Rice is an important food source for a large percentage of the world's population,
but it does contain relatively high concentrations of iAs due to the uptake of As
from the soil and water in which the rice plants are grown. Available As from soils
can be both naturally occurring and due to anthropogenic sources such as
As-based pesticides that were widely used until the 1970s. Clearly there is anurgent food-safety requirement for a simple and quick analytical method toscreen large numbers of rice and other food samples for iAs. In this study, a fastand sensitive method using hydride generation (HG) with ICP-QQQ is described
for the separation and detection of iAs in commercial rice samples.

Experimental
Instrumentation: A Hydride Generation (HG) accessory for Agilent’s ICP-MS
Integrated Sample Introduction System (ISIS) was used with an Agilent 8800
#100 ICP-QQQ. When treated with NaBH4 under acidic conditions, iAs is very
efficiently converted into volatile arsine (AsH3), whereas organically bound As
compounds are not converted, or form only less volatile arsine species such as
dimethylarsine (CH3)2AsH, which has a boiling point of 35°C. Adding highconcentrations of HCl further reduces the production of the less volatile arsines,
and iAs is almost entirely converted to arsine, enabling the measurement of iAs
without species separation using chromatography.
Plasma conditions and ion lens tune: RF power =1550 W, Sampling depth = 8.0mm and Carrier gas flow rate = 0.93 L/min were used with soft extraction tune,
Extract 1 = 0.5 V and Extract 2 = -170 V.
Acquisition parameters: MS/MS mass-shift mode using O2 cell gas at a flow rateof 2.0 mL/min. As was measured as the reaction product ion AsO+ at m/z 91.
Samples: Samples included 31 different rice products purchased from local
stores. Sub-samples (30g) of the commercially sourced rice samples wereground to a fine homogeneous powder using a coffee grinder. Two rice referencematerials IMEP-107 rice (Institute for Reference Materials and Measurements
Geel, Belgium) and rice SRM NIST 1568a Rice Flour were used as quality control
for iAs concentration measurements.

282

Sample prep: 0.15g of each rice sample was digested in 1 mL concentrated
HNO3 and 2 mL H2O2 (30 % w/w) using open vessel digestion in a CEM Mars
microwave system. All samples were diluted to a final volume of 30 mL using
deionized water.
Table 1. Cool plasma operating conditions.
Sample flow rate (mL/min)

0.5

HCl flow rate (mL/min)

2.5

NaBH4 flow rate (mL/min)

0.5

Reaction coil volume (mL)

0.23

Ar flow rate (for HG) (L/min)

0.3

Ar flow rate (for nebulization of IS) (L/min)

0.85-0.95

Results and discussion
The speciation results for iAs in IMEP-7 rice and NIST 1568a Rice Flour obtainedusing HG-ICP-QQQ were in good agreement with the values obtained using
HPLC-ICP-QQQ and with the reported values (Table 2).
Table 2. iAs results obtained using HG-ICP-QQQ and HPLC-ICP-QQQ.
Inorganic As
HG-ICP-QQQ (µg/kg)

HPLC-ICP-QQQ (µg/kg)

Reported value (µg/kg)

IMEP-7 rice

100 ± 11 (n=15)

110 ± 12 (n=15)

107 ± 14 [2]NIST 1568a

94 ± 8 (n=3)

105 ± 4 (n=3)

94 ± 12A summary of the values for iAs, DMA and total As determined in the commercial
rice samples is given in Table 3. The dominant arsenic species found in rice are
iAs and dimethylarsinic acid (DMA), with only trace amounts of methylarsonicacid (MA). The method uses HCl (5 M) and NaBH4 for the selective generation ofarsines where iAs and DMA are converted almost exclusively to AsH3, with only
minor (2-4%) conversion of DMA to dimethylarsine. MA forms methylarsine at
approximately 40% efficiency with the method; however, since MA is generally
absent from rice – or only present in trace amounts – this should not affect thequantification of iAs.

283

Table 3. Speciation results of iAs in 31 rice products determined by HG-ICP-QQQ and HPLC-ICPQQQ. Results are also given for DMA and MMA, and the total As concentration determined by
ICP-QQQ. All data ± SD, with n=3 for speciation and n=2 or 3 for total As.
Rice product
HG iAs(µg/kg)HPLC iAs(µg/kg)HPLC DMA(µg/kg)HPLC MMA(µg/kg)Total As(µg/kg)Arborio Risotto

113 ± 13120 ± 18

63 ± 7<LOQ

236 ± 15

Organic ArbRis

109 ± 12119 ± 1360 ± 8<LOD

150 ± 7

Basmati, 1

41 ± 453 ± 78±1<LOD

100 ± 12

Basmati, 2

76 ± 688 ± 628 ± 4<LOD

91 ± 8Basmati (white)

72 ± 1169 ± 924 ± 1<LOD

240 ± 5

Organic Basmati (white)

95 ± 3104 ± 321 ± 2<LOD

117 ± 13

Brown Rice

127 ± 6137 ± 535 ± 2<LOD

205 ± 2

Japanese Rice

101 ± 599 ± 5123 ± 1<LOQ

252 ± 10

Long Grain (white)

89 ± 285 ± 1

16 ± 1<LOD

121 ± 11

Long Grain Rice, 1

103 ± 294 ± 1218 ± 9<LOQ

392 ± 23

Long Grain Rice, 2

40 ± 252 ± 1039 ± 3<LOQ

111 ± 8Long Grain white

47 ± 261 ± 419 ± 4<LOD

102 ± 9Organic Long Grain (brown) 111 ± 7

131 ± 1454 ± 7<LOQ

207 ± 15

Organic (white)

65 ± 465 ± 211 ± 1<LOD

92 ± 4

Paella, 1

60 ± 565 ± 238 ± 1

1.2 ± 0.1

136 ± 1

Paella, 2

66 ± 470 ± 317 ± 1<LOD

121 ± 6

Spanish Paella

67 ± 267 ± 313 ± 1<LOD

109 ± 7

Pudding Rice

124 ± 9125 ± 1144 ± 5<LOD

202 ± 4

Rice Flour

40 ± 146 ± 519 ± 2<LOD

102 ± 6

Carnaroli Risotto Rice

81 ± 282 ± 484 ± 2<LOD

210 ± 15

Risotto Rice

97 ± 11114 ± 1072 ± 9<LOQ

221 ± 17

FLG Thai (white)

88 ± 3102 ± 352 ± 5<LOD

197 ± 9Thai Jasmine

61 ± 464 ± 349 ± 5<LOD

143 ± 3

Thai Jasmine (white)

62 ± 462 ± 349 ± 2<LOD

171 ± 5

Vietnamese Rice Paper

21 ± 228 ± 1<LOQ<LOD

58 ± 10White Rice

71 ± 576 ± 514 ± 4<LOQ

124 ± 1Whole Grain

133 ± 2127 ± 2151 ± 127.2 ± 0.3

370 ± 19

LOQ HG-ICP-QQQ: 5 µg/kg, HPLC-ICP-QQQ: 1.1 µg/kg

284

Conclusion
Inorganic arsenic (iAs) was quantified at low ppb levels in extracts of 31 rice
samples using an Agilent Hydride Generator/ISIS coupled to an Agilent 8800
ICP-QQQ. Results obtained using HG-ICP-QQQ were in good agreement with
HPLC-ICP-QQQ values across a wide linear range, with comparable limitsof detection.
Following a simple sample preparation using microwave extraction, quick
separation of iAs and DMA by HG-ICP-QQQ was performed online. A previous
study has shown that HG-ICP-QQQ requires only 4 minutes total run time persample (5 replicate measurements) compared to speciation with HPLC which
commonly takes between 5 and 10 minutes for each sample replicate [3].
Data handling for the HG method is also straightforward as no peak-integrationis necessary.
The new HG-ICP-MS method offers fast analysis time, high throughput, andsimple, reliable operation. This makes it ideally suited to screening large numbersof food samples to meet the increasing demand for the routine determination ofiAs in food, especially rice-based products.

References
1.	European Food Safety Authority, Scientific Opinion on Arsenic in Food. EFSA
Journal, 2009, 7(10):1351.
2.	de la Calle, M. B.; Emteborg, H.; Linsinger, T. P. J.; Montoro, R.; Sloth, J. J.;
Rubio, R.; Baxter, M. J.; Feldmann, J.; Vermaercke, P.; Raber, G., Does thedetermination of inorganic arsenic in rice depend on the method? Trac-Trends
Anal. Chem. 2011, 30, (4), 641-651.
3.	Stanislav Musil, Ásta H. Pétursdóttir, Andrea Raab, Helga Gunnlaugsdóttir,
Eva Krupp, and Jörg Feldmann, Speciation without Chromatography Using
Selective Hydride Generation: Inorganic Arsenic in Rice and Samples of Marine
Origin, Anal. Chem. 2014, 86, 993−999.

More information
For a full account of this application see publication: Ásta H. Pétursdóttir et al.,Hydride generation ICP-MS as a simple method for determination of inorganic
arsenic in rice for routine biomonitoring, Anal. Methods, 2014, 6, 5392-5396.

285

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Fast Determination of Inorganic Arsenic (iAs) in
Food and Animal Feed by HPLC-ICP-MS
Authors
Ana Jerše, Julie Storm Høgsbro,
and Jens J. Sloth1
Raquel Larios2
1
National Food Institute, Technical
University of Denmark (DTU Food)*,
Denmark2
Agilent Technologies, Madrid, Spain

Method compliant with EU regulations and in accordance with
two CEN standards on the analysis of iAs
Introduction
It is well known that the two inorganic forms of arsenic (iAs), arsenite, As(III),and arsenate, As(V), are more toxic than the organo-arsenic species (1).
The difference in the toxicity of As species is why regulations in many countries
specify the need to determine the iAs content of food and feedstuffs.
For example, European (EU) regulation 1881/2006 (2) includes maximum levels
of iAs in rice and rice products—between 0.1 and 0.3 mg/kg. EU directive
2002/32/EC (3) states that the iAs content must be lower than 2 mg/kg in certain
feedstuffs, such as feeds that contain seaweed. The European Commission is
expected to establish maximum levels for iAs in other food commodities,
especially foods that are widely consumed such as drinking water, milk, and dairy
products. These foods have the potential to contribute more to the total dietary
uptake of iAs.
HPLC-ICP-MS is widely used for As speciation studies. However, the separationof As species typically requires a long column, resulting in measurement times
greater than 10 minutes. To shorten the measurement time significantly, a fast
HPLC-ICP-MS method was developed by Jackson (4) and further modified byGray et al (5). These methods have been used successfully for the analysis ofiAs in rice (6) and wine samples (7).
To optimize a routine method that is suitable for official control of iAs in foodand feedstuffs, we based this work on those previous studies. The method alsoneeded to be compliant with current European regulations and meet theanalytical requirements of two CEN standards on the determination of iAs infood and feed. The two CEN standards are EN16802:2016 (food) (8) andprEN17374:2019 (animal feed) (9). The sample preparation guidelines stated in
the two CEN standards specify oxidation of As(III) to As(V) during the extraction
procedure, which simplifies the determination of iAs in foods and animal feeds.
In this study, the chromatographic conditions were optimized to separate iAs(as As(V)) from dimethylarsinic acid (DMA), and monomethylarsonic acid (MA)in under two minutes. Method optimization and evaluation were performed using
an Agilent 1260 HPLC coupled to an Agilent 8900 Triple Quadrupole ICP-MS(ICP-QQQ). The method can also be run using a single quadrupole ICP-MS, as the
ICP-QQQ was operated in single quadrupole mode with helium (He) as a collisiongas. The analytical performance of the method was tested, including limits ofdetection (LOD) and quantification (LOQ), linearity, spike recoveries, precision, andaccuracy. The method was validated with suitable beverage, food, and animal
feed reference materials (RMs).

286

Experimental
Reagents and standards
The As(V) standard solution for ICP-MS was bought from SCP Science (Canada).
The As(III) solution and DMA salt were bought from Sigma Aldrich (USA), and MA
was bought from Santa Cruz Biotechnology (USA). The arsenobetaine (AB) was acertified reference material (ERM-AC626) that was bought from the Institute for
Reference Materials and Measurements (IRMM, Belgium). For the mobile phase,ammonium carbonate ((NH4)2CO3, trace metal grade 99.999%, Alfa Aesar, USA),and methanol (HPLC grade from VWR Chemicals, USA) were used.
As(V) calibration standards (representing iAs) were prepared in duplicate
between 0.05 and 50 µg/L using the mobile phase as the diluent. MA and DMA
were also added to the calibration standards to check the separation of the iAs
peak from the organic compounds. The separation of the peak of the AB
standard from the iAs peak was also tested. The As(III) standard was used todemonstrate the quantitative oxidation to As(V) during the sample preparation
step (data not shown).
Reference materials and samples
A list of samples and RMs used in this study is given in Table 1. Some of the iAs
concentrations in the RMs were certified, reference values, or values establishedby collaborative trials and proficiency tests.
Table 1. Overview of samples and reference materials used in the study.
Sample/RM(Full name)

Sample/RM(Short namea)

iAs Conc(mg/kg)Comments

Water from Plastic Bottle(Commercial Sample)

Bottled water--Apple Juice (Commercial Sample)

Apple juice

-

-

Rice

0.124 ± 0.011b

Certified value

White Rice Flour (NMIJ CRM 7503-b)

White rice flour

0.153 ± 0.010b

Certified value

Brown Rice Flour (NMIJ CRM 7533-a)

Brown rice flour

0.530 ± 0.016b

Certified value

Leek0.086 ± 0.012c

Collaborative trial

Chili Powder (FAPAS T07288QC)

Chili powder

0.775 ± 0.024

Proficiency test

Bovine Liver (ERM-BB185)

Bovine liver-

Fish Protein (NRCC-DORM-4)

Fish protein

Blue Mussels (DTU Food)

Rice (ERM-BC211)

Leek (DTU Food)d-0.27 ± 0.038cCollaborative trial

Blue mussels

0.33 ± 0.049cCollaborative trial

Complete Marine Based Feed (DTU Food)

Marine based feed

0.802 ± 0.122

Collaborative trial

Mixed Corn Poultry Feed (FAPAS)

Mixed corn poultry
feed0.299 ± 0.010d

Proficiency test

Kelp Powder (NIST SRM 3232)

Kelp powder

0.247 ± 0.019e

Reference value

Hijiki10.1 ± 0.5

Certified value

Hijiki (NMIJ 7405a)cb… Short names of samples and RMs are used in the document… Expanded uncertainty with the coverage factor k = 2 (level of confidence of approx. 95%)
… Standard deviation of all the results from collaborative trial (duplicates from different laboratories)d… Uncertainty determined in proficiency test based on standard deviation of all the results
and number of participantse… Expanded uncertainty with the coverage factor k = 2.36
a

b
c

287

Sample preparation
The sample preparation guidelines stated in the two CEN standards were
followed (8, 9). For all solid samples, 0.1 M HNO3 in 3% (v/v) H2O2 was used as
the extraction solution. Approx. 0.2 g of solid sample was mixed with 10 mL ofthe extraction solution. To obtain the same acid concentration after mixing withthe sample at a ratio of 1:1, a more concentrated extraction solution was
prepared for liquid samples. 5 mL of liquid sample was mixed with 5 mL of themore concentrated extraction solution (0.2 M HNO3 in 6% (v/v) H2O2). Samples
were heated in a water bath at 90 °C for 60 min. The extracts were thencentrifuged for 10 min at 4000 rpm. The supernatants were transferred into filter
vials (0.45 µm pore size). The vials containing the extracts were refrigerated at
4 °C before analysis. Because the Hijiki sample had a high iAs content (10.1 ± 0.5
mg/kg), the extract was further diluted 20-fold with the extraction solution andfiltered, before analysis.
Instrumentation
An Agilent 1260 HPLC with a binary pump was coupled to an Agilent 8900
ICP-QQQ. The HPLC was fitted with a PRP-X100 (5 μm, 50 x 2.1 mm) column
and matching PRP-X100 analytical guard column (Hamilton Company, USA).
The 8900 ICP-QQQ was equipped with a standard sample introduction systemcomprising a glass concentric nebulizer, quartz spray chamber, quartz torch with
2.5 mm i.d. injector, and nickel-tipped interface cones. The ICP-QQQ was operated
in single quadrupole mode. Helium was used as a collision gas in the ORS4
collision/reaction cell (CRC) to remove the potential interference from 40Ar 35Cl on
75
As. Although the 8900 offers higher sensitivity and lower detection limits thansingle quadrupole ICP-MS, the method could be run on the Agilent 7800 or 7900
ICP-MS, which are also fitted with an ORS4. The instrument operating conditions
are summarized in Table 2.
Table 2. HPLC-ICP-MS operating conditions.
ICP-MS
RF Power (W)1550

Nebulizer Gas (L/min)

1.06

Sampling Depth (mm)8Spray Chamber Temperature (°C)

2

Peristaltic Pump Speed (rps)0.5aScan Mode

Single Quad

He Cell Gas Flow (mL/min)

3.5

Monitored m/z

75

As, 35Cl

HPLC

a
b

288

Column Temperature

Ambient

Injection Volume (µL)

5

Mobile Phase

40 mM ammonium carbonate in 3% methanol, pH 9

ElutionIsocratic

Mobile Phase Flow (mL/min)

0.65

Run Time (min)5b… Used for drain only…R
 un time was set to 5 min to make sure that no other compounds eluted after the iAs peak.
Figures 1 and 2 do not show the entire chromatogramResults and discussion
Optimization of a fast method
The method was based on the approach used in two previous studies (4, 5).
The relatively short anion exchange column was packed with small sizedparticles, allowing the use of a higher mobile phase flow rate and low volume
injections.
Different mobile phase flow rates of 0.45, 0.5, 0.55, and 0.65 mL/min were tested.
The fastest elution of arsenic compounds was achieved at 0.65 mL/min, withoutcompromising the separation of the peaks. Higher flow rates were not tested
since leaks were observed, due to the high backpressure. Since As(III) was
oxidized to As(V), fewer As species were determined, allowing a stronger mobile
phase to be used.
The chromatographic method achieved baseline separation of iAs from otherarsenic species in less than two minutes, without compromising resolution,
as shown in Figures 1 and 2. Figure 1 shows overlaid chromatograms of theindividual arsenic species standards and Figure 2 shows overlaid chromatograms
for a representative calibration set of standards from 0.05 to 50 μg/L. As shown,iAs (as As(V)) was well separated from the other As species.

Figure 1. Overlaid chromatograms of individual As species standards.

Figure 2. Overlaid chromatograms of calibration standards between 0.05
and 50 μg/L prepared in the mobile phase.

Helium was used as a collision gas in the ICP-MS to remove the potential
interference from 40Ar35Cl+ on 75As+. To check the retention times (RT) of Cl+ andAs+, both ions were monitored at m/z 35 and m/z 75, respectively. Figure 3 showsthat the RT of the chloride peak (black chromatogram) is distinct from the As(V)peak (green chromatogram), which complies with one of the requirements listed
in EN16802:2016 and prEN17374:2019. The absence of a peak at the RT of Cl in
the green chromatogram (although MA partly overlaps the Cl peak) suggests that
35 40
Cl Ar+ was removed in He mode.
289

Figure 3. Chromatogram of Rice ERM-BC211 showing the RT of As species (green chromatogram)and the chloride peak (black chromatogram).

Linear calibration
The calibration curve for iAs (as As (V)) showed good linearity, as shown in
Figure 4.

Figure 4. Calibration curve for iAs (represented by As(V)).

Limits of detection and quantification
To evaluate the LOD and LOQ, 10 blank samples of the extraction solution wereanalyzed. The iAs peak of the As contaminant in the blank samples was
integrated and the LOD and LOQ in solution were calculated using a 3-fold and
10-fold standard deviation, respectively. The LODs and LOQs in the samples werealso calculated. The values for the solid samples are based on a test portion sizeof 0.2 g extracted with 10 mL of the extraction solution. The values for the liquidsamples are based on 5 mL of sample diluted to 10 mL with the extraction
solution. All LODs and LOQs are given in Table 3.
Table 3. LODs and LOQs for iAs calculated in solution, and in the solid and liquid samples.
iAs in Solution(µg/L)iAs in Solid Sample(μg/kg)iAs in Liquid Sample(µg/L)

LOD

0.040

1.99

0.08

LOQ

0.133

6.64

0.27

The LOQ value for solid samples of 6.64 μg/kg (0.0066 mg/kg) satisfies theEuropean legislation for iAs determination in food (rice) of < 0.04 mg/kg (10).
The LOQ is also well below the maximum iAs value of 2 mg/kg specified inEuropean regulations for animal feed (3). The sensitivity of the method is
sufficient for official control of iAs in food and feedstuffs.

290

Spike recoveries and evaluation of matrix effects
Several samples were spiked with iAs at two different concentration levels toevaluate potential matrix effects. Bottled water, apple juice, and bovine liver wereselected as “unknown” samples, since no prior information on the iAs content
was available for these samples. The iAs concentration of the two other spiked
samples (leek and blue mussels) was obtained from collaborative trials.
Table 4 shows the spike recoveries were within 100 ± 10% range for all samples
apart from apple juice. The recoveries for apple juice were outside the 100 ± 10%
range for both the low and high concentration spike levels, indicating matrix effects.
Table 4. Spike recoveries of iAs in selected samples.
Low Spike
Concentration(µg/L)

Spike
Recovery(%)

High Spike
Concentration(µg/L)

Spike
Recovery(%)

Bottled Water

0.5

109 ± 9190.0 ± 0.6

Apple Juice

0.5

119 ± 1

1

111 ± 1

Bovine Liver0.5

110 ± 3

1

104 ± 5Leek

2

102 ± 105

106.7 ± 0.7

Blue Mussels

595 ± 161096 ± 4

SampleThe slope of the external calibration curve (solid line) was compared with theslopes of the standard addition curves (dotted lines; Figure 5). The trend lines forthe standard addition curves are shown to help the comparison. For most of thesamples, the difference in the slope between the external calibration curve andthe standard addition curve was lower than 10%. The small difference suggests
only minor matrix effects for these matrices, so external calibration can be used
for the quantification of iAs in these samples. However, the difference in the twoslopes for apple juice was higher than 20%, so standard addition is required forthe quantification of iAs in apple juice.

Figure 5. Comparison of the slope of the external calibration curve with the slope of the standard
addition curve.

291

Precision and accuracy
All samples and RMs were prepared in triplicate and analyzed on the same day.
The results of the three replicates were used to evaluate the precision of themethod, which is reported as relative standard deviation (RSD). To evaluate theaccuracy of the method, the average of the three replicates was compared to an
RM target value. The results are reported as recovery.
The measured results for iAs in different samples are shown in Table 5. Recoveries
were calculated using external calibration curves prepared in the mobile phase,
as well as with the standard addition curves generated for selected samples.
The original calibration for iAs was updated periodically through the sequence byrunning a QC check standard.
Precision of the measurements ranged from 0.3 to 9.4% RSD and iAs recoveries
ranged from 81.8 to 110.7% of their certified, reference, or informative values.
The results show that the method is suitable for the analysis of the different
drinks, food, and feed samples analyzed in this study.
Table 5. Quantitative results for iAs content in samples and RMs with %RSD and recoveries.
External Calibration Curve
Sample/RM

Measured Conc(μg/kg)RSD(%)

Recovery(%)

Measured Conc(μg/kg)Recovery(%)

Bottled Watera-

0.81 ± 0.08b

9.4

-

0.96b

-

Apple Juice-

0.85 ± 0.06

6.8

-

0.76

-

Rice

124 ± 11119 ± 32.1

96 ± 2--White Rice Flour

153 ± 10151 ± 21.0

99 ± 1--

Brown Rice Flour

530 ± 16496 ± 91.8

94 ± 2--ab

86 ± 1295 ± 21.8

111 ± 287

101.6

Chilli Powdera

775 ± 24860 ± 303.6

111 ± 4--

Bovine Liver-

12.5 ± 0.8

6.5

-

12

-

Fish Protein

270 ± 38

272.4 ± 0.8

0.3100.9 ± 0.3--

330 ± 49337 ± 41.3

102 ± 1

350

106.1

802 ± 122650 ± 30

4.1

82 ± 3--Mixed Corn Poultry Feed299 ± 10293 ± 51.7

98 ± 2--

Kelp Powder

247 ± 19230 ± 20

7.5

94 ± 7--10100 ± 500

8800 ± 600

7.0

88 ± 6--

Marine Based Feedaa

Hijikibb

LeekBlue MusselsaStandard Addition

Target Value(μg/kg)… no dry matter correction… in μg/L

292

Figure 6 shows chromatograms of several of the sample matrices.
Each chromatogram meets the requirements listed in the EN16802:2016 andprEN17374:2019 standard methods, which state that the chromatogramsmust show:
1. Selective separation of arsenate (As(V)) from the other arsenic compounds.
2. As(V) is separated from the nearest peak by a full peak width at 10% peakheight.
3. As(V) is separated from the chloride peak (as shown in Figure 3).

A

B

C

Figure 6. Chromatograms of several sample matrices. A: Chromatogram of Leek (DTU Food).
B: Chromatogram of Fish Protein (NRCC-DORM-4). C: Chromatogram of Blue Mussels (DTU Food).

The data presented in this note was run over several days, and minor differencesin the mobile phase composition and column conditioning led to some variationin the RTs between sequences. However, RT stability within each sample
sequence was excellent, as shown in Table 6.
Table 6. Retention time stability for iAs peak in all standards and samples for three separate
sample sequences.
Average RT (min)RSD (%)

1.61

1.24

Sequence 2 (n = 61)

1.41

1.28

Sequence 3 (n = 82)

1.85

1.73

Sequence 1 (n = 45)293

Conclusion
A fast HPLC-ICP-MS method was optimized for the analysis of iAs in beverages,
food, and animal feed matrices. Using a small injection volume, short ionexchange column, high strength mobile phase, and oxidizing As(III) to As(V)with H2O2 during sample preparation, iAs could be determined in less than two
minutes. The fast analysis time significantly increased sample throughput
compared to methods that use a conventional ion-exchange column.
Following clear separation of As(V) from the organic As species and detection
using an Agilent 8900 ICP-QQQ, LODs of 1.99 µg/kg (solid samples) and 0.08
µg/L (liquid samples) were obtained for iAs. The LOQs were lower than the LOQs
established by European legislation for the analysis of iAs in food and feed
samples. Several reference materials of different matrices with certified,reference, or informative values of iAs were analyzed with good accuracy (81.8
to 110.7%) and precision (0.3 to 9.4% RSD).
The HPLC-ICP-MS method is suitable for official control of iAs in food andfeedstuffs as it complies with European regulations and meets the CEN
standards’ analytical requirements (8, 9). Given the toxicity of iAs, this fast,routine method provides valuable information on the safety of products that are
widely consumed. It also enables food and feed producers to meet regulatory
requirements for the analysis of iAs in their products.

References1.

European Food Safety Authority, Scientific opinion on arsenic in food,
EFSA Journal, 2009, 7, 13512.

European Union Commission, 2006, Regulation (EC) No. 1881/2006 andlater amendments

3.

European Union Commission, 2002, Directive 2002/32/EC and later
amendments

4.

B. P. Jackson, Fast ion chromatography-ICP-QQQ for arsenic speciation,
J. Anal. At. Spectrom., 2015, 30, 1405–1407

5.

P. J. Gray, C. K. Tanabe, S. E. Ebeler, J. Nelson, A fast and fit-for-purpose
arsenic speciation method for wine and rice, J. Anal. At. Spectrom., 2017, 32,
1031–1034

6.

C. K. Tanabe, S. E. Ebeler, J. Nelson, Fast Analysis of Arsenic Species in
Infant Rice Cereals using LC-ICP-QQQ, Agilent publication, 5991-9488EN

7.

C. K. Tanabe, H. Hopfer, S. E. Ebeler, J. Nelson, Fast Analysis of Arsenic
Species in Wines using LC-ICP-QQQ, Agilent publication, 5991-8454EN

8.

EN 16802:2016: Determination of inorganic arsenic in foodstuffs of marine
and plant origin by anion-exchange HPLC-ICP-MS

9.

PrEN 17374:2019: Determination of inorganic arsenic in animal feed byanion-exchange HPLC-ICP-MS

10. European Union Commission, 2007, Regulation (EC) No. 333/2007 and later
amendments

Acknowledgment
Thanks to Michiko Yamanaka (Agilent) for her technical support.
294

> Return to table of contents> Search entire document

Multielement Analysis and Selenium Speciation in
Cattle and Fish Feed using LC-ICP-QQQ
Authors
Skyler W. Smith1, A. F. Oliveira1,2,3,
J. Landero1, A. R. A. Nogueira2,
M. A. Zanetti4, Jenny Nelson5
1. McMicken College of Arts andSciences, Cincinnati, USA
2. Embrapa Southeast LivestockSão Carlos, Brazil
3. University of São Carlos, Group of
Applied Instrumental Analysis, Brazil
4. University of São Paulo, Faculty ofAnimal Science and Food Engineering,Brazil
5. Agilent Technologies, Inc.,
Santa Clara, CA, USA

Validation of an extended FDA Elemental Analysis
Manual method
Introduction
In the USA, animal feed is subject to regulation under the Federal Food, Drug,and Cosmetic Act (FFDCA), which defines food as “articles used for food or drink
for man or other animals”. The US Food and Drug Administration’s (FDA) Center
for Veterinary Medicine (CVM) is responsible for regulations relating to the safetyof feed intended for animals (including but not limited to horses, cattle, swine,
poultry, and fish), under the Animal Feed Safety System (AFSS). The regulations
control many aspects of the production, storage, and labeling of animal feed,
and the permitted levels of additives and contaminants, such as potentially toxic
heavy metals.
Selenium (Se) has been approved by the FDA as a supplement for animal feed
since the 1970s. The FDA’s current method for Se quantification uses ICP-MS withhelium collision/reaction cell (CRC) for control of interferences [1], but thesensitivity of this method is affected when high levels of interferences are present.
Selenium is an essential trace nutrient for vertebrates and is involved inseveral vital metabolic processes. The recommended human dietary intake isapproximately 55 μg Se per day, which most people acquire through theconsumption of plant-based foods, such as cereals. However, Se in the soil is notevenly distributed geographically, so dietary supplementation is commonplace insome parts of the world. This approach requires caution though, as Se is toxic inexcess, with a tolerable upper intake level of about 200 μg/day depending on
gender and age [2].
Animal feeds including cattle feed and fish feed are often supplemented withselenium. Supplementation may be in the form of sodium selenite/selenate,
which is approved by the European Food Safety Authority (EFSA) as a foodadditive for all animal species [3]. Selenized yeast is also commonly used as anadditive; if properly produced, the fortified yeast should contain primarily
selenomethionine (SeMet). It is noted that the US regulations for supplemented
selenium applicable for cattle feed and other livestock do not apply to fish feed.
Total and speciation analysis of selenium
Determination of total Se concentration is commonly carried out as part of amultielement analysis using ICP‑MS. More recently, Se analysis has benefited
from the lower detection limits and greater freedom from spectral interferences
provided by triple quadrupole ICP-MS (ICP-QQQ) [4, 5]. However, the toxicity of Se
depends on the chemical form or species in which the Se occurs, so totalelemental concentrations do not provide a complete picture of the element’s
potential toxicity. As a result, separation and detection of the individual species(speciation) is required. The major Se species that occur naturally in the types ofcrop plant used to produce animal feed include two inorganic species, selenite
295

(Se(IV)) and selenate (Se(VI)), and some selenoamino acids: selenocystine(SeCys2), selenomethionine (SeMet), and Se-methyl selenocysteine (MeSeCys).
Selenoamino acids are considered to be less toxic than the inorganic forms,
with Se(IV) being the most toxic species [6]. In addition to the naturally occurring
selenium species, animal feeds may contain various selenium compounds
added during production to raise the level of total selenium in the animals’ diet.
Se speciation analysis typically uses the well-established analytical methodof HPLC (to separate the various Se-containing species) coupled to ICP-MS(to identify and quantify the individual Se species). HPLC-ICP-MS has been
widely employed for analyzing various sample types [7] but there are few studies
on selenium speciation in animal feed [8].
In this study, we developed an extraction and analytical method for themeasurement of total Se using ICP-QQQ, and for Se speciation using LC-ICP-QQQ.
The method provides low background and high sensitivity enabling low detection
limits for total Se and Se compounds to be achieved. We then applied thespeciation method to evaluate the selenium content and species distribution in
cattle feed and fish feed.

Experimental
Samples and sample preparation
Two commercial cattle feeds and four commercial aquaculture feeds werebought from local stores.
Total Se (and multi-element) analysis of feeds
Cattle and fish feed samples were weighed to approximately 100 mg dry mass andmicrowave digested in a 1:1 mix of trace metal grade HNO3 and distilled de-ionized(DDI) H2O. A solution containing various internal standards was added before
digestion, giving an internal standard concentration of 5 ng/g in the final diluted
solutions as analyzed. The microwave program consisted of a first step at 300 W
with a 10 min ramp to 95 °C and a second step at 300 W including a 10 min ramp
to 200 °C, followed by a 20 min hold time. After cooling, 1 mL of 30% H2O2 wasadded and a second digestion was performed using the same heating program.
The sample digests were diluted with DDI water to give a final acid concentrationof approximately 2% HNO3. Two certified reference materials (CRMs) NIST 1547
Peach Leaves (NIST, Gaithersburg, MD USA) and SELM-1 Selenium Enriched Yeast(National Research Council of Canada) were prepared as quality control samples.
Enzymatic extraction procedure for Se speciation in feeds
An extraction solution containing 50 mM ammonium phosphate monobasic
was prepared and the pH was adjusted to 7.5. Feed samples were weighed toapproximately 200 mg with 3 mL of the extraction solution [9]. Samples weresonicated using QSonica sonication probe. The sonication program consisted ofa 2 second pulse, followed by a 3 second rest at 60% amplitude for 2 minutes.
Following sonication, approximately 20 mg of protease type XIV (fromStreptomyces griseus, Sigma-Aldrich) and 10 mg of lipase (from Candida rugose,
Sigma-Aldrich) dissolved in buffer solution were added to each sample andplaced on a hot block for 12 hours at 37 °C. After 12 hours, the samples weresonicated again at 30% amplitude for 30 seconds and placed on the hot block
for a further 12 hours.
296

The “enzyme extract” was filtered with a 0.45 m Spin-X Centrifuge Tube Filter(Costar, USA). The resulting sample was then diluted 1:1 with mobile phase 1
ready for analysis by reversed phase ion pairing LC-ICP-QQQ.
Instrumentation
An Agilent 8800 Triple Quadrupole ICP-MS (ICP-QQQ) equipped with an Agilent
SPS4 autosampler was used for analysis of total selenium and other elements
in cattle and fish feed samples. Instrument operating conditions are given in
Table 1.
Table 1. ICP-QQQ operating conditions.
Parameter

No gasHe

Spray chamber temp (°C)

2

RF power (W)1550

Sampling depth (mm)8.5

Carrier gas (L/min)

1600
8
1.00

Make up gas (mL/min)
Cell gas (mL/min)

O2

0.10
0.0

0.15
3.4

0.5 (30%*)* Indicates % of full scale flow rate, as displayed in the ICP-MS MassHunter Tune screen

Agilent ICP-MS MassHunter software was used for the setup and operation of
the ICP-QQQ for total Se and multielement data analysis. ICP-MS MassHunter
with the optional Chromatographic Analysis module was used for combined
instrument control and sequencing of the LC-ICP-QQQ Se-speciation study.
For the speciation studies in cattle and fish feed, an Agilent 1100 Series HPLC
was coupled to the ICP-QQQ. Chromatographic separations were performed
using an Agilent ZORBAX Extend column (80 Å C18, 4.6 x 250 mm, 5 μm).
Details of the HPLC method used for Se speciation analysis of cattle and fish
feed are given in Table 2.
The six Se species of interest, Se(IV), Se(VI), selenocystine (SeCys2),
selenomethionine (SeMet), methyl selenocysteine (MeSeCys), andselenomethionine-Se-oxide (SeOMet), were calibrated using mixed standard
solutions containing each of the Se species at levels from 1 to 50 ng/g.
In common with any ion paring method, column equilibration is crucial toensuring long-term reproducibility when using this LC-ICP-QQQ method.
Equilibration is important after cleaning or when the column has been stored fora long time. To prevent deterioration of the column, 2 mM TBAH was added to
the 65% acetonitrile storage solution. Following storage or cleaning, the column
was equilibrated for 20 mins with 3x75 μL injections of 25 mM TBAH dissolvedin the mobile phase.

297

Table 2.HPLC method used for the analysis of cattle and fish feed sample extracts.
Salt gradient; reverse-phase ion-pairing

MethodInjection volume

25 μL

Mobile phase 1

5 mM ammonium acetate, 2 mM ammonium phosphate,
2 mM TBAH, 2% MeOH, pH 6.5

Mobile phase 1

15 mM ammonium acetate, 5 mM ammonium phosphate,
2 mM TBAH, 2% MeOH, pH 6.5

MethodMinute% Mobile phase 2

Flow rate (mL/min)

5

0

1

10

100

1

16

100

1

20

0

1

21

0

1.5

40

0

1.5

45

0

1

Interference removal
Routine determination of total selenium concentrations or analysis of Se species
using LC-ICP-MS does not necessarily require the use of ICP-QQQ. Conventional
quadrupole ICP-MS (ICP-QMS) fitted with a CRC is able to resolve the 40Ar38Ar+
dimer interference on 78Se sufficiently well to give acceptable results for Se
speciation analysis in many sample types [7]. However, doubly-charged ion
interferences such as 156/160Gd++ and 156/160Dy++ on 78/80Se can lead to positive bias
in samples containing relatively high levels of the rare earth elements (REEs) [5].
In these sample types, ICP-QQQ is able to completely resolve the doubly charged
REE interferences along with other spectral interferences, giving lower detection
limits and better accuracy than ICP-QMS for Se (and As).

Results and discussion
Multielement analysis
The multielement analysis results including total Se content of the feed and CRM
samples are summarized in Table 3. The measured value for total Se in Se-yeast
SELM-1 CRM was in good agreement with the certified value at 94% recovery.
The results validate the sample preparation method and the accuracy of the
ICP-QQQ results. Accurate recovery of Se in NIST 1547 Peach Leaves was also
obtained (102%, relative to the original 1991 certified value). This indicates theeffective control of interferences including doubly charged rare earth elements,
as NIST Peach Leaves contains up to 10 mg/kg (ppm) of the light rare earth
elements. Table 3 also includes instrument detection limits (IDLs) demonstrating
low ng/L (ppt) detection limits for most analytes.

298

Table 3. Total selenium dry weight concentration (mg/kg) determined in cattle feed, fish feed, and CRMs analyzed by ICP-QQQ.
Element

Tune

Q1  Q2 Set Mass

Cattle Feed 1

Cattle Feed 2

Fish Feed 1

Fish Feed 2

Mg

He

24–>24

2,278 ± 49

2,762 ± 26

1,873 ± 37

2,419 ± 17

KHe

39–>398,771 ± 77

9,556 ± 60

7,064 ± 129

10,080 ± 196

VHe

51–>511.37 ± 0.05

0.28 ± 0.01

0.30 ± 0.03

0.36 ± 0.02

CrHe

52–>52

1.79 ± 0.07

0.90 ± 0.03

1.16 ± 0.06

0.74 ± 0.06

FeHe

56–>56392 ± 21166 ± 25432 ± 10255 ± 3CoHe

59–>590.66 ± 0.02

1.3 ± 0.1

0.127 ± 0.001

0.67 ± 0.04

CuHe

63–>6331.1 ± 0.8

26 ± 28.68 ± 0.08

66 ± 2AsO2

75–>910.21 ± 0.02

0.11 ± 0.01

1.14 ± 0.09

0.30 ± 0.05

SeO2

78–>940.86 ± 0.04

0.69 ± 0.03

1.07 ± 0.08

0.98 ± 0.05

SrHe

88–>8811 ± 2

11.4 ± 0.5

49 ± 1

16.4 ± 0.6

MoHe

95–>951.35 ± 0.03

2.17 ± 0.01

0.77 ± 0.01

1.52 ± 0.02

CdHe

111–>111

0.094 ± 0.004

0.072 ± 0.003

0.40 ± 0.02

0.049 ± 0.002

Pb

No gas

208–>208

0.24 ± 0.03

0.12 ± 0.01

0.38 ± 0.06

0.23 ± 0.09

Element

Tune

Fish Feed 3

Fish Feed 4

NIST 1547a

ELM-1a

IDL, ppb

Mg

He

2,152 ± 29

1,586 ± 56

4,406 ± 72 (98)KHe

11,298 ± 110

7,520 ± 66

22,167 ± 364 (91)

7.16

V

He

0.42 ± 0.01

1.14 ± 0.08

0.341 ± 0.006 (93)0.0123Cr

He

2.37 ± 0.01

1.10 ± 0.05

1.067 ± 0.009 (107b)

0.0044FeHe

204 ± 15642 ± 50225 ± 3 (102)0.1027Co

He

0.146 ± 0.002

0.20 ± 0.01

0.068 ± 0.002 (97b)0.00050.2116Cu

He

16.2 ± 0.3

10.42 ± 0.08

3.8 ± 0.2 (101)

0.027

As

O2

0.171 ± 0.009

0.81 ± 0.03

0.08 ± 0.02 (133c)

0.0035Se

O2

0.55 ± 0.02

1.05 ± 0.04

0.122 ± 0.003 (102c)

Sr

He

40 ± 232 ± 262 ± 1 (117)Mo

He

1.67 ± 0.03

1.11 ± 0.03

0.063 ± 0.006 (104)

0.002

Cd

He

0.074 ± 0.004

0.056± 0.006

0.028 ± 0.001 (107)0.0039Pb

No gas0.25 ± 0.04

0.41 ± 0.03

0.82 ± 0.03 (94)0.19461911 ± 97 (94)0.0031
0.018

a. Values enclosed in parenthesis are recoveries of the certified value of reference material.
b. Recovery determined relative to a non-certified, information value.
c. Recoveries for As and Se are calculated relative to the original certified values (1991 revision). These certified values have subsequently been removed from thecertificate (2017 revision) so may not be reliable.

In the United States, the Association of American Feed Control Officials (AAFCO)
2011 Guidelines [10] and the US FDA’s 21 CFR Part 573, Section 573.920(Selenium) [11] state animal feeds intended for chickens, turkeys, swine, beef
cattle, dairy cattle (and in the AAFCO Guidelines, bison, sheep, goats, llamas,
alpacas, and horses) may contain selenium yeast at a level not to exceed 0.3 ppm(mg/kg) of selenium based on the complete feed [10]. Furthermore, the level ofinorganic species should not exceed 2% of the total Se content in the final yeast
product. Our results show that the two cattle feeds contained Se significantly
above the 0.3 mg/kg limit, at 0.86 and 0.69 mg/kg Se. Similar results were foundin the four fish feeds tested, which contained concentrations between 0.55 and1.07 mg/kg Se.

299

All feeds contained at least twice the maximum Se concentration of 0.3 ppm(mg/kg) in selenium supplemented feeds. The feeds were likely supplemented
by the addition of “antioxidants” including Se-yeast to increase the selenium
content. To further investigate the Se content of the feeds, speciation analysis
was performed to separate and quantify the individual Se species present in thefeed samples.
Selenium speciation analysis
Selenium speciation analysis was performed using LC coupled to ICP-QQQ.
Se was measured using the oxygen cell gas tune mode as for Se in themultielement analysis. The selenium species concentrations were calibratedusing mixed standard solutions containing each of the Se species at levels from
1 to 50 ng/g. The integrated peak areas for each species were plotted versus thestandard concentrations to generate calibration curves covering the required
calibration range.
The chromatogram shown in Figure 1 was obtained from the analysis of a mixed
standard containing each Se species at 25 ng/g. The chromatogram
demonstrates good sensitivity and peak separation for all species. Peak identities
were confirmed by retention time (RT) matching and/or the use of standard
spikes added to the extracts.
40000

Se CPS (78-94 m/z)

30000

20000

10000

0
1

2

3

4

5
6
Time (min)

7

18

20

22

Figure 1. LC-ICP-QQQ chromatogram of standard containing six selenium species at 25 ng/g.

Se species in cattle feed samples
The two cattle feed samples were analyzed using LC-ICP-QQQ. The overlaid
chromatograms in Figure 2 show that both samples contained primarily SeMet,
while cattle feed 2 also contained significant levels of Se(VI). Other species were
present at trace levels. The source of SeMet was likely to be selenized yeast,
which is often added intentionally to enrich the feeds. However, natural sources,
such as grains and soybeans, are common additives that have been found toaccumulate SeMet when supplied with inorganic Se sources [12–14]. Plants
naturally uptake Se from soils, and inorganic Se species tend to be more mobile,which leads to increased plant uptake compared with organic forms. Depending
on soil conditions, either Se (IV) or Se (VI) may be the major Se source for plants[15]. When Se (IV) is the main source of selenium, it gets metabolized to organic
Se compounds; while Se (VI) uptake generally results in higher accumulation
300

without transformation [12, 14]. It can be concluded that the Se (VI) found in the
cattle feeds for this study likely originated from the addition of high-selenium
plant additives often used in feed production.
3200

Cattle 1
Cattle 2

Se CPS (78-94 m/z)

2400

1600

800

0
1

2

3

4
Time (min)

18

20

22

Figure 2. LC-ICP-QQQ speciation analysis of two cattle feed samples.

Se species in fish feed samples
Figure 3 shows chromatograms for the four fish feed samples. As with the cattle
feeds, a variety of Se species were observed in these samples. SeMet was theprimary species in all feeds, but inorganic forms such as Se(IV) and Se(VI) werealso present. The quantitative results in Table 4 show that Se(IV) was
considerably higher in fish feed 1 compared to the other samples, while Se(VI)was higher in the cattle feeds than the fish feeds.
Selenium supplementation has been shown to improve growth and antioxidant
status for fish reared in the crowded conditions that are typical of mass
production methods [16]. Previous aquaculture studies have shown
supplementation with inorganic forms of Se, mainly Se(IV), leads to inferiorbioavailability compared to SeMet or selenoyeast [17, 18]. Due to greater
accumulation of Se in fillets and whole body, many studies currently use organic
Se for aquaculture and supplementation research [19, 20].
8000

Fish Feed 1
Fish Feed 2
Fish Feed 3
Fish Feed 4

Se CPS (78-94 m/z)

6000

4000

2000

0
1

2

3

4

5
Time (min)

12

15

18

21

Figure 3. LC-ICP-QQQ speciation analysis of four fish feed samples.
301

Table 4. Enzymatic extraction and quantification of Se species for cattle and fish feeds using LC-ICP-QQQ.
SampleExtraction total(μg/kg, ppb)

Extraction
efficiency (%)*

Cattle feed 1

386 ± 3Cattle feed 2
Fish feed 1

Quantification of known species (μg/kg, ppb)
SeOMetSeOMet

MeSeCys

SeMet

Se (IV)Se (VI)

45 ± 12±1

44 ± 415±1

112 ± 80±0

72 ± 3346 ± 1450 ± 2

6±3

4±2

3±1

97 ± 324 ± 27

128 ± 15648 ± 32

61 ± 35±2

19 ± 312 ± 179 ± 1161 ± 823 ± 3

Fish feed 2

484 ± 9049 ± 92±1

14 ± 69±1

117 ± 1110 ± 322 ± 4

Fish feed 3

363 ± 103

66 ± 194±2

17 ± 38±2

222 ± 83±530 ± 7

Fish feed 4710 ± 4368 ± 42±1

27 ± 114 ± 1

293 ± 39

14 ± 331 ± 1* Compared to total Se concentration (shown in Table 3).

Conclusion
Total concentrations of several elements, including selenium, were determinedin cattle and fish feed sample-extracts, using the Agilent 8800 ICP-QQQ. In all
samples, the concentration of Se was above the maximum of 0.3 ppm (μg/kg)
Se recommended in the AAFCO and FDA guidelines for selenium supplemented
feeds.
Reversed phase ion pairing LC-ICP-QQQ was then used successfully to separate
and detect the selenium species at low mg/kg levels in the feed samples (lowμg/L in the solutions analyzed). The method provided valuable information on the
Se species present in the feeds. SeMet was found to be the predominant species,
although the toxicologically relevant inorganic forms of Se (Se(IV) and Se(VI))
were also found to be present in most of the samples.

More information
For a full account of part of this application, see A. F. Oliveira, J. Landero, K.
Kubachka, A. R. A. Nogueira, M. A. Zanetti and J. Caruso, Development andapplication of a selenium speciation method in cattle feed and beef samples
using HPLC-ICP-MS: evaluating the selenium metabolic process in cattle.
J. Anal. At. Spectrom., 2016, 31, 1034. DOI: 10.1039/c5ja00330j

References
1.	Overview of FDA’s Animal Feed Safety System, accessed August 2017,
http://www.fda.gov/downloads/AnimalVeterinary/SafetyHealth/AnimalFeedSafetySystemAFSS/UCM277673.pdf
2.	Selenium in Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium andCarotenoids, Institute of Medicine, Washington, DC, 2000
3.	EFSA Panel on Additives and Products or Substances used in Animal Feed
(FEEDAP), Safety and efficacy of selenium compounds (E8) as feed additives
for all animal species: sodium selenite, EFSA Journal 2016; 14 (2): 4398,
www.efsa.europa.eu/efsajournal
4.	B.P. Jackson, A. Liba, and J. Nelson, Advantages of reaction cell ICP-MS on
doubly charged interferences for arsenic and selenium analysis in foods.
J. Anal. At. Spectrom. 2015, 30, 1179–1183
5.	N. Sugiyama, The accurate measurement of selenium in twelve diverse
reference materials using on-line isotope dilution with the 8800 Triple
Quadrupole ICP-MS in MS/MS mode, Agilent publication, 2012, 5991-0259EN
302

6.	C. B'Hymer and J. A. Caruso, J. Chromatogr. A, 2006, 1114, 1–20.
7.	Handbook of ICP-MS Hyphenated Techniques, 2nd Edition, Agilent publication,
2015, 5990-9473EN
8.	M. Stadlover, M. Sager and K. Irgolic, Die Bodenkultur, 2001, 52, 233–241
9.	L. H. Reyes, J. L. Guzmán Mar, G.M. Mizanur Rahman, B. Seybert, T.
Fahrenholz, H.M. Skip Kingston, Talanta 78, 3, 2009, 983–990
10.	Association of American Feed Control Officials: Official Publication, ed. M. K.
Walsh, 2011, ch. 5, pp.216–353.
11.	Code of Federal Regulations Title 21, Volume 6 [Revised as of April 1, 2017]
21CFR573.920
12.	H.F. Li, S. P. McGrath, and F. J. Zhao. Selenium uptake, translocation andspeciation in wheat supplied with selenate or selenite, New Phytologist 178.1,
2008, 92-102.
13.	Q. Chan, S. E. Afton, and J. A. Caruso. Selenium speciation profiles in seleniteenriched soybean (Glycine Max) by HPLC-ICPMS and ESI-ITMS. Metallomics
2.2, 2010, 147-153.
14.	P. D Whanger, Selenocompounds in plants and animals and their biologicalsignificance. Journal of the American College of Nutrition, 2002, 21(3),pp.223-232.
15.	S. Eich-Greatorex et al. Plant availability of inorganic and organic selenium
fertiliser as influenced by soil organic matter content and pH. Nutrient Cyclingin Agroecosystems, 79.3, 2007, 221-231.
16.	F. Z. Küçükbay et al. The effects of dietary organic or inorganic selenium inrainbow trout (Oncorhynchus mykiss) under crowding conditions. Aquaculture
Nutrition, 15.6, 2009, 569-576.
17.	C. Wang and R. T. Lovell. Organic selenium sources, selenomethionine andselenoyeast, have higher bioavailability than an inorganic selenium source,
sodium selenite, in diets for channel catfish (Ictalurus punctatus). Aquaculture
152.1-4, 1997, 223-234.
18.	M. Lorentzen, A. Maage, and K, Julshamn. Effects of dietary selenite or
selenomethionine on tissue selenium levels of Atlantic salmon (Salmo salar).
Aquaculture 121.4, 1994, 359-367.
19.	M. Abdel-Tawwab, M.A.A Mousa and F.E. Abbass. Growth performance andphysiological response of African catfish, Clarias gariepinus (B.) fed organic
selenium prior to the exposure to environmental copper toxicity. Aquaculture272.1, 2007, 335-345.
20.	S. Lee et al. Dietary selenium requirement and toxicity levels in juvenile Niletilapia, Oreochromis niloticus. Aquaculture 464, 2016, 153-158.

303

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Arsenic speciation analysis in apple juice using
HPLC-ICP-MS with the Agilent 8800 ICP-QQQ
Authors

Introduction

Mina Tanoshima*, Tetsushi Sakai*
and Ed McCurdy†

The presence of potentially toxic elements and compounds in foodstuffs is ofintense public interest, and so food producers as well as regulators require rapid,
reliable screening methods to accurately determine the levels of suchcontaminants in food and drink. In the case of arsenic (As), concentration levels
in foods may be increased through the historical use of As-containing
agrochemicals such as lead hydrogen arsenate (lead arsenate) or calcium
arsenate. These compounds were used for much of the 20th century as a
pre-harvest pesticide to control pests of fruit crops (primarily apples), such as
coddling moth, apple maggots, and fruit fly. While widespread use of thesepesticides ceased in 1970, lead and calcium arsenate are stable and persist in
soil, so may still affect crops grown in contaminated soil long after application
has ceased.

Agilent Technologies* Tokyo, Japan† Stockport, UK

As speciation is important in food safety because the toxicity of the element isstrongly dependent on the chemical form or species in which it occurs. Inorganic
arsenic species, arsenite (As(III)) and arsenate (As(V)) are known to be highly
toxic and carcinogenic, whereas the organic As species monomethylarsonic acid
(MMA) and dimethylarsinic acid (DMA) are less toxic, and arsenobetaine (AB) is
considered to be non-toxic. Levels of inorganic As are therefore routinely
monitored in many sample types including drinking water, food and beverages,
pharmaceuticals, and petrochemicals.
Separation of the various As-containing species by HPLC followed by detection
using ICP-MS is well established as the analytical method of choice for many
sample types, including drinking water and urine [1].
In this study, a novel sample preparation method involving simple filtration anddilution in deionized water was developed for fast, routine measurement of lowlevels of As species in apple juice. The established and proven method from
Reference 1 was used to separate and quantify the five As species discussed
above in six commercial apple juices, to determine whether this commonly
consumed fruit juice contains arsenic species at potentially harmful levels.
The maximum contaminant level (MCL) for total As in drinking water has been
established at 10 µg/L by the US Environmental Protection Agency (USEPA).
But As in food must be considered as part of the total dietary intake, which isrecommended by the USEPA and European Food Safety Authority to be
between 0.8 and 8 ug/kg body weight per day. Other dietary sources of arsenic(in a normal diet) include seafood, rice and other sources.

304

Experimental
Sample preparation
Six different apple juice samples (Apple Juice #1 to #6) were purchased in a
Japanese supermarket. The apple juice samples were filtered using two
disposable filters (Millex-LH, Millipore, USA, followed by TOYOPAK ODS M,TOSHO, Japan). The Millex-LH filter was used to remove the solid materials
contained in the apple juice, and the TOYOPAK ODS M filter was then used toremove non-polar compounds, to avoid overloading the HPLC column. Both filters
were washed and activated according to the manufacturers’ instructions.
After filtration, the apple juice samples were diluted by a factor of two withultrapure water. Aggressive sample digestion and large dilution factors were
avoided in order to minimize species inter-conversion and ensure the lowest
possible detection limits in the original samples.
In order to assess the method capability for accurate low-level measurement ofAs species, the potential for As species contamination during sample preparation
was evaluated. Preparation blank samples were prepared as follows to identify
any possible contamination arising from the different sample preparation steps:
1. Deionized water blank
2. Millex membrane filter blank
3. TOYOPAK ODS filter blank
4. Method blank (de-ionized water filtered twice as for samples).
All four preparation blank samples were measured using the establishedchromatography column, mobile phase and HPLC method from Reference 1, andthe chromatograms obtained are shown in Figure 1. The chromatograms for thefour preparation blanks are shown overlaid with a mixed As species standard(50 ng/L (ppt) each species), confirming that no detectable levels of As were
present in the preparation blanks.

Figure 1. Evaluation of preparation blanks, confirming undetectable levels of As species contamination from the reagents and sample preparation
filters. All four blanks are shown, overlaid with 50 ng/L (ppt) mixed As species standard.

305

It should be noted that the first peak that elutes is arsenobetaine (AB), which is
not retained on the column and so elutes in the void volume, where it might also
co-elute with other neutral or cationic species that are not retained on thecolumn. While AB can be measured using the LC-ICP-MS method described,
the results may be biased if other co-eluting species are present in the sample;
but this limitation is not a problem for food safety applications, since AB isconsidered to be non-toxic even at very high concentrations.
For the purposes of food safety, the critical species that must be separated andquantified accurately and at low level are As(III) and As(V), the sum of which canbe reported as ‘total inorganic arsenic’.

Instrumentation
An Agilent 1290 Infinity LC system comprising a binary pump, autosampler andvacuum degasser was coupled to an Agilent 8800 Triple Quadrupole ICP-MS(ICP-QQQ). An anion exchange guard column (Agilent part number G3154-65002,
4.6 mm id x 10 mm polymethacrylate) followed by As speciation column (Agilent
part number G3288-80000, 4.6 mm id x 250 mm polymethacrylate) were used forseparation. The columns were maintained at ambient temperature for all
experiments. HPLC and ICP-MS parameters are shown in Table 1.
Table 1. Operating conditions and parameters of the Agilent 1290 LC and 8800 ICP Triple Quad
1290 Infinity LC
Condition

Value

ColumnG3154-65002 (guard column), G3288-80000, 4.6 x 250 mm (analyticalcolumn)Mobile phase

2.0 mM PBS / 0.2 mM EDTA/10 mM CH3COONa / 3.0 mM NaNO3 / 2%
EtOH pH 11.00 adjusted with NaOH

Flow rate

1.0 mL/min

Temperature

Ambient

Injection volume

100 µL

8800 ICP Triple Quad
Parameter

Value

RF power

1550 W

Carrier gas flow rate

1.05 L/min

Spray chamber temperature

2 °C

Sampling depth

10 mm

Exact 1 lens

0V

Quadrupole mode

Single quad mode

Cell gas modeNo gas

The routine separation and analysis of As species does not require the use of
ICP-QQQ to resolve interferences, as potential polyatomic overlaps on As (m/z75) are resolved by the chromatography. As previously reported in Reference 1,
the inorganic chloride elutes between the As(III) and MMA peaks and so the ArCl+
polyatomic ion formed from the chloride does not affect any of the As
compounds of interest.

306

However, the interest in As speciation in food and beverages extends to themeasurement of the toxic inorganic compounds at extremely low concentrations(low ng/L or ppt levels) and the enhanced sensitivity and very low background of
the Agilent 8800 ICP-QQQ compared to conventional quadrupole ICP-MS may
therefore be beneficial. If slightly higher detection limits are acceptable within themethod requirements, the sample preparation and HPLC method described here
is completely transferable without any modification to the Agilent 7700 Series
ICP-MS, which offers around 2x lower sensitivity, but detection limits still in the
low tens ng/L (ppt) range.

Results and discussion
Detection limits for each arsenic species were calculated as three times thechromatographic peak-to-peak signal-to-noise (S/N) ratio, alternatively
sometimes expressed as the analyte concentration that would give a S/N of 3.
The detection limits of all five As species were between 10 ng/L and 22 ng/L assummarized in Table 2. Figure 2 shows the 500 ng/L As species standard used
for the S/N and LOD calculation, illustrating the good sensitivity and peakseparation of the five As species studied.
The calibration concentration range was from 10 ng/L to 500 ng/L, showing linear
response for each As species, as illustrated in Figure 3.
Table 2. 3x S/N detection limits for arsenobetaine (AB), dimethylarsinic acid (DMA), As(III) (arsenite), monomethylarsonic acid (MMA), and As(V)(arsenate). * Arsenobetaine (AB) elutes in the void volume and cannot be reliably quantified in the presence of some other co-eluting species.
Compound

RT (min)

Height

Area

Noise

S/N

LOD (ng/L)

Noise type

AB*

2.823

19584

249584153

127.9911.72

Peak-to-peak

DMA

3.602

22117

277103153

144.54

10.38

Peak-to-peak

As(III)

4.128

18022

265346153

117.7812.74

Peak-to-peak

MMA

6.566

14421

299863

153

94.24

15.92

Peak-to-peakAs(V)10.43110265

329325

153

67.08

22.36

Peak-to-peakFigure 2. Chromatogram of 500 ng/L (ppt) mixed As species standard showing good sensitivity and peak separation, and noise region used for
S/N and LOD calculation.

307

Figure 3. Calibration graphs for AB, DMA, As(III), MMA, and As(V).

308

Results of apple juice analysis
The As concentrations determined in the six different apple juices are
summarized in Table 3 (the 2x dilution factor has been applied to the results),
and the chromatograms are displayed in Figure 4. From the concentration results
it is clear that, while the majority of the As was in the toxic inorganic forms,
all of the apple juice samples contained much lower levels of total As than the
USEPA drinking water limit of 10 µg/L. The chromatograms in Figure 4 are allshown on the same intensity scale, to highlight the different relative
concentrations of each species.
Although As species were found in all six apple juices, both the total As
concentration and the relative concentrations of the different species variedamong them. However the total concentration of arsenic (sum of all species)
was below 5 µg/L in all tested juice samples, a level less than half the USEPA
maximum contaminant level for drinking water (10 µg/L). The total inorganic
As (sum of As(III) and As(V)) was less than 3 µg/L in all samples, and below
2 µg/L in five of the six apple juice samples measured.
Spike recovery test and reproducibility
In order to validate the method performance in real samples, a spike recovery
test was performed using the mixed As species standard solution. Apple juice
sample #1 was spiked with the As species standard at a level of 500 ng/L in the
2x diluted sample. The spiked sample was analyzed repeatedly as an unknown,
with seven separate injections being measured in total. Table 4 shows theretention time (RT) and concentration results for all the As species, indicating theexcellent reproducibility of both the RT and concentration for the seven separate
analyses. The %RSDs for all As species were less than 0.5% for retention timeand less than 1.6% for concentration. The overlaid chromatograms of all seveninjections are shown in Figure 5.

Conclusions
Five arsenic species including the toxicologically relevant inorganic forms As(III)and As(V) were determined at low- and sub-µg/L concentrations in commerciallyavailable apple juice, using an Agilent 1290 Infinity LC coupled to an Agilent 8800
ICP-QQQ. Detection limits of between 10 and 20 ng/L (ppt) were obtained for all
As species following a simple filtration and 2x dilution of the apple juice samples.
Arsenic (As) species were detected in all of the apple juice samples measured,although the concentrations of the different species varied among the brands.
None of the samples analyzed in this study contained more than 5 µg/L total As,
and the level of inorganic As (sum of the As(III) and As(V) species) was below 3µg/L in all samples and below 2 µg/L in five of the six brands analyzed.
On the basis of this small sample size of apple juice brands available in Japan,
our data supports the current US Food and Drug Administration (FDA) advice thatcommercial apple juice does not pose a significant risk to health from raisedlevels of inorganic As. Our results for apple juice available in Japan confirm thefindings of the FDA’s monitoring program in the US, that the level of inorganic As
is below the 10 µg/L drinking water limit in all apple juice samples tested.

Reference
1. Tetsushi Sakai and Steve Wilbur, Routine Analysis of Toxic Arsenic Species in
Urine Using HPLC with ICP-MS, Agilent publication 5989-5505EN.
309

Table 3. Quantitative results (µg/L) for all five As species in six commercial brands of apple juice measured by LC-ICP-QQQ
Concentration µg/L
Sample name

DilutionAB

DMA

As(III)

MMA

As(V)

Inorganic As

Total AsApple Juice 1

2

0.069

0.196

0.704

0.033

0.631

1.335

1.600

Apple Juice 2

2

0.066

0.037

0.062

0.006

0.008

0.070

0.173

Apple Juice 3

2

0.063

0.292

0.847

1.633

0.827

1.674

3.662

Apple Juice 4

2

0.052

0.276

1.014

1.475

1.977

2.991

4.794

Apple Juice 5

2

0.067

0.225

1.196

0.795

0.724

1.920

3.007

Apple Juice 6

2

0.043

0.254

1.218

0.005

0.095

1.313

1.610

Figure 4. Chromatograms of As species in six apple juice samples.

310

Table 4. Results of spike recovery (n = 7) of 1 µg/L standard added to the Apple Juice #1
Sample nameAB
RT (min)

Conc. (µg/L)

DMA
RT (min)

Conc. (µg/L)

As(III)
RT (min)

Conc. (µg/L)

MMA
RT (min)

Conc. (µg/L)

As(V)RT (min)

Conc. (µg/L)

Apple Juice 1 Spike 1

2.77

0.848

3.62

1.112

4.19

1.606

6.43

0.980

10.62

1.524

Apple Juice 1 Spike 2

2.76

0.862

3.61

1.116

4.19

1.632

6.43

0.996

10.63

1.560

Apple Juice 1 Spike 3

2.77

0.872

3.61

1.125

4.19

1.621

6.41

1.007

10.62

1.551

Apple Juice 1 Spike 4

2.77

0.886

3.61

1.122

4.18

1.632

6.41

1.003

10.63

1.554

Apple Juice 1 Spike 5

2.78

0.882

3.61

1.134

4.19

1.643

6.41

1.008

10.65

1.561

Apple Juice 1 Spike 6

2.78

0.873

3.61

1.146

4.17

1.637

6.37

1.016

10.68

1.597

Apple Juice 1 Spike 7

2.78

0.881

3.60

1.145

4.17

1.651

6.35

1.018

10.69

1.588

Average

2.78

0.872

3.61

1.128

4.18

1.632

6.41

1.004

10.65

1.562

Standard deviation

0.00760.01330.00580.01350.00960.01480.03060.01300.02910.0242

%RSD

0.28

1.53

0.16

1.20

0.23

0.91

0.48

1.29

0.27

1.55

Figure 5. Seven overlaid chromatograms of Apple Juice #1, spiked with 500 ng/L As standard.

311

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Speciated Arsenic Analysis in Wine Using HPLC-ICP-QQQ
Authors
C. K. Tanabe1, H. Hopfer1,2,3,
S. E. Ebeler1,2, J. Nelson1,2,4
1. Dept. Viticulture & Enology,
University of California (Davis), USA
2. Food Safety & Measurement Facility,
University of California, (Davis), USA
3. Depart. of Food Science, The
Pennsylvania State University,
Pennsylvania, USA
4. Agilent Technologies, USA

Validation of an extended FDA Elemental Analysis
Manual method
Introduction
In 2013, the US Food and Drug Administration (FDA) released Elemental Analysis
Manual (EAM) Method §4.10. The method describes the Determination of Four
Arsenic Species in Fruit Juice using High-Performance Liquid ChromatographyInductively Coupled Plasma-Mass Spectrometry [1]. To extend the method toinclude wine, a multi-laboratory validation (MLV) of the method was carried out
with three US-based laboratories sharing their data [2]. The data shown in thisapplication note is supplementary to the published data. In addition to the paper,
this note includes long term stability of the method, and extended quantitative
analysis of five commercially available wines. The method required separation
and analysis of all target species. This approach differs from another Agilent
application note, which focused on the development of a fast method forinorganic arsenic (iAs) [3].
The US Environmental Protection Agency (EPA) set a maximum threshold of
total As in drinking water of 10 μg/kg [4]. There is no equivalent US regulation for
As in wine. Studies have shown that As in wine can be the result of an
accumulation of As in the grapes from the environment [5] or introduced during
the wine making process [6].
Regulations in Canada (Vintners Quality Alliance VQA, Ontario) and Europe(International Organisation of Vine and Wine, OIV) specify limits for total As of
100 μg/L and 200 μg/L, respectively [7, 8]. However, the toxicity of As isdetermined by its chemical form. Because the inorganic forms of As (iAs) are
the most carcinogenic, the FDA has established an action limit for iAs in apple
juice of 10 μg/kg in 2013 [9]. FDA EAM Method §4.10 details a relatively simple
and robust method for the determination of As species in fruit juice using
HPLC-ICP-MS [1]. The method describes a procedure to determine iAs (the sumof arsenite, As(III), and arsenate, As(V)); dimethylarsinic acid (DMA); andmonomethylarsonic acid (MMA). The method also states that a solution
containing arsenobetaine (AB) and As(III) is analyzed to demonstrate adequate
separation between unretained arsenic-containing species and As(III).
Due to recent media attention on As levels in wine, and the lack of publishedresearch on As speciation in wine, extension of EAM §4.10 to include wine is alogical next step.

312

In this study, EAM §4.10 was modified for the determination of the main organic
arsenic species (DMA and MMA) and the more toxic inorganic forms (As(V) andAs(III)) in wine using HPLC coupled to a triple quadrupole ICP-MS (ICP-QQQ).
The ICP-QQQ was utilized to provide the highest possible sensitivity of all the
instruments available in the lab at UC Davis. ICP-QQQ also provides superior
resolution of potential spectral interferences, but the potential Cl-based
interferences on 75As are resolved chromatographically, so QQQ with MS/MS is
not essential. This application could also be done on a single quadrupole ICP-MS
such as the Agilent 7800 or 7900.

Experimental
Reagents
Arsenite (As(III)) and arsenate (As(V)) were bought as 1000 mg/L standard
solutions from Spex Certiprep (Metuchen, NJ, USA). Monomethylarsonic acid
(MMA, 98.5% purity) and dimethylarsinic acid (DMA, 98.9% purity) were boughtfrom Chem Service (West Chester, PA, USA). Arsenobetaine (AB, purum p.a.,≥95.0%) was bought from Fluka Analytical (Morris Plains, NJ, USA).
Samples and sample preparation
Five commercially available wine samples were bought from a local store in
Davis, California. The wines were selected to represent the main types (andstyles) of wine: red (Cabernet Sauvignon), white (Sauvignon blanc), rosé(Zinfandel), sparkling (sparkling white) and fortified (Port-style). To investigate therange of ethanol content that could be analyzed using the method, the alcohol
concentrations of the wines selected ranged from 9.5—20% (v/v).
The sample preparation and analysis details were carried out according to the
EAM §4.10 method. Each wine sample was diluted five times with de-ionizedwater and then filtered separately using syringe-filtration (0.45 μm PVDF
membrane).
Per EAM §4.10, calibration curves were prepared at nominal concentrationsof 0.4, 0.5, 1, 5, 10, 20, 40 μg/kg for the four arsenic species: As(III), DMA, MMA,
and As(V). However, for this method, a fifth, low-level calibration point was also
prepared at 0.1 μg/kg. NIST 1643e Trace Elements in Water standard referencematerial (SRM), used to assess recovery and stability, was prepared using a
15-fold dilution. All calibration standards and the SRM were prepared in a 3%
ethanol solution to approximately match the level of alcohol (carbon matrix) inthe diluted wine samples. In addition to the effect that a change in sample
viscosity has on sample transport and nebulization, the level of carbon also
affects (increases) the degree of ionization of some elements in the ICP, including
arsenic. Therefore, sample preparation for carbon-containing matrices should
ensure a reasonably consistent level of carbon across all samples and standards,
to avoid errors due to variable carbon enhancement in different sample solutions.

313

Instrumentation
An Agilent 1260 Infinity LC comprising a binary pump, autosampler, and vacuum
degasser was coupled to an Agilent 8800 Triple Quadrupole ICP-MS (ICP-QQQ).
HPLC and ICP‑QQQ parameters are shown in Table 1.
Table 1. HPLC-ICP-QQQ hardware system and operating conditions.
LC conditions

Value

ColumnHamilton PRP-X100 anion exchange (4.1 x 250 mm) column witha matching Hamilton PRP-X100 guard column

Mobile phase

Mobile phase, aqueous 10 mM ammonium phosphate dibasic,
1% ethanol, pH 8.25 (±0.05)

Flow rate (mL/min)

1.0

Temperature

Ambient

Injection volume (μL)

100

Column compartment time tablefor introduction of ISTD

0.1 min, column position 1, 1.0 min; switch to column position 2,
2.0 min; switch back to column position 1

ICP-QQQ parameters

Value

RF power (W)1550

Carrier gas flow (L/min)

1.0

Spray chamber temperature (°C)

2

Sample depth (mm)8.5

Peristaltic pump speed (rps)

0.3 (~1.2 mL/min)

Scan mode

MS/MS

Helium cell gas flow (mL/min)~2.0

Results and discussion
Method blanks (3% ethanol) spiked with low levels of As(III), DMA, MMA, andAs(V) were prepared and analyzed for the determination of the detection limits.
Figure 1 shows overlaid chromatograms obtained for the mixed As species
standards, demonstrating excellent peak separation of the As species of interest.
The calibration curves in Figure 2 show a linear response for each As species
across the concentration range from 0.1 to 40 μg/kg.
x104

0.4 ppb
0.5 ppb
1.0 ppb
5.0 ppb
10.0 ppb
20.0 ppb

5

0
5.0

10.0
RT (min)

15.0

Figure 1. Overlaid chromatograms of As species standards at nominal concentrations of 0.4, 0.5,
1, 5, 10, 20 μg/kg showing good peak separation. The 40 μg/kg standard is not shown, to allow thelower concentration levels to be seen.

314

75 ➝ 75 As [III] ISTD: 75 ➝ 75 Marker

75 ➝ 75 DMA ISTD: 75 ➝ 75 Marker

y = 1.546013* x -0.007378
R = 0.9991
DL = –
BEC = 0.004772 μg/kg

x102

Ratio

Ratio

x101

5

0

y = 1.860492* x -0.011782
R = 0.9997
DL = –
BEC = 0.006332 μg/kg

5

0
20.0

40.0

20.0

Conc (μg/kg)

75 ➝ 75 MMA ISTD: 75 ➝ 75 Marker
x102

75 ➝ 75 As(V) ISTD: 75 ➝ 75 Marker

y = 2.7133207* x +0.654013
R = 0.9998
DL = –
BEC = 0.241 μg/kg

x1021

y = 1.952109* x -0.055048
R = 0.9997
DL = –
BEC = 0.0282 μg/kg

Ratio

1

Ratio

40.0
Conc (μg/kg)

0.5
0.5

0

0
20.0

40.0

20.0

Conc (μg/kg)

40.0Conc (μg/kg)

Figure 2. Calibration graphs for As(III), DMA, MMA, and As(V).

The limits of detection (LOD) for the As species in wine were calculated as
described in the FDA’s Elemental Analysis Manual Section 3.2 [1]. The limits ofquantification (LOQ) for each species were calculated as LOQ = Dilution Factor(DF) x 30 x σ. The LOQs for As(III) and As(V) were 1.18 and 1.35 μg/kg,
respectively. The LOQ for total inorganic arsenic (calculated from the SD of thesum of the integrated peak areas for As(III) and As(V) in each repeat of the low
standard) was 2.53 μg/kg. The LODs and LOQs determined for the species DMA,
MMA, and total iAs (sum of As(III) and As(V)) using the optimized method are
given in Table 2. Results are reported for iAs since the current regulations only
specify iAs, and not the individual species As(III) and As(V).
Table 2. LODs and LOQs for DMA, MMA, and iAs.

DMA

LOD, μg/kg

LOQ, μg/kg

0.17

1.3

MMA

0.15

1.2

iAs

0.17

1.4

The iAs LOQ is well within the FDA’s 10 μg/L level of concern for iAs in juice
samples. The sensitivity of the method is therefore sufficient to determine iAs in
solution following a five-fold dilution of the samples.

315

Quantitative results
The five wines included in the MLV were analyzed in the lab at UC Davis using
LC-ICP-QQQ and the results are shown in Table 3. The average percent recoveryof the sum of the species compared to the total As present in the samples(determined using direct analysis without HPLC separation) was calculated using
the mass balance approach. The percent recovery for all samples was between
91–107%. The results were found to be in good agreement with the results
obtained from the other laboratories taking part in the MLV study [2].
Table 3. Quantitative results for the five wines analyzed at UC Davis as part of the MLV study. Average ± 1σ, n=3 for the individual species
Wine sample% Ethanol (v/v)

DMA
μg/kg

MMA
μg/kg

iAs
μg/kg

Sum of species
μg/kg

Total As
μg/kg

Mass balance%

Red (Cabernet)

9.5

0.81 ± 0.1*

<LOD

14.4 ± 1.0

15.2 ± 1.1

15.3 ± 1.2

99White (Chardonnay)

130.74 ± 0.04*<LOD

10.7 ± 0.2

11.4 ± 0.2

11.1 ± 0.8

103

Rosé (Zinfandel)

120.75 ± 0.1*<LOD

9.2 ± 0.4

9.9 ± 0.4

9.3 ± 1.1

107

Sparkling wine20

1.7 ± 0.1<LOD

2.1 ± 0.3

3.8 ± 0.3

3.6 ± 0.3

105

Port-style wine

14.5

0.45 ± 0.01*<LOD

1.5 ± 0.3

2.0 ± 0.3

2.2 ± 0.1

91

* Value between LOD and LOQ
Reprinted with permission from Courtney K. Tanabe et al., J. Agric. Food Chem., 2017, 65 (20), 4193–4199. Copyright 2017. American Chemical Society.

Long-term stability
To test the stability of the ICP-QQQ over an extended sampling period of 96 hours(four days), the wine samples were measured repeatedly in a continuous
sequence. Two quality control (QC) samples—a 2-ppb mixed As species standard
solution and NIST 1643e spiked with 3% ethanol— were analyzed after every
10 wine samples. The instrument was not recalibrated during the continuous
analytical run. The plots shown in Figures 3 and 4 show exceptional stability wasachieved over the course of the validation stability test.

CC Sample Conc Stability % (Outlier Setting)150

75 ➝ 75 As(III) [He]75 ➝ 75 DMA [He]75 ➝ 75 MMA [He]75 ➝ 75 As(V) [He]

100

50

0
2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

2ppb As Mix

Figure 3. Stability plot of the 2-ppb mixed As species standard solution, analyzed over 96 hours(four days).

316

CC Sample Conc Stability % (Outlier Setting)150

75 ➝ 75 As(V) [He]

100

50

0
NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

NIST 1643e

Figure 4. Stability plot of As in NIST 1643e spiked with ethanol and analyzed over four days.

Results of additional market basket wine analysis
In addition to the five wines used in the MLV study, an extra 60 wines wereanalyzed as part of the method validation [2]. In this study, a selection ofpreviously untested wines (S1 to S5) were analyzed. The results shown in Table 4
are consistent with the published data from the reference paper [2]. Most of the
As was in the more toxic, inorganic forms. While four of the five wine samples
contained levels of total As higher than the EPA drinking water limit of 10 μg/L,
the levels in all five wines were below the 100 and 200 ug/kg limits for total As inwine set in Canada and Europe, respectively. However, the measured
concentrations for iAs in four out of five of the wines exceeded the FDA’s action
limit of 10 μg/kg for iAs in apple juice.
Table 4. Quantitative results (μg/kg) for As species in five commercially available wines measured by
LC-ICP-QQQ.
iAs

DMA

MMA

Sum of Species

17.13 ± 0.22

0.83 ± 0.03

<LOD

17.96 ± 0.13

S2

7.49 ± 0.15

0.30 ± 0.06

0.77 ± 0.32

8.56 ± 0.17

S3

14.63 ± 0.40

0.80 ± 0.08

<LOD

15.43 ± 0.24

S4

25.03 ± 0.89

0.69 ± 0.26

0.47 ± 0.12

26.19 ± 0.42

S5

23.45 ± 1.12

0.32 ± 0.05

<LOD

23.77 ± 0.59

Wine Sample
S1

Spike recovery test
Table 5 shows the spike recoveries for the MLV samples fortified at levels of
approximately 5, 10, and 30 μg/kg for DMA, MMA, and iAs (the iAs spike
concentration was the sum of As(III) and As(V) each spiked at 50% of thelevels shown). The average recoveries of DMA, MMA, and iAs measured using
LC-ICP-QQQ were 99, 92, and 104%, respectively. All the recoveries are within
the FDA's EAM acceptability criteria of 100 ± 20% for iAs, DMA, and MMA [1].

317Table 5. Average spike recovery results for duplicate analyses of five samples spiked at 5, 10, and30 μg/kg with DMA, MMA, and iAs. n=30.

Average spike recovery, %Recovery range

DMA

MMA

iAs

99

92

104

93 – 107

72 – 11997 – 114

Conclusion
The As speciation results obtained using an Agilent 1260 Infinity LC coupled toan Agilent 8800 ICP-QQQ were used as part of an MLV to validate the extension
of Elemental Analysis Manual Method §4.10 to include wine. The method was
optimized for the analysis of four arsenic species including the toxicologically
relevant inorganic forms, As(III) and As(V).
In addition to the data published as part of the MLV, five more wines wereanalyzed. The total As levels of the five wines were between 8.56 and 26.19 μg/L.
These levels are below the Canadian and European regulatory limits for total As inwine of 100 and 200 μg/kg, respectively. The average percentage of As found in
the form of iAs in the five wine samples was 95%.

References
1.	S. D. Conklin, K. Kubachka, N. Shockey, Elemental Analysis Manual for Foodand Related Products, 4.10 HPLC-ICP-MS As Species in Fruit Juice (Ver. 1;
2013), http://www.fda.gov/EAM (accessed September 2017)
2.	C. K. Tanabe, H. Hopfer, S. E. Ebeler, J. Nelson, S. D. Conklin, K. M. Kubachka,
and R. A. Wilson, J. Agric. Food Chem., 2017, 65 (20), pp 4193–4199
3.	C. K. Tanabe, S. E. Ebeler, J. Nelson, Fast Analysis of Arsenic Species in Wines
using LC-ICP-QQQ, Agilent publication, 2017, 5991-8454EN
4.	National Primary Drinking Water Regulations. US E.P.A, In Title 40, EPA, Ed.
2014; Vol. AE 2. 106/3:40/
5.	D. Bertoldi, R. Larcher, M. Bertamini, S. Otto, G. Concheri, G. Nicolini, J. of Agriand Food Chem., 2011, 59, 7224–7236.
6.	M. V. Aguilar, M.C. Martinez, T.A. Masoud, Z. Lebensm-Unters-Forsch., 1987,
185, 185–187.
7.	Canada Ontario, V. Q. A., Wine Standards. 1999 http://www.vqaontario.ca/
Regulations/Standards (accessed August 2017)8.	OIV–Compendium of International Methods of Analysis. Maximum acceptable
limits of various substances contained in wine, 2011 issue. Europe
9.	US Department of Health and Human Services Food and Drug Administration
Center for Food Safety and Applied Nutrition, Guidance for Industry Arsenic in
Apple Juice: Action Level (draft), 2013. https://www.fda.gov/Regulatory
Information/Guidances/ucm360020.htm (accessed September 2017)

More information
For a full account of this study, see Courtney K. Tanabe, Helene Hopfer, Susan E.
Ebeler, Jenny Nelson, Sean D. Conklin, Kevin M. Kubachka, and Robert A. Wilson,
Matrix Extension and Multilaboratory Validation of Arsenic Speciation Method
EAM §4.10 to Include Wine, J. Agric. Food Chem., 2017, 65 (20), pp 4193–4199,
DOI: 10.1021/acs.jafc.7b00855
318

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Fast Analysis of Arsenic Species in Wines using
LC-ICP-QQQ
Authors

Introduction

Courtney Tanabe1-2, Susan E. Ebeler1-2,
Jenny Nelson1-3

Arsenic (As) occurs naturally in the environment but human activity has
contributed to the levels found in some locations. Man-made sources of As
include industrial processes such as mining, smelting and power generation, as
well as agricultural pesticides and timber preservatives [1]. Once contamination
has occurred, As persists in the environment for decades. For example, thewidespread use of As-containing agrochemicals ceased in the 1970s, but leadand calcium arsenate levels remain high in some soils. As can be absorbed fromsoil and water into crops. In the case of wine, the As content can also be affectedby the wine making processes.

1 Food Safety and Measurement
Facility, University of California,
Davis, USA
2 Department of Viticulture andEnology, University of California,
Davis, USA
3 Agilent Technologies, Inc.,
Santa Clara, USA

Arsenic exists in multiple forms in foods and beverages and not all forms havethe same toxicity. The inorganic forms of As (iAs), comprising As(III) (arsenite)
and As(V) (arsenate), are the most toxic, and are categorized as class 1
carcinogens. In contrast, arsenobetaine (AB), the most abundant form of As in
fresh seafood, is essentially non-toxic to humans. Due to the high variability in the
toxicity of the different species of As, and the potential health threat of iAs, it isimportant to determine the levels of the individual species in foodstuffs – and notjust the total As concentration. The US Food and Drug Administration (FDA) has
established an action limit for iAs in apple juice of 10 μg/kg (ppb) [2] but there are
currently no regulations in the US controlling the As content of wine. Canada(Vintners Quality Alliance VQA, Ontario) and Europe (International Organisation ofVine and Wine, OIV) have set maximum acceptable limits for total As in wine of
100 and 200 μg/L (ppb), respectively [3, 4].
Arsenic contamination of food is of great public interest. There is a clear demand
for rapid and reliable screening methods to accurately determine the levels ofiAs in food and drink to support existing and future regulations. One of the mostuseful and reliable approaches uses high performance liquid chromatography(HPLC) to separate the species, which are then quantified by inductively coupledplasma mass spectrometry (ICP-MS) [5].
The methodology described here is based on a previous As speciation method
developed by Jackson, who coupled HPLC to a triple quadrupole ICP-MS(ICP-QQQ) [6]. HPLC-ICP-QQQ was also used in this study. However, instead ofanalyzing the iAs species separately, As(III) was intentionally oxidized to As(V)with hydrogen peroxide before analysis [7, 8]. By converting As(III) and analyzing
all inorganic species as As(V), this method was able to separate
monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) from iAs(as As(V)) in less than 2 minutes. The analysis time is 10 times faster than thecurrent FDA methods used for the speciation of As [9].
In this work, oxygen reaction gas was used in the collision/reaction cell (CRC)of the ICP-QQQ to resolve the spectral interferences on 75As, while maintaining
excellent sensitivity. Results are presented that demonstrate the accuracy andreproducibility of the new method. The method was further validated using awine matrix that was analyzed by two participating laboratories.
319

Experimental
Standards
The As(III) and As(V) standards were purchased from Spex Certiprep (Christiansburg,
VA; Metuchen, NJ, USA). The MMA and DMA standards were purchased fromChem Service (West Chester, PA, USA). An AB standard was also purchasedfrom Chem Service to be used as a flow injection marker (internal standard) for
post-column injection. Calibration standards were prepared at 0.1, 0.5, 1.0, 5.0, 10
and 20 μg/L (ppb) for each of DMA, MMA, and total iAs (sum of As(III) and As(V)).
SamplesFive different California wines were used for the validation (V) study. Each wine
represented one of the five main styles of wine: red, white, rosé, sparkling, dessert.
Five additional California wines were analyzed for a commercial market basket(MB) study. Details of the wine style, cultivar, growing region, vintage, and alcohol
content for all samples are given in Table 1.
Table 1. Wine style, cultivar, regional origin, vintage, and alcohol content of the wine samples for thevalidation and commercial market basket studies.
SampleStyle

Cultivar

RegionVintage

Alcohol (%v/v)

V-1

Rosé

Zinfandel

Napa and Lodi

NA

9.5

V-2

White

Sauvignon blanc

Oakville/Napa County

2013

13.0

V-3

Sparkling

Sparkling white blend

County

NA

12.0

V-4

DessertPetite Sirah Port-style

Clarksburg/Yolo County

2012

20.0

V-5

Red

Cabernet Sauvignon

Monterey County

2013

14.5

MB-1

Red

Cabernet Sauvignon

North Coast

2009

13.5

MB-2

Red

Pinot noir

Appellation Central Coast

2004

13.8

MB-3

White

Chardonnay

Santa Barbara County

2013

13.5

MB-4

Rosé

Zinfandel

Napa and Sonoma

2013

10.5

MB-5

White

Chardonnay

Central Coast

2013

13.5

Sample preparation
H2O2 was added to all samples at a 1:1 ratio to oxidize As(III) to As(V). Eachsample was further diluted with de-ionized water to give a total dilution factor of
5 or 6 (there were no differences in results between the two dilution factors).
Each sample was then passed through a 0.45 μm syringe filter to remove any
particulates. Samples V-1, V-4, V-5 were spiked in duplicate with all As species
at three concentration levels: 5, 10, and 30 μg/kg.
Instrumentation
An Agilent 1260 HPLC fitted with a Hamilton PRP-X100 5 μm 50 x 2.1 mm
column was coupled to an Agilent 8800 Triple Quadrupole ICP-MS (ICP-QQQ).
The mobile phase was 40 mM ammonium carbonate ((NH4)2CO3, trace metal
grade 99.999% from Sigma Aldrich) with 3% v/v methanol (Optima LC/MS grade,
Fisher Chemical) adjusted to a pH of 9.0 with ammonium hydroxide (Optima
Grade, Fisher Scientific). The ICP-QQQ was equipped with a standard sample
introduction system comprising a quartz torch with 2.5 mm i.d. injector, a quartz
spray chamber, glass concentric nebulizer, and nickel-tipped interface cones.
Peak integration was carried out according to FDA EAM §4.10 and 4.11.15 [9].
The instrument operating conditions are summarized in Table 2.
320

Table 2. HPLC-ICP-QQQ operating conditions.
ICP-QQQ
Forward power

1550 W

Sampling depth

8.0 mmSpray chamber temp.

2 °C

Carrier gas

0.95 L/min

Make-up gas

0.20 L/min

Extract 1

0V

Octopole bias

-5.0 V

Energy discrimination-7 V

Cell gas (O2) flow rate

0.31 mL/min

Scan mode

MS/MS

Q1/Q2 mass

75/91 u

HPLC
Mobile phase flow rate

0.5 mL/min

Injection volume

5 μL

Sample temperature

4 °C

ISTD injection volume

5 μL

Results and discussion
Development of a fast method
For this study, the focus of the method development was to reduce the analysis
time per sample. In the development of this method, we followed Jackson’s useof a small injection volume, short ion-exchange column, oxygen cell gas, and ahigh mobile phase linear velocity [6].
Figure 1 shows overlaid chromatograms for a representative calibration set of
0.5, 1.0, 5.0, and 20 μg/kg standards. All As species are clearly separated in lessthan two minutes. Simply by oxidizing As(III) to As(V) and analyzing all iAs in
the form of As(V), the analysis time was reduced significantly compared to thecurrent FDA regulatory method [9].
x104

Count

4

0.5 ppb
1.0 ppb
5.0 ppb
20.0 ppb

2

0
0.5

1.0
RT (min)1.5

Figure 1. Overlay of the 0.5, 1.0, 5.0, and 20.0 μg/kg calibration standards. An AB internal standard(flow injection marker; fourth peak) was added post column via an external switching valve.

321Linear calibrations
The calibration curves for DMA, MMA, and iAs show good linearity (Figure 2).
All As concentrations in the wine samples were within the linear range except
iAs, which was measured at a maximum concentration of 150% of the highest
calibration standard.
75 ➝ 91 DMA

75 ➝ 91 MMA

x105

x105
2

Count

Count

2

1

0

1

0
10.0

20.0

10.0

Conc (ug/g)

20.0Conc (ug/g)

75 ➝ 91 iAs
x105

Count

2

1

0
10.0

20.0
Conc (ug/g)

Figure 2. Calibration curves for DMA, MMA, and total iAs (sum of converted As(III) and As(V)).

Detection limits
The limits of detection (LOD) and limits of quantitation (LOQ) given in Table 3 arebased on repeated measurements of the 0.05 μg/kg (ppb) mixed standard, n=15.
Table 3. LODs (3 sigma), LOQs (30 sigma), and estimated wine LOQ.
LOD, μg/kg

LOQ, μg/kg

Estimated wine LOQ, (6 x dilution) μg/kg

DMA

0.018

0.175

1.1

MMA

0.026

0.258

1.5

iAs

0.022

0.221

1.3

Spike recoveries
Samples V-1, V-4, V-5 were spiked in duplicate with each species (DMA, MMA,
and total iAs as As(V)) at 5, 10, and 30 μg/kg. The averaged recoveries for all
As species at the three different fortification levels were 100 ± 3% (Table 4).
Table 4. Percent recovery (mean and range) for three spiking levels of DMA, MMA and iAs in wines
V-1, V-4 and V-5.
DMA

322

MMA

iAs

Average, %

102

97

99

Range, %97 – 107

91 – 102

95 – 103

Quantitative results
All 10 wines were analyzed using the new HPLC-ICP-QQQ method. Table 5 lists
the measured concentrations for DMA and iAs. All MMA values were below thecalculated LOD (0.026 μg/kg) and could not be quantified. The measured
concentrations using the new method were compared to the values obtainedusing the FDA EAM §4.10 extension method [10]. The agreement between themeasurements was mostly within ±10%. iAs represented the majority of As in
all wines, while only one wine sample (MB-3) contained DMA levels significantly
above the LOQ of 1.1 μg/kg. A chromatogram of V-1 is shown in Figure 3.
Overall, the concentration of iAs ranged from 1.7 ± 0.3 to 32.9 ± 0.8 μg/kg(the latter being above the FDA’s action limit for iAs in apple juice of 10 μg/kg).
The sum of all As species (Table 5) ranged from a low of 2.2 ± 0.3 μg/kg toa high of 32.9 ± 0.8 μg/kg, which is under the Canadian limit of 100 μg/L andOIV limit of 200 μg/L.
x104

Count

2

Replicate 1
Replicate 2
Replicate 3

1

0
0.5

1.0

1.5

Figure 3. Chromatogram showing the overlay of the three replicates of wine sample V-1.
Table 5. Results from the fast and fit-for-purpose analysis method (measured at two different labs)
compared to the FDA EAM §4.10 extension results for the five validation (V) and five market basket(MB) wines. % Recovery (shown in parentheses) calculated as “Measured” divided by “EAM §4.10”
and “Sum of Species” divided by “Total”.
SampleDMA (μg/kg)
EAM §4.10

MeasurediiAs (μg/kg)
EAM §4.10

Measured

Total As (μg/kg)
Total

Sum of Species

V-1

0.81 ± 0.1*

0.72 ± 0.04 (89%)

14.4 ± 1.0

16.0 ± 0.5 (111%)

16.5 ± 0.02

16.7 ± 0.5 (101%)

V-2

0.74 ± 0.04*

0.72 ± 0.06 (98%)

10.7 ± 0.2

11.4 ± 0.4 (107%)12.6 ± 0.16

12.1 ± 0.3 (96%)

V-3

0.75 ± 0.1*

0.83 ± 0.04 (111%)

9.2 ± 0.4

9.5 ± 0.6 (103%)10.4 ± 0.11

10.3 ± 0.5 (99%)

V-4

1.70 ± 0.1

1.86 ± 0.06 (109%)2.1 ± 0.3

2.3 ± 0.4 (109%)

4.5 ± 0.01

4.1 ± 0.4 (92%)

V-5

0.45 ± 0.01* 0.47 ± 0.04 (105%)<LOD

1.5 ± 0.3

1.7 ± 0.3 (113%)

2.4 ± 0.03

2.2 ± 0.3 (90%)

30.2 ± 1.3

32.9 ± 0.8 (109%)34.4 ± 0.4

32.9 ± 0.8 (96%)

9.1 ± 0.4 (120%)

9.1 ± 0.3

9.1 ± 0.4 (100%)27.6 ± 0.7 (112%)28.9 ± 0.9

28.6 ± 0.7 (99%)

27.5 ± 0.9 (105%)27.9 ± 0.9

28.5 ± 0.9 (102%)4.5 ± 0.1 (129%)4.7 ± 0.1

4.5 ± 0.1 (96%)

MB-1

<LOD

MB-2

0.33 ± 0.04*<LOD

7.57 ± 0.49

MB-3

0.71 ± 0.08*

1.1 ± 0.0 (155%)

24.64 ± 0.40

MB-4

1.16 ± 0.09*

1.0 ± 0.1 (86%)

26.3 ± 0.89

MB-5

<LOD

<LOD

3.5 ± 0.25

Average ± 1σ, n=3. *Indicates value between LOD (0.17 μg/kg) and LOQ (1.3 μg/kg) for EAM §4.10 method.
Refer to Table 3 for Measured LODs and LOQs

323

Conclusion
This note describes a simple, robust, and fast HPLC-ICP-QQQ method to measure
the sum of the most toxic inorganic As species (As(III) and As(V)) and twoorganic As species in under two minutes. By oxidizing As(III) to As(V) with H2O2
during sample preparation, total iAs can be determined as As(V), leading to amuch faster separation of the species of interest in wine samples. The narrowbore column and 0.5 mL/min flow rate provided excellent sensitivity whichallowed low volume injections to be used. Compared to the current FDA method
for the determination of As in wines, sample run times were 10x faster withimproved limits of detection and quantification.
In this study, total As concentrations ranged from 2.2 to 32.9 μg/kg, which is well
below the limit defined in regulations set in Ontario, Canada (100 μg/kg) and the
maximum level established by the International Organisation of Vine and Wine inEurope (200 μg/kg). However, iAs was the predominant species present in thewines, and five of the wines tested contained iAs at concentrations that exceeded
10 μg/kg, which is the FDA’s action limit for iAs in apple juice.
The results obtained using the new fast and fit-for-purpose method were in good
agreement with data obtained using the FDA’s EAM §4.10.

References
1.	H. Garelick, H. Jones, A. Dybowska, E. Valsami-Jones, Arsenic pollution
sources, Rev Environ Contam Toxicol. 2008, 197, 17–60
2.	U.S. Department of Health and Human Services Food and Drug
Administration Center for Food Safety and Applied Nutrition, Guidance forIndustry Arsenic in Apple Juice: Action Level (draft), 2013, accessed August
2017: https://www.fda.gov/RegulatoryInformation/Guidances/ucm360020.
htm
3.	Canada Ontario, V. Q. A., Wine Standards. 1999, accessed August 2017:
http://www.vqaontario.ca/Regulations/Standards
4.	OIV–Compendium of International Methods of Analysis. Maximum
acceptable limits of various substances contained in wine, 2011 issue. Europe
5. B. Sadee, M. E. Foulkes, S. J. Hill, J. Anal. At. Spectrom, 2015, 30, 102–118
6.	B. P. Jackson, J. Anal. At. Spectrom., 2015, 30, 1405–1407
7.	S. Musil, Á. H. Pétursdóttir, A. Raab, H. Gunnlaugsdóttir, E. Krupp, J. Feldmann,
Anal. Chem., 2014, 86 (2), 993–999
8.	H. R. Hansen, A. Raab, A. H. Price, G. Duan, Y. Zhu, G. J. Norton, J. Feldmann,
A. A. Meharg, J. Environ. Monit., 2011,13, 32–34
9.	K. M. Kubachka, N. V. Shockey, T. A. Hanley, S. D. Conklin and D. T. Heitkemper,
Arsenic Speciation in Rice and Rice Products Using High Performance Liquid
Chromatography - Inductively Coupled Plasma-Mass Spectrometric
Determination version 1.1, accessed August 2017, https://www.fda.gov/
downloads/Food/FoodScienceResearch/LaboratoryMethods/UCM479987.
pdf
10.	C. K. Tanabe, H. Hopfer, S. E. Ebeler, J. Nelson, S. D. Conklin, K. M. Kubachka,
and R. A. Wilson, Matrix Extension and Multilaboratory Validation of Arsenic
Speciation Method EAM §4.10 to Include Wine, J. Agric. Food Chem., 2017, 65(20), 4193–4199
324

More information
For a full account of this study, see Patrick J. Gray, Courtney K. Tanabe, Susan E.
Ebeler, and Jenny Nelson, A fast and fit-for purpose arsenic speciation method forwine and rice, J. Anal. At. Spectrom., 2017, 32, 1031–1034; DOI: 10.1039/
C7JA00041C

Acknowledgement
The Food Safety and Measurement Facility at the University of California, Davis,
USA is supported by donations and gifts from Agilent Technologies, Gerstel US,
and Constellation Brands.

325

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Simultaneous Iodine and Bromine Speciation Analysis
of Infant Formula by HPLC-ICP-MS
Authors
Lawrence Pacquette
Abbott Nutrition,
Columbus, Ohio, USA
Jenny Nelson, Shuofei
Dong, Michiko Yamanaka
Agilent Technologies. Inc.

Determination of four halogen species in less than 6.5 minutes
Introduction
Babies and young children often rely on infant formula for their nutritional
requirements during early development, so regulators set high standards for thesafety and nutritional value of these products. Most countries specify minimum
levels for essential minerals in infant formulas, including iodine, to meet thenutritional needs of infants. If too little or too much iodine is consumed, babies
and young infants are susceptible to developing thyroid problems (1, 2).
Regulatory values for iodine in infant formula manufactured from cow’s milk orgoat’s milk proteins or protein hydrolysates relate to total iodine (Table 1). But thebio-availability of iodine depends on the chemical species present in a sample.
Iodide (I−) has a higher bio-availability compared to iodate (IO3−), which affects thenutritional status of iodine in food. For more information about the toxicity andhealth benefits of a food, elemental speciation is required to separate iodide andiodate from iodine (I2) and organic forms of iodine.
In the case of bromine, its toxicity is species-dependent. Bromide (Br−) has
low toxicity compared to bromate (BrO3−) which is possibly carcinogenic tohumans (3).
Table 1. Regulatory levels for iodine in infant formula.
Regulatory body

Minimum
concentrationµg/100 kcal

Maximum
concentrationµg/100 kcal

Reference

US FDA

5

75(4)

European Union

15

29

(5)

China

10.5

58.6

(6)

In this study, four species, iodide (I−), iodate (IO3−), bromide (Br−), and bromate(BrO3−), were determined in four commercially available milk-based infant
formulas using HPLC coupled to a triple quadrupole ICP-MS (ICP-QQQ).
HPLC-ICP-MS methodology is a well-established analytical technique that has
been used for the speciation analysis of arsenic in various food matrixes,
including infant formula (7, 8). This application could also be done using asingle quadrupole ICP-MS such as the Agilent 7800 or 7900 ICP-MS as theelemental detector.

326

Experimental
Reagents and Standards
Standards for bromide, bromate, iodide, and iodate were prepared from1000 ppm stock solutions. The bromide ion standard solution was bought from
Kanto Chemical Co., Inc., Tokyo. A 1000 ppm stock solution of bromate wasmade by dissolving NaBrO3 (Wako Pure Chemical Corporation, Osaka) in water.
Iodide and iodate stock solutions were prepared at 1000 ppm by dissolving
KI and KIO3 (Wako Pure Chemical Corporation, Osaka), respectively.
Standard reference material and samples
A milk-based standard reference material (SRM) NIST 1849a - Infant/Adult
Nutritional Formula I (Gaithersburg, MD, USA) was used to validate the analyticalmethod for the determination of total iodine.
Two of the four market basket infant formula samples were bought in Berkeley
California, USA, and two were bought in Beijing, China. All four samples were in
powder form.
Nitric acid (HNO3, ≥ 65%, Sigma-Aldrich) was used for microwave digestion andstandard/sample preparation. All dilutions were done using 18.2 MΩ·cm(Millipore, Bedford, MA, USA) de-ionized water (DIW).
Sample preparation
For total bromine determinations about 0.2 g of NIST 1849a and each sample
were weighed and digested in 5 mL of HNO3 by microwave digestion (Mars 6,
CEM) using the program outlined in Table 2. The fully digested samples were thendiluted to 40 mL with DIW. All samples and SRM were prepared in triplicate.
Table 2. Microwave digestion program.
StagesTemp (°C)

Ramp (min)Hold (min)

1

30

5

30

2

210

20

30

3

30

30

–

For I and Br speciation and total iodine determinations, about 0.2 g of eachsample was weighed into 20 mL DIW and then put in a water bath at 50 °C for
1 h. The samples were then filtered using a syringe filter (0.45 µm pore size).
Approximately 1 mL filtered solution was placed in 1 mL polypropylene HPLC
vials (Agilent part number 5182-0567), ready for analysis.

Instrumentation
An Agilent 1260 Infinity II LC system comprising a quaternary pump was coupled
to an Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) using the Agilent LC
connection kit (part number G1833-65200). The Agilent Chromium Speciation
Column for Drinking Water (part number G3268-80001) anion exchange column(4.6 mm internal diameter × 30 mm polyhydroxymethacrylate base resin) wasused for separation of the iodine and bromine species. Details of the operating
conditions and mobile phase are given in Table 3.
The Agilent 8900 ICP-QQQ (Advanced Applications configuration, #100) was
fitted with the standard sample introduction system comprising a glass
concentric nebulizer, quartz double-pass spray chamber, 2.5 mm injector quartz
torch, and Ni interface cones. The ICP-QQQ was operated in single quadrupole(SQ) mode using helium cell gas, so the application could also be done using an
Agilent 7800 or 7900 ICP-MS.
327

Table 3. HPLC and ICP-QQQ instrument operating conditions.
HPLC parameter

Setting

Mobile phase

5.0 mM NaH2PO4 / 15.0 mM Na2SO4 / 5.0 mM EDTA (pH 7.0)

ColumnAgilent column for Cr speciation (part number G3268-80001)

Mobile phase flow (mL/min)

1.0

Injection volume (μL)

100

Temperature

Ambient

Run time (min)8

ICP-QQQ parameter

Setting

Scan mode

Single quad mode

Sampling depth (mm)8.0

Nebulizer gas flow (L/min)

1.10

Spray chamber temp. (ºC)

2Extract 1 (V)0.0

Extract 2 (V)-250

Octopole bias (V)-20.0

Helium cell gas flow rate (mL/min)

2.0

Axial acceleration (V)1.0

Energy discrimination (V)3.0

Mass (m/z)

79 for Br, 127 for I

Integration time (sec/mass)

0.5

Results and discussion
Calibration
Calibration was carried out by analyzing solutions of iodide, iodate, bromide, andbromate, between 0 and 100 ppb. Figure 1 demonstrates calibration curves withexcellent linearity over the calibration range, with calibration linearity equal to or
better than 0.9999.

Figure 1. Calibration curves of IO3− (top left), I− (top right), BrO3− (bottom left), and Br− (bottom right).

328

A chromatogram of the 5 ppb iodine and bromine standard is shown in Figure 2.
All four species, IO3−, I−, BrO3−, and Br−, were separated and baseline-resolved inless than 6.5 minutes, all in the same run.

Figure 2. Chromatogram of 5 ppb standard showing IO3−, I−, BrO3−, and Br− in the same run.

Detection limits
Signal-to-noise (S/N) detection limits (DLs) were calculated from 3x thebackground noise divided by the signal for each peak of interest. The DLs of thefour species were between 0.072 and 0.667 ppb as shown in Table 4.
Table 4. S/N DLs for iodate, bromate, bromide, and iodide.
SpeciesStandard
concentration(ppb)

Signal

IO3—

0.98

BrO3—

1.07

Br—
I

—

Noise

S/N

DL in
solution (ppb)

27781

676.6

41.06

0.072

1979

320.2

6.18

0.519

0.9

1296

320.0

4.05

0.667

0.78

3379

677.2

4.99

0.469

Analysis of SRM
The four species were determined in the Infant/Adult Nutritional Formula SRM
using LC-ICP-QQQ (seven sample preparation replicates, run in triplicate; n=21).
The total iodine concentration was measured using the 8900 ICP-QQQ (without
HPLC separation). The results for the four species, total iodine, and total
bromine are shown in Table 5. No iodate or bromate was detected in the SRM.
The measured concentrations for 127I-, total iodine, and the certified concentration
for total iodine are all in good agreement, suggesting a good level of method
accuracy. Bromine isn’t certified in the SRM.
Table 5. Results for the analysis of NIST 1849a Infant/Adult Nutritional Formula SRM*. n=21.
Units: mg/kg.
127

IO3−

127 −

I

79

BrO3−

79

Br−

MeasuredND

1.31± 0.04ND

0.74± 0.12

Total I*

Total Br**

Reference

Measured

Measured

1.29 ± 0.11

1.33 ± 0.37
(103%)

0.77 ± 0.07(96%)***

ND = not detected. *Prepared using water bath extraction. **No certified value given for bromine. ***79Br-/Total bromine.

329

Quantitative analysis of infant formula products
Extracts of the four powder infant formula samples were prepared in duplicate
and analyzed in duplicate (n=4) using LC-ICP-QQQ. As shown in Table 6, no iodate
or bromate was detected in any of the samples. The recoveries of iodide
compared to the total iodine results range from 87 to 102%, suggesting the iodine
present in the samples was in the form of iodide. The recoveries of bromine to
the total bromine results ranged from 85 to 100%, suggesting the brominepresent in the samples was in the form of bromide.
The total iodine measured in the four infant formula samples ranged from 1232 to2592 µg/kg, which is equivalent to 25.9 to 54.5 μg/100 kcal. These concentrations
are within the United States and China national standards for total iodine; however,some results fall outside the EU maximum limit for iodine of 29 μg/100 kcal.
Table 6. Infant formula sample analysis results. Units: µg/kg. The percentages are the recoveries ofiodide and bromide compared to total iodine and bromine, respectively.
Sample ID

127

IO3−

127 −

I

79

BrO3−

79

Br−

Total I*

Total Br**

1-USA

ND

1157 ± 11

ND2993 ± 27

1333
± 16
(87%)

3112
± 151
(96%)

2-USA

ND

1455 ± 29

ND10826 ± 141

1426
± 50
(102%)

10815± 478 (100%)3-ChinaND1240 ± 15

ND25660 ± 230

1232
± 23
(101%)

29850± 2392 (86%)

4-ChinaND2372 ± 24

ND8529 ± 64

2592
± 44
(92%)

9997
± 389
(85%)

*Sample preparation with the water extraction method** Sample preparation with microwave digestion method

Spike recovery test
A spike recovery test was performed by spiking two infant formula samples with
IO3−, BrO3−, Br−, and I− at 20 and 40 ppb, before extraction. Each spiked sample
was prepared in triplicate and analyzed twice. Good recoveries for each of thefour species in actual samples at 20 ppb and 40 ppb-level were achieved overthe course of mulitple 100 μL injections (Table 7). The results indicate that themethod could be used for the accurate determination of the four-halogen species
in infant formula.
Table 7. Average spike recovery results for two infant formula samples spiked at 20 and 40 ppb with
IO3−, BrO3−, Br−, and I−, n=12.
127

330

IO3−

79

BrO3−

127 −

I

79

Br −

Average recovery, %96 ± 497 ± 598 ± 7100 ± 5

Recovery range, %90–100

89–101

88–104

94–105

Figure 3 shows the overlay of 79Br and 127I from the two infant formulas analyzed
per Table 7. The infant formulas from the US and China were spiked at two levels(~20 and 40 ppb) and each level prepared in triplicate. The chromatograms show
good repeatability for mulitple 100 μL injections.

Figure 3. Overlay of 79Br and 127I spiked at two levels (~20 and 40 ppb) in the USA infant formula(chromatogram on the right) and a Chinese infant formula (chromatogram on the left). n=6 foreach chromatogram.

Conclusion
For the first time, four halogen species were measured in the same run in infant
formula samples using an Agilent 1260 Infinity II LC system coupled to an
Agilent 8900 ICP-QQQ. Using an anion exchange column, baseline separations
were achieved in around 6.5 minutes with detection limits for I−, IO3−, Br−, andBrO3− all less than or equal to 0.67 ppb.
Speciation analysis of infant formula provides valuable information on iodine
bio-availability and the potential risk from bromate. Total elemental
determinations of iodine and bromine were also performed using the 8900
ICP-QQQ. The measured value for iodine in an infant formula SRM was in good
agreement with the certified value at 103% recovery. There was also good
agreement between the measured concentration of 127I− with the certified value
at 101% recovery. No certified value was provided with the SRM for bromine.
None of the four commercially available infant formula samples that wereanalyzed in the study contained iodate or bromate, only iodide and bromide.
The total iodine content in the samples ranged from 25.9 to 54.5 μg/100 kcal.
This range is within the US and China national standards for iodine in infant
formula, but outside the EU maximum limit of 29 μg/100 kcal.
To test the suitability of the method for the accurate determination of low
concentrations of the four species in infant formula samples, a spike recovery
test was carried out at 20 and 40 ppb. Baseline separations were achieved, withgood repeatability over the course of mulitple 100 μL injections.
331

References
A. Milanesi, and G. A. Brent, Molecular, Genetic, and Nutritional Aspects of Major
and Trace Minerals, J.F. Collins (Ed.), 2017, Elsevier, London, UK, 143–150
P. Ghirri, S. Lunardi, A. Boldrini, Iodine Supplementation in the Newborn, Nutrients,
2014, 6(1), 382–390
World Health Organization, International Agency of Research on Cancer, IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans, https://monographs.iarc.fr/wp-content/uploads/2018/07/ClassificationsAlphaOrder.pdf,(accessed February 2019)
CFR Chapter I: Food and Drug Administration, in Title 21: Food and Drugs, Ch. 1,
Part 107, Infant Formula, Code of Federal Regulations, U.S. Food and Drug
Administration, Silver Spring, MD
Commission Delegated Regulation No. 2016/127/EU (2015) Off. J. Eur. Union
L25, 1–29
GB 10765-2010: National Food Safety Standard Infant Formula, The Ministry of
Health of the People’s Republic of China, Beijing, China
Standard Method Performance Requirements (SMPRs) for Quantitation of
Arsenic Species in Selected Foods and Beverages, AOAC Int, 2015, Gaithersburg,
MD, Method 2015.006
B. P. Jackson, V. F. Taylor, T. Punshon, K. L. Cottingham, Arsenic concentrationand speciation in infant formulas and first foods, Pure Appl. Chem., 2012, 84,
215–223

More Information
For a full account of this study, see Jennifer Nelson, Lawrence Pacquette,
Shuofei Dong and Michiko Yamanaka, Simultaneous Analysis of Iodine andBromine Species in Infant Formula using HPLC-ICP-MS, JAOAC Int., 102, 2019,
DOI: 10.5740/jaoacint.18-0352

332

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Determination of Pesticides using Phosphorus and
Sulfur Detection by GC-ICP-QQQ
Authors

Introduction

Jenny Nelson, Fabio Silva,
Steve Wilbur, Jianmin Chen,
Shiota Ozawa, and Philip L. Wylie,
Agilent Technologies

The determination of pesticide residues in food products is important.
Most pesticide residue laboratories use some variation of the QuEChERS(Quick, Easy, Cheap, Effective, Rugged, and Safe) extraction methods.
Typically, the extracted material is analyzed using GC/MS/MS the thermallystable, less polar pesticides, or LC-MS/MS for the less volatile and/or more polar
ones. A more recently developed alternative technique involves coupling GC to
triple quadrupole ICP-MS (GC-ICP-QQQ). Pesticides can be quantified using
GC-ICP-QQQ by measuring the heteroatoms P and S (also Cl and Br) contained inmost pesticides. GC‑ICP‑QQQ offers good selectivity, specificity, and sensitivity
that can be greater than the established methods.

Helene Hopfer, Food Safety andMeasurement Facility, University ofCalifornia Davis

Keywords
pesticides, GC-ICP-MS, GC-ICP-MS/
MS, GC-ICP-QQQ, sulfur, phosphorus

Experimental
Instrumentation: An Agilent 7890 GC was coupled to an Agilent 8800 #100
ICP-QQQ using an Agilent GC-ICP-MS interface (G3158D).
GC: Two Agilent columns were used in series. The first column was a 5 m length
cut from a 20 m x 0.18 mm x 0.18 μm film thickness DB-35ms Ultra Inert (UI)
capillary column (p/n 121-3822UI). This column was installed between the inlet
and one end of the purged union. It was back flushed shortly before the run had
ended to prevent high boiling point contaminants from entering the second
column. The second column was a 15 m x 0.25 mm i.d. 0.25 μm film thickness
DB-5MS UI capillary column (p/n 19091S-431UI). The column was installed
between the other end of the purged union and the ICP-QQQ transfer line
connection inside the GC oven. Sample injections of 1 μL volume were madeunder splitless conditions with the inlet held at 280 °C. GC operating parameters
are detailed in a previous study [1].
ICP-QQQ: O2 mass-shift method was applied to detect P and S. The O2 flow rate
was 0.2 mL/min. P and S were detected as PO+ and SO+, respectively.
Samples and preparation: Three standard pesticide mixes were obtained from
Ultra Scientific (Kingstown, RI, USA) and Agilent Technologies (p/n 5190–0468).
The standard solutions were diluted with high purity grade acetonitrile to form
intermediate solutions. These solutions were then used to prepare calibration
standard solutions following serial dilutions in acetonitrile.

333

Results and discussion
Figure 1 shows overlaid chromatograms for P and S in a mixed pesticide
standard. The pesticides that contain more than one hetero-element can be
identified easily.
S Q1 =32 / Q2 = 48
P Q1 = 31 / Q2 = 47

Dichlofenthion
Phosphamidon

Chloropyrifos-methyl

Fonofos
Thionazin

Carbophenothion

Chlorfenvinphos

Ethion

Aspon

Leptophos

Trichlorfon
Fenitrothion

Famphur

Azinphos-ethyl
Dioxathion

PhosmetCrotoxyphos
4.0

6.0

8.0

10.0

12.0

Retention Time (min)Figure 1. Chromatograms showing the heteroatom traces for P and S in the mixed pesticide
standard, with identified pesticide compounds.
Reprinted with permission from J. Agric. Food Chem., 2015, 63, 4478−4483. Copyright 2015
American Chemical Society.

Table 1 summarizes the retention time and compound detection limits (DLs)of the pesticides. DLs for pesticides using current GC/MS/MS instrumentation
typically vary from about 0.1 to 10 μg/L depending on the pesticide andinstrument used. The data in Table 1 suggests that GC-ICP-QQQ offers similar orslightly lower DLs than GC/MS/MS for the determination of organophosphorus
pesticides. For S-containing pesticides, detection limits are similar to, or slightly
higher than DLs achieved by GC/MS/MS. All of the pesticides listed in Table 1,
which were detected via their P content, were quantified well below the 10 μg/L
limit of quantitation (LOQ) required by most food safety laboratories.

334

Table 1. Detection limits as the compound for pesticides.
Pesticide

RT (min)Compound DL (μg/L)
P

S

Trichlorfon

4.103

0.178

Thionazin

5.926

0.221

11.93

Terbufos

7.071

0.718

9.708

Fonofos

7.185

0.455

7.917

Phosphamidon

7.299

0.923

Dichlofenthion

7.858

0.362

15.8

Chloropyrifos-methyl

7.973

0.613

24.18

Fenitrothion

8.44

0.907

19.52

Aspon

8.705

0.200

9.912

Chlorfenvinphos

9.486

2.020

Crotoxyphos

9.541

3.338

Carbophenothion

11.158

0.583

9.585

Ethion11.527

0.707

11.51

Famphur

12.547

2.206

20.61

Phosmet12.851

3.829

Leptophos

13.263

1.125

18.35

Azinphos-ethyl13.827

1.812

21.33

Dioxathion

14.587

1.392

7.84

Conclusion
The GC-ICP-QQQ method is suitable for the selective and sensitive detectionof organophosphorus and organosulfur pesticides by measurement of theirheteroatoms. Due to the significantly lower background of the Agilent 8800
ICP-QQQ, GC-ICP-QQQ provides good sensitivity performance for thedetermination of organophosphorus pesticides compared to GC/MS/MS.

References
1. 	P. L. Wylie, C. Meng, A Method for the Trace Analysis of 175 Pesticides
Using the Agilent Triple Quadrupole GC/MS/MS, Agilent publication, 2009,
5990-3578EN
2. 	Jenny Nelson, Helene Hopfer, Fabio Silva, Steve Wilbur, Jianmin Chen, Kumi
Shiota Ozawa, and Philip L. Wylie, Evaluation of GC-ICP-MS/MS as a New
Strategy for Specific Heteroatom Detection of Phosphorus, Sulfur, and Chlorine
Determination in Foods, J. Agric. Food Chem., 2015, DOI: 10.1021/jf506372e

More information
Determination of pesticides in foods using phosphorus and sulfur detection by
GC-ICP-QQQ, Agilent publication, 5991-6260EN

335

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Petrochemicals
Title

336

Page

Determination of P, Si and S in acid digested lubricating oil using theAgilent 8800 triple quadrupole ICP-MS

337

Accurate sulfur quantification in organic solvents using isotope dilution
mass spectrometry

342

Determination of chloride in crude oils using an Agilent 8900 ICP-QQQ

346

Single nanoparticle analysis of asphaltene solutions using ICP-QQQ

351

Gas chromatographic separation of metal carbonyls in carbon monoxidewith detection using the Agilent 8800 ICP-QQQ

358

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Determination of P, Si and S in acid digested lubricating
oil using the Agilent 8800 Triple Quadrupole ICP-MS
Authors

Abstract

Renata S. Amais1, Clarice D. B. Amaral1,
Lucimar L. Fialho1, Daniela Schiavo2
and Joaquim A. Nóbrega1

A new method is described for the accurate determination of silicon (Si),phosphorus (P), and sulfur (S) in lubricating oil samples using an Agilent 8800
Triple Quadrupole ICP-MS (ICP-QQQ). An optimized oxygen (O2) mass-shiftmethod provided limits of detection for 28Si, 31P, 32S and 34S of 0.25, 0.01, 0.18 and0.75 ppb, respectively. The method was successfully applied to the determinationof Si, P and S in a lubricating oil standard reference material NIST 1848.
Recoveries in the sample digests ranged from 96.4–103%.

Group of Applied Instrumental
Analysis, Department of Chemistry,
Federal University of São Carlos,
São Carlos, SP, Brazil
1Agilent Technologies
São Paulo, SP, Brazil

2

Introduction
Due to its high sensitivity and fast multi-element capabilities, inductively coupledplasma mass spectrometry (ICP-MS) is used increasingly in chemical analysis.
However, spectral overlaps from isobaric concomitant species and polyatomic
ions formed in the plasma can compromise ICP‑MS sensitivity and accuracy inthe determination of some elements (1).
For example, Si, P and S are difficult elements to determine at low levels byquadrupole based ICP-MS due to intense polyatomic interferences: 28Si+, 31P+, 32S+
and 34S+ suffer spectral overlaps from 14N2+ and 12C16O+, 14N16OH+, 16O2+ and 16O18O+,
respectively (2). Since the enthalpies of reaction for P+ (-3.17 eV) and S+ (-0.34 eV)with O2 are negative and low for Si (0.11 eV) (3), some authors have studied thefeasibility of using Collision/Reaction Cell (CRC-)ICP-MS with O2 cell gas todetermine these elements as oxide ions (4, 5, 6). The method of using a reaction
product ion for the detection of an element is known as mass-shift mode.
Conventional CRC‑ICP‑MS has no control of the ions that enter the cell or thereactions that occur in the cell. In contrast, the Agilent 8800 ICP-QQQ has atandem mass spectrometer (MS/MS) configuration with two quadrupole massfilters, Q1 and Q2, positioned either side of the Octopole Reaction System (ORS3)
cell. This configuration is designed to control the reactions in the cell for more
effective removal of spectral interferences (Figure 1). In mass-shift mode using
O2 cell gas, Q1 is set to the mass of the target analyte ion so only the analyte andany on-mass interfering ions can enter the ORS3 and react with the O2 cell gas,
ensuring a well controlled and more efficient reaction in the cell. The second
quadrupole, Q2, is then set to the mass of the oxide ion of the element of interest,
so rejecting any interfering ions that have not reacted with the cell gas andtherefore remain at the original analyte mass. Balcaen et al. evaluated the MS/MS
mass-shift mode of the 8800 ICP-QQQ for the low level determination of sulfur inethanol-diluted biodiesel samples using isotope dilution (7).
In this study, mass-shift mode was evaluated for the low level analysis of Si, P
and S in lubricating oil samples. We demonstrate that the 8800 Triple Quadrupole
ICP-MS operating in MS/MS mode with O2 as the reaction gas provides low Limitsof Detection (LOD) for these difficult elements and enables their accurate
determination in a complex matrix such as lubricating oil.

337

Spray chamberand nebulizer

ICP torch

Q1

ORS3

Detector

Q2

Interface

Figure 1. Schematic of the Agilent 8800 Triple Quadrupole ICP-MS

Experimental
Instrumentation
All measurements were carried using a standard Agilent 8800 Triple Quadrupole
ICP-MS (option #100). The standard configuration is composed of an x-lens,a Peltier-cooled double-pass Scott-type spray chamber, a glass concentric
nebulizer, and a one-piece quartz torch with 2.5 mm internal diameter (ID)injector. Instrument operating parameters are summarized in Table 1.
Table 1. Agilent 8800 ICP-QQQ operating conditions
Parameter

Value

RF power

1550 W

Sampling depth

8.0 mmCarrier gas flow rate

1.08 L/min

Spray chamber temperature

2 ºC

Cell gas

O2

Cell gas flow rate

0.5 mL/min

Mass pair (Q1, Q2)(28, 44), (31, 47), (32, 48), (34, 50)

Reagents and standard solutions
Deionized water (> 18.2 MΩ cm) obtained from a Milli-Q water purification system(Millipore, Bedford, MA, USA) was used to prepare all solutions. Nitric acid (Merck,
Darmstadt, Germany) previously purified by a sub-boiling distillation system(Milestone, Sorisole, Italy) and 30% H2O2 (Labsynth, Diadema, SP, Brazil) wereused to digest the samples. Stock single element solutions containing 1000 mg/L
of Si, P and S (Tec-Lab, Hexis, São Paulo, SP, Brazil) were used to prepare thecalibration standard solutions by diluting in 1 % v/v HNO3.
Samples and sample preparation
A lubricating oil standard reference material (SRM 1848, National Institute ofStandard and Technology, Gaithersburg, MD, USA) was used to check the accuracyof the method. The SRM sample was microwave-assisted acid-digested(Milestone) using the following procedure. Aliquots of 0.25 g of the SRM 1848 were
weighed directly in PTFE-PFA digestion vessels and 2.5 mL of concentrated HNO3
was added to each flask. After standing for 30 min at room temperature, 2.5 mL of
distilled–deionized water was added to the mixture. An additional pre-digestion338

period of 30 min without any external heating was allowed before 3.0 mL of 30%
H2O2 was added to each digestion vessel. The microwave-assisted digestion of
the samples was then carried out according to the heating program presented inTable 2. The digestion flasks were allowed to cool to room temperature and thenthe volume of each solution was made up to 13.0 mL with distilled–deionizedwater. The procedure was performed in triplicate and each sample digest was
diluted 200x for Si and P and 2000x for S with distilled-deionized water.
Table 2. Heating program used in the microwave-assisted acid-digestion sample preparation
procedure
Step

Applied power (W)Time (min)Temperature (ºC)

1

250

2

80

2

0

3

80

3

550

4

120

4

650

5

180

5

750

5

200

Results and discussion
Figures of merit
The analytical performance of MS/MS mass-shift mode with O2 reaction gas wasevaluated for Si, P and S. O2 gas flow rate was optimized at 0.50 mL/min gas.
Calibration curves were prepared using calibration standard solutions ranging
from 0.5 to 500 ppb (Figure 2). LODs of 0.25, 0.01, 0.18 and 0.75 ppb wereobtained for 28Si, 31P, 32S and 34S respectively (Table 3) based on 10 consecutive
blank measurements using the optimized acquisition conditions given in Table 1
and an integration time of 3 s.
Table 3. Limits of detection for Si, P and S obtained using the 8800 ICP-MS operating in
O2 mass-shift mode
Element

Mass pair (Q1, Q2)

Silicon(28, 44)

Product ion
28

LOD (ppb)

SiO+

Phosphorus(31, 47)

31

0.25

PO

+

Sulfur(32, 48)

0.01

32

SO+

0.18

34

Sulfur(34, 50)

SO

0.75

+

Analytical application
The accuracy of the method for the determination of P, S, and Si in lubricating oil
was evaluated by analyzing a digest of NIST 1848. The results are given in
Table 4. The recoveries for all 3 analytes ranged from 96.4–103% indicating theeffectiveness of the method to separate the analytes from the interferences.
In MS/MS mode, non-target ions such as 44Ca+, 48Ca+, 47Ti+, 48Ti+ or 36Ar12C+ (thatwould potentially overlap with the target product ions SiO+, PO+ or SO+) areprevented from entering the ORS3 by Q1, thus allowing the accurate and sensitive
determination of these difficult elements in a complex matrix.
Table 4. Results of NIST 1848 analysis
Certified(mg/kg)Isotope

Mass pair(Q1, Q2)Si(28, 44)28

P(31, 47)

31

32

S

(32, 48)

34

S(34, 50)50a ± 228

Phosphorus

7880 ± 280b

31

Sulfur23270 ± 43b

Silicon

Product ion

Determinedconc. (mg/kg)

Recovery (%)

Si16O+

48.2 ± 2.1

96.4

P16O+

7650 ± 120

97.0

32

S16O+

24010 ± 820

103

34

S16O+

23985 ± 830

103

Reference value
Certified value

a

b

339

Figure 2. Calibration curves for 28Si16O +, 31P16O +, 32S16O + and 34 S16O +340

Conclusions
The Agilent 8800 ICP-QQQ operating in MS/MS mode with oxygen cell gas
effectively removes spectral interferences allowing the determination of thechallenging elements Si, P and S with sub-ppb (µg/kg) LODs. By mass-shifting
each of the 3 analytes by reaction with O2, and detecting the oxide product ions,
all potential interferences from polyatomic ions based on nitrogen and oxygen
are removed. Also, any ions that might overlap the analyte product ions createdin the cell are rejected by Q1, greatly improving the accuracy, reliability and easeof use of reaction gas mode. Si, P and S were accurately determined in a digested
lubricating oil SRM, validating the applicability of the method to the mostchallenging sample types.

Acknowledgments
The authors would like to acknowledge grants 2010/17387-7, São Paulo
Research Foundation (FAPESP) for scholarship and fellowship provided to R.S.A..
J.A.N. is thankful to Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq). We also acknowledge the technical support provided by
Agilent Technologies.

References
1.

J. S. Becker, Inorganic Mass Spectrometry: Principles and Applications;Wiley: Chichester, 2008.

2.

H. E. Taylor, Inductively Coupled Plasma – Mass Spectrometry, Practices andTechniques, Academic Press: San Diego, USA. 2001.

3.

Agilent 8800 Triple Quadrupole ICP-MS: Understanding oxygen reaction
mode in ICP‑MS/MS. Application note: 5991-1708EN, 2012.

4.

G. L. Donati, R. S. Amais, J. A. Nóbrega, Interference standard and oxide ion
detection as strategies to determine phosphorus and sulfur in fuel samples
by inductively coupled plasma quadrupole mass spectrometry. J. Anal. At.
Spectrom., 27, 1274-1279, 2012.

5.

C.-H. Yang, S.-J. Jiang, Determination of B, Si, P and S in steels by inductively
coupled plasma quadrupole mass spectrometry with dynamic reaction cell.
Spectrochim. Acta Part B, 59, 1389‑1394, 2004.

6.

S. D. Tanner, V. I. Baranov, D. R. Bandura. Reaction cells and collision cells for
ICP-MS: a tutorial review. Spectrochim. Acta Part B, 57, 1361-1452, 2002.

7.

L. Balcaen, G. Woods, M. Resano, F. Vanhaecke, Accurate determination of S
in organic matrices using isotope dilution ICP-MS/MS. J. Anal. At. Spectrom.,
28, 33-39, 2013.

341

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Accurate Sulfur Quantification in Organic Solvents using
Isotope Dilution Mass Spectrometry
AuthorIntroduction

Glenn Woods
Agilent Technologies (UK) Ltd.

Accurate measurement of sulfur in aqueous and organic media is relatively
difficult for ICP-MS due to intense spectral interferences from polyatomic ionsformed mainly from oxygen and nitrogen. Sulfur is an important element inenvironmental terms as it forms SOx when combusted, contributing to acid rain
and photochemical smog. It is also a catalyst poison for some industrial
processes and its accurate measurement can be critical.

Based upon the published work
“Accurate determination of S in organic
matrices using isotope dilution
ICP-MS/MS” J. Anal., At. Spectrom.
2012 DOI: 10.1039/c2ja30265a by:
Lieve Balcaen and Frank Vanhaecke,
Ghent University, Department ofAnalytical Chemistry, Ghent, Belgium
Martın Resano, University of Zaragoza,
Department of Analytical Chemistry,
Zaragoza, Spain
Glenn Woods, Agilent Technologies UK
Ltd., 5500 Lakeside, Cheadle RoyalBusiness Park, SK8 3GR, UK

Keywords
sulfur, ID-MS, biodiesel, environmental,
ethanol, NIST SRM 2773, oxygenmass-shift

Experimental
A quadrupole ICP-MS (ICP-QMS) with a collision/reaction cell set up for O2
mass-shift reaction chemistry can be used to avoid the 16O2+ overlap on 32S+ byconverting the S+ to SO+ reaction product ions that are then measured at a new
mass (m/z 48) that is free from the O2+ overlap. However, in practice, thisapproach has been of relatively limited use, as ICP-QMS has no way to rejectexisting ions at the mass of the new analyte product ions, so not all of theinterferences are eliminated, particularly when complex or variable matrices areinvestigated. There has also been some limited success reported by using Xe asa reaction gas to attenuate the O2-based interference particularly on the 34S
isotope. Neither of these approaches reduces the backgrounds significantly
enough to allow reliable trace level measurement of S, and they do notnecessarily preserve the S isotopic abundances. In this investigation, ethanol wasused as an example organic solvent and the Agilent 8800 ICP-QQQ was used todetermine S by ID-MS in a biodiesel reference material to assess themeasurement accuracy of MS/MS mode with O2 mass-shift for S determination.
Instrumentation: Agilent 8800 #100 with Micromist nebulizer (free aspiration).
For organic solvent analysis, a narrow injector torch with id 1.0 mm (G328080005) and Pt cones were used. 20% O2 balanced in Ar was introduced via an
option gas flow line to prevent carbon build up.
Plasma conditions: Plasma conditions were optimized manually. (RF power =1450 W, Carrier gas flow rate = 0.98 L/min, Option gas flow rate = 0.75 L/min andspray chamber temp. = -5˚C).
CRC conditions: O2 gas at 0.4 mL/min,
Octopole bias = -9 V, KED = -8 V.
Sample: Biodiesel certified reference material NIST SRM 2773.

342

Results and discussion
When using mass-shift mode for sulfur (or any element) it is important toeliminate any potential interferences at the target mass of the reaction production, as well as on the primary element mass (the precursor ion). If the target
mass suffers from interferences then the measurement would still becompromised. For sulfur, the corresponding isotopes are shifted as follows using
M + 16 u mass-shift:32

S  SO at 48 u

33

S  SO at 49 u

34

S  SO at 50 u

Unfortunately, the SO+ product ion masses (m/z 48, 49 and 50) can suffer frommultiple interferences including Ca+, Cr+, V+, Ti+, ArC+ and CCl+ in natural samples.
Furthermore, the 33S and 34S isotopes can suffer from overlaps due to othercombinations of SO+ product ions, as well as pre-existing ions at the target mass.
For example, the 34S16O+ product ion formed at m/z 50 is overlapped by 32S18O+
and 33S17O+, as well as 50Cr+, 50V+, 50Ti+, 38Ar12C+, and 13C37Cl+. When operating the8800 ICP-QQQ in MS/MS mass-shift mode, these overlaps are eliminated and thesulfur isotope pattern is preserved. Figure 1 provides a graphical representationof the ICP‑QQQ setup and the method of interference elimination.
O 2 reaction gas
Cr+, 50V+,
Ti , Ar12C +,
13 37
C Cl+
32 + 33 +
S, S
34 +
S
17
O 2+, 16O18O +
50

50

+ 38

34

Q1
34 u

S16O +Q2
50 u

Figure 1. Mechanism of MS/MS mass-shift for sulfur isotope analysis. The mass difference
between Q1 and Q2 is fixed at 16 u, so only the + 16O-atom transition is observed – the otheroxygen isotope transitions are eliminated so the original sulfur isotopic pattern is preserved.

343

This method would not be useful if the reaction were not quantitative, so tocheck for linearity, a blank ethanol sample was spiked with sulfur – see Figure 2.
Despite the wide variation in absolute sensitivity for the different S isotopes, theBEC was the same for all three isotopes, indicating that the background is due tosulfur in the ethanol.
105

32 ➝ 48 S [MSMSO 2]

001CALB d

x105

003CALS d
004CALS dy = 4724.5642 * x + 89926.6400
R = 1.0000
DL = 0.3584
BEC = 19.03

5005CALS d

100 µg/L

006CALS d

0

4

50.0

Conc

100.0

33 ➝ 49 S [MSMSO 2]
x103

SIGNAL – cps

6

50 µg/L

y = 40.1466 * x + 796.3533
R = 0.9994
DL = 2.86
BEC = 19.84

4

2

2

0
50.0

Conc

100.0

34 ➝ 50 S [MSMSO 2]
4x104

10 µg/Ly = 243.8137 * x + 4631.0983
R = 1.0000
DL = 0.8523
BEC = 18.99

5 µg/L
Blank

2

0
43

44

45

46

47

48

49

50

51

52

0
50.0

Q2 (Q2 = Q1+16)

Conc

100.0

Figure 2. Ethanol with 0, 5, 10, 50 and 100 µg/L sulfur spikes and corresponding calibration curves.

An isotope dilution (ID) method was used to evaluate the accuracy of the 8800
ICP-QQQ MS/MS method, using a biodiesel certified reference material (NIST
SRM 2773) and an enriched 34S spike. The biodiesel sample was simply diluted
into the ethanol solvent and the appropriate spike added. Reproducibility wastested by analyzing three separate samples of the CRM. The results arepresented in Table 1. Repeat measurements were within the expected recovery
limits for the material.
Table 1. Isotope dilution analysis of S in diluted biodiesel reference material NIST 2773.
SampleS conc.(µg/g)

SRM 2773 - Certified

7.39 ± 0.39

SRM 2773 - measured 1

7.234

SRM 2773 - measured 2

7.227

SRM 2773 - measured 3

7.231

Average (measured)

7.231

Standard Deviation

0.003

95% confidence interval

344

7.231 ± 0.015

Conclusion
Until the introduction of ICP-QQQ with MS/MS capability, it was impossible toobtain reliable results for reaction chemistry methods combined with an ID
approach, using a quadrupole-based ICP-MS. The novel QQQ configuration of the8800 ICP-QQQ enables operation in MS/MS mode, which ensures precise control
over the reaction chemistry in the cell. This allows the unique isotopic informationof the analyte to be retained, while removing the interferences that could affectboth precursor and product ions of the target analyte.

345

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Determination of Chloride in Crude Oils using
an Agilent 8900 ICP-QQQ
Jenny Nelson

Fast, accurate analysis of crude oils following direct dilution in
an o-xylene-based diluent

Agilent Technologies Inc.,
Santa Clara, California, USA

Introduction

Authors

Laura Poirier and Francisco LopezLinares
Chevron Energy Technology Company,
Richmond, California, USA

As stated in a recent study, chlorinated compounds are often removed fromcrude oil refinery streams (1). To avoid corrosion and fouling during distillation,
the concentration of chlorides in crude oil should be less than 1 mg/L. Despite its
sensitivity, there are no ASTM standard test methods that use inductively coupledplasma mass spectrometry (ICP-MS) for the measurement of chloride in crude
oils. However, ASTM D8110–17 test method specifies ICP-MS for the rapid
determination of seven elements in distillate petroleum products (2). Because ofits multi-element capabilities, ICP-MS is increasingly used to test petrochemicalbased samples for a wide range of elements. It would be convenient to also use
ICP-MS for the measurement of chloride.
The determination of chloride in complex matrices is challenging by conventional
single quadrupole ICP-QMS. Petroleum crude oil and derivatives may containsulfur (S), nitrogen (N), and oxygen (O) at variable concentrations, which could
promote multiple interferences in the plasma. The 35Cl isotope (75.8% naturalabundance) suffers polyatomic interferences from 16O18O1H+ and 34S1H+. Also, Cl
is poorly ionized in the plasma because of its high first ionization potential of
12.967 eV, which affects the sensitivity of measurements by ICP-MS. Collision/
reaction cells (CRCs) are used successfully to control many common polyatomic
interferences in ICP-QMS. However, ICP-QMS cannot reduce the 34S1H+
interference sufficiently to allow the accurate determination of Cl at trace levels
in samples that contain a high level of S (1).

Experimental
Calibration standard and crude oil sample preparation
The calibration standards were prepared using different concentrations of a Cl
organic solvent standard (Conostan, Quebec, Canada) prepared in a diluent.
The diluent comprised 90 parts o-xylene (Fisher Scientific, NJ, USA) to 10 parts
matrix modifier. The matrix modifier was made from mineral oil (80%, Fisher
Scientific), a dispersant (20%, Chevron Oronite), and scandium (Sc) and yttrium(Y) spiked at 0.1 mg/kg as internal standards (Conostan, Quebec, Canada).
Multiple calibration standards, ranging from 1 to 1000 mg/kg, were prepared byweight. The diluent (90% o-xylene to 10% matrix modifier) was run as a blank.
Direct dilution
The composition of the 12 crude oil samples used in this study ranged from C(84 to 89 wt.%), H (10 to 14 wt.%), S (0.3 to 2.5 wt.%), and N (400 to 2500 mg/kg).
The samples were diluted 1:5 or 1:10 (using diluent) to allow all Cl concentrations
to fit within the calibration range. Standard Reference Material (SRM) NIST 1634c
trace elements in fuel oil (Gaithersburg, MD, USA) was prepared at 1:5 and 1:10
dilution. All samples were shaken for two hours in a mechanical shaker. If any
residue was seen on the vial walls, a vortex shaker was used to improve sample
homogenization.
346

Instrumentation
An Agilent 8900 ICP-QQQ (#100 for advanced applications) was used.
The instrument was equipped with platinum sampling and skimmer cones, a
concentric glass nebulizer, quartz spray chamber, and quartz torch with 1 mm
injector. The diluted samples were introduced directly into the ICP-QQQ via a
peristaltic pump fitted with solvent-resistant tubing (0.89 mm i.d., bought from
Cole Parmer). Other parts were from the Agilent Organic Solvent Introduction kit(p/n G3280-60580). An optional gas ﬂow of 20% O2 in Ar was added to the carrier
gas to prevent carbon building up on the interface cones. An o-xylene rinse wasused between each sample to eliminate any carry-over from the sample
introduction system.
Based on the findings of previous studies, hydrogen was used as a reactive cellgas for the determination of 35Cl+ (4, 5). Cl+ reacts exothermically with H2 to form
HCl+, HCl+ then continues to react via a chain reaction to form ClH2+. This allows
the use of the “mass-shift” approach, where the analyte reacts with a reaction gas
in the cell to form a product ion, shifting it away from the interference. In thisstudy, Q1 was set to m/z 35 to allow 35Cl+ ions to enter the CRC. The analyte ionsthen reacted with H2 in the cell to form 35Cl1H1H+, while the polyatomic
interference ions (16O18O1H+ and 34S1H+) did not react with H2. Q2 was set to m/z
37, allowing the product of ion 35ClH2+ to pass to the detector, free of interference.
ICP-QQQ instrument operating parameters are detailed in Table 1. For
comparison purposes, chlorine was also measured using Instrumental Neutron
Activation Analysis (INAA), which was carried out by EAI-Elemental Analysis, Inc,an elemental testing facility located in Lexington, KY, USA.
Table 1. ICP-QQQ operating conditions.
Parameter

Value

RF power (W)1500

Nebulizer gas flow rate (L/min)

0.4

Sampling depth (mm)8Spray chamber temp (°C)–2

Option gas flow rate (mL/min); Ar 80%, O2 20%

0.35 (35%)

Make up gas flow rate (L/min)

0.1

Nebulizer pump speed (rps)

0.1

H2 cell gas flow rate (mL/min)

4.6

Octopole bias (V)–18

Octopole RF (V)180

Energy discrimination (V)0Monitored masses

Q1:35, Q2:37

Integration time (s)3347Results and discussion
The calibration plot for 35Cl is shown in Figure 1. Three sigma detection limits (DL),limits of quantification (LOQ), and background concentration (BEC) for 35Cl were
determined by measuring a blank solution (o-xylene diluent containing a matrix
modifier and internal standard) ten times. The results are shown in Table 2.

Figure 1. Calibration plot of Cl in o-xylene. Units: mg/kg (ppm).
Table 2. DL, LOQ, and BEC of 35Cl in a blank solution determined by ICP-QQQ in H2 mass-shift mode.
35

Detection Limit (mg/kg)

LOQ (mg/kg)

BEC (mg/kg)

0.01

0.04

0.24

Cl

Reference material analysis
Chlorine was determined in the petroleum feedstock SRM using the 8900
ICP-QQQ operating in H2 mass-shift mode. The reference value for chlorine in
NIST 1634c is 45 mg/kg. The SRM was diluted in o-xylene at two different dilution
factors. Other than carbon and hydrogen, real petroleum samples containheteroatoms, S, N, and O, and metals such as V and Ni, among others. The sulfur
content of NIST 1634c is around 2 wt.%, so the SRM is a useful test sample for
ICP-QQQ given the likely interference on 35Cl by 34S1H+. As can be seen from theresults presented in Table 3, excellent recoveries were obtained for 35Cl,
irrespective of the dilution factor (100 ± 10%). Since H2 effectively reacts with Cl+
to form ClH2+, the interferences on 35Cl can be avoided by measuring the production 35ClH2+ at m/z 37.
Table 3. Determination of Cl concentration in NIST 1634c SRM in o-xylene diluent using ICP-QQQ.
Dilution Factor 5

35

Cl*Recovery(%)

Concentration(mg/kg)*Recovery(%)

44.33 ± 1.00

99

48.28 ± 1.89

107

*NIST reference value for Cl = 45 mg/kg, S = 2 wt%

348

Dilution Factor 10

Concentration(mg/kg)Quantitative analysis of crude oil samples
Twelve petroleum crude oil samples with a sulfur content spanning from 0.38 up
to 2.01 wt.% and hydrogen to carbon (H/C) ratio from 1.68 to 1.88 were analyzed
by ICP-QQQ. The H/C provides an insight to the aromatic/paraffinic nature of thecrude samples, which has implications for trading, processing, and stability ofcrude. The quantitative results for Cl measurements are given in Table 4.
Table 4. Determination of the Cl concentrations in 12 petroleum crude oil samples in o-xylene
diluent using ICP-QQQ operating in H2 mass-shift mode. Dilution factor 1:5. n = 3.
Sample

S
(%)

H/C

35
Cl Measured
Concentration (mg/kg)

Sample

S
(%)

H/C

35
Cl Measured
Concentration (mg/kg)

S1

0.38

1.84

22.32 ± 0.36

S7

1.19

1.78

24.80 ± 1.04

S2

0.38

1.85

12.80 ± 0.07

S8

1.19

1.78

20.78 ± 0.08

S3

0.38

1.86

22.84 ± 0.16

S9

1.97

1.71

48.33 ± 2.38

S4

0.38

1.88

6.15 ± 0.05

S10

1.99

1.68

18.25 ± 0.24

S5

0.50

1.85

33.89 ± 0.31

S11

2.01

1.70

50.35 ± 3.00

S6

0.59

1.87

24.87 ± 0.15

S12

2.01

1.71

17.68 ± 0.55

Comparison of results
To further evaluate the accuracy of the ICP-QQQ method, quantitative results for
Cl were compared with the results obtained by INAA. The results obtained forthree crude samples are shown in Table 5.
Table 5. Comparison of measured Cl concentrations in crude oil samples obtained by ICP-QQQ(dilution factor 1:5) and INAA.
Measured Cl Concentration (mg/kg)
SampleICP-QQQ

INAA

S212.80 ± 0.07

14.40 ± 0.59

S4

6.19 ± 0.05

12.90 ± 0.53

S5

33.89 ± 0.31

25.30 ± 0.91

Depending on the sample, the agreement between the results obtained by
ICP-QQQ and INAA was reasonably close. The agreement for sample S2 wasaround 89%, whereas it was slightly higher at 134% for sample S5. A similar
observation was reported recently for these types of samples, using the same
techniques (6). The low bias of the ICP-QQQ result for sample S4 suggests thatthe sample may contain solids or is heterogeneous. A qualitative XRF analysisof S4 suggested the presence of solids (most likely NaCl), which would explain
why the ICP-QQQ result was low. It is likely that S4 wasn’t fully solubilized or welldispersed in the o-xylene diluent.

Conclusion
The Agilent 8900 ICP-QQQ is suitable for the determination of chlorine inpetroleum crude samples. Despite the complex matrix, potential interferences on
Cl ions originating from the crude petroleum samples were handled effectively
using MS/MS technology. MS/MS enables more consistent and reliable reaction
gas methods to be used for difficult elements, such as chlorine in complex
matrices, than single quadrupole ICP-MS.
In this study, a BEC of 240 µg/kg was achieved for the most abundant Cl isotope,
35 +Cl , using mass-shift mode and H2 cell gas. Interferences from 16O18O1H+ and
34 1 +S H on 35Cl+ were avoided by measuring the product ion 35ClH2+ at m/z 37.
349

A NIST trace element in fuel oil SRM and 12 crude oil samples were prepared
for analysis using direct dilution. The specially prepared diluent contained
o-xylene and a mineral oil matrix modifier, a dispersant, and internal standards.
Excellent recoveries of Cl (99 and 107%) in the SRM were determinedat two different dilution factors (5 and 10).
The petroleum crude samples were analyzed using ICP-QQQ, and some of theresults were checked using INNA. The results show the importance of fully
solubilized samples when using direct dilution as the sample preparation techniqueto avoid biased results due to the presence of particles.
Chloride was measured above the potential-corrosion trigger threshold of 1 mg/L
in all 12 crude oil samples, indicating a risk of corrosion at refining facilities fromthe formation of HCl.

References
1.

Jenny Nelson, Laura Poirier, and Francisco Lopez-Linares, Determination of
Chloride in Crude Oils by Direct Dilution using Inductively Coupled Plasma
Tandem Mass Spectrometry (ICP-MS/MS), J. Anal. At. Spectrom., 2019,
Advance Article, DOI 10.1039/C9JA00096H

2.

ASTM D8110–17 Standard Test Method for Elemental Analysis of Distillate
Products by Inductively Coupled Plasma Mass Spectrometry (ICP-MS).
ASTM International, West Conshohocken, PA, 2017,www.astm.org/Standards/D8110.htm

3.

Handbook of ICP-QQQ Applications using the Agilent 8800 and 8900,
Agilent publication, 5991-2802EN

4.

Naoki Sugiyama, Trace level analysis of sulfur, phosphorus, silicon andchlorine in NMP using theAgilent 8800 Triple Quadrupole ICP-MS, Agilent publication 5991-2303EN

5.

Kazumi Nakano, Ultra low-level determination of phosphorus, sulfur, silicon,
and chlorine using theAgilent 8900 ICP-QQQ, Agilent publication, 5991-6852EN

6.

Adriana Doyle, Alvaro Saavedra, Maria Luiza B. Tristão, Márcio Nele, Ricardo
Q. Aucélio, Direct chlorine determination in crude oils by energy dispersive
X-ray fluorescence spectrometry: An improved method based on a proper
strategy for sample homogenization and calibration with inorganic
standards, Spectrochimica Acta Part B. 2011, 66, 368–372

More information
For a full account of the method development, see Jenny Nelson, Laura Poirier,and Francisco Lopez-Linares, Determination of Chloride in Crude Oils by Direct
Dilution using Inductively Coupled Plasma Tandem Mass Spectrometry (ICP-MS/
MS), J. Anal. At. Spectrom., 2019, Advance Article, DOI 10.1039/C9JA00096H

350

> Return to table of contents> Search entire document

Single nanoparticle analysis of asphaltene solutions
using ICP-QQQ
Authors
Jenny Nelson
Agilent Technologies, USA
Michiko Yamanaka
Agilent Technologies, Japan
Francisco Lopez-Linares, Laura Poirier,and Estrella Rogel
Chevron Energy Technology Company,
USA

Agilent 8900 and ICP-MS MassHunter software module simplify
spICP-MS analysis
Introduction
Single Particle ICP-MS (spICP-MS) is increasingly being used to characterize
the nanoparticle (NP) content of samples dispersed in an aqueous media (1–5).
In several industries—including oil refining, petrochemicals, and semiconductor
manufacturing—there is also interest in determining NPs in hydrocarbon
matrices. In this study, we report a new method using triple quadrupole ICP-MS(ICP-QQQ) for the multi-element characterization of NPs in the heavy asphaltene
fraction of petroleum (6). The method can be used to differentiate between
metals present in NPs and the dissolved metal content. It will therefore extend
the understanding of the role and form of metals present in crude oils andpetroleum-based products. The method also has wider applicability to thecharacterization of NP populations in other hydrocarbon-based matrices,such as NMP, PGMEA, butyl acetate, and other organic solvents used in thesemiconductor industry.
In spICP-MS analysis, the ICP-MS uses a fast time resolved acquisition mode
to measure the signal generated by each NP as it passes through the plasma.
The high sensitivity and low background noise of ICP-MS enables the signals
generated from individual NPs to be distinguished, and these key performance
characteristics are greatly enhanced with ICP-QQQ. The superior control ofinterferences achieved using tandem MS (MS/MS) operation means that
ICP-QQQ is especially suitable for some of the elements of most interest in NP
analysis, such as Si, Ti, Fe, S, and others.
The intensity of the NP signal peak is proportional to the size of the particle andthe concentration (mass fraction) of the analyte element within the particle.
The frequency of the individual NP signals is directly proportional to the numberof NPs in the sample, allowing calculation of the NP size distribution, particle
number, particle concentration, and dissolved metal concentration, all from asingle ICP‑MS measurement. Nanoparticle method setup, acquisition, calibration,and data reporting are simplified using the optional Single Nanoparticle
Application Module of Agilent ICP-MS MassHunter software.
In this study, the spICP-MS acquisition mode of the Agilent 8900 ICP-QQQ wasused to identify and characterize trace elements in asphaltenes—a complex classof high molecular weight hydrocarbons found in heavy oil fractions and bitumens.
Asphaltenes are defined by their solubility class. They are soluble in aromatics
such as benzene or toluene, but insoluble in lighter paraffins, such as n-pentane
or n-heptane. Asphaltenes, together with waxes and resins, are of interest in
petrochemical processing as they can deposit in equipment and pipelines leading
to production problems. Asphaltenes also contain a high proportion of the metals
in crude oil, including elements such as V and Ni, which act as catalyst poisons,affecting the oil refining process.
351

Iron- and Mo-based NPs were identified in the asphaltene samples. In contrast,
V and Ni were found to be present mainly as dissolved metals, likely metal
porphyrins and other organometallic species. Data is provided on theconcentration and size distribution of Fe and Mo NPs in the asphaltene samples,
and the levels of dissolved metals is also presented. The results highlight thepotential of spICP-MS for the routine characterization of metal NPs—as well as
dissolved metals—in asphaltenes, crude oils, petroleum-derived materials, andother organic sample-types.

Experimental
Reagents and samples
Trace metal grade purity chemicals were used throughout (6).
Three separate samples of asphaltene were obtained from different sources:– Asphaltene A—a heavy Mexican crude oil (14° American Petroleum Institute,API).
– Asphaltene B—an asphaltenic deposit recovered from a submersible pump.
– Asphaltene C—an oxidized asphalt obtained from a commercial plant that
produces specialty asphalts.
Sample preparation
The asphaltenes were extracted from the sample matrix using n-heptane at asample/solvent ratio of 1/20. The blended crude oil/heptane was heated to 80 °C.
After one hour, the undissolved asphaltenes were recovered by filtering the
mixture through a 0.8 μ membrane filter.
Calibration standard preparation for total metals
Calibration standard solutions for direct analysis were prepared from Conostan(Quebec, Canada) S-21+K oil-based multi-element organometallic standard.
The diluent comprised trace metal grade purity o-xylene (Fisher Scientific),a matrix modifier (made from mineral oil; Fisher Scientific), and a dispersant(Chevron Oronite). Scandium and yttrium were used as internal standards,
spiked at 0.1 and 5 mg/kg, respectively.
Multiple calibration standards ranging from 1 to 1000 μg/kg for each of thetarget elements were prepared by weight from the 10 mg/kg Conostan multielement standard and o-xylene diluent. The diluent solution was used as theblank for calibration.
Nanoparticle reference materials and sample preparation
A 60 nm silver (Ag) NP reference material (nanoComposix) was used to calculate
the nebulizer efficiency. The Ag NP reference material and the three asphaltene
samples were diluted to a particle concentration of between 40 and 1000 ng/gwith o-xylene (via propylene glycol methyl ether acetate, PGMEA). The solutions
were sonicated for 5 min to ensure sample homogeneity. Elemental response
factors were determined by measuring elemental standards for each target
analyte (10.0 μg/g) prepared with o-xylene.

352

Wet acid digestion for total metals
One to 5 g of each sample was heated on a hot plate at 100 °C for four hours with
1 to 2 mL of H2SO4 (93–98 % w/w). The solution was then subjected to an ashing
sequence, as described in reference 6. Six mL HCl (34 to 37 % w/w) and 2 mL
HNO3 (67 to 70 % w/w) were added, before further heating on a hot plate at
100 °C for 1 hour. Before analysis, Sc was added as an internal standard (to givea final Sc concentration of 5 mg/kg) and the solution was brought to a final
volume of 25 mL with Milli-Q water.
Instrumentation
An Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) equipped with the standard
glass concentric nebulizer and Peltier-cooled quartz spray chamber was used.
For the analysis of samples prepared in organic solvent (spICP-MS analysis andtotal metals determinations in the diluted asphaltene samples), an optional“organics” quartz torch with a 1 mm ID injector was used in place of the standard
quartz torch, which has a 2.5 mm injector.
For the organic sample analyses, oxygen (20% in Ar) was added to the injector
gas stream after the spray chamber. O2 addition serves to decompose the carbon
matrix thus avoiding carbon deposition on the interface cones. The more reactive
plasma environment with O2 addition requires the use of the more chemicallyresistant optional platinum-tipped sampling and skimmer cones.
The high sensitivity of the ICP-QQQ enabled the samples for NP analysis to bediluted by a factor between 1:2100 and 1:2700 in o-xylene. Applying a highdilution factor minimizes the risk of colloidal particles forming an agglomerate
after nebulization. The dilution ensures that the NPs are dispersed in the solution
so that each NP passes through the plasma separately from any other NPs. As aresult, the signal peaks measured are each generated by a single particle eventand not from multiple, overlapping particle signals.
Signal intensities for each NP target element were acquired in fast Time Resolved
Analysis (fast TRA) mode using a dwell time of 0.1 ms (100 μs) per point, withno settling time between measurements. For Fe and Mo NPs, the signals were
measured on-mass in MS/MS mode. For on-mass measurements, both
quadrupoles (Q1 and Q2) were set to the target analyte ion mass of m/z 56(for Fe) and m/z 95 (for Mo). Helium (He) cell gas was used in the 8900 ORS,
to control the polyatomic interferences (mainly ArO on Fe at m/z 56). On-massmeasurement with He cell gas was also used for the measurement of V and Ni(dissolved concentrations only—no NPs detected). ICP-QQQ operating conditions
are given in Table 1.
Table 1. ICP-QQQ operating conditions.
Parameter

Value

RF power (W)1600

Sampling depth (mm)10

Carrier gas (L/min)

0.35

Spray chamber temperature (°C)-5

Option gas (L/min) (Ar 80%, O2 20%)0.35

Dwell time (ms)0.1

He cell gas flow rate (mL/min)

5.0
353

Simplified workflow
The optional Single Nanoparticle Application Module of the ICP-MS MassHunter
software was used for NP data acquisition and analysis. The spICP-MS Method
Wizard guides the user through the process of nanoparticle method setup, dataacquisition, data analysis, and presentation of the NP results data.
Nebulization efficiency
Nebulization efficiency is the ratio of the amount of analyte (aerosol) delivered to theplasma as a proportion of the amount of analyte (solution) entering the nebulizer.
In this work, the nebulization efficiency was determined using the Ag NP referencematerial of known (60 nm) particle size. The reference material was first dispersedin PGMEA, and then further diluted in o-xylene. Nebulization efficiency, calculated
from the certified size of Ag NP reference material, was found to be 0.065 or 6.5%.

Results and discussion
Nanoparticle size distributions
Nanoparticles containing Fe and Mo were detected in the asphaltene samples
using the sp-ICP-MS method. By contrast, the signals for V and Ni were
continuous, rather than the discrete signal pulses caused by the presence ofclusters or particles of these elements. This finding indicates that V and Ni weremost likely in the form of dissolved metal complexes. The TRA signal charts for Fe
in sample B (Figure 1) and Mo in sample A (Figure 2) show the signal-intensity as
a function of time. In spICP-MS, the peak area for each particle signal “plume” canbe used to calculate the particle mass and therefore size.
According to the literature, the Fe NPs are most likely to be present as iron oxides(Fe2O3 or Fe3O4) (7) and pyrrhotite (FeS) (8). The Mo NPs are most likely present asmolybdenite (MoS2) (9), which is readily formed from oil-soluble Mo complexes
present in heavy fractions from crude oils (10, 11).
x107

CPS

1

0.5

0
20.0

40.0
Time (sec)Figure 1. Asphaltene sample B: typical signals in counts per second (cps) for Fe (m/z 56)
as a function of time.

CPS

x106

1

0
20.0

40.0
Time (sec)354

Figure 2. Asphaltene sample A: typical signals in counts per second (cps) for Mo (m/z 95)
as a function of time.

The Fe and Mo NP size distribution plots for the three different asphaltene
samples were calculated on the assumption that the Fe NPs were composed of
Fe2O3, and the Mo NPs were composed of MoS2. As shown in Figure 3, theaverage size of the Fe NPs varied among the samples. In contrast, the particle
size distributions for Mo NPs are similar, with an average particle diameter in therange 70 to 80 nm (Figure 4).

Normalized Frequency

100

A

100

50

B

100

50

0

50

0
200

400

C

0

600

200

400

600

200

400

600

Particle size (nm)Figure 3. Comparison of size distributions for Fe NPs as Fe2O3 in the three asphaltene samples:
A, B, and C. Modified with permission from J. Nelson et al., Energy Fuels, 2017, 31 (11), 11971–
11976. © 2017 American Chemical Society.

Normalized Frequency

100

A

100

50

B

100

50

0

50

0
100

200

C

0
100

200

100

200

Particle size (nm)Figure 4. Comparison of size distributions for Mo NPs as MoS 2 in the three asphaltene samples:
A, B, and C. Modified with permission from J. Nelson et al., Energy Fuels, 2017, 31 (11), 11971–
11976. © 2017 American Chemical Society.

Concentration of the different forms of Fe and Mo
Uniquely, spICP-MS can distinguish between metal content that is containedin NPs (insoluble) and metal content that is dissolved in the sample matrix.
The relative NP and soluble concentration data for Fe and Mo in the threeasphaltene samples is given in Table 2. The data indicates that there was somevariation in the distribution of metals among the asphaltene samples. In samples
A and B, Fe was mostly present as NPs (76 and 91 wt. %, respectively), while inasphaltene sample C, less than half the Fe content was present as NPs.
By contrast, Mo was almost all present as soluble forms (between 60 and 99 wt.
%) in all three asphaltene samples, as shown in Table 2.
Table 2. Interference check results for 48Ti in various matrices, with and without cell gas.
Asphaltene
samples

Iron concentration, mg/kg

Molybdenum concentration, mg/kg

NPs

SolubleTotal,
spICP-MSTotal, direct
dilution

Total, wet aciddigestion

NPs

SolubleTotal,
spICP-MSTotal, direct
dilution

Total, wet aciddigestion

A

54.0 (76%)

17.0

71.0

39.5

68.0

3.48

5.33 (60%)

8.81

39.7

40.4

B

173 (91%)

0.001

0.18

0.054

0.001

0.04

3.23 (99%)

3.27

0.78

0.52

C

457 (47%)

508

965

420

750

0.07

6.33 (99%)

6.40

5.89

6.22

Reprinted with permission from J. Nelson et al., Energy Fuels, 2017, 31 (11), 11971–11976. © 2017 American Chemical Society.

355

Total concentration of Fe and Mo
The total concentrations of Fe and Mo from the spICP-MS analysis (sum of theparticle concentration and the dissolved concentration) were compared to thetotal metal concentrations measured by direct dilution and wet acid digestion.
The results, which are given in Table 2, indicate that there was some variation
between the three separate results for total concentrations of Fe and Mo.
The spICP-MS and acid digestion approaches gave similar results for total Fe
in all three samples, with the direct dilution results being consistently lower.
This low bias for Fe present as particles in samples prepared and introduced
using direct dilution has been reported in the literature (12). A study using Laser
Ablation-ICP-MS (13) has also shown that large particles are not completely
vaporized and ionized in the plasma. This finding could account for the low
recovery observed for Fe in the direct analysis of the diluted samples.
The difference compared to the spICP-MS total concentration may be due to theway the relatively large particles in these asphaltene samples are calibrated in
spICP-MS vs the effect of incomplete dissociation and ionization of these larger
particles measured by direct dilution.
The concentrations for Mo following direct dilution compare well with thoseobtained using wet acid digestion. For sample C, the total concentration foundusing spICP-MS also agrees well. But for the other two samples, the spICP-MS
results do not tally with the total Mo concentrations found by the dilution anddigestion methods. Total Mo by spICP-MS was found to be lower in Sample A
and higher in Sample B, compared to total Mo determined by the other two
approaches. Further studies are underway to investigate the discrepancies in the
total concentration values for Mo calculated using the spICP-MS method
compared with direct dilution and wet acid digestion.

Conclusion
Single particle-ICP-MS is becoming a widely used and well-establishedtechnique for the characterization of NPs in aqueous-based solutions. In thisstudy, we show the potential for the spICP-MS methodology to be applied tocomplex hydrocarbon-based matrices of interest in petroleum refining andother industries.
The Agilent 8900 ICP-QQQ is especially suited to spICP-MS analysis because of
its high sensitivity, low background, and unmatched control of spectralinterferences. Setup and analysis for NP applications is facilitated by the optional
Single Nanoparticle Application Module for ICP-MS MassHunter software.
Iron and molybdenum NPs were determined in three asphaltene samples fromdifferent sources associated with oil refining and petroleum-related productprocessing. No nickel or vanadium-containing NPs were detected in the heavy
petroleum fractions suggesting that these elements are more likely to form
dissolved organometallic complexes, such as porphyrins. This spICP-MS method
is also able to differentiate between metal-containing NPs and dissolved metals.
Further work is in progress to expand the spICP-MS method for the routine
characterization of metals in petroleum-derived samples, as well as in otherhydrocarbon-based samples.

356

References
1.	S. Sannac, Single particle analysis of nanomaterials using the Agilent 7900
ICP-MS, Agilent publication, 2014, 5991-4401EN
2.	S. Wilbur, M. Yamanaka and S. Sannac, Characterization of nanoparticles inaqueous samples by ICP- MS, Agilent publication, 2015, 5991-5516EN
3.	M. Yamanaka, K. Yamanaka, T. Itagaki, S. Wilbur, Automated, high sensitivity
analysis of single nanoparticle using the Agilent 7900 ICP-MS with Single
Nanoparticle Application Module, Agilent publication, 2015, 5991-5891EN
4.	S. Nunez, H. Goenaga Infante, M. Yamanaka and T. Itagaki, Analysis of 10 nm
gold nanoparticles using the high sensitivity of the Agilent 8900 ICP-QQQ,
Agilent publication, 2016, 5991-6944EN
5.	M. Yamanaka and S. Wilbur, Accurate Determination of TiO2 Nanoparticles inComplex Matrices using the Agilent 8900 ICP-QQQ, Agilent publication, 2017,5991-8358EN
6.	J. Nelson, M. Yamanaka, F. A Lopez-Linares, L. Poirier, and E. Rogel,
Characterization of dissolved metals and metallic nanoparticles in asphaltene
solutions by Single Particle ICP-MS, Energy Fuels, 2017, 31 (11), pp 11971–
11976
7.	L. Carbognani, Effects of iron compounds on the retention of oil polarhydrocarbons over solid sorbents, Petroleum Science and Technology, 2000,
18, 335–360.
8.	W. R. Biggs, R. J. Brown, J. Fetzer, Elemental profiles of hydrocarbon materials
by size-exclusion chromatography/inductively coupled plasma atomic
emission spectrometry, Energy & Fuels, 1987, 1, 257–262.
9.	F. L. Hess, Molybdenum Deposits. A Short Review, United States Geological
Survey, Bulletin 761, p. 2, Government Printing Office, Washington 1924.
10.	I. Watanabe, Y. Korai, I. Mochida, M. Otake, M. Yoshimoto, K. Sakanishi
Behaviors of oil-soluble molybdenum complexes to form very fine MoS2
particles in vacuum residue, Fuel, 2002, 81, 1515–1520.
11.	I. Aydin, F. Aydin, C. Hamamci, Molybdenum speciation in asphaltite bottomash (Seguruk, SE Anatolia, Turkey), Fuel, 2012, 95, 481–485.
12.	L. Poirier, J. Nelson, G. Gilleland, S. Wall, L. Berhane, F. Lopez-Linares,
Comparison of Preparation Methods for the Determination of Metals in
Petroleum Fractions (1000 °F+) by Microwave Plasma Atomic Emission
Spectroscopy, Energy & Fuels, 2017, 31, 7809−7815.
13.	M. Guillong, D. Günther, Effect of particle size distribution on ICP-induced
elemental fractionation in laser ablation-inductively coupled plasma-mass
spectrometry, J. Anal. At. Spectrom., 2002, 17, 831–837.

357

> Return to table of contents> Search entire document

Gas chromatographic separation of metal carbonyls
in carbon monoxide with detection using theAgilent 8800 ICP-QQQ
Authors

Introduction

William M. Geiger, Blake McElmurryand Jesus Anguiano

Carbon monoxide (CO) gas is used in a number of industries and applications.
For example, the semiconductor industry uses it to moderate the etch rateof silicon wafers and improve selectivity for greater control of the process.
In pharmacology, CO has been used therapeutically to mitigate organ rejection
in transplant patients. It can also be a major constituent in cogeneration gas orsyngas. However, CO can form a metal carbonyl on contact with various
metals including chromium, molybdenum, iron, nickel, cobalt, and several more.
Iron carbonyl [Fe(CO)5] and nickel carbonyl [Ni(CO)4] are the most common
examples [1].

CONSCI, Ltd., Pasadena, Texas, USA

Metal carbonyls are highly toxic and the therapeutic use of carbon monoxide
can lead to exposure to carbonyls that may be more harmful than the CO itself.
In the etching process, if a metallic carbonyl residue forms on the surface of thewafer, it can cause electronic device failure. Similarly, if CO is present at highlevels in syngas, the deposition of carbonyls on gas turbine fan blades may leadto the catastrophic failure of the turbine. Because of the potential harm caused bymetal carbonyls, it is important that the concentration of metal carbonyls in CO
used in mixed gases is known or controlled before the gas is used.
Gas chromatography with electron capture detection (ECD) can be used forthe analysis of nickel and iron carbonyl, with excellent sensitivity [2]. However,
the method requires a laborious and complicated calibration strategy that canlead to poor accuracy due to errors introduced during sample handling andanalysis. A novel approach using a GC coupled to a triple quadrupole ICP-MS(ICP-QQQ) operating in MS/MS mode offers an efficient and elegant alternative
approach for the analysis of Ni, Fe and other metal carbonyls.
There are several challenges that need to be addressed for GC-ICP-QQQ analysis
to be successful. Since metal carbonyl gas standards are not readily available,
a calibration strategy must be developed. As both nickel and iron carbonyls caneasily form or deposit on steel surfaces in a carbon monoxide matrix, achromatographic system without metal in the flow path must be used to avoid
erroneous measurements. Finally, for optimum performance, two tune conditions
are required for the ICP-QQQ as the best performance for nickel is achieved using
helium gas in the ORS collision/reaction cell, while performance for iron issuperior with hydrogen cell gas.

358

Experimental
Instrumentation
An Agilent 7890B Gas Chromatograph was coupled to an Agilent 8800 Triple
Quadrupole ICP-MS, using a combined gas/liquid introduction interface, as
illustrated in Figure 1.
All sample wetted parts were composed of PEEK, including tubing, samplinglines, and a Valco 10 port gas sampling valve (GSV). The GSV was used to
introduce two gas volumes to the GC column (Figure 2). A sample loop of 280 µL
was used for the introduction of the calibration standard or carbon monoxide
sample, and a standard addition loop of 70 µL was used as an internal
calibration/check standard.
The combination GC-ICP-QQQ interface (with both GC effluent connection andconventional nebulizer/spray chamber) enabled the liquid standard solution or
blank (introduced via the nebulizer) to be mixed with the gaseous effluent fromthe GC, before being passed to the plasma torch [3]. GC operating conditions are
given in Table 1.
Table 1. Agilent 7890 GC conditions
Carrier

Helium @ 13 psig

Column

30 m x 0.53 mm x 1.5 µm DB-5Oven

40 °C Isothermal

Sample size

280 µL

Figure 1. GC-ICP-QQQ interface for the simultaneous aspiration of liquid standard or blank and
GC effluent

InjectLoad
Carrier

ColumnCarrier

Std
Loop

Std
Loop
Sx Loop

ColumnLoop

Figure 2. Valco 10 port PEEK gas sampling valve (GSV) flow path providing standard addition
capability.
359

Acquisition conditions
In this study, the 8800 ICP-QQQ was operated in MS/MS mode using helium as
the collision gas for the on-mass measurement of Ni at m/z 58 (integration time
0.1 seconds/mass). Hydrogen cell gas mode was used for the on-massmeasurement of Fe at m/z 56 (integration time 0.5 seconds/mass). Tuning
conditions were almost identical for the two modes, the only differences were in
the KED voltage and the cell gas flow. Bromine was determined in He mode atm/z 79 (integration time 0.1 seconds/mass).
Table 2. Agilent 8800 ICP-QQQ operating conditions
He modeH2 modeRF power (W)1550

Sample depth (mm)8.0

Dilution gas flow (L/min)

0.2

Extract 1 (V)0.0

Extract 2 (V)-165.0-160.0Kinetic Energy Discrimination (V)

3.0

0.0

Cell gas flow (mL/min)

3.30

7.00

Ni, Br: 0.1

Fe: 0.5

Integration time/mass (seconds)

Calibration
Calibration was performed by the aspiration of aqueous standards (Inorganic
Ventures, Christiansburg, Virginia, USA, standard IV-ICPMS-71A) of nickel(0.17 μmoles/L), iron (0.18 μmoles/L), and a bromine standard (12.8 μmoles/L).
This allowed the relative response of Ni and Fe to Br to be determined, as
illustrated for Ni in Figure 3. In order to determine nickel or iron carbonyl
concentrations, a gas standard of methyl bromide (101 ppb) was introduced to
the GC via the GSV. Relative response factors were used to quantitate for the
unknowns as illustrated in Figure 4 [4]. The methyl bromide gas phase standard
was prepared at 101 ppb by dynamically diluting a higher level standard (certified
as 9.90 ppm NIST traceable, sourced from United Specialty Gases, Houston,
Texas, USA).
Ni signal = 38,816(0.17 µmoles/L)
Counts/µmole = 228,329
101 ppb Methyl Bromide(Peak area 18874)

Br signal = 99,852(12.8 µmoles/L)
Counts/µmole = 7801

Figure 3. Calculation of relative response factor(RRF) for Ni, from aspiration of aqueous nickel
and bromine standards
carbonyl.
360

CO matrix

Unknown Ni(CO)4(Peak area 16711)

DL ~ 80 ppt

Figure 4. Analysis of known gas phase bromine
standard as a surrogate standard for thedetermination of unknown nickel carbonyl.

The ICP-MS MassHunter software allows multiple tune conditions to be appliedin series during a single time resolved analysis (TRA) acquisition. Mode switchingallows the acquisition mass and cell mode to be changed mid-run, so nickel andiron can be measured under optimum conditions (using helium and hydrogen cellgas, respectively), in the same analytical run. As there is a reasonable interval
between the elution of nickel carbonyl and iron carbonyl, there is sufficient time
for switching tune conditions so that both elements can be measured from asingle injection. Since two tune modes were used in the analysis (He mode for Ni
and Br, and H2 mode for Fe) there was a virtual gain in sensitivity when switchingmode since only one mass was monitored at a time allowing for better signal
averaging. This is illustrated in Figure 5.

Figure 5. Tune mode switching for optimum measurement conditions during TRA acquisition.

Limits of Detection
The detection limit (DL) for nickel carbonyl was estimated to be 80 ppt based on
2x signal-to-noise (S/N). Since the iron carbonyl peak is broader, the integration
time was increased from 0.1 to 0.5 seconds/mass in the second tune so that the
S/N ratio was improved. For comparison purposes, two different methods wereused to establish the DL for iron carbonyl. A simple 2 x S/N calculation gave a DLof ~70 ppt. Applying a t-test to eight replicate analyses resulted in a morestatistically valid value of 140 ppt. The nickel DL was improved at least twofold
using He gas mode compared to no gas. Similarly, the DL for iron was improved
about three fold using hydrogen versus helium as the cell gas.
An important matter in achieving very low detection limits, particularly for ironcarbonyl, is the cleanliness of the blank solution. Figure 6 shows the signal plot
for a suspect blank compared to a five level calibration. Note that the suspectblank is over 2 ppb on a weight basis, which would raise the noise level andtherefore the detection limit for the gas phase analysis.

361

Figure 6. Aqueous standards (top) versus contaminated blank (bottom)

Conclusions
The Agilent 8800 ICP-QQQ’s ability to use multiple tune conditions in a single
chromatographic analysis makes it possible to use optimum acquisition settingsfor each analyte. This enables the GC-ICP-QQQ to achieve excellent detection
limits for nickel carbonyl and iron carbonyl, two of the most analyticallychallenging contaminants in carbon monoxide. The detection levels of 70-80 ppt
are comparable to GC-ECD detection and are well below what is currently
required by the various industries. However, the multi-element capability of
ICP-QQQ ensures that other metal carbonyls can also be successfully measured
with this method, including Co2(CO)8, Cr(CO)6, Mo(CO)6, and Fe2(CO)9.
The GC was interfaced to the ICP-QQQ via a second inlet connection to thestandard ICP spray chamber, to allow simultaneous aspiration of an aqueous
standard. This approach is essential to performing quantitative measurementsof carbonyl species, for which gas phase standards are not typically available.
The simultaneous aspiration of an aqueous standard also provides sufficient
oxygen to prevent carbon buildup on the torch or cones from the carbon
monoxide, avoiding the need to add additional oxygen.

References

362

1.

D.H. Stedman, D.A. Hikade, R. Pearson, Jr., E.D. Yalvac, Science,
1980, 208, 1029

2.

A. Harper, Analyst, 1991, 149-151

3.

E.M. Krupp, et. al., Spectrochimica Acta Part 56, 2001, 1233-1240

4.

W.M. Geiger, M.W. Raynor, D. Cowles, Trace Analysis of Specialty andElectronic Gases, 2013, Wiley, Chapter 6, 182-185.

> Return to table of contents> Search entire document

Geology and geochemistry
Title

Page

Lead isotope analysis: removal of 204Hg isobaric interference on 204Pb using
ICP-QQQ MS/MS reaction cell

364

Fractionation of sulfur isotope ratio analysis in environmental waters

368

Measurement of 87Sr/86Sr isotope ratios in rocks by ICP-QQQ in
mass-shift mode

372

Direct strontium isotopic analysis of solid samples by LA-ICP-MS/MS

378

Resolution of 176Yb and 176Lu interferences on 176Hf to enable accurate
176
Hf/177Hf isotope ratio analysis using an Agilent 8800 ICP-QQQ with
MS/MS

382

363

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Lead Isotope Analysis: Removal of 204Hg Isobaric
Interference on 204Pb using ICP-QQQ MS/MS
Reaction Cell
AuthorIntroduction

Glenn Woods
Agilent Technologies, UK

Lead isotope ratio analysis is important as it is used for Pb-Pb dating in
geochronology, and to trace the origin of artifacts, precious metals and evenfoodstuffs. The natural isotopic pattern of lead varies more than any otherelement in the periodic table, because three of its isotopes are formed from theradioactive decay of uranium (235U  207Pb; 238U  206Pb) and thorium (232Th
208Pb). The Pb isotopic pattern can therefore vary depending upon the geologyof the rocks and minerals from which the lead was extracted, and the age of thematerial. In geochronology, the constant rate of U/Th decay allows the Pb/Pb,
U/Pb and Th/Pb ratios to be used to date the age of rocks using a so-called
geological clock.

Keywords
lead, isotope, ratio, geochronology,
dating, mercury, artifacts, precious
metals, food, ammonia, on-mass

When Pb ratios are measured, it is often necessary to correct for the leadnaturally present in the sample, and the only non-radiogenic isotope of Pb (204Pb;
natural or common lead), is used for this purpose. For Pb-Pb dating, 204Pb is thereference isotope against which the radiogenic isotopes are compared(206Pb/204Pb; 207Pb/204Pb). Unfortunately, 204Pb is directly overlapped by an isotopeof Hg (204Hg), which makes accurate measurement of 204Pb impossible by
ICP-MS. Mass resolution of 204Pb from 204Hg is far beyond the capability of any
commercial high-resolution (HR-) ICP-MS system, and until recently there has
been no reliable chemical means to remove the Hg interference, so mathematicalcorrection has been employed, which introduces error. Mercury does howeverundergo a gas-phase charge-transfer reaction with ammonia gas (NH3),
a reaction that can be utilized in the collision/reaction cell of a suitably equipped
ICP-MS as follows:
Hg+ + NH3  Hg0 + “NH3+”
This reaction offers the potential to remove the 204Hg interference from 204Pb,
and could be applied to either solution or laser-based ICP-MS analysis.

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/General purpose.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -170 V.
CRC conditions: NH3 gas (10% in He) at 1.7 mL/min, Octopole bias = -8 V,
KED = -8 V.

364

Acquisition parameters: Three acquisition modes were compared:– No gas: No reaction cell gas; Single Quad (SQ) mode with Q1 operating as
an ion guide.
– NH3 bandpass: Ammonia reaction gas; SQ mode with Q1 operating as a
bandpass filter.
– NH3 MS/MS: Ammonia reaction gas; MS/MS mode with Q1 operating as amass filter at unit mass resolution.

Results and discussion
Removal of 204Hg+ interference on 204Pb+
A preliminary study showed that Pb is almost unreactive with NH3 cell gas(<0.5% loss of Pb signal) indicating that on-mass sensitivity for Pb should bemaintained. On-mass measurement of Pb in NH3 cell gas mode was therefore
investigated in the presence of Hg at 10 ppb. Figure 1 displays the spectra
obtained in no gas (left) and NH3 cell gas (right) modes. The 204Hg interference
on 204Pb can be clearly seen in the no gas spectrum, while it has been completely
removed under NH3 reaction mode with MS/MS. A perfect isotopic patternmatch was confirmed for Pb in NH3 mode.
No gas mode

NH 3 mode

x105

x105

3

3

Hg overlap on 204Pb

Pb, 206Pb, 207Pb and 208Pb

204

204

2
Signal – cps

Signal – cps

2

1

190

195

200
Q2

205

210

TI and 205TI

203

1

190

195

200

205

210

Q2

Figure 1. Standard solution (1 ppb each of Pb and Tl) spiked with 10 ppb Hg without cell gas (left) and with NH3 (right) using MS/MS mode.
Note the 204Hg interference on 204Pb in no gas mode.

365

Effectiveness of MS/MSThe NH3 reaction that removes the 204Hg interference would also work in thereaction cell of a single quadrupole ICP‑MS (ICP-QMS), but ammonia is a highly
reactive gas and can produce many adduct cluster ions, for example from Rare
Earth Elements (REEs), see Table 1. The complex matrix composition of many
natural samples means that the results obtained with NH3 cell gas in ICP-QMS
are often extremely unreliable. With the 8800 ICP-QQQ, MS/MS mode allows all
the co-existing matrix elements to be rejected by Q1, so only the target ions
(204Pb and 204Hg) enter the CRC. The NH3 reactions are therefore controlled andconsistent, and no overlapping reaction product ions are formed from otherelements in the sample.
Table 1. Some possible Rare Earth Element cluster ions that can formin the CRC of an ICP-QMS when using NH3 reaction gas – the list is by
no means exhaustive.
Mass

Potential Cluster Ions of REE

204

Eu(NH3)3; Yb(NH3)2; Ce(NH3)4205

Yb(NH3)2; Gd(NH3)3

206

Yb(NH3)2; Lu(NH2)2; La(NH3)4 ; Ce(NH3)4; Gd(NH3)3207

La(NH3)4; Yb(NH3)2; Gd(NH3)3

208

Ce(NH3)4; GdNH(NH3)2; TbNH(NH3)2; Yb(NH3)2; Gd(NH3)3

To check the formation of cluster ions, the ICP-QQQ was operated with NH3 cell
gas; “Single Quad bandpass” and MS/MS modes were compared for themeasurement of a 50 ppb REE mix. Figures 2a and 2b display the spectra
obtained using bandpass and MS/MS conditions, respectively.
Single Quad (Q1 as bandpass ﬁlter)

3.0E+05

2.5E+05

2.5E+05

2.0E+05

2.0E+05
Signal – cps

Signal – cps

3.0E+05

1.5E+05

1.5E+05

1.0E+05

1.0E+05

5.0E+04

5.0E+04

0.0E+00
190

195

200
Q2

205

210

MS/MS (Q1 as 1 u mass ﬁlter)

0.0E+00
190

195

200

205

210

Q2

Figure 2. Cluster ion formation for 50 ppb REE standard in ammonia mode. Figure 2a (left): REE cluster ion formation using ammonia cell gas inbandpass mode; REE’s are allowed into the cell if Q1 is operated as a bandpass filter. The REE cluster ions can be seen at all masses including thosefor Hg, Tl, Pb and Bi. Figure 2b (right): The identical sample under the same ammonia conditions but this time with Q1 operated at unit mass resolution(MS/MS mode). The REE’s are removed from the ion beam before they can enter the cell and form reaction by-products.

366

204

Pb/208Pb isotope ratio analysis in presence of Hg

To check the effectiveness of the 204Hg removal, the 204Pb/208Pb ratio wasmeasured in a 1 ppb lead solution spiked with increasing Hg concentration.
Table 2 displays the measured Pb ratio results (without any mass bias
correction), showing that the Pb isotope ratio remained constant, regardlessof the Hg content.
Table 2. Uncorrected isotopic ratios measured in 1 ppb Pb solutions containing mercury at varying
concentrations. The lead isotopic ratio 204/208 is not influenced by the presence of Hg.
204

Pb

Sample208

Pb

IR (204/208)

CPS

TheoreticalNANA

0.02671Pb

3518.5136124.8

0.02585

Pb Hg 5 ppb

3510.0139585.9

0.02515

Pb Hg 10 ppb

3439.2132796.4

0.02590Pb Hg 20 ppb

3464.8134417.7

0.02578

Conclusion
With the successful removal of the 204Hg interference on the natural 204Pb isotope,
ICP-QQQ displays great promise for Pb/Pb and U/Pb dating and for otherapplications where accurate measurement of 204Pb is required.

367

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Fractionation of Sulfur Isotope Ratio Analysis in
Environmental Waters
AuthorIntroduction

Naoki Sugiyama
Agilent Technologies, Japan

Sulfur isotope ratio (IR) data is a useful indicator in geochemical and biochemical
studies [1]. In stable sulfur isotope analysis, the variation in the 34S/32S IR is
calculated and reported as a deviation or delta (δ) in 34S abundance relative to a
standard material, the troilite (iron sulfide) mineral from the Canyon Diablo
meteorite. This standard is referred to as δVCDT (Vienna Canyon Diablo Troilite).
Natural variations in 34S abundance, expressed in parts per thousand or “per mil”(‰), can be of the order of -50‰ to +40‰ (and occasionally much greater),due to redox reaction [2]. In this study, triple quadrupole ICP-MS (ICP-QQQ) wasinvestigated as a fast and simple technique for S IR analysis. ICP-QQQ is atandem ICP-MS that can resolve spectral interferences using reaction cell
technologies. Using the method described in this paper, ICP-QQQ can measure S
at a low concentration (background equivalent concentration < 0.2 ppb in UPW)
with high sensitivity (32S > 10000 cps/ppb).

Keywords
sulfur, sulfur isotope ratio, isotope ratio
analysis, fractionation, mass-shift

Experimental
Instrumentation: Agilent 8900 Advanced Applications configuration ICP-QQQ
with PFA nebulizer. Self-aspiration mode was used for better precision.
Tuning: O2 mass-shift method. Tuning conditions are summarized in Table 1.
Method: the following procedures were used for the accurate determination of
sulfur IRs:
– Matrix matching: all samples were diluted by the matrix blank, whichcontained 50 ppm Ca and 100 ppm NaCl in 1% HNO3.
– Concentration matching: each sample was diluted by the matrix blank to~0.5 ppm S concentration. This dilution was done to remove any errors
caused by signal count differences. For example, NASS 5 was diluted 2000
times and mineral water A was diluted 10 times.
– Mass bias correction: to correct mass bias (including mass-bias drift), samplestandard bracketing was applied. IR of 0.5 ppm IAEA-S-1 [3] was measured
before and after the IR analysis of each sample. The average of the IRs for the
standard was used to correct the mass-bias and the drift.

368

Table 1. ICP-QQQ tuning and method parameters.

PlasmaLens

Cell

Tuning parameter

Unit

Value

RF powerW

1550

Sampling depth

mm

8.0

Nebulizer gas flow rate

L/min

0.90

Make-up gas flow rate

L/min

0.30

Extract 1

V-80

Extract 2

V

-150

Omega

V

10.0

Omega bias

V

-120

Octp Bias

V-5.0

Axial Acceleration

V

2.0

KED

V

-8.0

Cell gas

Data acquisition

Rinse

Sample load

OxygenCell gas flow rate

mL/min0.45

Method parameter

Unit

Value

Integration times

1 and 5 for 32S and 34S

Number of sweeps

–

1000

Number of replicates–

10

1% HNO3 rinses20

50 ppm/100 ppm NaCl rinses30

Load times

30

Stabilization time

s

30

369

Results and discussion
Figure 1 shows a spectrum of three sulfur isotopes in a blank and 10 ppb S
standard measured by ICP-QQQ in O2 mass-shift mode. The two spectra show
the low BEC of sulfur in the blank, which allows accurate S IR analysis.

Figure 1. Spectra of S isotopes measured in O2 mass-shift mode. The blank is indicated in blue andthe 10 ppb S standard in grey. The spectra show that the BEC of the blank is < 200 ppt.

Synthetic samples were prepared and analyzed. Two standards, IAEA S-1(34δ = -0.3‰) and IAEA S-2 (34δ = +22.6‰), were mixed to make four synthetic
samples with a theoretical S IR of 34δ = -0.3, 5.4, 11.2 and 22.6 ‰. Each sample
was measured six times, and the average IR and precision (as two times thestandard deviation) were calculated. As shown by the linearity of Figure 2, themeasured 34δ values were in excellent agreement with the theoretical values.
Synthetic samples IR analysis
25
20
Experimental 34δ (‰)

15
10
5
0
-5

0
-5

5

10

15

20

Theoretical 34δ (‰)

Figure 2. Sulfur IR of four synthetic samples.

370

25

The developed method was used to analyze seven samples: sulfuric acid
(Tamapure AA-100); a Japan river water CRM, JSAC0301; a hot spring water,
IKAHO; three mineral waters A, B, and C; and a seawater SRM, NASS-5.
The concentration of S was first determined in each sample. The samples
were then diluted with the matrix blank (50 ppm Ca + 100 ppm NaCl) to~0.5 ppm of S. The IR of each sample was measured 10 times to determine theaverage value and precision (as two times the standard deviation). The results
given in Figure 3 show ±1.2 to ±1.7 ‰ error.
25

Measured 34δ (Error bar shows 2x SD [n = 10])
21.5

20

17.9
13.9

5

5
0

12.9

9

10

34

δ‰

15

-1.2

.5
H2SO4

JSAC0301

IKAHO

Mineralwater A

Mineralwater B

Mineralwater CNASS 5Figure 3. Measured δ 34 S of seven samples.

Conclusion
The Agilent 8900 Advanced Applications configuration ICP-QQQ is ideally suited
to 34S/32S isotope ratio analysis. The analysis can provide valuable information forsample characterization in natural systems or to monitor anthropogenic impact.
The 8900 ICP-QQQ provides a low background and high sensitivity for sulfur,
which enabled a method to be developed that required the sample to be diluted
with the matrix blank before analysis. The precision of the IRs achieved was
excellent at 1.2–1.7 ‰ (as two times the standard deviation).

References
1.	J. Ryu, R.A. Zierenberg, R.A. Dahlgren et al., 2006, Chemical Geology 229:
257-2722.
2.	H.G. Thode, Mineral. Soc. Amer. Spec., 1970, Pap. 3: 133–144
3.	National Institute of Standards and Technology certificate sheet for Reference
Material 8554 -IAEA-S-1 (Sulfur Isotopes in Silver Sulfide)

More information
Sulfur isotope fractionation analysis in mineral waters using an Agilent 8900
ICP-QQQ, Agilent publication 5991-7285EN

371

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Measurement of 87Sr/86Sr Isotope Ratios in Rocks by
ICP-QQQ in Mass-Shift Mode
Authors
Xiaoming Liu
Yahui Yue1
Yibo Yang1
Shuofei Dong2
1

Institute of Tibetan Plateau Research,
Chinese Academy of Sciences, Beijing
100085, China
1

Agilent Technologies Co., Ltd. (China),
Beijing 100102, China
2

The direct Agilent 8900 ICP-QQQ method removes need forchromatographic separation of 87Sr and 87Rb
Introduction
Triple quadrupole ICP-MS (ICP-QQQ) instrumentation is increasingly used forisotope ratio (IR) analysis studies (1–5). Geologists use radioactive isotopes thathave long half-lives to date rocks and sediments, often with the choice of dating
method dependent on the type of samples under investigation. For example,
rubidium (Rb) is abundant in many potassium-containing rocks, so the
Rb-strontium (Sr) β-decay scheme is used in geochronology studies of igneous,and sometimes metamorphic rocks and minerals (5, 6).
Strontium (Sr) has four naturally occurring isotopes: 84Sr (0.56% abundance),86
Sr (9.86% abundance), 87Sr (7.00% abundance), and 88Sr (82.58% abundance).
While these are the four stable isotopes of Sr, the abundance of 87Sr varies overlong periods of time due to the formation of radiogenic 87Sr following β-decay of87
Rb. The level of 87Sr compared to 86Sr is dependent on the original concentrationof Rb in the environmental or geological system. Therefore, 87Sr/86Sr IR
measurements can also serve as a tracer of ecosystem processes (7).
Traditional IR measurement techniques such as thermal ionization mass
spectrometry (TIMS) or multicollector inductively coupled plasma mass
spectrometry (MC-ICP-MS) offer excellent accuracy and high precision for mostIR studies. However, they are less efficient for the measurement of β decay
product isotopes, due to isobaric interferences of the daughter isotope by theirrespective parent isotope. For example, 87Sr must be separated from 87Rb before
analysis by TIMS or MC-ICP-MS to avoid the isobaric spectral overlap at mass 87.
This process is labor-intensive and time consuming, especially for large sample
numbers that are typical of geological and environmental survey studies.
By contrast, no Rb/Sr separation is needed before analysis using ICP-MS/MS
methodology, simplifying the analysis and improving sample throughput.
ICP-MS/MS methods use “chemical resolution” to resolve isobaric interferences,as demonstrated in previous studies using Agilent ICP-QQQ instrumentation(1, 5).
In those studies, reactive gases were used in the collision/reaction cell (CRC) of
the ICP-QQQ to separate the isobaric overlap from 87Rb on 87Sr, avoiding the needfor chromatographic separation. Isobaric ion interferences can be separatedusing ICP-QQQ when the cell gas reacts quickly with one of the elements to forma product ion, while the other element does not react (or reacts slowly). Although
reaction cell gases such as CH3F, N2O, and SF6 provide a higher reaction rate with
Sr+ than O2, O2 is more widely available in laboratories and is more suited toroutine applications.

372

The aim of this study was to develop a fast, high throughput, routine method
suitable for the accurate determination of 87Sr/86Sr IR with precision below
0.1% RSD. To achieve the objective, an Agilent 8900 ICP-QQQ was operated in
MS/MS mass-shift mode using O2 as the cell gas.
87

Sr/86Sr IR analysis by ICP-QQQ in O2 mass-shift mode

The Agilent 8900 Triple Quadrupole ICP-MS (ICP-QQQ) uses two identical,
full-sized quadrupoles (Q1 and Q2), one before and one after the ORS4 reaction
cell. Like the analyzer mass filter, Q2, Q1 operates in a high vacuum region, so it
provides excellent resolution and abundance sensitivity. This allows precise
selection of which ions enter the cell, ensuring the reactions used to resolve theanalyte ions from their on-mass interferences are consistent and predictable.
As shown in Figure 1, by setting Q1 to m/z 87, only Rb-87 and Sr-87 enter the cellthat is pressurized with O2. In the cell, 87Sr+ reacts with O2 to form 87Sr16O+ production, while 87Rb+ does not react. The second quadrupole (Q2) is set to m/z=103,
which allows 87Sr16O+ to pass to the detector, free of interference.
Reaction cellgas (O2)

Q1 (m/z 87) –rejects all ions
except m/z 87

ORS 4
Rb+ + O2 no reaction(or very slow)

Q2 (m/z 103) –rejects all ions
except m/z 103

Figure 1. Determination of 87Sr as 87Sr16O+ product ion using ICP-QQQ operating in mass-shift modewith O2 cell gas.

Efficiency of using mass-shift mode to separate Sr from Rb
When Sr+ ions react with O2 in the cell, not all Sr+ ions complete the reaction toform SrO+ ions during the short transit time in the cell. To optimize the O2 flow
rate, counts per second (cps) of both 86Sr+ (at m/z 86) and 86Sr16O+ (atm/z 102) were monitored. For the calculation, the measured cps of Q1 (m/z = 86)
 Q2 (m/z = 102) was divided by the cps of Q1 (m/z = 86)  Q2 (m/z = 86).
The mass-shift efficiency of Sr in O2 reaction mode ranged between the expected
range of 10 and 14% (8). The variation was mainly due to instrument conditions
on the day of measurement.
To evaluate whether 87Rb16O+ formed in the cell sufficiently to affect themeasurement of 87Sr16O+, 85Rb was used as a proxy for 87Rb. The signals at m/z 85(for 85Rb+) and m/z 101 (for 85Rb16O+) were monitored during method
development. First, Q1 and Q2 were both set to m/z = 85. The measured cps of85
Rb+ in the reference materials (RMs) and rock samples were between 6×105 and4×106 (the cps of 85Rb+ in the solution blank was typically below 1). Then Q2 was
set to m/z 101 and the measured cps range was below 1, suggesting minimal
formation of 85Rb16O+ in the cell. Using the natural abundance of 85Rb (72.17%)
and 87Rb (27.83%), we calculated that the conversion of 87Rb+ to 87Rb16O+ would
lead to a measured cps for 87Rb16O+ at m/z = 103 below 0.4 cps.
In this study, the Sr concentration of the RMs and rock samples measured by
ICP-QQQ were mostly around 100 ng/mL. This concentration is equivalent to over1 × 105 cps for 87Sr+ as 87Sr16O+ (m/z = 103). Therefore, the interference effect of87
Rb16O+ (m/z = 103) on 87Sr16O+ (m/z = 103) is negligible in this study.
373

Experimental
Standards and sample preparation
To determine the accuracy and precision of the method, three US Geological
Survey (USGS) RMs were used: Basalt, Columbia River (BCR-2), Basalt, Hawaiian
Volcanic Observatory (BHVO-2), and Andesite (AGV-2). Twenty-three rocksamples were analyzed in the study, including basalt (Rb/Sr concentration ratio
0.02–0.12), dolerite (Rb/Sr concentration ratio 0.04–0.10), andesite (Rb/Sr
concentration ratio 0.76–0.87), and rhyolite (Rb/Sr concentration ratio 5.6–9.1).
All RMs and samples were prepared at the Institute of Tibetan Plateau Research,
Chinese Academy of Sciences (ITP-CAS) using a classic pressurized aciddigestion method for trace element measurements. Approximately 50 mg of eachsample was digested using 1 mL each of purified HNO3 and HF in a closed vessel
oven, heated at 190 °C for 36 hours. Following the addition of 0.25 mL of HClO4,
the sample was evaporated to incipient dryness on a hot plate at 130 °C. This
procedure was repeated with the addition of 0.5 mL of HNO3. The sample wasfurther heated at 170 °C until white fumes were seen. 0.5 mL of 40% HNO3 wasadded, and the sample was oven-heated at 130 °C for 3 h. After cooling, 49.5 mLof de-ionized water was added to the sample, ready for analysis by ICP-QQQ.
Instrumentation
An Agilent 8900 ICP-QQQ was used. The sample introduction system consisted ofa quartz torch with 2.5 mm i.d. injector, a quartz spray chamber, glass concentric
nebulizer, and nickel-tipped interface cones. Samples were introduced into the
ICP-QQQ using a standard peristaltic pump and Agilent SPS 4 autosampler.
Sr and 86Sr were determined in mass-shift mode using O2 as the cell gas.
The isobaric interference on 87Sr by 87Rb was avoided by measuring the Sr
product ions 87Sr16O+ and 86Sr16O+ at m/z=103 and m/z=102, respectively.
Typical instrument operating parameters are listed in Table 1.
87

Throughout the analytical workflow, a BCR-2 RM sample solution containing 100
ng/mL Sr was measured after every two or three samples to ensure that themass bias calibration was up to date. Instrument mass bias occurs when ions ofdifferent element masses transmit through the ICP-MS with different efficiencies,
resulting in inaccurate IR measurements. The Agilent ICP-MS MassHunter
software automatically updates the mass bias.
Table 1. ICP-QQQ operating parameters and acquisition settings for 87Sr/86Sr IR analysis.
Parameter

Setting

RF Power (W)1550

Sampling Depth (mm)8.0

Nebulizer Gas Flow Rate (L/min)

1.15

KED (V)–6.0

Cell Gas Flow Rate (mL/min)
Axial Acceleration (V)1.0

Q1Q2 Masses (m/z)

86 10287 103

Q2 Peak Pattern

1 point

Replicates

7

Sweeps1000

Integration Time of Each Mass (s)3740.45 (30% of full scale)9Results and discussion
Determination of 87Sr/86Sr IRs in the RMs
Sr/86Sr IRs were measured in BCR-2 and BHVO-2 RMs using the ICP-QQQ
mass-shift method with O2 cell gas. To confirm that chromatographic separationof Sr wasn’t needed for successful ICP-QQQ analysis, data was acquired with andwithout the Sr purification stage. Each RM was measured seven times in different
batches or on different days, with seven replicate measurements.
87

The 87Sr/86Sr ratio results in Figure 2 show that there was no significant differencein the results for BCR-2 and BHVO-2 with and without Sr purification. Both sets ofmeasured data are within the literature reported values that were obtained using
TIMS and MC-ICP-MS (9). The ICP-QQQ method is accurate enough to study87
Sr/86Sr ratios in natural samples/systems with a wide range of 87Sr/86Sr
distributions. Also, the sample preparation procedure doesn’t affect the precisionof the ICP-QQQ measurements.
The error bars show two times the standard deviation (SD) of the average of seven
separate measurements of the two RMs, which range between 0.0003 and 0.0005(n=7) or between 0.02 and 0.04% RSD. This deviation is significantly higher than the
RSD of the MC-ICP-MS method. However, the results show that ICP-QQQ candistinguish 87Sr/86Sr ratios of materials within 0.001 (i.e. 0.1%) precision.
0.7060

BCR-2
BCR-2With
withSrSrpurification
purification
BCR-2
BCR-2without
withoutSrSrpurification
purification

0.70550.7050

BHVO-2
BHVO-2withwithSrSrpurification
purification
BHVO-2
BHVO-2without
withoutSrSrpurification
purification
Avg.
Avg.BCR-2
BCR-2With
withSrSrpurification
purification
Avg.
Avg.BCR-2
BCR-2Without
withoutSrSrpurification
purification

87Sr/86Sr ratio

Avg.
Avg.BHVO-2
BHVO-2withwithSrSrpurification
purification

0.7045withoutSrSrpurification
purification
Avg.BHVO-2
BHVO-2without
Avg.

0.70400.70350.70300.7025Figure2. Comparison of the measured 87Sr/86Sr ratios of BCR-2 and BHVO-2 with and without Srpurification column chemistry by ICP-QQQ with literature values (9) represented by the shaded bands.
Circle symbols: average value of each measurement, the error bar is 1SD of the seven replicates ofeach measurement. Square symbols: the average value of the seven measurements of BCR-2 and
BHVO-2, the error bar represents 2SD of the seven measurements.

The effect of the Sr concentration in the samples
To optimize the level of sample dilution of the sample digests, we investigated theeffects of the concentration of Sr in the rock samples on the analysis. Three fully
digested rock samples (andesite, dolerite, and basalt) were diluted to give a Srconcentration between 60 and 350 ng/mL. A BCR-2 solution containing 100 ng/
mL of Sr was used for online instrumental mass bias correction.
The results in Table 2 show that, within the measured concentration range, the Srconcentration doesn’t significantly affect the 87Sr/86Sr ratios of each type ofsample. Therefore, the digested samples could potentially be diluted into a certain
range, such as from 60 to 350 ng/mL, according to a standard operation
procedure, simplifying the analysis.

375

Table 2. Measured 87Sr/86Sr IRs of three different rock samples (one sample of each type of rock)with four different Sr concentrations.
SampleSr Concentration (ng/mL)

BasaltDolerite

Andesite87

Sr/86Sr Ratio

2SD (n=3)700.70360.00091000.70550.0002175

0.70430.0008350

0.70600.0009700.70350.0015100

0.70470.00091700.70390.0016340

0.70460.000860

0.71140.0013100

0.71260.00061400.71200.0015280

0.71260.0014

Analysis of Sr IRs of rock samples by ICP-QQQ
The 23 rock samples were analyzed in triplicate (n=3) using the ICP-QQQ massshift method, without Sr purification. As shown in Figure 3, the samples cover alarge 87Sr/86Sr ratio range from 0.705 to 0.748. This range is typical of common
rocks (Figure 3), as well as minerals, waters, and plants (4).
The accuracy of the 87Sr/86Sr ratio measurements obtained by ICP-QQQ wascompared with data obtained by MC-ICP-MS. There was good agreement
between the two methods (4), with a variation of between 0.00001 and 0.0016 of
the mean of the 87Sr/86Sr ratio. The variation wasn’t dependent on the 87Sr/86Sr
ratio range.
The precision of the 87Sr/86Sr ratio measured by ICP-QQQ varied between 0.0001
and 0.0019 (2SD, n=3) or between 0.01 and 0.13% (RSD, n=3). While this precision
is lower than the precision of the MC-ICP-MS method, it is sufficient for
applications with large 87Sr/86Sr ratio differences, such as the identification of87
Sr/86Sr ratio in between certain rock types. Andesite, rhyolite, and dolerite rocksamples have significant 87Sr/86Sr ratio variations, as shown in Figure 3. However,distinguishing rock types within a narrow range of 87Sr/86Sr ratios, e.g., low87
Sr/86Sr basalts, could be challenging.
ICP-QQQ method
MC-ICP-MS method

BasaltDolerite

Rhyolite
Andesite
0.70000.71000.72000.73000.74000.75000.760087Sr/86Sr ratio

Figure 3. 87Sr/86Sr IR distribution for typical rocks. Triangle symbol: 87Sr/86Sr IR of ICP-QQQ method,
error bar in 2SD (n=3). Circle symbol: 87Sr/86Sr IR of MC-ICP-MS method, error bar in 2SD (n=3) whichfalls within the circle mark.
376

Conclusion
The study has shown that the Agilent 8900 ICP-QQQ can be used for the accurate
measurement of 87Sr/86Sr isotope ratios in a range of rock samples. The isobaric
interference of 87Rb on 87Sr was resolved using a mass-shift method with O2 cellgas. Because Sr reacts with oxygen at a much faster rate than Rb, 87Sr wasmeasured as 87Sr16O+, free from interference from 87Rb. This method is simpler,
faster, and less costly than TIMS or MC-ICP-MS methods, as both TIMS and
MC-ICP-MS require chromatographic separation of Sr from Rb before analysis.
The ICP-QQQ mass-shift method is also suited to nonspecialist laboratories thataren’t equipped with TIMS or MC-ICP-MS.
The distribution of 87Sr/86Sr IRs of natural samples is generally between 0.70 and
0.77, although it can range from 0.700 to 0.943 (4). The accuracy and precision of
the ICP-MS/MS method is sufficient to differentiate between various sources
when the 87Sr/86Sr ratio varies by more than 0.001. Therefore, this method has thepotential to be used in applications that require source identification, such asenvironmental pollutant source tracing, large-scale geological surveys, andagricultural product authenticity studies.

More information
For detailed information, please see Liu, X, Dong, S, Yue, Y, et al. 87Sr/86Sr isotope
ratios in rocks determined by ICP-MS/MS in O2 mode without prior Sr purification.
Rapid Commun Mass Spectrom. 2020, https://doi.org/10.1002/rcm.8690

References
1.

E. Bolea-Fernandez, L. Balcaen, M. Resano, F. Vanhaecke, Tandem ICP-mass
spectrometry for Sr isotopic analysis without prior Rb/Sr separation. J Anal
At Spectrom., 2016, 31, 303-310

2.

Glenn Woods, Resolution of 176Yb and 176Lu interferences on 176Hf to enableaccurate 176Hf/177Hf isotope ratio analysis using an Agilent 8800 ICP-QQQ
with MS/MS, Agilent publication, 5991-6752EN

3.

Glenn Woods, Lead isotope analysis: Removal of 204Hg isobaric interference
from 204Pb using ICP-QQQ in MS/MS mode, Agilent publication, 5991- 5270EN

4.

X. Liu, S. Dong, Y. Yue, et al. 87Sr/86Sr isotope ratios in rocks determined by
ICP-MS/MS in O2 mode without prior Sr purification. Rapid Commun Mass
Spectrom., 2020, accessed May 2020, https://doi.org/10.1002/rcm.8690

5.

T. Zack, K. J. Hogmalm, Laser ablation Rb/Sr dating by online chemical
separation of Rb and Sr in an oxygen-filled reaction cell. Chem Geol. 2016, 437,
120–133

6.

G. Faure, J. L. Powell, Strontium Isotope Geology. Springer-Verlag, New York,
1972

7.

R. C. Capo, B. W. Stewart, O. A. Chadwick, Strontium isotopes as tracers of
ecosystem processes: theory and methods. Geoderma. 1998, 82, 197-225

8.

Naoki Sugiyama and Kazumi Nakano, Reaction data for 70 elements using
O2, NH3 and H2 gases with the Agilent 8800 Triple Quadrupole ICP-MS; Agilent
publication, 5991-4585EN

9.

K.P. Jochum, U. Nohl, K. Herwig, E. Lammel, B. Stoll, A. W. Hofmann,
GeoReM: A new geochemical database for reference materials and isotopic
standards. Geostand Geoanal Res. 2005, 29, 333–338
377

> Return to table of contents> Search entire document

Direct Strontium Isotopic Analysis of Solid Samples
by LA-ICP-MS/MS
Authors

Introduction

Eduardo Bolea-Fernandez, Stijn J. M.
Van Malderen, Lieve Balcaen, andFrank Vanhaecke, Ghent University,
Belgium

Strontium has four stable isotopes: 84Sr (0.56%), 86Sr (9.86%), 87Sr (7.0%), and88
Sr (82.58%). 87Sr is either formed during nucleosynthesis with other stable Sr
isotopes or via beta decay from 87Rb (half-life of 4.88 x 1010 years): 87Rb  87Sr +β- + ῡ. Consequently, a high 87Sr/86Sr ratio is observed in rocks that are
geologically old or which contain a high concentration of Rb (high Rb/Sr ratio).
The 87Sr/86Sr ratio has been widely studied and reported in geological studies [1].

Martín Resano,
University of Zaragoza, Spain

Keywords
isotopic analysis, LA-ICP-MS/MS,
LA-ICP-QQQ, strontium, geology

Measuring the 87Sr/86Sr ratio using mass spectrometry techniques is challenging
because of the isobaric overlap of the signals from 87Rb and 87Sr. Chemical
separation can be used to isolate Sr from Rb before analysis by ICP-MS. However,a simpler method uses triple quadrupole ICP-MS (ICP-QQQ) and chemical reactionin the CRC with a reactive gas. In this study, Laser Ablation coupled to ICP-QQQ(LA-ICP-QQQ) in MS/MS mode with CH3F/He reaction gas was used to resolve the87
Rb interference on 87Sr. This approach allowed the direct Sr isotopic analysis ofsolid samples [2].

Experimental
A preliminary study showed that better precision was obtained using wet plasma
conditions. The experimental setup shown in Figure 1 was used throughout.
De-ionized water was continuously aspirated using a standard nebulizer.
The sample aerosol that was generated by the LA system was carried by heliumgas. Before being delivered to the plasma, the dry aerosol was combined withthe liquid aerosol in the spray chamber, which was chilled to 2 °C.

Laser

MakeupAr gasLA cell

Nebulizer
Ar gasNebulizer

He gasTo ICP
Peristltic pumpSpray chamber

H 2O

Figure 1. Schematic diagram of LA-ICP-QQQ using wet plasma conditions.

378

Instrumentation: An Analyte G2 193 nm ArF*excimer-based LA-unit (Teledyne
CETAC Technologies, USA) equipped with a HELEX 2 ablation cell was coupled toan Agilent 8800 #100. The ICP-QQQ was fitted with a standard sample
introduction system.
Method: Tuning conditions and method parameters are given in Table 1.
Reaction cell method: The CH3F/He (1:9) cell gas was introduced via the
ICP-QQQ’s fourth cell gas mass flow channel (0-1 mL/min as O2). Rb+ ions do
not react with CH3F, whereas Sr+ reacts with CH3F to form SrF+. Thus 86Sr+, 87Sr+,
and 88Sr+ can be measured as the corresponding 86SrF+, 87SrF+ and 88SrF+ reaction
product ions, free from interference.
Mass bias correction: The instrumental mass bias was corrected for using adouble correction approach: internal correction assuming a constant 88Sr/86Sr
isotope ratio (Russell’s law, given below), followed by external correction in asample-standard bracketing (SSB) approach using NIST 612 glass SRM.

f

R87Sr/86Sr sample, corrected = R87Sr/86Sr sample, measured x (m87Sr/m86Sr)
f = ln [R88Sr/86Sr true / R88Sr/86Sr measured] / ln [m88Sr/m86Sr]

Samples: Seven geological reference materials (RMs) were analyzed for theirSr isotopic composition. The RMs were selected to cover a wide range ofmatrix composition, Sr concentration, and Rb/Sr elemental ratio, as summarizedin Table 2.
Table 1. LA-ICP-QQQ tuning conditions.
Laser Ablation
Energy density

J/cm2

3.54

Repetition rate

Hz

40

Scan speed

μm/s

15

Beam size

μm

20-85

He carrier gas flow

L/min

0.42

RF powerW

1550

Sampling depth

mm

3.5

Nebulizer gas flow

L/min

1.0

Make-up gas flow

L/min

0.33

ICP-QQQ

CH3F/He cell gas flow

mL/min0.90

Dwell time per acquisition point

ms

300

Acquisition time per replicates60

Number of replicatesTotal analysis time per sample

12
min

15.55
379

Results and discussion
Removal of 87Rb overlap using MS/MS mass-shift mode with CH3F/He cell gas
Seven RMs were selected to cover a wide range of Rb/Sr ratios. The 87Sr/86Sr ratio
was measured in each RM. For comparison purposes, the analysis was doneusing a no gas on-mass method and the CH3F/He mass-shift method. Figure 2
shows the measured 87Sr/86Sr and 88Sr/86Sr ratios obtained with the two methods
as a function of the Rb/Sr ratio.
With both methods, a constant 88Sr/86Sr ratio was obtained regardless of thesample type. However, the measured 87Sr/86Sr ratio increased in no gas mode,indicating an interference from 87Rb on 87Sr. In contrast, the 87Sr/86Sr ratio measured
in CH3F/He mode remained constant, regardless of the Rb/Sr ratio, showing thatthe method was effective at removing the 87Rb isobaric overlap on 87Sr.

Raw 87Sr/86Sr

Raw 88Sr/86Sr in no gas
Raw 88Sr/86Sr in CH 3F/He

9.5

2.5

9.0

2.0

8.5

1.5

8.0

1.0

7.5

Raw 88Sr/86Sr

Raw 87Sr/86Sr in no gas
Raw 87Sr/86Sr in CH 3F/He

3.0

0
0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Rb/Sr ratio

Figure 2. 87Sr/86Sr and 88Sr/86Sr isotope ratios measured using LA-ICP-QQQ in no gas and CH3F/He
cell gas modes. Reproduced from J. Anal. At. Spectrom., 2016, 31, 464–472 with permission fromthe Royal Society of Chemistry.

Determination of 87Sr/86Sr ratio in seven RMs
The method was used to determine the 87Sr/86Sr ratio in seven RMs. The results
are summarized in Table 2. After mass bias correction, excellent agreement was
obtained between the measured 87Sr/86Sr ratios and the recommended reference
values, even in samples with a high Rb content.
Table 2. 87Sr/86Sr isotope ratio results in seven reference materials.
Referencematerial

Type

Rb/Sr
ratio

Chemical composition of the reference materials (%)
Al2O3

CaO

FeO

K2O

MgO

MnO Na2O

SiO2

87

Experimental

Sr/86Sr ratio
Recommended

Error (%)

USGS BHVO-2G

Basalt

0.02

13.6

11.4

11.3

0.51

7.13

0.17

2.4

49.3

0.70351±0.00034

0.703469 ±0.000007

0.006

USGS NKT-1G

Nephelinite

0.03

10.5

13.4

12.2

1.27

14.2

0.24

3.85

38.9

0.70363±0.00017

0.703509 ±0.000019

0.017

USGS TB-1G

Basalt

0.11

17.12

6.7

8.67

4.52

3.51

0.18

3.56 54.29

0.70576±0.00030

0.705580 ±0.000023

0.026

USGS GSD-1G

Basalt

0.55

13.4

7.2

13.3

3

3.6

3.6

53.2

0.70924±0.00029

0.709416 ±0.000050-0.025USGS BCR-2G

Basalt

0.14

13.4

7.06

12.4

1.74

3.56

3.23

54.4

0.70486±0.00038

0.705003 ±0.000004-0.020MPI-DING T1-G

Diorite

0.28

17.1

7.1

6.44

1.96

3.75 0.127 3.13

58.6

0.70990±0.00035

0.710093 ±0.000017-0.027

MPI-DING ATHO-G Rhyolite

0.67

12.2

1.7

3.27

2.64 0.103 0.106 3.75

75.6

0.70310±0.00026

0.703271 ±0.000015-0.024

0.19

Reproduced from J. Anal. At. Spectrom., 2016, 31, 464–472 with permission from the Royal Society of Chemistry.

380

Conclusion
LA-ICP-QQQ with wet plasma conditions can be used for the direct determinationof the 87Sr/86Sr isotope ratio in geological samples. The isobaric interference from87
Rb on 87Sr was overcome using MS/MS mass-shift mode with CH3F/He cell gas.
The Sr+ ions react in the CRC to form SrF+ reaction product ions, while Rb+ ionsdo not react. 87Sr/86Sr ratios were accurately determined in seven referencematerials, regardless of the matrix composition, Sr concentration, and Rb/Srelemental ratio.

References
1.	R. A. Bentley, J. Archaeol. Meth. Theor., 2006, 13, 135–187.
2.	E. Bolea-Fernandez, S. Van Malderen, L. Balcaen, M. Resano, and F. Vanhaecke,
Laser ablation-tandem ICP-mass spectrometry (LA-ICP-MS/MS) for direct Sr
isotopic analysis of solid samples with high Rb/Sr ratios, J. Anal. At. Spectrom.,
2016, 31, 464–472

381

> Return to table of contents> Search entire document

Resolution of 176Yb and 176Lu interferences on176
Hf to enable accurate 176Hf/177Hf isotope ratio
analysis using ICP-QQQ with MS/MS
AuthorIntroduction

Glenn Woods
Agilent Technologies, UK

Hafnium 176Hf to 177Hf isotope ratio analysis can provide insight into thedifferent geological events and processes that a mineral underwent during its
formation/metamorphosis; 176Hf/177Hf ratios are also used for geochronology
dating studies. Isotope geochronology is a dating technique in which the age ofa rock or mineral is derived from differences in the abundance of two isotopesof an element. Changes in isotopic abundance may be caused by isotopic (mass)fractionation, or by radioactive decay; in each case, the ratio acts as a geologicalclock, allowing the time that the mineral was formed to be estimated. Hf has
lower mobility than lead (Pb) in metamict minerals such as zircon, xenotime,
euxenite etc., so Hf isotope ratios can offer an alternative to Pb/Pb or Pb/U ratios
for dating these minerals.

Keywords
Hafnium, Hf, geology, dating studies,rock dating, isotopic abundance

Of the Hf isotopes of interest, 177Hf is free from direct isobaric overlap from anyother element and does not typically suffer from polyatomic interference fromother co-existing elements. However, the second Hf isotope used in the isotope
ratio calculation, 176Hf, suffers isobaric overlap from 176Lu and 176Yb, as shown in
Figure 1. In order to obtain accurate Hf ratios, it is therefore necessary to separate
the 176Hf signal from the overlapping Lu and Yb signals.

Figure 1. Hf (red peak template) in the presence of Lu and Yb matrix. The poor template fit for 176Hf(highlighted in blue outline) is due to the contribution from 176Lu and 176Yb to the signal at m/z 176.

382

The mass resolution required to separate 176Hf from the Lu and Yb isobaric
interferences (M/ΔM of ~140,000 for 176Lu and >150,000 for 176Yb) is far beyond
the capability of commercial High Resolution Sector Field ICP-MS (SF-ICP-MS),so sample preparation (chemical separation) is required prior to analysis.
In cases where chemical separation cannot be performed, for example in-situ
measurement by Laser Ablation (LA), the Lu/Yb overlaps mean that accurate Hf
isotope ratio analysis is not possible or must rely on mathematical corrections(and the errors they can introduce).
An alternative direct approach is “chemical” resolution within a collision/reaction
cell (CRC), using specific gas phase ion-molecule reaction(s) that will either:– React with the interfering ion to neutralize it or move it to a new mass.
– React with the analyte to create a new product ion at a different,
non-interfered mass.
In this study, the second approach, known as “mass-shift”, was used. Hf reacts
efficiently with ammonia cell gas to form Hf-ammonia cluster ions, while Lu
and Yb are relatively unreactive. However, ammonia will react with the other
Hf isotopes and other co-existing ions present in a typical sample matrix.
These other ions also form ammonia-adduct ions, creating new interferencesthat vary depending on the matrix composition. These ammonia-adduct ionswould interfere with the original Hf isotope pattern, making Hf isotope analysis
unreliable, so control over the reaction process is essential.
The solution to this problem is to use a tandem mass spectrometer, which has
an additional mass filter before the CRC. This extra mass filter prevents all ionsapart from the target mass from entering the CRC, so the reaction chemistry is
precisely controlled and unwanted side-reactions are avoided. This double massfilter approach is only possible with a tandem MS (or MS/MS) configuration,
which provides unprecedented control of the ion/molecule reaction chemistry
used in CRC-ICP-MS methods.
The Agilent 8800 and 8900 Triple Quadrupole ICP-MS (ICP-QQQ) instruments
have an additional quadrupole mass filter (Q1), positioned in front of the CRC,
with the capability of operating at unit mass resolution (MS/MS mode).
In MS/MS operation, only a single mass-to-charge ratio (m/z) is transmitted
through Q1, so the other Hf isotopes and any co-existing elements are rejected
before they can enter the CRC. Unwanted side-reactions and potentiallyoverlapping product ions are therefore eliminated. This method was used tomeasure Hf isotope ratios in a variety of samples containing Lu, Yb and mixed
rare earth elements (REE). For this proof of concept, all work was performed
using solution sample introduction, which allowed a greater flexibility to test
interference removal. However, the same cell gas and MS/MS method can also
be applied successfully to sample analysis using laser ablation (LA-ICP-QQQ).

383

Experimental
Instrumentation
The Agilent 8800* ICP-QQQ was configured with an SPS 4 autosampler andthe standard sample introduction system consisting of a Micromist nebulizer(free aspiration), quartz spray chamber and torch, and Ni interface cones.
Table 1 shows the key instrument parameters used for the analysis.
Table 1. Instrument parameters.
Parameter

Value

RF power

1550 W

Sampling depth

7.0 mmNebulizer gas

1.15 L/min

Spray chamber temp
Ammonia (10% in He) cell gas

2 °C
22% of full scale (~2.2 mL/min)

Octopole bias

-6.0 V

Energy discrimination-8.0 V

Samples and sample preparation
Due to the reactivity of ammonia, its use as a cell gas leads to a complex
population of product ions, even in a simple sample matrix. However, selectionof the most appropriate adduct ion is relatively simple with ICP-QQQ, byperforming a Product Ion Scan. Unique to the MS/MS mode of operation, aProduct Ion Scan uses a fixed mass setting for Q1, combined with a Q2 scanacross the selected mass range. To identify useful 176Hf- ammonia product ions,
Q1 was fixed to mass (m/z) 176 u, and Q2 was scanned across the mass range
from m/z 170 to m/z 260, while aspirating a solution of 5 µg/L Hf. The resulting
mass spectrum can be seen in Figure 2. Initially, the reaction product ion spectra
may appear complex, but it should be noted that the use of a fixed mass settingfor Q1 means that all these ammonia product ions are derived from the 176Hfisotope. The most abundant ammonia adduct ion was Hf(NH)(NH2)(NH3)3+, which
occurs at M + 82 u (m/z 258 for the 176Hf isotope); this adduct was selected as
the preferred mass transition.
It should be noted that the Hf adduct ion used is sensitive to CRC conditions,particularly the acceleration voltage applied from the Octopole Bias.
This parameter was optimized to a lower value than is typically used, in order tofavor the preferred transition and maximize the yield of the desired product ion.
The cell gas flow rate was then re-optimized using the ICP‑MS MassHunter
autotune routines to further improve the product ion signal.

384

Figure 2. Product Ion Scan from m/z 170 to m/z 260 showing ammonia adduct reaction product ionsformed from 176Hf precursor ion (Q1 set to m/z 176).

A graphical representation of the 176Hf transition can be seen in Figure 3; thisschematic illustrates how Q1 (set to m/z 176) eliminates all ions apart from thoseat m/z 176, and Q2 (set to m/z 258) eliminates the unreacted 176Lu and 176Yb
isotopes. The same mass transition is used for the other isotope of interest, 177Hf,using Q1 and Q2 settings of m/z 177 and m/z 259, respectively.
NH3 reaction gas

Lu+
Yb+

176

176

Lu+
Yb+
176
Hf+

176

176

All
other isotopes

Hf+ -> Hf(NH)(NH2)(NH3)3+
Q1 176 u

Q2 258 u

Hf (NH)(NH2)(NH3)3+
passed to detector

Figure 3. Schematic of the 176Hf isotope reaction with ammonia cell gas in MS/MS mode.

To check that the Hf isotope pattern was maintained, a Neutral Gain Scan was
performed where both Q1 and Q2 were scanned together, with a fixed massdifference of +82 u applied to Q2. Figure 4 shows the resultant spectrum,
confirming that the Hf-ammonia product ions match the overlay of the theoretical
Hf isotopic abundances. Note that the higher mass Hf isotopes (178/179/180Hf) are
not of interest in the isotopic analysis and were not measured. This spectrum
demonstrates the unique benefit of MS/MS mode, which ensures that interisotope overlaps cannot occur, as only one Hf isotope mass is present in the cellat any given time.

385

Figure 4. Neutral Gain Scan of the Hf isotopes as Hf(NH)(NH2)(NH3)3+ clusters; theoretical Hf
isotopic abundances are shown in red, confirming that the isotope ratios are preserved in the
product ion spectrum.

To simulate real-world sample analysis, several potential sources of interference
were introduced to assess whether bias or new interferences were created.
The test solutions included:– Hf standard (5 ppb) – also used for Mass Bias Calibration– 100 ppb Yb and 5 ppb Hf– 100 ppb Lu and 5 ppb Hf– 100 ppb Yb + Lu and 5 ppb Hf– Mixed 100 ppb “REE1” standard and 5 ppb Hf– Mineral2 sample with 100 ppb “REE1” and 5 ppb Hf
Hf isotope ratio measurement
In order to provide comparative performance data, the ICP-QQQ was set tomeasure 176/177Hf isotope ratios in three separate acquisition modes:– No cell gas, “Single Quad” mode
“Base” ICP-MS data not utilizing any mechanism to reduce isobaric overlaps– NH3 reaction gas, Single Quad Bandpass mode
Non-MS/MS operation, allowing a limited mass range “window” into the CRC– NH3 reaction gas, MS/MS mode
Q1 operating as a mass filter with unit mass resolution, allowing only a single
m/z into the CRC
Table 2 displays the Hf isotope ratio (IR) data for each of the test solutions ineach instrument mode. It can be seen that there was a large positive deviationfrom the expected ratio (i.e. the 176Hf signal was high relative to its theoreticalabundance) in both of the Single Quad modes of operation (no gas mode andammonia mode with bandpass filtering). This indicates that “Single Quad”
operation did not resolve the Yb and Lu isobars at m/z 176, or stop the formationof new reaction product ion interferences.
1. Agilent Standard 8500-6944 containing La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, plus Sc, Y, Th.
2. Natural mineral sample containing approximately 500 ppm Ca, 120 ppm Mg, 15 ppm Na, 5 ppm K, 1500 ppm SO4386

By contrast, MS/MS mode with NH3 cell gas gave consistent, accurate Hf IR datain all the sample matrices.
To visualize and further investigate the potential overlaps that could have caused
the poor Hf isotope ratio performance in Single Quad mode, a mass scan of themineral sample was performed using Single Quadrupole Bandpass mode with
NH3 reaction gas. The spectrum can be observed in Figure 5. The measured
Hf isotopic pattern (far right of the spectrum) does not match the theoreticalabundance template, showing that the Hf isotopes suffer overlap from newcell-formed cluster ions, due to the lack of control over the reaction processes.
In a complex sample matrix, numerous cell-formed interferences are created,precluding the accurate analysis of many target product ions.

Table 2. 176/177Hf isotope ratio (IR) data measured in samples containing various sources of interferences, using three different ICP-QQQ operating
modes. The “deviation” is the error in the measured ratio relative to the true ratio of 0.282796.
No gas Single Quad

NH3 Single Quad bandpass

NH3 MS/MS

SampleIR

DeviationIR

DeviationIR

Deviation

Hf 5 ppb

0.27981

0.989

0.28252

0.999

0.28196

0.997

Hf 5 ppb, Yb 100 ppb

15.25251

53.9350.30461

1.077

0.28370

1.003

Hf 5 ppb, Lu 100 ppb

3.18739

11.2711.060623.750

0.28051

0.992

Hf 5 ppb, Yb, Lu 100 ppb

18.51262

65.463

1.062673.758

0.280990.994

Hf 5 ppb, REE mix 100 ppb

15.26995

53.996

0.646032.284

0.28139

0.995

Hf 5 ppb, Mineral REE mix 100 ppb

16.16150

57.1490.63479

2.245

0.28230

0.998

Figure 5. Mass spectrum of the mineral sample acquired under Single Quad Bandpass mode using
ammonia as the reaction gas. The poor fit of the measured Hf isotopic pattern (far right) illustrates
the interferences that occur in Single Quad mode. Some examples of cell-formed ammonia cluster
ions are shown.

Many matrix elements and other analytes can react with ammonia to produce
higher order reaction products, so MS/MS mode is essential to remove theseprecursor ions before they enter the cell and form new interferences.

387

The 8800 and 8900 ICP-QQQ use an additional quadrupole mass filter, operating
at unit mass resolution and positioned before the CRC, to control which ionsenter the reaction cell. This ensures unprecedented levels of control over thereaction processes that occur within the cell. MS/MS mode can quickly switch
between on-mass measurement and off-mass measurement within a single
acquisition, supporting multi-element analysis in each gas mode. Figure 6 showsthe Hf isotopes measured using off-mass mode (Q2=Q1 + 82 u) and the othermasses measured on-mass (Q1=Q2). The small, residual peaks for unreacted
Th and U can be seen, along with ThO and UO. Most of the Th and U would havereacted with ammonia cell gas, forming adduct species that are not measured in
MS/MS on-mass mode. Any undesired side reactions are eliminated before they
can proceed, so the underlying analyte isotope ratios are preserved in the production spectrum.

Figure 6. Mass spectrum of the mineral sample measured using NH3 mass-shift mode for Hf andon-mass mode for all other isotopes. The Hf isotopic pattern illustrates that all of the interferencesthat occurred in Single Quad mode (shown in Figure 5) have been resolved.

Conclusion
The MS/MS capabilities of Agilent’s ICP-QQQ measured Hf isotope ratios withexcellent accuracy—even in samples containing high levels of co-existing andpotentially interfering matrix elements.
The isobaric overlaps from 176Lu and 176Yb on 176Hf were eliminated using NH3 as
the reaction gas. The reaction chemistry was controlled in the cell by operating
the first quadrupole mass filter at unit mass resolution set to m/z 176. This
excluded all ions apart from those at m/z 176 (176Lu, 176Yb and 176Hf). Since only
Hf reacts readily with NH3, 176Hf was free to be measured via its most appropriate
cluster ion at m/z 258, effectively avoiding the isobaric overlaps from Lu and Yb.
Together with the corresponding ammonia cluster ion formed from the 177Hf
isotope, this method allowed accurate Hf isotope analysis to be performed in arange of complex synthetic sample matrices.

388

In summary:
Chemical resolution using a reaction gas offers a powerful alternative to mass
resolution, allowing access to isobars beyond the maximum resolution available
with commercial High Resolution SF‑ICP‑MS.
Control over the reaction processes is essential to avoid new, unexpectedinterferences forming from the sample matrix and other coexisting elements andisotopes.
MS/MS technology affords unprecedented control over the reaction processes,
greatly simplifying methodology regardless of the process or sample matrix.
Crucially, MS/MS operation allows access to higher order reaction product(cluster) ions, while still preserving the analyte’s original isotopic information.

389

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Nuclear
Title

390

Page

Analysis of radioactive iodine-129 using MS/MS with O2 reaction mode

391

Feasibility study on the analysis of radioisotopes: Sr-90 and Cs-137

395

Determination of trace 236U as UOO+ using ICP-QQQ O2 mass-shiftmethod398

Measurement of neptunium in the presence of uranium: benefits of low
abundance sensitivity and oxygen reaction mode

401

Direct analysis of zirconium-93 in nuclear site decommissioning samples
by ICP-QQQ

404

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Analysis of Radioactive Iodine-129 Using MS/MS with
Oxygen Reaction Mode
Authors

Introduction

Yasuyuki Shikamori, Kazumi Nakano
and Naoki Sugiyama
Agilent Technologies, Japan

Iodine-129 is a long-lived radionuclide (half-life of 15.7 My) which has beenreleased into the environment as a result of human activities such as nuclear
weapons testing, accidents at nuclear power plants and especially by emissions
from spent nuclear fuel reprocessing plants. The determination of iodine-129 inenvironmental samples is very difficult by ICP-MS due to the element’s relatively
low sensitivity, the very low concentrations at which 129I must be determined,
relative to potentially high levels of 127I, the high background caused by 129Xe
impurities in the argon plasma gas, and possible polyatomic interference from
127
IH2+. Iodine analysis is further complicated by the fact that it is rapidly
volatilized from samples prepared using the acid digestions that are normal for
ICP-MS analysis, so an alternative, alkaline sample solubilization and stabilization
strategy is required. The isobaric interference from 129Xe+ can be significantly
reduced using ICP-QMS with an Octopole Reaction Cell operated in O2 reactionmode, resulting in a measured ratio for 129I/127I of 10-7 in NIST 3231 SRM Level I(1). However, the problem of potential overlap due to tailing from 127I and 127IH
remains, as the relative abundance of the 129I to 127I will typically exceed 10-7,
which is of the same order as the abundance sensitivity (ability to separate
adjacent peaks) of quadrupole ICP-MS (ICP‑QMS). In order to overcome thesechallenges, ICP‑QQQ operating in MS/MS mode with O2 reaction gas was applied
to determine ultratrace levels of iodine-129 in aqueous samples.

Keywords
radionuclide, iodine, 129I, environmental,
nuclear, xenon, NIST 3231 Level I andII, abundance sensitivity, oxygen
on-mass

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/Low matrix.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -190 V.
CRC conditions: O2 gas at 0.8 mL/min,
Octopole bias = -18 V and KED = -1.5V. MS/MS O2 on-mass mode was applied tomeasure iodine-127 and iodine-129 (Q1 = Q2 = 127 for iodine-127; Q1 = Q2 = 129
for iodine-129).
Reference materials and calibration standards: Calibration standards wereprepared by diluting 129I isotopic standards NIST SRM 3231 Level I and II (NIST,
Gaithersburg MD, USA) with 0.5% TMAH in deionized water. The Level I Certified
Value for 129I/127I = 0.981x10-6 ± 0.012x10-6, Level II = 0.982x10-8 ± 0.012x10-8.
These reference materials were used to check the calibration linearity of theiodine isotopes and to validate the isotopic ratio of iodine-129 and iodine-127.

391

Results and discussion
Optimization of oxygen cell gas flow
The oxygen gas flow rate was optimized by varying the O2 flow over the full rangeof the mass flow controller (0–1.12 mL/min), while monitoring the 127,129I signal
and blank intensity, as shown in Figure 1. As the flow rate of O2 increases,
the background signal (due to 129Xe) at m/z = 129 decreases rapidly, and theiodine signal remains high, dramatically improving the DL for 129I.
1.0E+06

100

10
I BEC/ng/L

1.0E+04
1.0E+03

1.0E+02

1

129

Signal intensity/cps

1.0E+05

1.0E+01
1.0E+00

0.1
20

0

40

60

80

100

O 2 gas flow / %m/z 127 10 ppb I Std [cps]m/z 129 Blank [cps]

I BEC [ppt]129

Figure 1. Profile of 127I+, 129Xe + signals and estimated 129I BEC. For the BEC calculation, thesensitivity of 129I was assumed to be the same as 127I. Scale of O2 flow: 100% = 1.12 mL/min.

Abundance sensitivity
Scan spectra over the mass range 127 to 129, covering both 127I and 129I, wereacquired for the two SRMs, NIST 3231 Level I and II, using the Agilent 8800
ICP‑QQQ in MS/MS on-mass mode with O2 reaction gas. The overlaid spectra areshown in Figure 2. Excellent abundance sensitivity can be seen, with the sides of
the intense (>109 cps) 127I peak reaching baseline with no tailing of 127I+ or 127IH+
on 129I+.
1010

MS/MS, O2 reaction (Q1=Q2)

109008SMPL.d

10009SMPL.d

8

I

127 +

107
106
I

129 +

105
104
103

I/127I = 10-6

129

102

I/127I = 10-8

129

10
120

125

130

135

m/z

Figure 2. Iodine spectra showing both 127I and 129I acquired using MS/ MS on-mass mode with
O2 cell gas. 127IH+ remains to some extent while 127IH2+ is completely removed, as noted later.

392

Calibration curves for 127I and 129I
In order to check the linearity of both iodine isotopes, different concentration
solutions of NIST 3231 SRM Level I were prepared in 0.5% TMAH and analyzed
as calibration standards, as shown in Figure 3. The BECs for 127I and 129I were
2.9 µg/L and 0.04 ng/L respectively, and the detection limits (3σ, n=10) were0.26 µg/L for 127I and 0.07 ng/L for 129I.
127 ➝ 127 [MsMs10x]
x109

x103
2

y = 16.6171 * x + 0.6800
R = 0.9998
DL = 0.07039 ng/L
BEC = 0.04092 ng/L

CPS

CPS

2

129 ➝ 129 [MsMs10x]y = 17770162.1269 * x + 52850.4420
R = 0.9998
DL = 0.0002616 mg/L
BEC = 0.002974 mg/L

1

1

0

0
50.0

100.0

50.0

100.0

Conc (ng/L)Conc (mg/L)

Figure 3. Calibration curve for iodine-127 (top) and iodine-129 (bottom) obtained from multiple
dilutions of NIST 3231 SRM.

Analysis of NIST 3231 SRM Level I and Level II
The 129I/127I ratio in 10x diluted NIST 3231 SRM Levels I (129I/127I = 0.981 x 10-6) andII (129I/127I = 0.982 x 10-8) was measured using ICP-QQQ in MS/MS on-mass modewith O2 cell gas. The results are summarized in Table 1. After subtracting the 129I
blank, the measured 129I/127I ratio of NIST 3231 SRM Levels I and II corresponded
well with the certified values of 0.981x10-6 and 0.982x10-8 respectively. The good
agreement with the certified ratio indicates that the potential interference of127
IH2+ on 129I+ is completely removed by O2 reaction with MS/MS mode.
Table 1. Analytical results for NIST 3231 Level I and Level II.
Sample name

Dilution Q1=Q2=127
factorCPSNIST 3231 1010(129I/127I = 0.981 x 10-6)-6

NIST 3231 1010(129I/127I = 0.982 x 10-8)-8

NIST Blank

10

Q1=Q2=129
CPS

129

I/127I129 127
I/ I
RSD(average n = 5) (%)

594,277,896

585.6

0.971 x 10-6

592,633,576

597.4

0.994 x 10-6

590,000,723

586.5

0.980 x 10-6

593,387,443

588.5

0.978 x 10

592,834,056

588.9

0.979 x 10-6

608,737,949

15.1

1.12 x 10-8

608,536,242

14.8

1.07 x 10-8

602,626,536

14.2

0.979 x 10-8

603,091,763

13.9

0.929 x 10-8

603,250,003

14.5

1.03 x 10-8

600,444,851

8.3—

0.981 x 10-6

0.8

1.02 x 10-8

7.2

—

—

-6

393

Reference
1.	The ultratrace determination of iodine 129 in aqueous samples using
the 7700x ICP-MS with oxygen reaction mode, Agilent application note,
5990-8171EN.

More information
The ultratrace determination of iodine 129 using the Agilent 8800 Triple
Quadrupole ICP MS in MS/MS mode, Agilent publication, 5991-0321EN

394

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Feasibility Study on the Analysis of Radioisotopes:
Sr-90 and Cs-137
Authors

Introduction

Yasuyuki Shikamori andKazumi Nakano
Agilent Technologies, Japan

ICP-MS can be an effective analytical tool for the analysis of long half-liferadioisotopes due to its high sensitivity, speed of analysis, low sample
consumption, and ease of sample preparation. The challenge for ICP‑MS analysisof radioisotopes arises from interferences; not only by polyatomic ions but also
atomic isobar ions that cannot be separated even by high-resolution (HR-) ICP-MS.

Keywords
radioisotopes, radioactive,
environmental, nuclear, strontium,
90
Sr, zirconium, cesium, 137Cs, barium,
abundance sensitivity, oxygen andhydrogen on-mass, nitrous oxide
on-mass

Trace analysis of the radionuclide 90Sr (half-life = 28.74 years) in environmental
samples is of great interest. 90Sr is a main fission product that may be present in
the environment following accidental releases from nuclear power plants.
Geiger-Muller (GM) detectors or Liquid Scintillation Counters (LSC) are used tomeasure 90Sr, though both techniques require complex chemical separation prior
to analysis, or long integration times. ICP-MS is also used to measure 90Sr,
especially when a quick turn-around time is desired. However, detection limits ofquadrupole ICP-MS are compromised by a spectral overlap from 90Zr; in common
with all direct isobaric interferences, the 90Zr overlap is too close in mass to the90
Sr to be resolved using sector field HR‑ICP‑MS, which is limited to a maximum
resolution (M/ΔM) of 10,000. This note describes a method for measuring trace
90
Sr in the presence of 90Zr using ICP‑QQQ in MS/MS reaction mode. Since it isn't
possible to obtain 90Sr, a natural isotope of strontium (88Sr) was used to estimate
the DL for 90Sr. A similar approach was applied to 137Cs (half-life = 30.0 years).

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/Low matrix.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -190 V.
CRC and acquisition conditions: The following conditions were used for the
analysis of 90Sr and 137Cs:– For 90Sr: MS/MS on-mass mode (Q1 = Q2 = 90) with O2 + H2 cell gas: 1 mL/minof O2 and 10 mL/min of H2, Octopole bias = -5 V and KED = -13 V.
– For 137Cs: MS/MS on-mass mode (Q1 = Q2 = 137) with N2O cell gas: 7 mL/minof N2O (10% N2O balanced in He, introduced via the 3rd cell gas flow line),
Octopole bias = -5 V and KED = -13 V.

395

Results and discussion
Radioactive Sr-90 (O2 + H2 on-mass mode)
Figure 1 shows spectra of a solution containing Sr and Zr (natural isotopes)
acquired on the 8800 ICP-QQQ operated in Single Quad mode (Q1 operated as anion guide to emulate conventional quadrupole ICP-MS) with no cell gas (left), andin MS/MS mode with O2+ H2 cell gas (right). As can be seen in the left hand
spectrum, the overlap of 90Zr+ on 90Sr+ precludes the low-level determination of90
Sr by conventional quadrupole ICP‑MS. The spectrum on the right indicates that90
Sr+ could be measured on-mass at m/z = 90 free from interference by 90Zr+,
since Zr+ reacts readily with the O2 + H2 gas to form ZrO+ and ZrO2+. The signal-tonoise ratio for 90Sr was improved by six orders of magnitude using MS/MS
O2 + H2 reaction cell mode.
1.0E+09

SQ – No gas

1.0E+09

1.0E+08

1.0E+08

1.0E+07

1.0E+07Sr+

1.0E+06

1.0E+06

Zr

Signal – cps

Signal – cps

MS/MS-O2 + H2+

1.0E+05
1.0E+04

1.0E+05

ZrO+

1.0E+04

1.0E+03

1.0E+03

1.0E+02

1.0E+02

1.0E+01

1.0E+01

1.0E+00

ZrO2+

Sr+

1.0E+00
80

85

90

95

100

105

110

115

120

125

130

80

85

90

Q2

95

100

105

110

115

120

125

130

Q2

Figure 1. Mass spectra of a solution containing 20 ppb Sr + 5 ppm Zr: (left) SQ no gas mode and (right) MS/MS O2 + H2 reaction mode.

Figure 2 is a spectrum of 100 ppm Sr acquired using MS/MS on-mass mode with
O2 + H2 reaction gas. The excellent abundance sensitivity (peak separation) of
MS/MS mode can be confirmed. The peak sides reach the baseline with no tailingfrom the intense peak of the natural isotope of 88Sr+. In addition, no 88SrHH+ at
m/z = 90 is formed in cell, even in a solution containing 100 ppm natural Sr.
1.E+10Sr+

1.E+09Sr

1.E+081.E+07
1.E+06
1.E+05
1.E+04
1.E+03
1.E+02
1.E+01
1.E+00
75

80

85

90

95

Figure 2. Spectrum of 100 ppm Sr solution
acquired using MS/MS O2 + H2 on-mass mode.

396

Radioactive Cs-137 (N2O on-mass mode)
Figure 3 shows spectra of a solution containing Cs and Ba (natural isotopes)
acquired on the 8800 ICP-QQQ operated in Single Quad mode with no gas mode
(left), and in MS/MS mode with N2O cell gas (right). As can be seen in the left
hand spectrum, the 137Ba+ overlap on 137Cs+ is a problem in conventional
quadrupole ICP‑MS. As with 90Sr, the right hand spectrum shows that 137Cs+ could
be measured on mass at m/z = 137, free from the 137Ba+ interference. Ba+ reacts
readily with N2O to form BaO+ and BaOH+ while a part of the Cs+ analyte ion signal
remains at its original mass (as shown by the substantial peak for 133Cs in theright-hand spectrum).
1.E+09

1.E+09Ba+

137

1.E+081.E+07

1.E+081.E+07Cs+

133

1.E+06Signal – cps

Signal – cps

1.E+06
1.E+05
1.E+04

1.E+04

1.E+03

1.E+03

1.E+02

1.E+02

1.E+01

1.E+01

1.E+00130

BaO, BaOH +1.E+05Cs+

133

1.E+00
135

140

145

150

155

160

130

135

140

145

Q2

150

155

160

Q2

Figure 3. Mass spectra of a solution containing 20 ppb Cs + 5 ppm Ba: (left) SQ no gas and (right) MS/MS N2O reaction mode.

Estimated BEC and DL for Sr-90 and Cs-137
The BEC and DL for two radioisotopes, 90Sr and 137Cs, were estimated from these
spectra as summarized in Table 1. This feasibility study demonstrates thepotential of ICP-QQQ for the measurement of radioisotopes such as 90Sr and 137Cs.
Table 1. Estimated BEC and DL for 90Sr and 137Cs.
Radioisotope

BEC (ng/L)

DL (ng/L)

Sr

0.08

0.23

Cs

2.9

15

90

137

397

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Determination of Trace 236U as UOO+ using ICP-QQQ
Oxygen Mass-shift Method
AuthorIntroduction

Naoki Sugiyama
Agilent Technologies, Japan

Uranium-236 is a long-lived radionuclide that is created from the naturally
occurring trace isotope 235U (0.72% abundance) by thermal neutron capture.
This process leads to a natural abundance of 236U in the range from 10-14 to 10-13
relative to the major 238U isotope (236U/238U). 236U is also created during theprocess of uranium enrichment for nuclear fuel or weapons. The 236U/238U ratio
is increased up to 10-3 in spent nuclear fuel, with background levels in theenvironment at around 10-7 to 10-8 as a result of global fallout. The 236U/238U
isotope ratio can therefore be used as a sensitive method to trace the accidental
release of enriched uranium fuel, spent fuel, and nuclear waste.

Keywords
uranium, uranium-236, O2 cell gas,
mass-shift, extended mass range

The challenges for ICP-MS for this application are the interference on 236U+ by the
hydride ion 235UH+, and the contribution at m/z 236 from tailing of the 235U+ and238 +U peaks. The hydride overlap and peak tailing are more problematic in samples
that have been enriched, as these samples contain a higher proportion of 235U.
Uranium was measured via its dioxide ion, UO2+, due to the efficient conversion(almost 100%) of U+ to UO2+ with O2 cell gas.

Experimental
Instrumentation: Agilent 8900 Advanced Applications configuration ICP-QQQ
with PFA nebulizer (p/n G3139-65100).
Plasma tuning: RF power = 1550 W, sampling depth = 8.0 mm, nebulizer gas flowrate = 0.80 L/min, make-up gas flow rate = 0.30 L/min, and peristaltic pump =0.1 rps.
Cell tuning: Octopole bias = 0 V, KED = -10 V, O2 cell gas flow = 0 to 35% of fullscale (0 to 0.53 mL/min).
Sample preparation: Uranium solutions were prepared at suitable concentrations
by diluting SPEX multi element standard XSTC-331 (SPEX CertiPrep, Metuchen,
NJ, USA) with de-ionized water. All samples, blank, and rinse solutions werespiked with high purity TAMAPURE 100 HNO3 (Tama Kagaku, Saitama, Japan) toa concentration of 1%.

398

Results and discussion
UO+ and UOO+ formation as a function of O2 cell gas flow rate
The rate of formation of UO+ and UO2+ was studied as a function of O2 cell gas
flow rate. A solution containing 10 ppb uranium (1000x dilution of XSTC-331)
was introduced into the ICP-QQQ. The signals of 238U+, 238U16O+, and 238U16O16O+
were measured via three mass pairs (Q1Q2) = (238238), (238254), and(238270), and plotted against the O2 cell gas flow rate. The octopole bias
(Octp Bias) voltage was optimized to give the maximum UO2+ signal (0 V).
Figure 1 shows that UO+ formation reaches a maximum at an O2 flow rate of 5%
of full scale (equivalent to 0.074 mL/min as O2). Above 0.075 mL/min flow rate,
the formation of UO+ decreased, while the formation of UO2+ increased, reachinga maximum at an O2 flow of 22% of full scale (0.33 mL/min). This indicates theconversion of UO+ to UO2+ via a chain reaction. The 8900 ICP-QQQ was optimized
for highest sensitivity for the UO2+ product ion.
800000U +, UO+ and UOO+ as a function of O2 flow rate

700000600000500000400000300000200000100000
0
0

10

20

30

40

O 2 cell gas flow rate (% of FS - FS = 1.5mL/min)
238/238

238/254

238/270

Figure 1. U+ (238  238), UO+ (238 254), and UO2+ (238 270) as a function of O2 cell gas flow rate.

Effect of product ion selection on hydride ion formation rate
The hydride ratio was measured at the optimal O2 flow rate for U+ and each of the
U-oxide product ions: 238UH+/238U+, 238UOH+/238UO+, and 238UO2H+/238UO2+.
A sample containing 50 ppb U (200x diluted XSTC- 331) was introduced for themeasurement of the hydride formation ratio. Ten replicate measurements were
made, with integration times of 1 s and 10 s for the analyte and hydride ions
respectively. The results are summarized in Table 1. The data shows thatmeasuring UO+ decreases the hydride ratio by a factor of ~20, while measuring
UO2+ leads to more than a three orders of magnitude improvement, reducing thehydride ratio to 10-8.

399

Uranium detection limit
The detection limit (DL) of U was estimated using the UO2+ method. A blanksolution was introduced and the signal of the mass pairs (236268 and238270) corresponding to 236U+236UO2+ and 238U+238UO2+ were measured
using an integration time of 10 s. The results in Table 2 are based on 10 replicate
measurements. The DL for 236U was calculated from the concentration equivalent
to three times the standard deviation of the background, using the sensitivity of238
UO2+ given in Table 1 and the background for mass pair 236268 in Table 2.
The DL for uranium-236 was calculated to be 0.50 ppq (fg/g).
Table 1. UH+/U+ ratios obtained by measuring uranium as U+, UO +, and UO2+.
O2 cell gas
flow rate (%)

U+ analysis

UH+ analysis

UH+/U+

Mass pairfor U+Counts

RSD

Mass pairfor UH+Counts

RSD

Q1/Q2

cps

%

Q1/Q2

cps

%

as U+

0

238/23824168974

2.8

239/239

1578.5

0.6

6.53E-05

as UO+

5

238/25414152816

4.2

239/255

48.9

4.3

3.46E-06

as UOO+ 22

238/27040527770

2.0

239/271

2.3

20.8

5.68E-08

Table 2. Uranium background noise.
236/268

238/270

CountsRSD

Counts

RSD

cps

%

cps

%

0.15

90.3

0.18

51.1

Conclusion
The Agilent 8900 ICP-QQQ operating in MS/MS mode with O2 cell gas is suitable
for the measurement of U via its reaction product ion UO2+. This approach was
successful in reducing the contribution from the hydride ion (i.e. 235UH overlap on
236
U). The formation of 235UH was decreased by three orders of magnitude
compared to direct, on-mass measurement of U+. MS/MS mode with O2 cell gas
gave a UO2H+/UO2+ ratio in the 10-8 range, without the use of a desolvation
system. The results suggest that the approach could be successful in reducing
the interference of 235UH+ on 236U+, even in samples containing enriched U.

More information
Using ICP-QQQ for UO2+ product ion measurement to reduce uranium hydrideion interference and enable trace 236U isotopic analysis, Agilent publication
5991-6553EN

400

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Measurement of Neptunium in the Presence of
Uranium: Benefits of Low Abundance Sensitivity andOxygen Reaction Mode
AuthorIntroduction

Glenn Woods
Agilent Technologies, UK

Neptunium is present in the environment at ultratrace levels due to natural
neutron capture, nuclear bomb testing, and as a decay product of 241Am. 241Am isused in ionizing smoke detectors, radiography, and a neutron source, among
other uses. By far the greatest quantity of Np is formed during energy production
within uranium fission reactors. The predominant isotope formed is 237Np, withapproximately 50 metric tonnes per annum being produced in nuclear waste.
As the half-life of 237Np is ~2.14 billion years, 237Np in existence today is solely
from the previously mentioned processes rather than remaining from theformation of the earth. However, the relatively long half-life ensures its
persistence. Np will readily form aqueous solutions (more so than any otheractinide element). It also attaches to particles and colloids rather than getting
trapped in humic media (such as soil and peat). These properties mean that Np
is fairly mobile once in the environment. Its high affinity for calcium-rich media
causes it to concentrate within concrete, shells, etc.

Keywords
neptunium, radiochemistry, abundance
sensitivity, oxygen reaction mode

Trace and ultratrace measurement of 237Np is hindered by the presence ofuranium within the sample. The biggest potential interference comes from peakbroadening of the adjacent 238U isotope. This Abundance Sensitivity (AS)interference is difficult to overcome. AS depends on the fundamental design ofthe spectrometer – such as the mass separation process (e.g. quadrupole ormagnets), vacuum system, and electronics. Furthermore, minor but importantpolyatomic interferences from the hydrides of lighter U isotopes; 236U1H, 235U1H2,
235 2
U H, 234U1H2H hinder the measurement of 237Np. Regardless of the interference
source, its affect will vary depending on the concentration of uranium (and its
isotope ratio), potentially causing false and variable measurements.

Experimental
Instrumentation: An Agilent 8900 Advanced Applications configuration ICP-QQQ
was used. The instrument version features Axial Acceleration across the ORS4
collision/reaction cell that gives a higher product ion yield when using reaction
chemistry.
Tuning: Np was measured under two sets of MS/MS conditions: on-mass (using
no gas) and mass-shift (using O2 reaction gas). In the latter mode, 237Np is shiftedaway from the UHx interferences allowing Np to be measured as the product ion
NpO2+, free from interference, at m/z 269.
Calibration: Np was spiked into a 10 mg/L (ppm) U matrix to produce a set ofcalibration standards at 0.0, 0.19, 0.95, 1.9, 19.0, 95.0 ng/L (ppt).

401

Results and discussion
The Single Quad mass scan in Figure 1 shows the problem associated with AS
when the U concentration is relatively high. As can be seen, the 238U peak overlaps
the 237Np peak, impeding the trace level measurement of Np. Conversely when
operating the ICP-QQQ in MS/MS mode, the peak overlap on Np is eliminated.
This improvement is due to two separate mass separations taking place, improving
the AS from ~10-7 to <<10-10. The background is significantly reduced under MS/MS
mode but not eliminated. Uranium can form various hydride interferences that are
not related to (or removed by) AS. However, reaction chemistry can be used toremove interference-based background levels.
Single Quad Scan

MS/MS Scan

8.E+048.E+04

7.E+04

7.E+04

6.E+04

6.E+04
5.E+04237
Np swampedby the 238U peak

4.E+04SignalSignal

5.E+04

3.E+04

3.E+04

2.E+04

2.E+04

1.E+04

1.E+040.E+00
233

234

235

236

237

238

237
Np separated
from the 238U peak

4.E+040.E+00
233

239

234

235

236

Q2

237

238

239

Q2

Figure 1. Spectrum of 237Np in presence of 10 ppm U. Left: Single Quad scan and Right: MS/MS
mode. MS/MS mode eliminates the peak tail on the low mass side of the intense 238U peak.

To check the reaction efficiency of oxygen as a cell gas for this study, a spiked
U matrix was measured under MS/MS mass-shift mode with O2 reaction gas.
The Np spike was 1000x lower than the previous scans at 950 ppq (0.95 ng/L).
Figure 2 shows the mass scan of the NpO2 (and UO2) product ions. It is worth
noting that during quantitative analysis (rather than scanning, as shown in
Figure 2), all the U isotopes would be eliminated by Q1, which would be set tom/z 237. The conversion efficiency of Np to NpO2 was found to be 99%. Only 1%of total Np signal converted to NpO.
4.E+03Signal3.E+03

2.E+03

1.E+03
NpOO+

237

0.E+00
262

263

264

265

266

267

268

269

270

Q2

Figure 2. 950 ppt Np in 10 ppm U measured in MS/MS mass-shift mode with O2 cell gas.

402

Figure 3 shows the calibration graphs for Np in a 10 ppm U matrix generated in
no gas mode (left) and oxygen reaction gas mode (right). Identical solutions
were analyzed in both cases. The improvement in BEC and DL can be clearlyseen in oxygen mass-shift mode. The DL and BEC under no gas conditions were
1.9 ppq and 2.4 ppq. Using O2 mode and measuring Np as NpO2 improved the
DL to 0.56 ppq and the BEC to 0.32 ppq (pg/L).
237 ➝ 237 Np [No Gas] ISTD :209 ➝ 209 Bi [No Gas]x10 -2y = 1.4085E-004 * x + 3.3860E-007
R = 1.0000
DL = 0.001888 ng/I
BEC = 0.002404 ng/I

237 ➝ 269 Np [O2] ISTD :209 ➝ 209 Bi [No Gas]x10 -2
1.5

y = 1.1838E-004 * x + 3.8015E-008
R = 1.0000
DL = 0.00056 ng/I
BEC = 0.0003211 ng/I

Ratio

Ratio

1
1

0.5

0

0
50.0

100.0
Conc (ng/I)

50.0

100.0
Conc (ng/I)

Figure 3. Np calibration in a 10 ppm U matrix. Left: no gas mode. Right: O2 reaction gas mode –showing a 7.5x reduction in BEC. All UH-based interferences were avoided by measuring 237N as
237
Np16O2.

Conclusion
The Agilent 8900 ICP-QQQ in MS/MS mode performs two mass selection steps,
increasing the abundance sensitivity performance and allowing an ultratraceelement to be measured in the proximity of a major matrix isotope. For thedetermination of Np, the removal of uranium-based interferences is essential,
as U is present within the environment at significantly higher concentrations than
Np. The unique MS/MS capability of the 8900 ICP-QQQ removes peak overlaps
and uranium hydride-based interferences.

403

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Direct Analysis of Zirconium-93 in Nuclear Site
Decommissioning Samples by ICP-QQQ
AuthorHeather Thompkins1
Ben Russell1
Sharon Goddard2
1
Nuclear Metrology Group and2
Gas and Particle Metrology Group,
National Physical Laboratory,
Teddington, UK

Using MS/MS mass-shift mode to resolve 93Zr from 93Nb withoutchemical separation
Introduction
Zirconium-93 is a long-lived radionuclide that is produced by nuclear fission of
uranium and plutonium. It is also formed by neutron activation of stablezirconium in nuclear fuel cladding in pressurized water reactors. Therefore, 93Zr is
an important element to monitor during the decommissioning of nuclear sites.
The long half-life of 93Zr (1.61 × 106 years (1)) means it is a significant contributor
to the total waste inventory over long timescales. Clearly, there is a need toaccurately quantify 93Zr in various complex decommissioning wastes as part ofthe initial site characterization process. Also, monitoring of waste repositories
and the environment around nuclear sites following decommissioning is needed.
Zirconium-93 decays to stable 93Nb by beta emission, but with a low decay energythat makes measurement by decay counting methods challenging. With its
long-half-life, 93Zr is well suited to measurement by ICP-MS (1 Bq/g is equivalent
to 1.1 × 104 pg/g), which offers a high throughput alternative to decay counting
techniques. However, accurate measurement by ICP-MS is affected by theisobaric interference from 93Nb (100% abundance), as well as potential
radioactive 93Mo, and polyatomic ion interference from 92Mo1H+ and 92Zr1H+.
The removal of these interferences traditionally requires time-consuming,
multistage extraction and/or chromatographic separation before measurement,using a significant number of reagents and materials (2, 3). Also, since 93Nb is
monoisotopic, it is challenging for the analyst to be confident that complete
interference removal has been achieved before measurement.
In this study, triple quadrupole ICP-MS (ICP-QQQ) was used for the rapid anddirect low-level measurement of 93Zr in decommissioning samples below
International Atomic Energy Agency (IAEA) regulatory limits (4). Reactive gases
were used in the collision/reaction cell (CRC) of the ICP-QQQ to separate theisobaric overlap from 93Nb on 93Zr, eliminating the need for chromatographic
separation. Isobaric ion interferences can be separated using ICP-QQQ when thecell gas reacts quickly with one of the elements to form a product ion, while theother element does not react (or reacts slowly). This “chemical” resolution
method significantly reduces the procedural time and secondary waste
associated with decay counting and alternative mass spectrometric procedures.
With its fast analysis times, ICP-QQQ offers a cost-effective method for the
analysis of nuclear decommissioning samples.
ICP-QQQ with MS/MS mode
ICP-QQQ is a well-established technique that is especially suitable for improved
control of spectral, doubly charged ion, and isobaric interferences using reactive
cell gas methods (5). Compared to conventional single quadrupole ICP-MS,
ICP-QQQ has an additional mass filter before the CRC. This extra mass filter404

prevents all ions apart from the target mass from entering the CRC, so thereaction chemistry in the cell can be controlled. This double mass filter approachis only possible with a tandem MS (or MS/MS) configuration, which provides
unprecedented control of the ion-molecule reaction chemistry used in CRC-ICPMS methods.

Experimental
Standards and sample preparation
Calibration standards were prepared by diluting an NPL-standardized 93Zr stock
solution in 0.3 M HNO3 over a concentration range of 53.8 to 1.1 × 105 pg/g
(equivalent to 5.0 × 10-3 to 10.0 Bq/g). To provide matrix matched calibration
standards, the same standards were also prepared in dissolved steel andaqueous decommissioning waste solutions. To determine the separation factorof 93Zr and 93Nb, increasing concentrations of 93Nb were spiked into 0.3 M HNO3
and steel solutions which contained the same concentration of 93Zr.
Instrumentation
An Agilent 8800 Triple Quadrupole ICP-MS (ICP-QQQ) was used for all work on
active samples containing 93Zr. The sample introduction system consisted of aquartz torch with 2.5 mm i.d. injector, a quartz spray chamber, glass concentric
nebulizer, and nickel-tipped interface cones.
To separate 93Zr and 93Nb using ICP-QQQ, both O2 and NH3 cell gases were
investigated. Helium was added as a buffer gas and H2 was also added to thecell to see if it enhanced product ion formation.
Instrument operating conditions were established using stable isotope standards.
A 10 ng/g mixed stable element standard containing 90Zr and 93Nb was analyzed
and product ion scans were obtained for each precursor ion mass. Q1 was first
set to m/z 90 (for Zr) and then m/z 93 (for Nb), while Q2 was scanned to identify
the most abundant product ions formed from reactions of 90Zr and 93Nb witheach cell gas. The optimal cell gas for interference removal was found to be NH3
with He and H2. The instrument conditions were then optimized for sensitivity,
focusing on cell gas flow rate, octopole bias, and energy discrimination.
The operating conditions (Table 1) were validated using active samples.
Table 1. 8800 ICP-QQQ operating conditions.
Parameter

Setting
Stainless Steel

Scan Mode
Plasma Conditions

Aqueous Waste Samples

MS/MS (Q1=93, Q2=195)
HMI

Integration Time (s)General Purpose
0.1

Carrier Gas (L/min)

0.60

Dilution Gas (L/min)

0.35

0.95
0.00

Helium Flow Rate (mL/min)

2.0

Hydrogen Flow Rate (mL/min)

3.0

Ammonia Flow Rate (% of maximum flow rate)

15 (1.5 mL/min)

Octopole Bias (V)–2.8

Energy Discrimination (V)–9.0

Octopole RF (V)

180

405

Results and discussion
Calibration
The zirconium-93 calibration standards were analyzed using the 8800 ICP-QQQ
using the General Purpose parameters in Table 1. The detection limit wascalculated as 6.5 pg/g (0.6 mBq/g).
Instrument sensitivity and interference removal
During method optimization using a 10 ng/g mixed stable element standard,different product ions were monitored to assess interference removal efficiency.
The product ion scans identified multiple product ions using both O2 and NH3 asreaction gases. A Zr/Nb separation factor of > 5 × 103 was achieved using Zr-NH3
product ions: Zr(NH3)2NH2+ (mass-shift of 50) and Zr(NH3)5+ (mass-shift of 85),
and Zr-O2 product ions: ZrO3+ (mass-shift of 48), and Zr(OH)3+ (mass-shift of 51).
However, the optimal Zr/Nb separation was achieved with a mass shift of 102,
measuring the product ion Zr(NH3)6+. This finding agrees with a previous study
that first demonstrated measurement of 93Zr by ICP-QQQ (6).
Figure 1 shows that, if 93Zr was measured on mass, Nb concentrations of
10 pg/g and above would contribute to the signal at m/z 93, leading tointerference on 93Zr (blue bars). By comparison, when mass 195 (93Zr(NH3)6) wasmonitored in MS/MS mass-shift mode, the background counts from Nb remained
below 10 cps at concentrations up to 5 × 104 pg/g Nb (white bars). The results
show the successful removal of the 93Nb isobaric interference on 93Zr up to
5 × 104 pg/g Nb, using the MS/MS mass-shift method.
Q1 (93) --> Q2 (93)Q1 (93) --> Q2 (195)

Figure 1. Background at m/z = 93 and 195 with increasing Nb concentration(Q1 set to m/z = 93 in both cases).

Measurement of decommissioning samples
Spiked stainless steel
Inactive stainless steel dissolved in concentrated nitric acid was provided aspart of a European Metrology Research Program (EMRP) project. Samples were
evaporated to near-dryness and made up in an equal volume of 0.3 M HNO3.
A further 1 in 10 dilution was made, giving approximately 20x total dilution (5%total dissolved solids, TDS). A semiquantitative scan of the sample was
performed using the 8800 ICP-QQQ to determine the sample composition.
The most abundant elements detected in the diluted solution were Fe (out ofrange), Cr (2 µg/g), Mg (20 µg/g), Ni (2.5 µg/g), Cu (10 µg/g), Mo and Sn (both
1 µg/g). The Nb concentration in the diluted steel samples ranged from 0.5 to 1.4 ×406

104 pg/g. The steel samples were run using the optimized operating conditions
for the measurement of 93Zr (Table 1). No background was measured at m/
z=195, which also demonstrates removal of any potential polyatomic ion
interferences on 93Zr from 92Mo1H+ and 92Zr1H+.
The spiked steel samples (spiked with 93Zr and 93Nb) were initially run on the8800 without dilution, using 101Ru as an internal standard. However, even using
the High Matrix Introduction (HMI) system with aerosol dilution on the 8800, the
5% steel matrix caused significant matrix deposition on the cones after running
four to five samples. The nominal TDS limit for HMI is 3%. The matrix tolerance
could potentially be improved with the UHMI available on the 8900 ICP-QQQ,
which allows matrix levels up to 25% TDS to be analyzed.
Following a 1 in 10 dilution, the instrument sensitivity for the spiked steel was
similar to the 93Zr calibration standards. Figure 2 shows the calibration curve of93
Zr in the dissolved stainless steel matrix, measured as Zr(NH3)6+. The method
detection limit (MDL) was 8.6 pg/g (0.8 mBq/g), which is significantly lower thanthe exemption limit of 10 Bq/g defined by IAEA/RS-G 1.7 (4).

Figure 2. Dissolved stainless steel spiked with 93Zr, measured as Zr(NH3)6+ using ICP-QQQ.

Aqueous waste samples
Aqueous wastes containing a range of decommissioning radionuclides were
measured without any sample treatment using the 8800 ICP-QQQ. General
Purpose plasma conditions were used rather than HMI mode. The maximum
Nb concentration was 1 × 104 pg/g, with a background of <20 cps at m/z=195,
compared to ~40,000 cps when measured on mass at m/z=93 in He mode.
The average ICP-MS/MS reaction cell interference removal factor (equivalent to
the decontamination factor quoted for radiochemical separation experiments)
was 3.5 × 103, with an MDL of 1.1 pg/g (0.1 mBq/g). This DL is significantly below
the IAEA out-of-scope limit, and the World Health Organisation (WHO) drinking
water regulation limit of 0.1 Bq/mL (4, 7). The results show that this ICP-QQQ
method is suitable for the direct measurement of 93Zr in drinking water samples.
Comparing the 8900 and 8800 ICP-QQQ
At NPL we also have access to a newer Agilent 8900 ICP‑QQQ, but this
instrument is in a laboratory that does not handle radioactive samples.
To evaluate the relative performance of the 8800 and 8900, we used a stable,
natural Zr standard to run a comparative test between the two instruments.
For this comparison, the 90Zr(NH3)6 product ion was used as an analog of thetarget 93Zr(NH3)6 product ion. The 8900 was operated using the same General
Purpose instrument operating conditions shown in Table 1.
407

The product ion scans obtained by the 8900 ICP-QQQ using the 10 ng/g
mixed stable element standard agreed with the 8800 ICP-QQQ scan results.
Both instruments identified Zr(NH3)6+ at m/z 192 as the most intense 90Zr production, using a mass shift of 102. As shown in Table 2, measuring Zr as Zr(NH3)6+
offered the most efficient Nb interference removal method. The results also
show that a maximum separation factor of >10,000 was achieved with the 8900
compared to 6,200 on the 8800. The 8900 also detected intense 90Zr product ions
not detected on the 8800, most notably at m/z 206 (90ZrN(NH3)6) and 207(90ZrNH(NH3)6) (Table 2).
Table 2. Zr/Nb separation factors for 8800 and 8900 ICP-QQQ. Based on product ion scans of90
Zr and 93Nb in a 10 ng/g mixed stable element standard. Zr-90 counts were scaled to 100%abundance for this calculation.
Q1/Q2 (m/z)

90/15590/15990/17590/17690/17790/19290/20690/207Mass-shift

65

69

85

86

87

102

116

117

Zr/Nb Separation
Factor (8800)

<1

<1

<1

1

4

6,200

<1

<1

Zr/Nb Separation
Factor (8900)

2,300

470

715

155

400

10,200

2,800

4,300

The 8900 offers higher sensitivity and lower backgrounds compared to the 8800,
as verified by the data presented in Table 3. The stable element calibration
standards were measured by both instruments. The counts per second (cps) for
the 90Zr(NH3)6 product ion at m/z 192 obtained by the 8900 were significantly
higher than the 8800 (Table 3). The sensitivity improvement of the 8900 is due tomore efficient ion transmission in the interface vacuum stage. Also, axial
acceleration (0.5 V in this study) improves reaction product ion energy,
overcoming collisional attenuation and space-charge effects.
Table 3. Difference in instrument sensitivity and instrument detection limit (IDL) for stable
Zr standards.
Parameter

8800 ICP-QQQ

Q1/Q2 (m/z)

90/90

Zr sensitivity (cps, 10 ng/g)

1,800

90

8900 ICP-QQQ

90/192

90/90

2,000

53,00090/192
166,000*IDL (pg/g)

6.5

0.1

*IDL (mBq/g)

0.6

8.8 × 10-3

*IDLs were calculated from the 90/192 data.

Conclusion
ICP-QQQ has been successfully used for the direct and accurate measurementof the long-lived radionuclide 93Zr in decommissioning samples below IAEA
out-of-scope limits. Since ICP-QQQ with MS/MS uses reaction chemistry in the
CRC to separate analytes and interferences, there was no need for a separationstep before measurement, simplifying and speeding up the analysis.
Both active and stable element standards containing Nb and Zr were used duringmethod development. The study shows the Agilent 8800 ICP-QQQ with MS/MS
can eliminate isobaric overlaps from 93Nb on 93Zr using NH3/H2 as the reactiongas. Nb doesn’t react with NH3/H2 in the CRC, so Nb remains at m/z 93, allowing
93
Zr to be measured as 93Zr(NH3)6+ at m/z = 195, free from interference.
The integrated HMI aerosol dilution technology extends the matrix tolerance ofAgilent ICP-QQQ for the analysis of high matrix samples. The 8800 was used toanalyze 93Zr in dissolved steel (using HMI) and aqueous waste samples.
408

An MDL of less than 1 mBq/g was achieved in both matrices, which is several
orders of magnitude lower than regulatory limits for decommissioning wastes
and drinking water. The study showed that the newer Agilent 8900 ICP-QQQ
offers higher sensitivity and lower backgrounds compared to the 8800.
Compared to decay counting techniques, ICP-QQQ reduces the preparation timeof samples dramatically, with sample-throughput further improved by the shortmeasurement times of the technique. The ICP-QQQ method will be beneficial toanalysts working in nuclear decommissioning and environmental monitoring labs.

References1.

Decay Data Evaluation Project, accessed September 2019,http://www.nucleide.org/DDEP_WG/Nuclides/Zr-93_tables.pdf

2.

P. Cassette, F. Chartier, H. Isnard, C. Fréchou, I. Laszak, J. P. Degros, M. M. Bé,
M. C. Lépy, I. Tartes, Determination of 93Zr decay scheme and half-life.
Applied Radiation and Isotopes, 2010, 68 (1), 122–130

3.

F. Chartier, H. Isnard, J. P. Degros, A. L. Faure, C. Fréchou, Application of theisotope dilution technique for 93Zr determination in an irradiated cladding
material by multiple collector-inductively coupled plasma mass spectrometry.
Int. J. of Mass Spectrom., 2008, 270 (3), 127–133

4.

IAEA Safety Standards Series Safety Guide No. RS-G 1.7 Application of theconcepts of exclusion, exemption and clearance, accessed September 2019,http://www-pub.iaea.org/MTCD/publications/PDF/Pub1202_web.pdf

5.

Fourth Edition of Handbook of ICP-QQQ Applications using the Agilent 8800
and 8900, Agilent publication, 5991-2802EN

6.

P. Petrov, B. Russell, D. N. Douglas, H. Goenaga-Infante, Interference-freedetermination of sub ng kg−1 levels of long-lived 93Zr in the presence of highconcentrations (μg kg−1) of 93Mo and 93Nb using ICP-MS/MS. Anal. Bioanal.
Chem, 2018, Volume 410 (3), 1029–1037

7.

World Health Organisation Guidelines for Drinking Water Quality Fourth
Edition, accessed September 2019, https://apps.who.int/iris/bitstream/handle/10665/254637/9789241549950-eng.pdf%3bjsessionid=92EE6E44405FC
8DBD781EA0B1C957B18?sequence=1

409

> Return to table of contents> Search entire document

Clinical research
Title
Manganese analysis in whole blood: expanding the analytical capabilities
of ICP-MS

411

Measurement of titanium to assess joint replacements

415

Measurement of selenium in the presence of Gd-based MRI contrasting
agents418

Evaluation of the elemental content of a single cell using fast time-resolved
analysis (TRA) ICP-MS

421

For Research Use Only. Not for use in diagnostic procedures.
410

Page

> Return to table of contents> Search entire document

Manganese Analysis in Whole Blood: Expanding theAnalytical Capabilities of ICP-MS
AuthorIntroduction

Amir Liba
Agilent Technologies, USA

Analysis of clinical research samples is challenging due to their complex
matrices. While ICP-MS is an immensely powerful multi-element analyticaltechnique, it does suffer from some well-documented spectral interferences.
Achieving low detection limits is limited by background signal from low level
impurities and the presence of polyatomic interferences, which require the use of
CRC technology for their removal. Although the use of CRC-ICP-MS has alleviatedmany of these analytical challenges, some spectral interferences remain
problematic for quadrupole ICP-MS (ICP-QMS). One such interference is thesignal overlap on 55Mn due to peak tailing from both 54Fe and 56Fe. Whole blood
contains an average of 500 ppm of Fe, and with the level of Mn in whole blood
being roughly 10 ppb, analytical results for Mn tend to bias high due to thesignificant signal tailing and overlap from the adjacent Fe peaks. In this work,
we use the superior abundance sensitivity of the 8800 ICP-QQQ to remove any
signal overlap from Fe, allowing accurate determination of Mn in whole blood.

Keywords
manganese, whole blood, iron,abundance sensitivity, helium MS/MS

Experimental
Instrumentation: Agilent 8800 #100.
Plasma conditions and ion lens tune: Preset plasma/General purpose with
soft extraction tune: Extract 1 = 0 V.
Method: Samples were analyzed using the 8800 ICP‑QQQ in both Single Quad
(SQ) mode and MS/MS mode. In this study, the mass range of interest(from m/z 50 to 60) was scanned at twenty points per peak in both no gas andhelium (He) modes. For the measurement of Mn in blood, MS/MS mode withon-mass measurement (Q2 set to the same mass as Q1) was used, with helium
cell gas (typical flow of 4.3 mL/min) to remove polyatomic ion interferences suchas FeH+ and ArOH+.
Sample preparation: A 5 ppb solution of Mn was prepared from a stock of1000 ppm Mn and either analyzed separately or spiked into “base” whole blood(low level Mn). Whole blood was diluted using an alkali matrix containing
ammonium hydroxide, EDTA, Triton X-100, and butanol.
Abundance sensitivity
The abundance sensitivity (AS) of a mass spectrometer is the contribution thatthe signal at mass M makes to the signals at the adjacent masses (M±1),
expressed as a ratio (M-1/M on the low-mass side and M+1/M on the high-massside). Simply put, AS is the measure of the “peak tailing” to adjacent masses,
which will contribute to a false positive signal, such as that seen on 55Mn (present
at trace levels) from the large contribution from 54Fe and 56Fe (which exists at very
high concentration) in whole blood. The abundance sensitivity of the best
quadrupole ICP-MS systems is of the order of 10-7.

411

Results and discussion
Abundance sensitivity study in SQ and MS/MS mode
SQ and MS/MS spectra for a 500 ppm Fe solution acquired in no gas mode areshown in Figure 1. The spectrum on the right illustrates the improvement inpeak-to-peak resolution of the 8800 ICP-QQQ operated in MS/MS mode. Although
no interference removal for polyatomic ions was employed, the elimination of thecontribution to mass 55 from adjacent peaks is clearly evident in MS/MS mode.
The “flat-top” peak shapes are the result of the logarithmic scale.
Abundance sensitivity plays an important role when samples contain a large
concentration of Fe. Figure 1 looks at the contribution of “peak tailing” on 55Mn
due to high levels of Fe. The high concentration of Fe together with the ArN+
and ArO+ contribution in no gas mode resulted in the signals at 54 and 56
being over the range of the detector, and so they were automatically skipped.
However, the signal contribution from 56Fe on mass 55 is clearly visible in the
SQ mode (indicated by the blue box) while it is absent in the MS/MS mode.
MS/MS mode

1.E+09

1.E+09

1.E+081.E+081.E+07

1.E+07

1.E+06

1.E+06Signal – cps

Signal – cps

SQ mode1.E+05
1.E+04

1.E+05
1.E+04

1.E+03

1.E+03

1.E+02

1.E+02

1.E+01

1.E+01

1.E+00

1.E+00
51

52

53

54

55
Q2

56

57

58

59

60

51

52

53

54

55

56

57

58

59

60

Q2

Figure 1. Comparison of no gas mode spectra for 500 ppm Fe solution, measured in SQ mode (left) and MS/MS mode (right). The signal colored blue
was obtained in pulse counting while the green signal was obtained in analog mode. The dotted lines indicate over-range peaks (automatically skipped
to protect the EM detector).

412

Figure 2 shows three spectra obtained in MS/MS mode with He cell gas.
When He cell mode is used for interference removal, precise and accurate
analysis is easily achieved. In He MS/MS mode, all interferences (arising fromsignal overlap from tailing of adjacent peaks and polyatomic ions isobaric
interferences) are removed, yielding unbiased analysis and accurate results.
5 ppb Mn
1.E+09
1.E+08Signal – cps

1.E+07
1.E+06
1.E+05
1.E+04
1.E+03
1.E+02
1.E+01
1.E+00
51

52

53

54

55

56

57

58

59

60

Q2

500 ppm Fe
1.E+09
1.E+08Signal – cps

1.E+07
1.E+06
1.E+05
1.E+04
1.E+03
1.E+02
1.E+01
1.E+00
51

52

53

54

55

56

57

58

59

60

56

57

58

59

60

Q2

5 ppb Mn + 500 ppm Fe
1.E+09
1.E+08Signal – cps

1.E+07
1.E+06
1.E+05
1.E+04
1.E+03
1.E+02
1.E+01
1.E+00
51

52

53

54

55
Q2

Figure 2. He MS/MS mode spectra: (top to bottom) 5 ppb Mn, 500 ppm Fe,
and 5 ppb Mn + 500 ppm Fe

413

Figure 3 is an overlay of three spectra measured using He MS/MS mode; 1)
Blank, 2) 10x whole blood, and 3) 500 ppt Mn spike in 10x whole blood. Table 1
summarizes the results of 10x diluted whole blood analysis and 500 ppt Mn spikerecovery test. As shown, very low blank levels were achieved, 55Mn was clearly
resolved in the spectrum and good spike recoveries were obtained.
x104

Blank
10X Blood

Signal – cps

10X Blood Spike
1

0.5

0
51

52

53

54

55

56

57

58

59

60

Q2

Figure 3. Spectra of three samples: blank, 10x diluted blood and 10x diluted blood spiked with
500 ppt Mn
Table 1. 10x diluted whole blood analysis results for Mn
Blood sample

Blood sample + 500 ppt Mnµg/L

Spike recovery%

Sample A

0.413

0.983

114

Sample B

0.432

0.924

98

Conclusion
Quadrupole ICP-MS has been almost universally accepted for low level analysisof trace analytes in complex matrices. However, many challenging interferences
remain unresolved, especially when trace analytes must be measured close tomatrix element peaks in complex samples. The Agilent 8800 ICP-QQQ with
MS/MS capability has abundance sensitivity better than 10-10, which enables theanalysis of trace analytes (such as Mn) in the presence of a high concentrationof adjacent elements (such as Fe).
For Research Use Only. Not for use in diagnostic procedures.

414

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Measurement of Titanium to Assess Joint Replacements
AuthorIntroduction

Glenn Woods
Agilent Technologies (UK) Ltd.

Although titanium (Ti) has little or no direct biological role, it is widely used in dental,
artificial/replacement joints, and surgical reconstruction applications. Its benefits
include high strength, light weight, and the fact it is biocompatible. It is also used
extensively as a pigment and abrasive polishing agent (as TiO2) and is used as anadditive in foods and toothpaste due to its inertness and high opacity.

Keywords
titanium, biological, serum, urine,
joint-replacement, Seronorm, ammonia
mass-shift

Metal-on-metal (rather than ceramic or polymer based) joint replacements canlead to the release of metal particles or ions. These can pass into the bloodstream
and be excreted through urine. A raised concentration of Ti might therefore be asign of degradation in Ti-based joint. It would be useful to develop a method thatis able to determine the concentration of Ti at normal levels in biological fluids.
This would allow identification of the basal or reference concentration, above
which a raised level could be flagged for investigation.

Experimental
The determination of Ti at ultratrace levels is challenging for conventional
ICP-MS, due to the spectral interferences from sulfur (as SO), phosphorus(as PO), and calcium, which affect all the Ti isotopes. It is possible to use NH3reaction cell gas to create a higher mass Ti+ product ion, separating the Ti fromthe interfering species. However, the use of highly reactive cell gases in single
quadrupole ICP-MS (ICP-QMS) is prone to severe errors, as there is no way tocontrol the ions that enter the CRC. This means that the reaction chemistry andthe product ions created can change dramatically, with even slight differences insample matrix or co-existing analyte concentrations. For this application, the8800 ICP-QQQ was used to provide controlled reaction chemistry with ammonia
as the reaction gas and measuring Ti as the TiNH2(NH3)4+ cluster ion at the M +84 u transition.
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/General purpose.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -170 V.
CRC conditions: NH3 gas (10% in He) at 1.7 mL/min, Octopole bias = -8 V,
KED = -8 V.
Samples and sample preparation: Certified reference materials of serum andurine were purchased from Seronorm (Norway). They were prepared in duplicate
by 10x dilution into a basic diluent consisting of NH4OH (0.5%), H4-EDTA (0.01%),
BuOH (2%) and Triton X-100 (0.01%) in ultrapure water. The same diluent wasused to prepare the calibration standards, with no further matrix matching.

415

Results and discussion
Selection of product ion for Ti measurement
In order to select the most appropriate Ti cluster ions in NH3 mode, a product ion
scan was performed for the 48Ti isotope by introducing a 10 ppb Ti solution(Figure 1). Q1 was set to m/z 48, allowing only ions at the mass of the target
precursor ion to enter the cell; Q2 was scanned over a selected mass range tomeasure all the product ions formed in the cell by NH3 reactions with 48Ti. Basedupon this scan, the two most abundant cluster ions (Q1 + 84 u [TiNH2(NH3)4] andQ1 + 102 u [Ti(NH3)6]) were selected for further study. For each of the tworeaction transitions identified above, neutral gain scans (where Q1 and Q2 arescanned synchronously, with a set mass difference between them (Q2 = Q1 + 84
and Q2 = Q1 + 102 in this case)) were performed. These scans are shown in
Figure 2 confirming the correct natural isotopic abundances for the different Ti
isotopes. Without MS/MS capability, it would be impossible to preserve theisotopic information for this element due to inter-isotope overlaps from the
Ti-ammonia adducts. The instrument cell conditions were optimized using simple
HNO3 acidified Ti standards and applied to the analysis of the CRMs.
TiNH(NH 3)4+
TiNH 2(NH 3)4+
Ti(NH 3)5+Signal – cps

x104
6

TiNH(NH 3)5+
TiNH 2(NH 3)5+
Ti(NH 3) 6+

4

TiNH(NH 3)2+
TiNH 2(NH 3)2+
Ti(NH 3)4+2

Ti+

TiNH +

50

60

48

0

TiNH(NH 3)2+
TiNH(NH 3)+

70

80

90

100 110

120

130

140

150

160

Q2

Figure 1. Product ion scan for 48Ti+ in NH3 modex104
6

Signal – cps

TiNH 2(NH 3)4+ for 46Ti+,
47 + 48 + 49 +Ti , Ti , Ti and 50Ti+
4

Ti(NH 3) 6+ for 46Ti+,
47 + 48 + 49 +Ti , Ti , Ti and 50Ti+

2

0
130

135

140

145

150

Q2 (Q1 = Q2 - 84 or Q1 = Q2 - 102)

Figure 2. Neutral gain scan for two Ti  Ti cluster ion transitions: For TiNH2(NH3) 4+ cluster ions,
Q2 = Q1+ 84 u, and for Ti(NH3)6+ cluster ions, Q2 = Q1+102 u. The preservation of the natural Ti
isotope abundance pattern (46Ti+, 47 Ti+, 48Ti+, 49Ti+ and 50Ti+) can be seen, confirming that MS/MS
mode provides complete control over the complex Ti-NH3 reaction chemistry.

416

Table 1 displays the results for the serum and urine CRMs measured against a
the same calibration. In addition to the NH3 cell gas mode, the 8800 ICP-QQQ wasoperated in no gas and He mode to provide comparative data. Three Ti isotopes
were monitored for the same cluster ion transition, to give confirmation of theresults.
Table 1. Urine and serum sample recovery (μg/L) for Ti in Seronorm CRM using TiNH2(NH3)4+ cluster
Sample Name

Target47

Urine blank

4.6 (2.2-7.0)

Urine blank

4.6 (2.2-7.0)

Ti [No gas]

Ti [He]47 -> 131 Ti 48 -> 132[NH3]
Ti [NH3]

49 -> 133
Ti [NH3]

1989.79

41.44

2.80

2.79

2.92

2004.91

44.30

3.50

2.93

3.33

Urine trace elements

1789.92

51.41

14.81

15.27

14.42

Urine trace elements

1749.13

52.58

14.99

15.49

15.50

47

Serum L1

1.28 (0.86-1.80)

144.18

3.79

1.21

1.15

1.14

Serum L1

1.28 (0.86-1.80)

128.97

2.95

1.27

1.18

1.09

Serum L2

100.16

3.95

1.76

1.92

1.61

Serum L2

95.65

3.02

1.82

1.64

1.76

Conclusion
Titanium was only certified in two of the four materials measured but the 8800
ICP-QQQ data were all comfortably within the measured ranges when operating
under ammonia MS/MS mode, in contrast to no gas and He mode data. Importantly,
the three Ti isotopes measured under ammonia MS/MS mode all gave equivalent
data; this could indicate applicability of the method to the use of isotope-based
analysis such as isotope dilution (ID) or isotope tracer analysis. The use of ammonia
combined with MS/MS greatly simplifies the analysis of Ti in biological media forseveral isotopes. Furthermore, because MS/MS mode provides control over thereaction chemistry, no special attention needs to be paid to specific matrix matching
regardless of the fluid investigated.
For Research Use Only. Not for use in diagnostic procedures.

417

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Measurement of Selenium in the Presence of GadoliniumBased Magnetic Resonance Imaging Contrasting Agents
AuthorIntroduction

Glenn Woods
Agilent Technologies (UK) Ltd.

Selenium is an important micronutrient and is contained within several co-factors
and enzyme systems.

Keywords
selenium, MRI contrasting agents,
gadolinium, molybdenum, zirconium,
neutral gain scan, oxygen mass-shift

Magnetic Resonance Imaging (MRI) is a commonly used radiology imaging
technique. However, for some soft tissues, a “contrasting agent” is needed to
improve the image quality to enable tissue differentiation. There are several
contrasting agents which are salts or chelates of gadolinium (III) (Gd(III)), trade
names are given in brackets:
Gadodiamide (Omniscan), Gadobenate (MultiHance), Gadopentetate (Magnevist),
Gadoteridol (ProHance), Gadofosveset (Ablavar, formerly Vasovist),
Gadoversetamide (OptiMARK), Gadoxetate (Eovist), Gadobutrol (Gadavist)
Unfortunately for analysis of samples by ICP-MS, Gd has a relatively low second
ionization potential (12.09 eV) meaning it can form doubly-charged (Gd++) ions in
the plasma. These Gd++ ions appear at half their true mass, as a quadrupole
separates ions based on their mass to charge ratio or m/z. This means that theGd++ ions appear between m/z 76 and 80 where they form interferences on all of
the main analytical isotopes of Se. This is complicated to a greater extent as Gd
has several odd-mass isotopes which form Gd++ interferences at half-massvalues (e.g., 155Gd++ would appear at m/z 77.5). This makes the spectrum in themass region of the Se isotopes quite complex when Gd is present in the sample.
In a typical post-MRI sample, the Gd concentration can vary between zero toseveral thousand parts per billion (µg/L). Because of the variability in Gd levelfrom sample to sample a simple mathematical correction cannot always be
made or a constant “background” be assumed.

Experimental
In order to avoid the Gd++ interference, Se+ can be reacted with oxygen cell gas in
the collision/reaction cell to produce SeO+ product ions. The Se-O reaction isslightly endothermic (ΔHr = 0.71 eV) which means that the reaction yield for SeO+
would be relatively low. However, the bias voltage on the ORS can be adjusted toincrease the ion energy, which improves the reaction yield significantly overa more “thermalized” approach. These conditions are referred to as high ORS
bias conditions.
Instrumentation: Agilent 8800 #100.
Plasma conditions: Preset plasma/General purpose.
Ion lens tune: Soft extraction tune: Extract 1 = 0 V, Extract 2 = -170 V.
CRC conditions: O2 gas at 0.3 mL/min, Octopole bias = -15 V, KED = -8 V.

418

Results and discussion
O2 mass-shift method
Using O2 mass-shift, the analyte is measured at M +16 u (e.g. 78Se+ is measured
as 78Se16O+ at 94 u). With conventional quadrupole ICP-MS, any 94Mo or 94Zr
present in the sample would interfere with the measurement at this mass.
However, with ICP-QQQ in MS/MS mode, 94Mo and 94Zr are removed by Q1 as it is
set to the mass of the Se+ precursor ion at 78 u. The 156Gd++ remains at m/z 78
and so is eliminated by Q2, which is set to the SeO+ product ion mass of 94 u.
Even if Gd did form GdO++ this would also be eliminated by Q2 as the apparent
mass (m/z) of 156Gd16O++ is 172/2 (86 u). Figure 1 is a graphical representation of
the MS/MS method.
To check for efficient conversion of Se+ to SeO+, a neutral gain scan covering themass range of all the SeO+ product ions was performed for a 5 ppb Se solution.
Figure 2 displays the isotope pattern of the + 16O-atom transitions for all the Se
isotopes, showing a perfect match with the theoretical isotopic abundances.
O 2 reaction gas
Mo +, 94Zr+

Gd++, GdO ++94

Mo +, 94Zr+

94

Gd++

156
78

Se +

78

1st Quad (Q1)
Rejects ALL masses except
analyte (Se +) and on-massinterferences (Gd++).
Mo + and Zr+ are eliminated

ORS 3 Cell
Converts Se + to SeO +product ion

Se16O +

2nd Quad (Q2)
Set at Q1+16 u
Rejects all cell formed ionsapart from SeO +Figure 1. Representation of ICP-QQQ setup with Q1 set to 78 u and Q2 set to 94 u. Mo and Zrbased interferences are eliminated by Q1 and Gd++ is eliminated by Q2 allowing the measurementof 78Se as 78Se16O +.

Se measurement
Instrument cell conditions were optimized using a Se standard in a simple HNO3
matrix. A serum matrix was prepared by 10x dilution into a basic diluent
consisting of NH4OH (0.5%), H4-EDTA (0.01%), BuOH (2%) and Triton X-100(0.01%) in ultrapure water. The sample was prepared unspiked and spiked with
Gd equivalent to 250, 500 and 1000 µg/L in the original sample, and analyzed
using the 8800 ICP-QQQ in no gas and O2 mass-shift modes for comparison.
The data is summarized in Table 1. The results show that, under no gas
conditions, the apparent Se concentration is influenced by the variable Gd++interference. Recovery based upon the original unspiked sample demonstrates anover-recovery of almost 130% for the no gas data when Gd is at a concentrationof 1000 µg/L. In contrast, the Se data measured with MS/MS mass-shift moderemains very consistent at all levels of Gd matrix. This shows that the O2 massshift reaction allows accurate analysis of Se independent of the Gd concentration,
indicating that the ICP-MS/MS approach is highly applicable to this relatively
difficult measurement.

419

Table 1. Serum sample data and recovery for Se with variable Gd concentration. Recovery is
calculated based on determined Se concentration in unspiked serum sample. All data is dilution
corrected.
No gas mode

O2 mass-shift

Conc. ppb

Recovery %Conc. ppb

Recovery %

Serum

93.64

NA

91.42

NA

Serum with 250 µg/L Gd

99.97

106.7

91.38

100.0

Serum with 500 µg/L Gd

112.1

120.0

91.70

100.3

Serum with 1000 µg/L Gd

121.1

129.3

91.78

100.4

For Research Use Only. Not for use in diagnostic procedures.

420

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Evaluation of the Elemental Content of a Single Cell
using Fast Time-Resolved Analysis (TRA) ICP-MS
Authors
Yu-ki Tanaka , Yasumitsu Ogra ,Tetsuo Kubota2
1

1

Graduate School of Pharmaceutical
Sciences, Chiba University, Chiba,
Japan
1

2

Agilent Technologies, Inc.

Determination of Mg, P, Fe, and Zn in a single yeast, green alga,
and red blood cell by Agilent 8900 ICP-QQQ
Introduction
Advances in ICP-MS technology mean that elemental signals from single
particle-like materials such as nanoparticles and living cells can now be detected,
measured, and reported more easily. Known as single particle (SP-) or single-cell(SC-) ICP-MS, these techniques are of interest in a range of industries and fieldsof study, including semiconductor, environmental, foods, and clinical research.
For successful SP/SC-ICP-MS analysis, the ICP-MS must be operated in fast time
resolved analysis (TRA) mode. Suspension solutions containing particles or cells
are introduced directly into the ICP through a nebulizer where they aredecomposed, atomized, and ionized. The ion plume is detected within 1 ms,
which is much faster than the signal integration time used in conventional
ICP-MS measurements (10–100 ms). To measure the signals from individual
single particles or single cells, the fast TRA mode of Agilent single quadrupole
ICP-MS or Agilent triple quadrupole ICP-MS (ICP-QQQ) uses an integration timeof 0.1 ms.
In this study, a precise quantification method was developed using SC-ICP-MS
for the determination of biologically important elements, Mg, P, Fe, and Zn, in asingle yeast, green alga, and red blood cell (RBC). To validate the accuracy of the
SC-ICP-MS method, which measures intact cells, data was also obtained using a
conventional “bulk” ICP-MS analysis method following acid digestion of the cells.
The acid digestion step destroys the individual cell structure, so the reported
metal concentration results are derived from the mean values measured fromthousands of cells. Compared with bulk analysis, SC-ICP-MS requires significantly
fewer cells owing to the enhanced signal-to-noise ratio (S/N) of the signal in fast
TRA mode. Requiring fewer cells for a successful analysis is a major advantageof the technique, especially in applications such as biological and clinicalresearch where sample volumes may be limited.
When samples with a complex matrix are analyzed by ICP-MS, matrix-basedpolyatomic interferences are more likely to form that affect the accurate
measurement of some analytes. For example, in biological samples, phosphorus(31P) can be affected by high background noise at m/z 31 arising frominterferences such as 12C18OH+, 14N16OH+, 15N2H+, 15N16O+, and 13C18O+. Also, P hasa high first ionization potential (IP) of 10.5 eV. The high IP means that a relatively
low number of ions is formed in the argon plasma compared to elements with an
IP between ~6 and 8 eV, leading to lower sensitivity.
The Agilent 8900 ICP-QQQ is suitable for SC-ICP-MS studies due to its highsensitivity, low background, and interference removal capabilities. The 8900 is atandem MS instrument that uses MS/MS mode for reliable reaction chemistry inthe collision/reaction cell (CRC) to resolve polyatomic ion interferences on421

analytes such as P. Using MS/MS, the instrument can measure analytes‘on-mass’ or in ‘mass-shift’ mode, as explained elsewhere (1, 2). A mass-shiftmethod with O2 cell gas is often used to measure 31P via its oxide ion, 31P16O+,
at m/z 47 (3). MS/MS methods provide a reliable and reproducible way to avoid
polyatomic ion interferences on analytes of interest.
To simplify SC-ICP-MS analysis using Agilent ICP-MS or ICP-QQQ instrumentation,
Agilent has developed the Single Nanoparticle Application Module (p/n G5714A)
for Agilent ICP-MS MassHunter instrument control software. The Agilent particle
detection technique, which has been patented in the United States, provides clear
signal distribution data even in biological samples that have a high ionicbackground arising from the cell-suspended solution.
In this study, SC-ICP-MS was evaluated as a potential technique for metabolism
studies of essential elements in fungus, plant, and animal cells. It is an importantarea of research, as many elements are essential for cell health, and an imbalance,
deficiency, or excess of certain metals may disrupt natural cell processes.

Experimental
Cell samples and chemicals
Three kinds of cells of approximately 1 to 5 μm in diameter were investigated, as
shown in Figure 1. Commercially available dried yeast (Saccharomyces cerevisiae)
was bought from Sala Akita Shirakami Corporation (Akita, Japan). Green
unicellular alga, C. reinhardtii (NIES-3379) was obtained from Microbial Culture
Collection at the National Institute for Environmental Studies (Tsukuba, Japan).
Red blood cells were collected from 11-week-old male Wistar rats (Japan SLCInc.). The cell samples were washed and suspended in 0.9% NaCl solution before
analysis by SC-ICP-MS.

Figure 1. Microscopic images of three types of cell suspended in 0.9% NaCl solution.

Ionic standards were prepared by mixing single element standards for Mg, Si,
P, Fe, and Zn. Details are given in Table 1. To matrix match the standards andsamples, the 0.9% NaCl solution was added to each ionic standard.
Table 1. Details of the element standards and calibration range.

422

Element

Ionic Standard Concentrationfor SC-ICP-MS (ppb)

Calibration Range for Bulk
Concentration Analysis (ppm)

Supplier

Mg

10

0–15

Kanto Chemical

Si

100

-

Kanto Chemical

P

1000

0–20

FUJIFILM Wako Pure
Chemical

Fe

10

0–5

Kanto Chemical

Zn

10

0–1

Kanto ChemicalA SiO2nanoparticle certified reference material (Merck Sigma Aldrich) with anominal internal particle diameter of 200 nm was diluted to 2 ppb in ultrapure
water. The SiO2 nanoparticle and ionic Si solutions were used to estimate
nebulization efficiency.
Instrumentation
For the SC-ICP-MS study, single cell samples were introduced into an 8900
ICP-QQQ using an MVX-7100 autosampler (Teledyne Cetac Technologies,
Omaha, NE, USA), as shown in Figure 2. The 8900 was fitted with a MicroMist
glass nebulizer and a Single-Cell Sample Introduction System (Glass Expansion,
Victoria, Australia) total consumption spray chamber.

Figure 2. Configuration of SC-ICP-MS system.

For bulk concentration analysis, digested cell samples were introduced into an
Agilent 8800 ICP-QQQ equipped with a standard sample introduction system.
The method parameter settings of the two ICP-QQQ instruments are shown in
Table 2. The same cell gases were used in both methods. Mg and Zn were
measured in no gas mode. 31P was measured as the 31P16O product ion by
operating the ICP-QQQ in O2 mass-shift mode, and Fe and Si were measured
on-mass in H2 mode.
Table 2. ICP-QQQ operating conditions for the SC-ICP-MS and conventional bulk cell ICP-MS methods.
Parameter

MethodSC-ICP-MS

Bulk Concentration Analysis by ICP-MS

ICP-QQQ Instrument Model

8900

8800

RF Power (W)

1600

1550

0.65/0.20

1.0/0.3

Nebulizer Gas/Make-up Gas (L/min)
Cell Gas Mode

No gasO2

H2

No gas

O2

H2

-

0.38

5.5

-

0.38

5.5

Cell Gas (mL/min)
Analytes*
Measurement Mode24

Mg, 66Zn

31

P**

56

Fe, 28Si

Single particle

24

Mg, 66Zn

31

P**

56

Fe

Full quantitative

Integration Time (ms)

0.1

100

Nebulization Efficiency (%)~55

Not applicable*All elements were measured in MS/MS mode.
**MS/MS mass-shift mode with O2 cell gas; the quadrupole mass filters, Q1 and Q2, were set to m/z 31 and 47, respectively.

Sample preparation
The sample preparation procedure is described in detail elsewhere (4).
The number of cells for the three cell types were counted using a Bürker-Türk
hemocytometer. The measurements were used in the calculations of the bulk
concentration analysis section of this note.

423Determination of the elemental content of a single cell
Four essential elements (Mg, P, Fe, and Zn) were measured in a single cell using
SC-ICP-MS. The mass of each analyte element (m) in a single cell was obtainedusing the following equation (eq. 1).

m=

I Cell⋅ f ⋅ CStd ⋅ v(I Std − I Blk )ICell, IStd, and IBlk represent signal intensity of a single cell, ionic standard, and 0.9%
NaCl blank solution, respectively. f, CStd, and v denote nebulization/transport
efficiency of the sample aerosol, concentration of ionic standard solution, andsample flow rate (0.015 mL/min), respectively.
Nebulization/transport efficiency (f) was calculated from the signal intensitiesof 28Si measured in both an ionic Si solution and SiO2 nanoparticle suspension
solution using equation (eq. 2). ISi and ISilica represent signal intensity of ionic Si
solution and intensity of transient signals for SiO2, respectively. Mass of Si (mSilica)
in a single SiO2 nanoparticle was calculated from the radius (100 nm), density(2.63 g/cm3), and mass fraction (Si/SiO2~28/60) of the SiO2 nanoparticle solution.
CSi is the concentration of ionic Si solution (100 ng/mL). In summary, thetransport efficiency is calculated by comparing the sensitivity factor of 28Si
between the ionic solution ((ISi-IBlk)/CSi·v) and the SiO2 nanoparticle (ISilica/mSilica)
solution.

The Single Nanoparticle Application Module of the ICP-MS MassHunter software
automatically performed all calculations.
Bulk concentration analysis
A small aliquot (0.1 mL) of yeast, green alga, and RBC suspended in NaCl solution
was digested with 0.5 mL HNO3 (60%). The cell samples were prepared in a
glass test tube, which was heated on a hot plate at 100 °C. The digested cellsamples were diluted with Milli-Q water before elemental analysis by ICP-MS.
The elemental concentrations were determined from external calibration curves.
The elemental content per cell was calculated as follows:
ICP-MS determined concentration (fg/mL))/counted cells (cell/mL)

424

Results and discussion
Transient signals for Mg, P, Fe, and Zn were detected in yeast, green alga, andRBC using the 8900 ICP-QQQ operating in fast TRA mode. Typical signal profiles
are shown in Figure 3, using Fe and P as examples. A cell suspension solution
with a cell density of ~106 cells/mL provided enough signal for detection.

Figure 3. Signal profiles of Fe (top, 1a to 1c) and P (bottom, 2a to 2c) in the three types of cellobtained by ICP-QQQ in fast TRA mode.

The mass (fg/cell) of each element in a single cell was automatically calculatedby the ICP-MS MassHunter software. The results can be displayed in a histogramof mass per cell against frequency of that mass. Figure 4 shows the Fe and P
content of a single cell. Mass distributions of Fe and P in each of the three cells
can be clearly distinguished from the background noise on the Y-axis.

Figure 4. Histograms for the mass of Fe (top, 1a to 1c) and P (bottom, 2a to 2c) in a single cell.

A comparison of single cell (SC-ICP-MS, blue bars) and bulk cell (ICP-MS, yellowbars) results for Mg, P, Fe, and Zn is shown in Figure 5. The SC-ICP-MS results
show that the average contents of each element varied significantly among thethree types of cell.

425

Green alga was characterized by the higher Mg content than for yeast and RBC,
possibly due to the presence of chlorophyll. Mg is required for photosynthesis in
the cell. P and Zn in RBC were lower than in other two types of cells, since P and
Zn are highly contained in the cell nucleus, and RBCs are enucleated during its
differentiation. The higher Fe content of 70 fg in RBC may be due to the presenceof hemoglobin.

Figure 5. Elemental content of yeast (top), green alga (middle), and RBC (bottom).

For yeast and green alga, there was general agreement between the results
obtained by SC-ICP-MS and the bulk analysis method (Figure 5) (4). In the RBC,
the results obtained by SC-ICP-MS for P, Fe, and Zn were lower than the results
obtained by bulk analysis. However, the SC-ICP-MS result for Fe in RBC wasconsistent with reference data (66.5 fg/cell) calculated using the certified Mean
Cell Hemoglobin (MCH) value (5), as shown in Figure 6. Possibly the data fromthe bulk analysis included a contribution from elements in lysed RBC and/or
serum in suspension, resulting in an over-estimation of the results for a single
RBC. The confirmation of the Fe data suggests that SC-ICP-MS provides moreaccurate results than the conventional acid digestion bulk cell method for thedetermination of the elemental content of single cells.

Figure 6. Fe mass in RBC measured by SC-ICP-MS.
*The reference value was calculated from the certified mean hemoglobin content in RBC for an 11-week-old male Wistar rat
provided by the vendor.

426

Conclusion
The high sensitivity, low background, advanced interference removal capabilities,
and fast TRA mode of the Agilent 8900 ICP-QQQ enabled the multi-element
analysis of a single yeast, green alga, and red blood cell using SC-ICP-MS. All the
calculations needed for the analysis of a single cell were automatically performedby the integrated Single Nanoparticle Application Module data analysis softwarefor ICP-MS MassHunter.
The results for Mg, P, Fe, and Zn in yeast and green alga obtained by SC-ICP-MSand conventional bulk ICP-MS analysis were in good agreement, verifying the
SC-ICP-MS method. The accuracy of the result for Fe in RBC by SC-ICP-MS was
confirmed against a calculated reference value. Since SC-ICP-MS provided amore reliable result for Fe than conventional ICP-MS, the results for Mg, P, and Zn
were also likely to be more accurate. By measuring the content of intact RBCs,
SC-ICP-MS avoids contamination from elements originating from lysed RBC and/or serum in suspension, leading to more accurate results.
The study demonstrates the potential of SC-ICP-MS as a useful and powerful
technique for the quantitative analysis of the elemental content of a single cell.

References
1.

E. Bolea-Fernandez, L. Balcaen, M. Resano, F. Vanhaecke. Overcoming
spectral overlap via inductively coupled plasma-tandem mass spectrometry(ICP-MS/MS). A tutorial review, J. Anal. At. Spectrom., 2017, 32, 1660–1679,
https://doi.org/10.1039/C7JA00010C

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E. McCurdy, G. Woods, N. Sugiyama. Method Development with ICP-MS/MS:
Tools and Techniques to Ensure Accurate Results in Reaction Mode,
Spectroscopy, 2019 (9):20–27, http://www.spectroscopyonline.com/
method-development-icp-msms-tools-and-techniques-ensure-accurateresults-reaction-mode

3.

K. Nakano, Ultralow level determination of phosphorus, sulfur, silicon, andchlorine using the Agilent 8900 ICP-QQQ, Agilent publication, 5991-6852EN

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Y. K. Tanaka, R. Iida, S. Takada, T. Kubota, M. Yamanaka, N. Sugiyama,
Y. Abdelnour, Y. Ogra, Quantitative Elemental Analysis of a Single Cell byUsing Inductively Coupled Plasma Mass Spectrometry in Fast Time-Resolved
Analysis Mode. Chem Bio Chem, 2020, 21 (22), 3266−3272, https://doi.
org/10.1002/cbic.202000358

5.

Japan SLC Inc., Wistar rat mean corpuscular haemoglobin (MCH), accessed
October 2021, http://www.jslc.co.jp/pdf/data/2007/wistar2007.pdf

427

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Life science
Title
Simultaneous quantitation of peptides and phosphopeptides bycapLC-ICP-QQQ

429

Analysis of selenoproteins in rat serum using HPLC-ICP-QQQ

432

Absolute quantification of intact proteins in snake venom by capLC-ICP-QQQ

435

For Research Use Only. Not for use in diagnostic procedures.
428

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Simultaneous Quantitation of Peptides andPhosphopeptides by capLC-ICP-QQQ
Authors

Introduction

Silvia Diez Fernández1, Naoki
Sugiyama2, Jorge Ruiz Encinar1
and Alfredo Sanz-Medel1

LC-MS/MS is used for the quantification of proteins in pharma/biopharma andclinical research. The approach generally relies on the use of synthetic,
isotopically-labeled forms of each target protein and peptide, which are used ascompound-specific standards for the quantitation of the corresponding target
compound. In contrast, the high temperature plasma ionization source used in
ICP-MS ensures that elemental response is practically independent of theoriginal form of the compound in which the element occurs. This enables
non-species-specific (or compound-independent) quantitation of compounds bymeasuring the signal for an element contained in the target compound. In thisway, different proteins and peptides containing the heteroatoms S and P can bequantified using a known S- or P-containing compound as a generic standard.
Unfortunately, with conventional quadrupole ICP-MS, the DLs for P and S arecompromised by their high ionization potential and by multiple polyatomic
interferences. The Agilent 8800 ICP-QQQ can effectively remove thoseinterferences using reaction cell chemistry combined with the unique MS/MS
mode, achieving excellent DLs for P and S even in organic solvents. This paper
demonstrates the advantage of ICP-QQQ for the determination of proteins andpeptides by measurement of P and S heteroatoms.

Department of Physical and Analytical
Chemistry, University of Oviedo, Spain,
2
Agilent Technologies, Japan
1

Keywords
proteins, peptides, phosphorus,
phosphopeptides, sulfur, S-containing
peptides, heteroatom, isotope ratio,
pharmaceutical, clinical research,drugs, metabolites, environmental,
pesticides, nanotechnology,
nanoparticles, oxygen mass-shift

Experimental
Instrumentation: An Agilent 8800 Triple Quadrupole ICP-MS was used with an
Agilent 1260 Series low flow capillary LC system. The standard 2.5 mm internal
diameter (id) injector torch was replaced with the narrow injector, 1.5 mm id torch(G3280-80080) used for the analysis of volatile organic solvents. The exit of the
LC column was interfaced to the ICP-MS via an Agilent capillary LC interface kit(G3680A) featuring a total consumption nebulizer and micro-volume spraychamber. O2 gas (20% O2 in Ar) was supplied to the plasma as an option gas at
0.08 L/min to prevent carbon build-up on the interface cones. Agilent ICP-MS
MassHunter chromatographic software was used for integrated control of the
LC-ICP-MS system and for data analysis.
CRC conditions: O2 cell gas flow rate at 0.35 mL/min, Octopole bias = -18 V and
KED = -6 V.
Acquisition conditions: MS/MS O2 mass-shift method was applied for P and S
measurement as shown in Figure 1.
LC conditions: An Agilent Zorbax SB C18 (5 μm, 150 x 0.3 mm) reverse phasecolumn was used with a flow rate of 5 μL/min. Mobile phases of water (A) and
acetonitrile (B) were used for a gradient elution with the following profile: 0-3 min:
1% B; 3-35 min: 1-60% B linear. Both mobile phases contained 0.1% formic acidand 10 ppb Ge as ISTD and for tuning. The injection volume was 2 μL.

429

Reagents: Bis-4-nitro-phenyl phosphate (BNPP, 99% purity) and methionine(≥ 99% purity) (Sigma- Aldrich, Steinheim, Germany) were used as calibration
standards for phosphopeptides and S-containing peptides respectively. Aminoacid sequences of the phosphopeptides were LRRA-pS-LG and KRS-pY-EEHIP,
and the S-containing peptides were A-C-TPER-M-AE and VP-M-LK. All peptides
were purchased from AnaSpec (Fremont, CA, USA) with purity ≥95%.
A

Oxygen

O 2+

16

S+

32

SO +

32

Ca , Ar C ,other ions
48

+ 36

12

+

Q1=32

B

Cell

Q2=48

Detector

Q2=47

Detector

OxygenN16O +, 14N16O +
P

15

31 +

Ti+, 12C35Cl+,
other ions

PO +

31

47

Q1=31

Cell

Figure 1. 8800 ICP-QQQ MS/MS operation in mass-shift mode to remove interferences
on S (A) and P (B).

Results and discussion
Calibration and DL
Calibration standards containing 25, 50, 100 and 200 ng/ mL (ppb) of both P and
S (BNPP and methionine, respectively) were injected and measured. Excellent
linearity and RSD of <4% was obtained.
The chromatogram for the 50 ng/mL standard was used for signal to noise (S/N)
and DL calculation. The DL achieved was 0.10 ng/mL for P and 0.18 ng/mL for S.
As the injection volume was 2 μL, the DLs in absolute weight were calculated tobe 6.6 fmol and 11 fmol for P and S, respectively.
Measurement of phosphopeptides and S-containing peptides
Finally, a sample containing a mixture of phosphopeptides and S-containing
peptides was analyzed. The sample was also spiked with the standards
methionine and BNPP for non-species-specific calibration. The chromatogram
shown in Figure 2 illustrates the excellent peak shape and S/N obtained,
demonstrating the exciting potential of ICP‑QQQ for quantitative protein andpeptide analysis using measurement of P- and S-heteroatoms.

430

5.E+05
Q1=31/Q2=47
Q1=32/Q2=48

Signal – cps

4.E+05
Lys-Arg-Ser-pTyr-Glu-Glu-His-IIe-Pro

Ala-Cys-Thr-Pro-Glu-Arg-Met-Ala-Glu

3.E+05
Leu-Arg-Arg-Ala-pSer-Leu-Gly

Val-Pro-Met-Leu-Lys

2.E+05
Methionine

BNPP

1.E+050.E+00
0

200

400

600

800

1000

1200

1400

1600

1800

2000

2200

2400

(sec.)

Figure 2. Chromatogram of phosphopeptides and S-containing peptides. Sample: 45 ng/mL of
two phosphopeptides and two S-containing peptides, and 105 ng/mL of BNPP and methionine(conc. as P or S).

More information
Simultaneous quantitation of peptides and phosphopeptides by capLC-ICP-MS
using the Agilent 8800 Triple Quadrupole ICP-MS, Agilent publication,
5991-1461EN
For Research Use Only. Not for use in diagnostic procedures.

431

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Analysis of Selenoproteins in Rat Serum using
HPLC-ICP-QQQ
Authors

Introduction

Yasumi Anan, Yoshiko Hatakeyama,
Maki Tokumoto, Yasumitsu Ogra

Selenium (Se) is an essential micronutrient in animals and is present in severalof the key proteins found in plasma. Two selenoproteins which contain Se as
selenocysteine (SeCys) in their primary structures, extracellular glutathione
peroxidase (eGPx, GPx-3) and selenoprotein P (Sel P), have been detected inanimal plasma. Other Se-containing proteins which have Se incorporated into
their peptide sequence as selenomethionine (SeMet), are also detected because
animals are unable to discriminate SeMet from methionine (Met). The mostabundant Se-containing protein in human plasma is albumin. However, somestudies have indicated that no or little Se-containing albumin is detected in the
blood plasma of experimental animals compared to human plasma [1-3].
This can be explained by the fact that humans ingest Se mainly as SeMet,
whereas the major Se species in the feeds given to experimental animals is
inorganic Se, such as selenite and selenate.

Showa Pharmaceutical University,
Tokyo, Japan

Keywords
selenium, selenoprotein P, Sel P,
glutathione peroxidase, eGPx, GPx-3,
serum, biological, rat, mouse, hamster,guinea pig, speciation, mass-shiftmethod, oxygen reaction mode

The three most abundant Se isotopes, 80Se (49.6%), 78Se (23.8%), and 76Se
(9.36%), suffer from interference by several polyatomic ions originating from theAr plasma, namely, 40Ar40Ar+, 40Ar38Ar+, and 38Ar38Ar+, respectively. 77Se is also
subject to interference by 40Ar37Cl+ when chloride is present in the sample matrix,
as is the case with biological samples. Sample matrix components such as S,
Ca and K may also contribute polyatomic overlaps on isotopes of Se, for example
39 37 +K Cl on 76Se+, 32S216O+, 32S16O3+ and 40Ca2+ on 80Se+, and 79/81BrH+ on 80/82Se+.
ICP-QQQ can operate with oxygen cell gas and mass-shift mode, using O-atom
addition to move the analyte ions away from the interference for detection at
M+16 u. For example, 78Se+ is measured as 78Se16O+ at 94 u; 80Se+ is measured at
96 u; and 82Se+ is measured at 98 u. The aim of this study is to evaluate theperformance of ICP-QQQ for the speciation of Se in rat serum.

Experimental
Instrumentation: Agilent 8800 #100 was used with an HPLC system.
CRC conditions: O2 cell gas at a flow rate of 0.30 mL/min.
Acquisition conditions: MS/MS O2 mass-shift method:Se signals were monitored as SeO+ at m/z 94, 96, and 98
LC conditions: A multi-mode gel filtration column, Shodex Asahipak GS-520HQ(7.5 i.d. x 300 mm, with a guard column, 7.5 i.d. x 75 mm, Showa Denko, Tokyo,
Japan), was used. A 200 μL aliquot of serum sample was injected onto thecolumn and then eluted with 50 mmol/L Tris-HCl, pH 7.4, at a flow rate of
0.6 mL/min. The eluate emerging from the column was introduced directly into
the nebulizer of the ICP-QQQ.
Reagents: The instrument was tuned using an inorganic Se standard.
Tris(hydroxymethyl) aminomethane (TRIZMA base and TRIZMA HCl) werepurchased from Sigma (St. Louis, MO, USA).

432

Results and discussion
Elution profiles of Se in rat serum
Blood was collected from the experimental rats after one week; the blood wasseparated by centrifugation, and the serum samples were stored at -30 °C prior to
analysis by LC-ICP-QQQ. Two well-separated Se peaks were detected at retention
times of 11.7 and 14.3 min (Figure 1). The former and latter peaks wereassignable to eGPx and Sel P, respectively, per a previous study [4]. It wasreported that albumin was eluted at the retention time of 15.0-16.0 min on thiscolumn [5]. However, we did not detect a Se peak at a retention time of 15.0-16.0
min, suggesting that SeMet was not incorporated into albumin in place of Met.
ICP-QQQ (Q2 mass-shift)
20000(a) m/z 78 ➝ 94
Intens ity / cps

15000

eGPx

10000

Sel P

5000

0
0

5

10

15

20

25

30

40000

(b) m/z 80 ➝ 96
Intens ity / cps

30000

20000

10000

0
0

5

10

15

20

25

30

8000

(c) m/z 82 ➝ 98
Intens ity / cps

6000

4000

2000

0
0

5

10

15
20
Retention time/min

25

30

Figure 1. Elution profiles of Se in rat serum. A 200-μL aliquot of a rat serum sample wasinjected into a GS-520HQ column and the eluate was monitored by ICP-QQQ (a-c) at m/z 94 (a),96 (b), and 98 (c).

433

Conclusion
Two major selenoproteins, eGPx and Sel P, in rat serum were well separated on
an HPLC column. ICP-QQQ was a more accurate detector for the speciation ofserum selenoproteins than conventional quadrupole ICP-MS, because the
ICP-QQQ analysis was completely free of interferences originating from the Ar
plasma source and any matrix elements.

References
1. P. Òscar, and R. Łobiński, Talanta, 2007, 71, 1813.
2.	Y. Kobayashi, Y. Ogra, and K. T. Suzuki, J. Chromatogr. B Biomed. Sci. Appl.,
2001, 760, 73.
3.	H. Koyama, Y. Kasanuma, C. Y. Kim, A. Ejima, C. Watanabe, H. Nakatsuka, and
H. Satoh, Tohoku J Exp Med, 1996, 178, 17.
4.	Y. Anan, Y. Hatakeyama, M. Tokumoto, and Y. Ogra, Anal. Sci., 2013, 29, 787.
5.	Y. Tsuji, T. Mikami, Y. Anan, and Y. Ogra, Metallomics, 2010, 2, 412.

More information
Analysis of selenoproteins in rat serum by Triple Quadrupole ICP-MS, Agilent
publication, 5991-2750EN
For Research Use Only. Not for use in diagnostic procedures.

434

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Absolute Quantification of Intact Proteins in Snake Venom
by capLC-ICP-QQQ
Authors

Introduction

Francisco Calderon-Celis, Jorge Ruiz
Encinar, Alfredo Sanz-Medel

Venoms are complex biological fluids that contain unique mixtures of peptides
and proteins. Identifying and quantifying the composition of venoms is ofincreasing scientific interest. It is especially important to characterize the toxins
responsible for the severe biological effects of the venom on humans. Better
understanding of the symptoms of envenoming would help with the developmentof effective therapies. Also, venoms are being investigated as potential sources of
new compounds in drug development.

Department of Physical and Analytical
Chemistry, University of Oviedo, Spain
Juan Jose Calvete
Instituto de Biomedicina de Valencia,
Consejo Superior de Investigaciones
Científicas (CSIC), Valencia, Spain

In this study, an absolute quantification method suitable for the direct
quantification of intact proteins was applied to the analysis of the venom of theMozambique spitting cobra (Naja mossambica). This cobra is one of the mostdangerous snakes in Africa. The cobra’s venom is mainly toxic to cells (cytotoxic),
causing swelling of the bite wound that may evolve into tissue necrosis andgangrene [1, 2]. The cytotoxic components of the cobra venom have been
identified mainly as members of the three-finger toxin (3FTx) and phospholipase
A2 (PLA2) protein families [3, 4].
The methodology was based on capillary liquid chromatography (capLC) coupled
to a triple quadrupole ICP‑MS (ICP-QQQ). Absolute protein quantification wasachieved by measuring the sulfur heteroelement in the proteins, calibrated using
online isotope dilution analysis (IDA). ICP-QQQ uses MS/MS mode to control
reaction chemistry in the collision/reaction cell (CRC), giving consistent removalof spectral interferences using reactive cell gases [5]. Efficient removal of spectral
overlaps using MS/MS allows access to multiple isotopes of biologicallyimportant elements such as iron, sulfur, and selenium. ICP-QQQ enables thequantification of metalloproteins and peptides using IDA, without the need forcompound-specific calibration standards [6, 7].
Most proteins (> 95%) contain sulfur from methionine and cysteine residues [8, 9],but sulfur determination is difficult by conventional single-quadrupole ICP-MS.
The challenges are due to the element’s high ionization potential (10.4 eV) that
leads to low sensitivity, and the occurrence of spectral interferences from multiple
polyatomic ions that overlap all isotopes of sulfur. ICP-QQQ provides low
backgrounds and high sensitivity, and removes multiple matrix interferencesusing MS/MS, freeing up the three most abundant S isotopes for accurate
measurement using IDA.
In this study, capLC-ICP-QQQ was used for the quantitative analysis of intact
proteins, isolated, and present in simple mixtures. The method was also applied
to the analysis and quantification of the major toxins comprising the venom
proteome of the Mozambique spitting cobra.

435

Experimental
Reagents and samples
Methionine and BOC-Met-OH (Sigma-Aldrich, Germany) were used as standards.
Bovine serum albumin (BSA), transferrin, β-casein, and cytochrome C (SigmaAldrich, Germany); and intact monoclonal antibody (mAb) Mass Check Standard(Waters, USA) were used as protein standards in the recovery study. Other
reagents included sulfur (1000 mg/L S) ICP standard (Merck KGaA, Germany);solid isotopically enriched 34S (Isoflex USA); and sodium hydroxide (VWR
Chemicals Belgium). Lyophilized Naja mossambica venom was obtained from thespecialist venom supplier Latoxan S.A.S., France. The venom was collected froma snake from Tanzania, and was stored at -20 °C before use. All solutions wereprepared in Milli-Q water (ChemLabor Millipore system, with 0.22 μm filter,
Millipak - Millipore). Mobile phase B was prepared in acetonitrile (ACN) Optima®
LC/MS (Fischer Scientific, USA). Formic acid (FA) was bought from Merck KGaA
(Germany).
Instrumentation
Capillary LC separation was performed using an Agilent 1200 Series HPLC
system fitted with a BIOShellTM A400 C4, 3.4 μm, 150 mm x 0.3 mm reversedphase column (Sigma-Aldrich, Germany) and autosampler. Chromatographic
column and post-column connections comprised Agilent PEEK-coated fusedsilica capillaries 200 mm x 100 μm id (ICP and syringe connection) and 50 μm(column connection), and a 0.03" (0.8 mm) Agilent zero-dead volume T-connector.
Post-column flow was provided by a syringe pump system kdScientific (Holliston,
MA, USA). The column was heated using a Spark Holland oven (Mistral,
The Netherlands) to improve chromatographic efficiency.
Sulfur isotope measurements were carried out using an Agilent 8800 Triple
Quadrupole ICP-MS (ICP-QQQ). The capLC column was connected to the
ICP-QQQ using the Agilent capillary LC interface kit (Agilent product number
G3680A). The kit consists of a total consumption nebulizer with single pass spraychamber. Enriched 34S was added to the LC eluate solution post-column to allow
sulfur quantification by IDA [10]. Sulfur isotopes were measured by ICP-QQQ
using an oxygen mass-shift MS/MS method which successfully resolves a range
of interferences on both the 32S and 34S isotopes. BOCMet-OH was used as theinternal standard (IS) to correct for any injection errors. capLC-ICP-QQQ operating
conditions are given in Table 1.

436

Table 1. capLC-ICP-QQQ operating conditions.
ICP-QQQ
RF power (W)1550

Sampling depth (mm)8.0

Carrier gas flow rate (L/min)

0.85

Makeup gas flow rate (L/min)

0.00

O2 cell gas flow rate (mL/min)

0.16

Data acquisition ion pairs,
Q1 (S+) » Q2 (SO+) mass (m/z)

34  5032  48

capLC
Chromatographic flow rate (μL/min)

4.5; 3.5*

Mobile phase A

H2O/0.2% FA

Mobile phase B

AcN/0.2% FA

Temperature (°C)

80

Chromatographic gradient
BSA and Intact mAb standards

Naja mossambica sample

Time range (Min)% mobile phase B

0

2

2

2

16

60

18

90

0

1.5

8

1.5

10

10

40

30

47

90

* Conditions for measurement of venom sample

Results and discussion
Absolute protein quantification
Absolute quantification of proteins was achieved through the measurementof sulfur by capHPLC-ICP-QQQ, with postcolumn IDA. Two individual protein
samples (BSA and mAb) were spiked with BOC-Met-OH IS. Quantitative ID(mass purity) results for BSA, 95 ± 5% (n=3), compared well with the sample
purity data provided by the manufacturer (≥ 98 %). The ID mass purity result for
Intact mAb was 77 ± 4% (n=3).
To confirm the accuracy and specificity of the ICP-MS/MS analysis, digests ofthe two protein standards were quantified using external calibration of sulfur.
The results obtained by external calibration were 96 ± 1% for BSA and 79 ± 2%
for Intact mAb. These results are in good agreement with the ID mass purity
results for BSA and Intact mAb shown above.

437

Quantitative analysis of snake venom proteome
The method was applied to the analysis and quantification of the proteinspresent in a snake venom sample. Before analysis, chromatographic recovery
was calculated by measuring the sulfur mass of a sample eluting from thechromatographic column and comparing this to the sulfur mass recorded
directly by flow injection (FI). Chromatographic recovery for a series of protein
standards (cytochrome C, β-casein, transferrin, BSA, Intact mAb) was higher
than 98%. For the Naja mossambica protein content, it was 99 ± 1% (n=3).
The total sulfur mass content corresponded almost exactly to the sum of thesulfur contained in the different venom protein peaks detected via their sulfur
heteroelement content (Figure 1). The excellent recovery obtained for thecomplex sample shows that quantitative protein recoveries for thechromatographic column are species (individual protein) independent.
Parallel capLC-ESI-MS analysis was used to identify the proteins from theirmolecular weight, according to database information (Table 2). By identifying
the proteins, it was possible to know the S-to-protein stoichiometry of eachpeak. This information was then used to translate the measured sulfur massinto individual protein quantities, in μmol protein per gram of venom sample.
The quantified results are summarized in Table 2.
2.5

ng S / min

2

1.5

1

0.5

0
0

5

10

15

20

25
30
Time (min)

35

40

45

50

Figure 1. capLC-ICP-QQQ mass flow chromatogram of Naja mossambica venom. All the venom
protein species eluted between 20 and 50 min (S detection). The 27 sulfur-containing peaks arenumbered—see Table 2 for More information.
Reprinted with permission from Anal. Chem., 2016, 88 (19), 9699–9706. Copyright 2016
American Chemical Society.

438

Table 2. Matching of the masses of protein peaks from Naja mossambica venom to known protein
families. Closest available protein species, estimated exact mass, and calculated concentration arelisted. Uncertainty corresponds to one standard deviation (n=3).
Peak

FamilyClosesthomolog

Mol wt (Da)μmol protein/g
venom sample

1

3FTx

–

7064.2

1.99 ± 0.06

2

3FTx

~P29179

7417.40.471 ± 0.066

3

3FTx

~P291797451.60.325 ± 0.040

4

3FTx

~P014206892.41.10 ± 0.13

5

3FTx

~Q9W6W6

7786.4

< 0.1

6

3FTx

~P01452

7277.30.680 ± 0.050

7

3FTx

~P01452

7306.30.668 ± 0.057

8

3FTx

–

7246.21.35 ± 0.10

9

3FTx

P255176832.45.09 ± 0.28

10

3FTx

P014526704.319.0 ± 0.8

11

3FTx

–

6686.30.183 ± 0.035

12

3FTx

–

6829.30.220 ± 0.039

13

3FTx

–

6687.3

< 0.1

14

PLA2

P0060413280.9

7.76 ± 0.32

15

3FTx

P014706882.4

9.54 ± 0.27

16

3FTx

P255176813.316.2 ± 0.4

17

3FTx

P014676814.327.8 ± 0.8

18

3FTx

~P014697046.45.13 ± 0.26

19

PLA2

P0060413237.8

3.40 ± 0.14

20

PLA2

P0000213196.6

7.35 ± 0.33

21

PLA2

–

13179.70.805 ± 0.049

22

Minor

–

42000

0.102 ± 0.009

23Endonuclease

–

30000

0.619 ± 0.050

24

SVMP

Q1074946700

0.165 ± 0.009

25

SVMP

Q1075046700

0.264 ± 0.013

26

SVMP

Q1075146700

0.097 ± 0.006

27

SVMP

Q1075246700

0.257 ± 0.006

Reprinted with permission from Anal. Chem., 2016, 88 (19), 9699–9706.
Copyright 2016 American Chemical Society.

Conclusion
The capLC-ICP-QQQ method uses measurement of sulfur by IDA to enable theabsolute quantification of intact proteins without the need for protein-specificstandards.
Agilent ICP-QQQ instrumentation is especially suited for IDA analysis of S as it
uses MS/MS to remove multiple spectral interferences from several S isotopes
using an oxygen mass shift method. By adding enriched 34S post-column andspiking each sample with a generic S-containing internal standard, multiple
S isotopes can be measured as SO+ product ions. MS/MS ensures that each
S isotope mass enters the CRC in isolation, so no interfering product ions canbe formed from the other isotopes of S. This approach allows the sulfur content
of the proteins to be determined by IDA.

439

The method was applied successfully to the quantification and mass purity
confirmation of protein standards. If quantitative chromatographic recoveries
can be assured, it is even possible to quantify nonpure protein samples using
this method. The potential of the methodology for the quantification of intact
proteins present in relatively complex samples was demonstrated by separating
and quantifying 27 proteins in snake venom.

References
1.	D. A. Warrell, Lancet, 2010, 375, 77–88.
2.	J.M. Gutiérrez, D. Williams, H.W Fan, D.A. Warrell, Toxicon, 2010, 56 (7),1223-1235
3.	D. Petras, L. Sanz, Á. Segura, M. Herrera, M. Villalta, D. Solano, M. Vargas,
G. León, D. A. Warrell, R. D. G. Theakston, R. A. Harrison, N. Durfa, A. Nasidi,
J. M. Gutiérrez, and J. J. Calvete, J. Proteome Res. 2011, 10 (3), 1266–1280.
4.	I. Méndez, J.M. Gutiérrez, Y. Angulo, J.J. Calvete, B. Lomonte, Toxicon, 2011,58 (6–7), 558–564.
5.	Technical Overview of Agilent 8900 Triple Quadrupole ICP-MS, Agilent
publication, 2016, 5991-6942EN
6.	Y. Anan, Y. Hatakeyama, M. Tokumoto, and Y. Ogra, Analysis of selenoproteinsin rat serum by Triple Quadrupole ICP-MS, Agilent publication, 2013, 59912750EN
7.	P. De Raeve, J. Bianga, Fast and accurate absolute quantification of proteins
and antibodies using Isotope Dilution-Triple Quadrupole ICP-MS. Agilent
publication, 2016, 5991-6118EN
8.	M. Wind, A. Wegener, A. Eisenmenger, R. Keller, W.D. Lehmann, Angewandte
Chemie International, 2003, 42:3425–3427
9.	H. Zhang, W. Yan, R Aebersold, Current Opinions Chem. Biol. 2004, 8 (1)66–75
10.	F. Calderon-Celis, S. Diez-Fernandez, J. M. Costa-Fernandez, J. R. Encinar,
J.J. Calvete, and A. Sanz-Medel, Elemental Mass Spectrometry for Absolute
Intact Protein Quantification without Protein-Specific Standards: Application
to Snake Venomics, Anal. Chem., 2016, 88 (19), 9699–9706.

More information
The full results of the study were published in: Francisco Calderón-Celis et al.,Elemental Mass Spectrometry for Absolute Intact Protein Quantification without
Protein-Specific Standards: Application to Snake Venomics, Anal. Chem., 2016,
88 (19), 9699–9706.
For Research Use Only. Not for use in diagnostic procedures.

440

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Pharmaceutical
Title

Page

Quantitative analysis of active pharmaceutical ingredients using
heteroatoms as elemental labels

442

Fast and accurate absolute-quantification of proteins and antibodies using
ID-ICP-QQQ

446

Determination of diclofenac and its related compounds using
RP-HPLC-ICP-QQQ

449

Characterization of rare earth elements used for radiolabelingapplications by ICP-QQQ

456

For Research Use Only. Not for use in diagnostic procedures.
441

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Quantitative Analysis of Active Pharmaceutical
Ingredients using Heteroatoms as Elemental Labels
Authors

Introduction

Naoki Sugiyama1, Yasumi Anan2 andYasumitsu Ogra2

Organic molecules and proteins can be detected and quantified indirectly using
ICP-MS to measure a heteroatom “tag” element contained within the targetedcompound. For example, a large number of Active Pharmaceutical Ingredients(API) contain sulfur (S), phosphorus (P) or halogens. Unfortunately, S, P and thehalogens have high first ionization potentials so they are poorly ionized in the
ICP‑MS plasma, leading to low sensitivity. S, P and chlorine (Cl) are also difficult
to measure by conventional quadrupole ICP‑MS (ICP-QMS) due to intense
spectral interferences. As a result, accurate analysis of S, P, and the halogens at
the analytical ranges that are relevant to pharmaceutical molecules is nearly
impossible to achieve by ICP‑QMS. However, ICP‑QQQ operating in MS/MS
reaction cell mode can be applied to resolve these spectral interferences,
allowing the quantification of S, P and Cl at far lower levels (biologically relevant
concentrations) than was previously possible by ICP‑QMS.

Agilent Technologies, Tokyo, Japan,
Showa Pharmaceutical University,
Tokyo, Japan
1

2

Keywords
protein, heteroatom, API, monoclonal
antibody, mAb, sulfonamide, sulfur,
zoledronic acid hydrate, phosphorus,
clonidine hydrochloride, chlorine,
mass-shift, oxygen reaction mode,hydrogen reaction mode

In this study, five APIs and a monoclonal antibody (mAb) were analyzed using
ICP-QQQ. The targeted compounds included small (m = 250–320 Da) and large(m = 146 kDa for the mAb) molecules.

Experimental
Instrumentation: An Agilent 8800 ICP-QQQ #100 was coupled to an Agilent 1260
Infinity Bio-inert HPLC system with quaternary pump (G5611A) and autosampler(G5667A). An HPLC flow rate of 0.4 mL/min and an injection volume of 20 μL wereapplied throughout the study.
CRC conditions: O2 at 0.3 mL/min. H2 flow at 3.0 mL/min. Octopole bias =-4 V and KED = -8 V.
Acquisition conditions: MS/MS O2 mass-shift method for S and P measurementand H2 mass-shift method for Cl measurement.
LC conditions: Two types of columns were used: an Agilent ZORBAX plus C18,
2.1 x 100 mm, 3.5 μm (Agilent # 959793-902) was used for the analysis of thesmall molecules, and an Agilent Bio SEC-3 300 Å, 4.6 x 150 mm, 3 μm (Agilent #5190-2514) was employed for the mAb analysis.
Reagents: Sulfamethizole, sulfamethazine, sulfamethoxazole, zoledronic acid
hydrate and clonidine hydrochloride were purchased from Sigma Aldrich(St. Louis, MO, US). The monoclonal antibody (IgG2a) was obtained from Agilent
Technologies (Agilent #200473).

442

Results and discussion
Sulfur-containing APIs
Three sulfonamide APIs, sulfamethizole, sulfamethazine and sulfamethoxazole,
were dissolved separately in methanol or methanol/water. Each sample wasfiltered, diluted with the LC mobile phase of 13% acetonitrile with 0.1% formic
acid, and injected into the HPLC using an isocratic separation. The resulting
overlaid chromatograms are shown in Figure 1. The method detection limit (MDL)
for the compound sulfamethizole was calculated to be 23 nM (6.3 ppb as thecompound and 1.5 ppb as S).
Full Time Range EIC(32 ➝ 48) : 007SMPL_NS20131204S2.D
N

x104

N

3

O

CH3

Sulfamethizole (C9H10N4O2S2)

S
NH
S

O

Sulfamethazine (C12H14N4O2S)

Count

NH
S

CH3

O

N

N
O

Sulfamethizole (C10H11N3O3S)

CH3

CH3
NH2

2

N
O
O

NH
S

O

1
NH2
NH2

0
0

6.0

12.0

18.0

RT(min)Figure 1. Overlaid chromatograms of three sulfur-containing APIs. The concentration of S in all
three APIs injected is 100 ppb.

Antibodies are glycoproteins that contain about 1% sulfur and are therefore
excellent targets for quantification via sulfur determination by ICP-QQQ.
A mAb (IgG2a) obtained from Agilent was diluted with UPW and injected into
the HPLC. An isocratic mobile phase of 50 mM phosphate buffer adjusted to
pH 7.0 was used. Figure 2 shows the overlaid chromatograms obtained for two
different concentrations of IgG2a. The MDL was calculated to be 14 nM (40 ng)
as the compound.
Full Time Range EIC(32 ➝ 48) : 015SMPL.dx106015SMPL.d

Exp. RT=3.559

Count014SMPL.d

5mAb (1gG2a)Exp. RT=7.428

0
0

5.0

10.0

15.0

RT(min)Figure 2. Overlaid chromatograms of 0.5 mg/mL and 1.0 mg/mL mAb (IgG2a) obtained by
HPLC-ICP-QQQ.

443

Phosphorus-containing API
ZOMETA® is a commercial phosphorus-containing drug. It contains zoledronic
acid monohydrate (C5H10N2O7P2·H2O). A 5 mL vial of commercially supplied
ZOMETA® (containing 4.264 mg of the API) was prepared by diluting the drug
2000-fold with the LC mobile phase to give a final API concentration of 426.4
μg/L. The isocratic mobile phase consisted of a 70:30 mixture of A: 6 mM
tetra-butyl-ammonium bromide and 5 mM acetic acid adjusted to pH 6.5 with
NH3(aq), and B: 95% MeOH. A calibration curve was prepared using zoledronic
acid monohydrate standards, and the API in the sample was quantified based on
the response for P compared to the external calibration. The concentration of the
API in the sample was determined to be 433 ng/mL, which is a recovery of 102%.
The MDL for the drug compound was calculated to be 25 nM (144 pg; 7.2 ppb ascompound and 1.5 ppb as P).
Chlorine-containing API
Catapres® is a commercial drug that contains clonidine hydrochloride(C9H9Cl2N3·HCl). A tablet of Catapres® (containing 75 μg of the API) was dissolvedin 50 mL water and sonicated for 60 minutes. The solution was then filtered andanalyzed by HPLC-ICP-QQQ. A calibration curve was prepared by analyzingclonidine hydrochloride standards, and the API in the sample was quantified byexternal calibration. The isocratic HPLC method used a mobile phase consistingof 20% acetonitrile with 0.1% formic acid adjusted to pH 7.0 by NH3(aq).
The calibration curve for Cl measured as 35ClH2+ at m/z 37 and the chromatogramof clonidine hydrochloride measured in the Catapres® sample are presented
in Figure 3. The concentration of the API in the sample was determined to be1444 ppb, which is a recovery of 96%. The MDL of the compound was 146 nM(780 pg; 39 ppb as compound and 15 ppb as Cl).
35 ➝ 37 Cl(1)
x106
1.5

Full Time Range EIC(35 ➝ 37) : 007SMPL.dy = 121898.703888 * x + 1879.395631
R = 0.9999
DL = –
BEC = 0.01132 ppb

007SMPL.dx104

Exp. RT=1.259

Count

Count

2

1

(HCI)
Exp. RT=0.778

Clonidine (C9H9Cl2N3)

N

NH
NH

CI

(HCI)
CI

1

0.5

0

0

5.0

10.0
Conc (ppb)0

5.0
RT(min)Figure 3. (Top) Calibration curve for Cl (measured as 35ClH2+) in clonidine hydrochloride (C 9H9Cl2N3·HCl) standards. (Bottom) Chromatogram ofclonidine hydrochloride in Catapres® sample

444

10.0

Conclusion
The advanced capability of the Agilent 8800 ICP‑QQQ operating in MS/MS mode
has been successfully applied to the analysis of APIs and mAb, based on
the measurement of the heteroatoms S, P and Cl — an analysis that is normally
carried out using molecular-MS techniques. These preliminary studies arepresented here in order to demonstrate the potential use of HPLC‑ICP‑QQQ in
drug development and post manufacturing QA/QC control.
For Research Use Only. Not for use in diagnostic procedures.

445

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Fast and Accurate Absolute-quantification of Proteins
and Antibodies using ID-ICP-QQQ
Authors

Introduction

Philippe De Raeve, Juliusz Bianga
Quality Assistance S.A., Contract
Research Organization, Belgium

Triple quadrupole ICP-MS (ICP-QQQ) dramatically improves the efficiency andreliability of removing spectral interferences on a wider number of elements
than conventional ICP-MS. Challenging elements such as sulfur (S), whichsuffer intense spectral overlaps, can be analyzed at low levels by ICP-QQQ.
Furthermore, the effective removal of spectral overlaps allows access to multiple
isotopes of elements, enabling quantification of metalloproteins and peptides
using isotope dilution mass spectrometry (IDMS) analysis. IDMS is an absolute
quantification technique that eliminates the requirement for compound-specificcalibration standards. It allows accurate quantification without the need for areference standard, which is a major benefit of ID-ICP-MS/MS for life science
research, where many compounds are unknown.

Keywords
proteins, antibody, absolutequantification, isotope dilution,
ICP-MS/MS, ICP-QQQ

In this study, we evaluated an Agilent 8800 ICP-QQQ and isotope dilution
analysis (ID-ICP-QQQ) of sulfur, for the quantification of NIST Bovine Serum
Albumin (BSA) 927e standard reference material (SRM) [1] and a monoclonal
antibody, trastuzumab.

Experimental
Instrumentation: An Agilent 8800 #100 was used.
Acquisition conditions: two sulfur isotopes, 32S and 34S, were measured in MS/MS
mass-shift mode with oxygen (O2) reaction gas.
Plasma conditions: RF power =1550 W, nebulizer gas flow rate = 0.25 L/min, anddilution gas flow rate of 0.85 L/min.
Double isotope dilution method: in a simple ID method, a sample containing an
unknown amount of S, which is primarily composed of the major 32S isotope(94.93% abundance), is spiked with a known amount of a certified enrichedisotopic standard solution containing 34S. An aliquot of the resulting solution isanalyzed, and the ratio of 34S to 32S is measured. From the measured ratio andthe known amount of 34S added, it is possible to calculate the amount of 32S and
therefore the total S concentration (based on natural isotopic abundances)in the original sample.
However, as the 34SO42- spiking solution used in this study was prepared byoxidation of a powder of 34S sulfur, the exact concentration of 34S present in the
spike was unknown. Therefore, a high accuracy technique known as double
IDMS was employed in this study per Equation 1. The concentration of 34S in the
H234SO4 solution was determined by reverse IDMS, using a National Institute ofStandards and Technology (NIST) certified solution of SO4 with a natural sulfur
isotopic abundance as the reference standard.

446

• x refers to the sample• y and y’ refer to the 34SO4 spiking solution• z refers to the NIST SO4 standard solution• wx is the sulfur mass fraction (µg/g) in the sample• wz is the sulfur mass fraction (µg/g) in the NIST SO4 standard
solution• mi is the mass of sample, standard, or spiking solution• Ri is the 34S/32S ratio measured by ICP-QQQ in the unspiked andspiked solutions• Rx is the 34S/32S ratio measured in the sample solution• Ry is the 34S/32S ratio measured in the spiking solution• Rz is the 34S/32S ratio measured in the SO4 standard solution• mx is spiked with my and ratio Rxy is measured• mz is spiked with my’ and ratio Rzy is measured
Equation 1. The double IDMS equation used in this study.

Samples: Sample solutions were prepared by microwave digestion. First, anamount of sample (BSA standard and trastuzumab solution) estimated to containapproximately 50 μg sulfur was weighed into a disposable glass tube. 50 μg of34
S (as H234SO4) was added, followed by 2 mL of 69% HNO3, 0.5 mL of 37% HCl,and 1 mL of 30 % H2O2. Once the microwave digestion program had finished,
the digest was transferred and diluted to 50 mL with H2O. The concentration of
S in solution was about 1 ppm.
A standard was also prepared for the double IDMS method. 50 μg of a 1000 mg/L
sulfur ICP-MS standard (natural isotopic abundance) was weighed into anotherglass tube. The above procedure was then carried out.

Results and discussion
Six samples of NIST BSA 927e were quantified using the ID-ICP-MS/MS method.
The average recovery to the certified value (67.38 ±1.38 g/L as S) was 101.26 %and the RSD of six analyses was 0.22%.
Matrix effects were also investigated. The same amount of BSA was spiked withdifferent formulation ingredients. The solutions were then digested and analyzed.
The results in Figure 1 show good recoveries were obtained for S in all matrix
solutions.
Trastuzumab is a monoclonal antibody (mAb) that was quantified using thedeveloped method. The average recovery to expected value (21 mg/mL as S) was
97.8% and the RSD of three analyses was 0.02%.

104

Recovery % of measured BSA

103
102
Recovery (%)

101
100

100.27100.24100.16

0.9% NaCl

PBS

10%sucrose100.76100.2699.61

100.33

99
98
97
96
95
94
0.1%
PS-80

15 mg/mL 15 mg/mL
glycinehistidineAllmatrices

Figure 1. Recovery % (average of n = 3) of measured BSA in various matrix solutions.
The error bars show the standard deviation of the three analyses.

447

Conclusion
The Agilent 8800 ICP-QQQ with MS/MS mode provides high analytical sensitivity
and effective interference reduction for the determination of multiple sulfur
isotopes. This capability allows the accurate analysis of biological moleculesthat contain sulfur, using isotope dilution analysis. The ID-ICP-QQQ method issuitable for the accurate and precise quantitative analysis of biological molecules,
such as pure proteins and antibodies, without the need for compound-specificcalibration standards.

References
1.	National Institute of Standards & Technology SRM 927e certificate
2.	P. De Raeve, J. Bianga, Agilent publication, 2015, 5991-6118EN

More information
Fast and accurate absolute-quantification of proteins and antibodies
using Isotope Dilution-Triple Quadrupole ICP-MS, Agilent publication, 2015,
5991-6118EN
For Research Use Only. Not for use in diagnostic procedures.

448

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Determination of Diclofenac and Its Related Compounds
using RP-HPLC-ICP-QQQ
Authors
Balazs Klencsar1, Lieve Balcaen1,
Filip Cuyckens2, Frederic Lynen3,Frank Vanhaecke1
1 Ghent University,
Department of Analytical
Chemistry, Belgium
2 Janssen R&D,
Pharmacokinetics, Dynamics& Metabolism, Belgium
3 Ghent University,
Department of Organic andMacromolecular Chemistry,
Belgium

Compound structure-independent quantification of drugs
Introduction
Quantitative drug metabolite profiling is an important application in thepharmaceutical industry. Researchers involved in drug development require an
analytical technique with a response that is independent of compound structure.
This compound-independent response enables accurate quantification of the
drug and its metabolites, without requiring compound-specific calibration.
Currently, radiolabeling techniques followed by HPLC separation andradiodetection are used for this application, but a simpler, quicker, and safer
alternative approach is desirable.
The very high temperature plasma ion source and elemental ion-based
measurement of ICP-MS enables compound structure-independent
quantification, so individual standards for the metabolites of the (candidate)drug are not required. ICP-MS also links seamlessly with chromatographysystems, for example HPLC, for speciation studies.
HPLC-ICP-MS is used in a wide range of applications, including speciation
studies of metals and metalloids, such as arsenic, mercury, selenium, chromium,and antimony [1]. However, many drugs contain nonmetal heteroatoms such as
phosphorus, sulfur, chlorine, fluorine, or bromine, rather than metals andmetalloids. The determination of these nonmetals is difficult by conventional
single quadrupole ICP-MS, due to poor ionization, spectral overlaps, highbackgrounds, or a combination of these factors. Except for F, these “difficult”
elements can be measured accurately at low levels by triple quadrupole ICP-MS(ICP-QQQ) operating in MS/MS mode with a reactive cell gas. Reversed phase(RP) HPLC coupled to ICP-QQQ can introduce further analytical challenges due tothe changing composition of the mobile phase during the gradient elution. In thisstudy, it was necessary to compensate for the effect of gradient elution on the
instrumental response during the RP-HPLC-ICP-QQQ analysis [2].
This note describes the quantitative determination of the drug diclofenac andits related degradation compounds. Diclofenac is a prescription non-steroidal
anti-inflammatory drug (NSAID). Compounds were quantified based on
measurement of the Cl heteroatom using RP-HPLC-ICP-QQQ.
Chlorine is not a typical analyte for ICP-MS, due to its poor ionization, highbackground signal, and the presence of intense spectral overlaps. The element’s
very high first ionization potential of 12.967 eV means that Cl atoms are only
converted to positive ions (Cl+) with an efficiency of about 0.13 % in an argon
plasma operating at a nominal temperature of 7000 K. Chlorine is also a common
contaminant in the laboratory, either from handling of sample containers, sample
preparation equipment, or instrument hardware. Also, HCl acid is commonly used
for stabilization of many elements, and chlorine tablets are often used as abiocidal treatment in deionized water systems, leading to high background.
449

Finally, both isotopes of Cl (35Cl and 37Cl) suffer from polyatomic interference frompolyatomic ions including O2H+, SH+, and ArH+.

Experimental
Samples
Diclofenac sodium (99.9% purity) and 4’-hydroxydiclofenac (99.0% purity) werebought from Sigma-Aldrich (St. Louis, MO, USA). Mixed working solutions
containing diclofenac sodium and 4’-hydroxydiclofenac were used for method
development, external standard calibration, and method validation. Full details
are given in Reference 2. Diclofenac was synthetically degraded to generatedegradation products covering a broad hydrophobicity range [2]. The syntheticallydegraded diclofenac samples were used as part of the mass balance study.
Sample preparation details are given in Reference 2.
Instrumentation
An 8800* Triple Quadrupole ICP-MS (ICP-QQQ) was used for all measurements;
the instrument was fitted with a PFA nebulizer and platinum cones. The spraychamber was set to a temperature of -1 °C and a plasma torch with a 1.0 mm
internal diameter injector was used. These changes helped ensure plasma
stability with the high vapor pressure from the volatile organic acetonitrile-based
mobile phase. Oxygen (20% O2 in Ar) was added to the carrier gas flow at
0.20 L/min to prevent the build-up of carbon on the interface.
To address the spectral overlaps on Cl, the major isotope 35Cl (75.78%
abundance) was measured by ICP-QQQ in MS/MS mode using a mass-shiftmethod with H2 cell gas. In this mode, ICP-QQQ avoids the interferences on 35Cl
by measuring the product ion 35ClH2+ at m/z 37 [3]. ICP-QQQ operating conditions
and acquisition parameters are given in Table 1.
Table 1. ICP-QQQ operating conditions and acquisition parameters.
Parameter

Value

RF power (W)1570

Ar carrier gas flow rate (L/min)
Optional gas (20% O2 in Ar) mass flow controller setting

0.30
20% (0.2 L/min)

Spray chamber temp (°C)-1

H2 cell gas flow rate (mL/min)Monitored transitions/masses, Q1  Q2 (m/z)

3.5
35 (Cl )  37 (ClH2+)+

Data collection mode

TRA

Integration time (s)0.4 for m/z 37

The ICP-QQQ was coupled to an Agilent 1260 Infinity HPLC System equipped withan Agilent 1260 Infinity Vacuum Degasser, an Agilent 1260 Infinity Binary Pump,an Agilent 1260 Infinity Autosampler, an Agilent 1290 Infinity Thermostatted
Column Compartment, and an Agilent 1290 Infinity Series 2-position/10-port
Microvalve. Column details and operating conditions are given in Table 2.

* The 8800 ICP-MS has been superseded by the 8900 model.
450

To compensate for the increased sensitivity for Cl caused by the changing levelof acetonitrile during the gradient elution, a mathematical correction was applied
to the Cl response (measured as 35ClH2+). The correction was based on themeasured variation of the Cl response with increasing acetonitrile concentration,
as shown in Figure 1.
The chromatographic peaks for the drug and metabolite compounds wereidentified by retention times (RT), and each peak area was then integrated.
The organic solvent concentration at the RT of each peak was calculated fromthe LC gradient program. The appropriate response factor for each peak was thendetermined from the organic solvent concentration and the response curve.
Finally, the corrected Cl concentration of each peak was calculated based on thepeak area and the corresponding response factor.
Table 2. HPLC operating conditions.
Online preconcentration
Analytical column

1570

Eluent A

0.1% (v/v) formic acid in MQ water

Eluent B

0.1% (v/v) formic acid in acetonitrile

Gradient-1

Flow rate (mL/min)

1.0

Sample temp (°C)

5

Column temp (°C)

22–23 (room temp)

Injection volume (μL)

50

Acetonitrile
x10000

Response factor (Area/ppm)

26

y = 1606.5x + 104598
R 2 = 0.9961

24
22
20
18
16
14
12
10
10

30

50

70

90

Figure 1. Measured response curve demonstrating the Cl ionization enhancement effect causedby the organic solvent (acetonitrile) content of the mobile phase. The Cl response measured
by ICP-QQQ is shown for both inorganic Cl and diclofenac-Cl (95% confidence intervals, n = 3).
The response factor was found to be independent of the chemical form, as expected.

451

Method Development and Method Validation
Selectivity
Compound selectivity—the ability of a technique to distinguish an individualcompound from other (often related) compounds—was confirmed by comparing
the chromatograms shown in Figure 2. The chromatograms include (i) a blank,(ii) a mixture of 4’-hydroxydiclofenac and diclofenac, each at a concentrationequivalent to 1 mg/L (ppm) Cl (iii) synthetically degraded diclofenac at aconcentration equivalent to 10 mg/L Cl, and (iv) synthetically degraded diclofenac(at 10 mg/L Cl) spiked with 4’-hydroxydiclofenac (at 1 mg/L Cl).

x1000014

Intensity of 35ClH 2+/CPS

12

10

8

1

2

6

4

(iv)

2

(iii)
(ii)
(i)

24
0

5
10
15
20
25
t / min
Blank (i)Standard (ii)
Degraded diclofenac (iii)
Degraded diclofenac = 1mg/L Cl as 4’-hydroxy-diclofenac (iv)

Figure 2. Chlorine chromatograms for (i) a blank, (ii) 4’-hydroxydiclofenac plus diclofenac, each ata concentration equivalent to 1 mg/L Cl, (iii) synthetically degraded diclofenac at 10 mg/L Cl, and(iv) synthetically degraded diclofenac at 10 mg/L Cl, spiked with 4’-hydroxydiclofenac at 1 mg/L Cl.
Peak 1: 4’-hydroxydiclofenac; peak 2: diclofenac; other peaks: degradation products with unknown
chemical structure.

Accuracy and precision
Accuracy and precision were investigated by spiking blank plasma with
4’-hydroxydiclofenac and diclofenac at three concentration levels (three replicatesat each level). The recovery was determined for both compounds. To assess
the precision of the method, both intraday and interday precision were studied.
As summarized in Table 3, excellent results were obtained with recoveries
between 90-100% and RSDs below 4%.
Table 3. Accuracy and precision of the results for 4’-hydroxydiclofenac and diclofenac spiked into plasma matrix.
Cl conc (mg/L)

Recovery (%)

Intraday precision (RSD%)Interday precision (RSD%)

4’-hydroxy-diclofenac

Diclofenac

4’-hydroxy-diclofenac

Diclofenac

4’-hydroxy-diclofenac

Diclofenac

0.5

92.4

97.5

2.7

3.2

3.1

2.5

1.0

95.0

97.2

1.8

1.8

1.9

2.3

3.0

91.9

91.8

0.2

0.3

0.3

0.6

452

Linearity and Limit of Quantitation
The linearity of the method was tested by injecting diclofenac standard solutions
at concentrations equivalent to between 0.05 and 5.0 mg/L Cl. Excellent linearity
was achieved with an R2 > 0.99 and with the origin included in the 95% confidence
interval of the intercept.
The limit of quantification (LOQ) was determined according to the signal-to-noise(S/N) method described in the ICH Q2(R1) guidelines (Part II, section 7.2). The
LOQ for diclofenac was a compound concentration equivalent to 0.05 mg/L Cl.
Mass balance study
The mass balance study was performed using a blank solution and a plasma
matrix. Each solution was spiked with synthetically degraded diclofenac at a level
equivalent to a nominal total Cl concentration of 10 mg/L (the actual total spikeamounts are shown in Table 4). The total Cl content of all the compounds in the
spiked samples was measured and the concentration and recovery results are
given in Table 4.
The recovery for the total Cl content was excellent, both in the absence andpresence of the plasma matrix (92 and 93 %, respectively). This matrix-independent
response was further confirmed by comparing the results separately for eachdegradation product peak with and without the plasma matrix. The relative percent
differences (RPDs) observed were mostly less than 5%. Slightly higher differences—
up to 12% RPD—were observed for compounds that were present at levels close to
the LOQ of 0.05 mg/L. It can be concluded that the plasma matrix does not
introduce any bias to the results obtained using this method.
Table 4. Comparison of mass balance studies with and without plasma sample matrix.
RT/minv/v % of acetonitrile*

Cl conc without plasma (mg/L)

Cl conc with plasma (mg/L)

Relative difference (%)**

1.4

30.0

2.10

2.10

0.0

4.4

38.3

0.10

0.10

-2.3

11.1

57.1

0.43

0.44

3.3

11.8

59.2

1.29

1.30

1.5

12.7

61.6

1.25

1.27

1.0

14.7

67.2

0.07

0.07

-9.3

14.8

67.6

0.15

0.14

-5.6

17.0

73.6

2.89

2.94

1.5

18.9

79.0

0.15

0.16

0.2

8.49

8.57

Measured total Cl content (mg/L)
True spike amount (mg/L)

9.21

9.21

Recovery (%)

92.2

93.1

*The eluent composition in which the compound with the indicated retention time is eluted.
**Results in spiked plasma, relative to the values obtained without plasma matrix.

453

Enhancing Sensitivity for Cl
Online sample preconcentration
To improve the sensitivity of the method and enable metabolite profiling of
low-dose Cl-based drugs, a simple sample preconcentration procedure was used.
The drug-related compounds present in plasma were trapped on a trapping column(Waters XBridge BEH C18 4.6x20 mm; 3.5 μm) before analytical separation and
ICP-QQQ detection. No additional sample pretreatment was required. The injection
volume was increased to 1500 μL to load the preconcentration column. Moredetails can be found in Reference 2. Using preconcentration, the LOQ for diclofenac
was equivalent to 0.002 mg/L Cl – a 25-fold improvement. Plasma blanks werespiked with 4’-hydroxydiclofenac and diclofenac at three concentration levels
between 0.005 and 0.05 mg/L Cl (5 to 50 μg/L, ppb). Excellent recoveries between
94 and 98% were obtained for both compounds at all concentration levels, as
shown in Table 5.
Table 5. Recoveries obtained for 4’-hydroxydiclofenac and diclofenac in the presence of plasma matrix,
when using a simple sample preconcentration procedure.
Cl conc (μg/L, ppb)

Recovery (%)
4’-hydroxydiclofenac

Diclofenac

5

95.7

96.7

30

97.8

95.7

50

97.4

93.9

Conclusion
A reversed phase HPLC-ICP-QQQ method has been successfully used for thecompound-independent quantitative determination of diclofenac and its related
compounds. Based on the measurement of the Cl heteroatom, the new HPLCICP-QQQ approach is quicker, simpler, and safer than the traditional radiolabeling
HPLC technique.
Since Cl has a high first ionization potential and is poorly ionized in the ICP
plasma, ICP-MS sensitivity is usually low. This was overcome using a simple
online sample preconcentration procedure. The drug-related compounds from alarger injection volume of plasma were trapped on the preconcentration column,
leading to a 25-fold improvement in the LOQ of Cl. This step broadens theapplication to metabolite profiling of low-dose pharmaceutical drugs containing
Cl at sub mg/L levels.

References
1.	Handbook of Hyphenated ICP-MS Applications, Agilent publication, 2012,
5989-9473EN
2.	Balazs Klencsar, Lieve Balcaen, Filip Cuyckens, Frederic Lynen, Frank
Vanhaecke, Analytica Chimica Acta 974, 2017, 43–53
3.	Naoki Sugiyama, Trace level analysis of sulfur, phosphorus, silicon and chlorine
in NMP using the Agilent 8800 Triple Quadrupole ICP-MS, Agilent publication,
2013, 5991-2303EN

454

More information
For a full account of this application, see Balazs Klencsar, Lieve Balcaen, Filip
Cuyckens, Frederic Lynen, Frank Vanhaecke, Development and validation of a novel
quantification approach for gradient elution reversed phase high-performance liquid
chromatography coupled to tandem ICP-mass spectrometry (RP-HPLC-ICP-MS/MS) and its application to diclofenac and its related compounds, Analytica Chimica
Acta 974, 2017, 43–53, doi.org/10.1016/j.aca.2017.04.030.
For Research Use Only. Not for use in diagnostic procedures.

455

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Characterization of Rare Earth Elements used forRadiolabeling Applications by ICP-QQQ
Authors

Analysis of radiogenic REE isotopes in bulk REE matrices

B. Russell1, P. Ivanov1
B. Webster1,2, D. Read1,2

Introduction

Nuclear Metrology Group, National
Physical Laboratory, Teddington, UK
2
School of Chemistry and Chemical
Engineering, University of Surrey,
Guildford, UK
1Radiolabeling refers to a technique where a compound or substance is labeled(or tagged) with a radioactive isotope of an element. The labeled material canthen be used for controlled delivery of the radiation emitted by the active isotope,or detected and traced from the radioactivity of the isotopic label.
The use of radiolabeled materials is growing steadily, with the market forradiolabeled pharmaceutical compounds expected to be worth over 5 billion
US dollars by 2024 (1). Elements that can form useful radioisotopes include thelanthanides – also known as rare earth elements (REEs). Radio-lanthanide
compounds are used in pharmaceutical and imaging applications.
To meet the rising demand for radio-lanthanides, there is a critical need foranalytical techniques to support the production of traceable, high purity, labeledlanthanides (2). Production scale chemical purification and labeling ofradio-lanthanides is challenging though, because all the lanthanides have similar
chemical properties and tend to behave as a consistent group. To prepare a pureradio-lanthanide, it is necessary to accurately characterize the chemicalcomposition of the non-radioactive natural or isotopically enriched starting
material used. Before a candidate starting material can be used for routine
radionuclide production, each batch must be tested and validated to ensure thatradionuclide yields will be of the desired quantity and quality (3). To carry out thislevel of quality assurance (QA), accurate analytical procedures are needed,
particularly to determine the level of trace lanthanide contaminants in the purelanthanide starting material. Since any impurities need to be removed, the QA
data is also useful to guide the design of robust, reproducible chemical separation
methods (4). Determining the type and quantity of impurities present in thestarting material also helps manufacturers predict whether unwanted radioactiveside-products will be produced during irradiation.
Table 1 lists several radio-lanthanide product isotopes that have chemical andradioactive decay properties that make them suitable for applications inradiolabeling. In most of these examples, the starting material is a different
element to the intended radio-lanthanide product isotope. This avoids theradio-lanthanide product isotope being affected by high concentrations of astable isotope of the same element in the irradiated target, which cannot be
removed by subsequent chemical separation. Typically, the radionuclides areproduced by irradiating a lanthanide or lanthanide oxide starting material target
at a nuclear reactor or cyclotron facility. For example, terbium-155 can beproduced from gadolinium (III) oxide (Gd2O3) starting material in a cyclotron.
The stable isotope 155Gd is converted to the radioisotope 155Tb via a (p, n)reaction, where a proton enters the nucleus and a neutron leaves the nucleus
simultaneously.

456

Table 1. Starting materials and production route for radio-lanthanides used in labeling applications.
Radio-lanthanide
153

Sm

Starting Material*
152

Sm

149

Tb

151

155

Tb

155

Gd

161

Tb

160

Gd

Ho

164

Er

168

Lu

176

166

169
177

Possible Nuclear Reaction Production Route**
152

Eu

Dy

151

Eu(3He, 5n) ----> 149Tb

155
160
164

Gd(p, n) ----> 155Tb

Gd(n, γ)161Gd ----> 161Tb + β-Dy(n, γ)165Dy(n, γ)166Dy ----> 166Ho + β-Er

YbSm(n, γ) ----> 153Sm

168
176

Er(n, γ) ----> 169Er

Yb(n, γ)177Yb ----> 177Lu + β-

* Starting materials are often isotopically enriched targets.
**n (neutron), p (proton), γ (gamma), 3He (helium-3).

The accurate characterization of REE materials is challenging for conventional
single quadrupole ICP-MS. The REEs form hydride (MH+), oxide (MOx+), andhydroxide (MOH+) polyatomic ions in the plasma or during ion extraction, andthese polyatomic ions can overlap the measured isotopes of other REEs. Highintensity REE matrix element peaks can also cause peak tail overlaps on trace
REE isotopes measured at adjacent masses. This peak tailing effect, known as
the abundance sensitivity (AS), is different for different types of mass
spectrometer. On commercial single quadrupole ICP-MS instruments, the AS is
typically 10-7, which means that every 10 million counts at a high intensity peak
contributes one count to the adjacent masses. This AS performance means thatan intense major element peak can cause peak tailing overlaps on trace analytes
at adjacent masses when measured by single quadrupole ICP-MS.
Compared to single quadrupole ICP-MS, Agilent triple quadrupole ICP-MS(ICP-QQQ) instruments offer superior resolution of polyatomic interferences using
reactive cell gases. This performance improves accuracy in complex sample
types, including analysis of trace REEs in geological samples and materials
applications (5, 6). Also, Agilent ICP-QQQ instruments use a tandem mass
spectrometer configuration (MS/MS) with two full-sized quadrupole mass
analyzers, Q1 and Q2, both housed in high vacuum regions. Two mass filtering
steps reduce peak tail overlaps, as the overall AS in MS/MS is the product of the
AS of the two quadrupoles, so 10-7 x 10-7, or 10-14 (7).
Previous studies suggest that ICP-QQQ methods can improve the accuracy ofanalysis of trace impurities in the lanthanide starting materials/targets used forradio-lanthanide production. Also, assessment of the concentration of impurities
in the starting material recovered after chemical separation of the radioisotope
could allow for re-use of the recovered material.
The chemical separation methods used to purify radio-lanthanide isotopes canbe designed and optimized using stable isotopes of each lanthanide, rather than
the radioactive material. ICP-QQQ can be used to measure the intended
lanthanide product element at trace (ppt) levels in the presence of a highconcentration (ppm level) of the bulk target material. This capability enables
realistic testing of the separation scheme while using cheap, safe, and readily
available natural REE materials.
In this study, several pairs of trace REE analytes and adjacent mass neighboring
REE matrix elements relevant to radio-lanthanide production were measured by
ICP-QQQ. The samples included materials that are typically used as irradiation
targets for radio-lanthanide production. The use of ICP-QQQ for optimizing
radiochemical separation of target lanthanides, and for measuring REE impurities
in irradiated targets, was also demonstrated. The developed methods will enable457

end users to compile a REE impurity profile of materials of relevance to the
production of radionuclides for labeling applications.

Experimental
Sample preparation
For the detection limit (DL) study, calibration standards from 1 ppt to 100 ppb wereprepared for each trace REE in solutions containing 10 ppm of the neighboring REE
matrix element. All solutions were stabilized with 2% HNO3. These bulk-trace
lanthanide pairs are summarized in Table 2. Similar solutions were prepared to test
the extraction chromatography-based chemical separation procedures.
Table 2. Pairs of natural REE matrix elements and trace REE analytes used for preparation ofcalibration standard sets to test resolution of adjacent mass interferences.
Bulk REE Matrix(Isotopic abundance, %)139

La (99.91)

140

Ce (88.45)

Ce (88.45)

141

Gd (24.84)

159

140
158

Trace REE Analyte(Isotopic abundance, %)164

Dy (28.18)

165

Ho (100)166

Er (26.78)

169

Yb (31.83)

175

165
168
174

Pr (100)

Tb (100)

Ho (100)

Er (33.61)
Tm (100)

Lu (97.41)

The performance of the ICP-QQQ MS/MS method with O2 cell gas wasinvestigated using analysis of Tb in the presence of a Gd matrix. Gadolinium (III)oxide powder (Gd2O3, 99.999 % purity) was gently dissolved in 8 M HNO3,
evaporated to dryness, and then redissolved in 2% HNO3 to give a final
concentration of 10 ppm Gd.
Irradiated Gd2O3 targets were dissolved in concentrated HNO3. To determine thetarget radio-lanthanide activity levels and any other radionuclides produced, analiquot was taken for measurement by gamma spectrometry. Following thisanalysis the sample was left for enough time to allow short-lived radionuclides todecay, after which the stable REE impurities were determined by ICP-QQQ.
Instrumentation
An Agilent 8800 ICP-QQQ was used in this study. The 8800 was equipped witha standard sample introduction system comprising a glass concentric nebulizer,
a quartz spray chamber, a quartz torch with 2.5 mm i.d. injector, and nickel-tippedinterface cones. The general instrument operating conditions are summarizedin Table 3.
Table 3. ICP-QQQ operating parameters.
Parameter
Scan Mode
Plasma Conditions

MS/MS
Low matrix

RF Power (W)1550

Extract 1 (V)0Extract 2 (V)–175

Reaction Cell Gas

OxygenOxygen Flow Rate (mL/min)

458

Setting

0.3 (30% of full-scale)

Octopole Bias (V)–5.0

Energy Discrimination (V)–7.0

Octopole RF (V)200

Results and discussion
Instrument sensitivity and interference removal
To remove the matrix element hydride and peak tailing interferences for each of
the trace REE analytes investigated, the 8800 ICP-QQQ was operated in MS/MS
mode with O2 cell gas. To compare the performance of single quadrupole ICP-MS,
the measurements were also performed using the 8800 in single quad mode,
where Q1 does not perform any mass selection.
Using the example of trace Tb analysis in a Gd matrix, Tb was measured as the
product ion 159Tb16O+ at m/z 175 using mass shift. In single quad mode, the158
Gd1H and 158Gd tailing interferences were not effectively avoided using O2cell gas. A 10 ppm Gd standard gave a signal at m/z = 175 of approximately
1.3×106 counts per second (cps). This high background meant Tb could not bemeasured at concentrations below 100 ppt.
Using MS/MS mode with Q1 and Q2 set to m/z = 159 and 175, respectively, them/z 175 background signal in the 10 ppm Gd matrix was reduced to ~4,400 cps,
which enabled accurate low-level Tb measurement. Using MS/MS, a detection
limit of 2.1 ppt was achieved for Tb in the 10 ppm Gd matrix with backgroundsubtraction (Figure 1).

Figure 1. Calibration for Tb in the presence of 10 ppm 158Gd. Tb measured as 159Tb16O + by
ICP-MS/MS in O2 mass-shift mode.

A similar trend was seen for the other trace lanthanides listed in Table 4.
Operating the 8800 in MS/MS with on-mass or mass-shift mode using O2 cell gas,
DLs in the low ppt range were achieved for most analytes. Only Ho (measured at
m/z 165) in a Dy (164) matrix and Er (166) in a Ho (165) matrix showed higher
DLs, up to 1.1 ppb in the case of Ho in Dy. The ppt level DLs are equivalent topurity levels of up to 2.1×10-7 relative to the 10 ppm concentration of each
respective matrix element. This sensitivity is significantly better than the purity
information currently provided by the manufacturers of lanthanide powders.
The purity analysis also provides valuable information about possible
radionuclides that may be formed from contaminants during irradiation of thelanthanide starting material powders.
The single O2 cell gas mode used for this study gave acceptable data for all trace
lanthanides studied. The DLs for some REEs, e.g., trace Ho in Dy, could be
improved by further optimizing the cell conditions or using an alternative reaction
gas such as N2O or NH3 (6).

459

Table 4. Detection limits achieved by 8800 ICP-QQQ for trace REEs in REE matrices. Analysis basedon measurement of natural, stable isotope elemental standards.
Trace Element(Measured isotope)

Q1 / Q2

Matrix Element(10 ppm)

DL of Trace
Element (ppt)

Ce (140)140/156

139

Pr (141)

141/157

140

La

12.2

Ce

11.9

Gd

2.1

Dy

1100

Ho

186

Er

2.3

Yb

9.3

Tb (159)

159/175158

Ho (165)

165/181164

Er (166)

166/182165

Tm (169)

169/185

168

Lu (175)

175/191

174

Measurement of lanthanide oxide samples
The concentrations of trace lanthanides in a solution containing 10 ppm Gd2O3
powder were determined using the 8800 ICP-QQQ with O2 cell gas. As shown in
Figure 2, most REEs were measured on-mass. Only 159Tb, 172Yb, and 175Lu were
measured as oxide product ions in mass-shift mode to avoid interferences from158
Gd1H at m/z 159, 156Gd16O at m/z 172, and 158Gd16O1H at m/z 175 (Figure 2).

Figure 2. Impurity profile and ICP-MS measurement uncertainties (2σ) of Gd2O3 powder used
for irradiation.

Elemental standard solutions are used to test chemical separation procedures,
so the same ICP-QQQ method was used to measure impurities in a Gd singleelement ICP standard. The results are shown in Figure 3. The relatively highmeasured concentration of YbO in the powder and ICP standard suggests thatthe interference from 156Gd16O and 156Gd16O2 on 172Yb and 172Yb16O, respectively,
were not fully resolved. Yb is also not very reactive with oxygen cell gas, leading
to low sensitivity for the YbO+ product ion. The method could potentially be
improved through further optimizing the cell conditions or using an alternativecell gas such as N2O or NH3 (6, 7).

Figure 3. Impurity profile and ICP-MS measurement uncertainties (2σ) of a Gd ICP standard using
8800 ICP-QQQ in MS/MS mode with O2 cell gas.
460

Chemical separation results
Operating the 8800 in MS/MS mode with O2 cell gas and using stable element
analogs in place of short-lived radioactive samples enables the optimization of
separation procedures under realistic conditions. Realistic conditions refer to theseparating of a trace level target lanthanide in the presence of highconcentrations of a neighboring lanthanide. This approach enables thedevelopment of robust radiochemical procedures before testing with active
samples. It also avoids the cost and safety issues of handling active materials
during method development.
In this study, Tb was separated from Gd using an extraction chromatography
column packed with a LN (lanthanide) resin (50–100 μm particle size, Triskem
International). Figure 4 shows an elution profile for Gd and Tb at a 4.5×104 excess
of Gd. Gd was expected to elute with 0.75 M HNO3, while Tb was expected to beretained until conditions were switched to 1.0 M HNO3 (8). To check if theseparation scheme had been effective, each 1 mL fraction was collected andmeasured using ICP-MS/MS in O2 mass-shift mode. The results showed that asmall amount of 159Tb was recovered in the 158Gd fraction.
The effectiveness of the ICP-QQQ method to resolve Tb from Gd has been
demonstrated using trace Tb standards in a Gd matrix. This performance gives
confidence that the signal at m/z 159 seen in the Gd fraction was due to trace
159
Tb eluting together with the Gd, rather than an interference from 158Gd1H. Also,
based on the starting concentration of Tb added to the column, the total Tb
recovery was <100%, suggesting little or no contribution from Gd to the measured
Tb signal.

Figure 4. Elution profile for Tb and Gd.

461

Measurement of impurities in irradiated samples
A compacted Gd2O3 powder target was irradiated to produce 155Tb (half-life of
5.32 days). The irradiated target was then dissolved in concentrated HNO3 and an
aliquot was used to measure the activity level of 155Tb and other short-lived
radionuclides by gamma spectrometry. After leaving the sample enough time forthe radioisotopes to decay, the stable REE isotopes remaining in the Gd2O3 sample
were measured using ICP-QQQ.
Lanthanum and Ce were the only REE contaminants detected in the final sample
at concentrations of ~13.1 and 3.5 ppm, respectively. However, the concentrationof both La and Ce was reduced to below background levels after chemical
separation. The detection of La and Ce in the irradiated Gd2O3 powder shows thepotential for stable and long-lived radionuclide impurities to be formed during
irradiation. The findings illustrate the importance of chemical separation in the
production of high purity radio-lanthanides.
The ICP-QQQ method can be used for post-separation analysis of the final
radio-lanthanide product to assess the concentration of stable impurities stillpresent, and to help assess the effectiveness of the chemical separation.
Depending on the application, enriched or recycled target materials may be usedthat contain lanthanides at non-natural abundances, which will affect the level of
impurities that can be measured. The measurement of such impurities isimportant as a QA measure, as high concentrations of impurities can lead tocompetition for the chelating agent used, which can reduce the radiolabelingefficiency.

Conclusion
The use of radio-lanthanides is of increasing interest in pharmaceutical andimaging applications. Preparation of high purity radio-lanthanides often requires
separation of the low concentration target isotope from the high concentration
stable REE matrix. To check the purity of the starting REE materials, the Agilent
8800 ICP-QQQ was operated in MS/MS mode with O2 cell gas to measure all REE
impurities in high-purity REE matrices. The ICP-QQQ method was much more
effective at removing REE matrix-based polyatomic and peak tailing interferencescompared to single quadrupole ICP-MS.
The measurement of trace levels of Tb in the presence of bulk Gd was used as an
example. The results obtained from analyzing stable element standards showedthat the method was useful for a range of radio-lanthanides.
Overall, the ICP-MS/MS method improved accuracy and confidence of themeasurements needed for a complete REE impurity profile of materials used in
the production of radionuclides for pharmaceutical and imaging applications.
The study has shown that the method is suitable for:
– The measurement of REE impurities in the starting powders used forirradiation.
– Optimizing chemical separation conditions using
stable element analogs.
– Assessing the REE impurities present in the irradiated target material
post-irradiation.

462

References
1.

Markets and Markets, Nuclear Medicine/Radiopharmaceuticals Market by
Type (Diagnostic (SPECT - Technetium, PET- F-18), Therapeutic (Beta
Emitters – I-131, Alpha Emitters, Brachytherapy – Y-90)), Application(Oncology, Cardiology) - Global Forecast to 2024, accessed online August
2020, https://www.marketsandmarkets.com/Market-Reports/
radiopharmaceuticals-market-417.html

2.

M. Van de Voorde et al. Radiochemical processing of nuclear-reactorproduced radio lanthanides for medical applications. Coordination Chemistry
Reviews 2019, 382 (1), 103–125

3.

The International Pharmacopoeia, Ninth Edition.
https://apps.who.int/phint/en/p/docf/

4.

B. Webster et al. Chemical Purification of Terbium-155 from Pseudo-Isobaric
Impurities in a Mass Separated Source Produced at CERN, Nature Scientific
Reports 2019, 9, 1–9

5.

N. Sugiyama, Removal of hydride ion interferences (MH+) on Rare EarthElements using the Agilent 8800 Triple Quadrupole ICP-MS, Agilent
publication, 5991-1481EN

6.

N. Sugiyama and G. Woods, Direct measurement of trace rare earth elements(REEs) in high-purity REE oxide using the Agilent 8800 Triple Quadrupole
ICP-MS with MS/MS mode. Agilent publication, 5991-0892EN

7.

N. Sugiyama, Direct Analysis of Ultratrace Rare Earth Elements in
Environmental Waters by ICP-QQQ, Agilent publication, 5994-1785EN

8.

F. Monroy-Guzman and E. J. Salinas, Separation of Micro-Macrocomponent
Systems: Ho-Dy and Lu-Yb by Extraction Chromatography, J. Mex. Chem.
Soc., 2015, 59, 143–150

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GlossaryA
Acquisition
conditions

Parameters including: Peak profile, mass, integration time,scan number and replicate.

ADME

Acronym of absorption, distribution, metabolite, and excretion
studies.

Ammonia, NH3

A reaction gas used in the collision/reaction cell. NH3 is avery reactive gas, which is used both in on-mass methods
and mass-shift methods to remove/avoid interferences.

amu

Atomic mass unit. An obsolete, non-SI unit that is still incommon use in its abbreviated form “amu”, meaning thesame thing as “unified atomic mass unit” (u) or Dalton (Da).
All are used to indicate the atomic mass of ions, atoms or
molecules, based on the carbon 12 standard.

API, Active
Pharmaceutical
Ingredient

An API is a compound in a drug which has remedy effects
on the target disorder.

AS, abundance
sensitivity

The measure of an analyzer’s ability to separate adjacentpeaks differing greatly in intensity. Agilent ICP-QQQ with
MS/MS operation delivers unmatched peak separation(abundance sensitivity <10-10), as the resolution performanceis the product of the abundance sensitivity of the twoquadrupoles.

ASX-520

Autosampler suitable for medium to high sample throughput
applications, with rack configurations providing up to 360 vial
positions (up to 720 with the extended rack XLR-8 version).

Axial Acceleration

A function of the ion guide to accelerate/decelerate ions along
the axis of the ion guide.

B
Bandpass

464

Mode of operation of a multipole ion guide, where both alow-mass cut-off and high-mass cut-off are applied, rejecting
ions below and above a certain m/z. A bandpass filter passes
a “window” of masses (typically covering a 20-30 m/z range)
through the ion guide, and is therefore distinct from a massfilter, which is capable of unit mass resolution (single m/z
mass selection).

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Batch

The acquisition batch contains all the information required fora sample analysis or experiment, including peripump program,tuning conditions, acquisition parameters, sample list anddata analysis (calibration) parameters. The data analysis (DA)batch contains the measured results for the batch of samples,and includes the calibration plots, internal standard signals
and QC flags.

BEC, Background
Equivalent
Concentration

The magnitude of a signal in a blank, expressed as aconcentration.

BED, Background
Equivalent
Diameter

BED is the diameter equivalent to the background noise insingle particle analysis.

C
Charge transfer

A reaction mechanism that relies on the exchange of charge
between ions and cell gas molecules,e.g., Ar+ + NH3  Ar + NH3+

Collision mode

A cell mechanism to remove interferences either by collisional
dissociation or by kinetic energy discrimination (KED). With
KED, ions entering the collision/reaction cell collide with thecell gas (such as helium). Since polyatomic ions have a larger
ionic cross-section than mono-atomic analyte ions at thesame mass, the polyatomic ions undergo more collisions than
the analyte ions, and so lose more energy. By the cell exit, thelower energy ions (the polyatomics) can be separated fromthe higher energy (analyte) ions by applying a bias voltage“step”. This is known as kinetic energy discrimination (KED).

Cool plasma

A technique used to reduce interferences. Under low
temperature plasma (cool plasma) conditions, the formationof interferences such as Ar+, ArO+ and ArH+ is suppressed,
allowing the detection of Ca+, Fe+ and K+ at the trace level.
Typical RF power for cool plasma is 600-900 W.

CRGS, Carrier gas

Carrier gas is an Ar gas supply flowing through the nebulizer
to convert a liquid sample into a fine aerosol. It is a tuning
parameter of the plasma.

CRC, Collision/
Reaction Cell

Device used to remove interferences from the ion beam, using
settings such as cell gas, cell gas flow rate, octopole bias
voltage, KED bias and deflection lens.

D

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DL

Abbreviation of Detection Limit. Also called LOD (limit ofdetection). Usually calculated as the concentration that isequivalent to 3 times the standard deviation (SD) of the
background signal.

Desolvation
system

A device to remove solvent from the aerosol generated by
the nebulizer.

DIGS, Dilution Gas

Argon gas flow added to the carrier gas via a dilution gas port
located between the torch and the spray chamber. A dilution
gas is used for Aerosol Dilution with HMI or UHMI. The gas
supply used for the DiGS can also be switched automatically to
add the gas flow to the spray chamber instead (known as
make-up gas or MUGS). It is a tuning parameter of the plasma.

DMPK: Drug
Metabolism andPharmacokinetics

An approach used to assess the effectiveness and safety of adrug under development.

Dynamic range oranalytical working
range

The range of linearity of an analytical instrument. Agilent
ICP-QQQ instruments are fitted with an advanced, dual-mode,
discrete dynode electron multiplier (DDEM) that provides afull nine orders dynamic range under standard operating
conditions.

Dwell time

The period of time that the analytical instrument accumulates
the signal.

E
Enthalpy ofreaction, ∆HrAmount of energy (heat) absorbed or released by a reaction.
When ΔHr is positive (ΔHr > 0), the reaction is endothermic,
meaning energy is required (absorbed) for the reaction to
occur. When ΔHr is negative (ΔHr < 0), the reaction is
exothermic, meaning energy is released by the reaction,
which is spontaneous.

G
GC Interface kit

Agilent's GC-ICP-MS interface features a fully heated inert
transfer line and separately heated inert torch injector thatprovides reliable separation of volatile compounds.

H
HMI, High Matrix
Introduction

HMI Aerosol Dilution technology is standard on Agilent
ICP-QQQ, extending the TDS range to % level, while eliminating
the added cost, time and potential errors of conventionalliquid dilution.

UHMI, Ultra High
Agilent’s second generation aerosol dilution system, which
Matrix Introduction allows the direct analysis of 25% NaCl solutions.

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Hard extraction

A tuning condition when a negative voltage is applied to theextraction lens. Hard extraction provides higher sensitivity atlower plasma temperature than soft extraction. Cool plasma
conditions require hard extraction.

Helium mode,
He modeSee collision mode.

HR-ICP-MS,
high-resolution
ICP-MS

Also known as magnetic sector, sector field or double
focusing. Magnetic sector based ICP-MS instruments arecapable of resolution (M/ΔM) of up to 10,000 and are able toresolve most polyatomic species from analytes at the same
nominal mass.

I
I-AS, Integrated
Auto sampler

Integrated, covered auto sampler with pumped rinse station;ideal for ultratrace analysis and small sample volumes(as low as 0.5 mL). Flexible rack configurations offer amaximum capacity of 89 vials, plus 3 rinse vials.

ICP

Inductively coupled plasma, generated by applying a highpower radio frequency (RF) field to a flow of argon gas.
The plasma is a high temperature ion source, up to 10,000 K
maximum and around 7,500 K in the central channel.

ICP-MS

Inductively coupled plasma mass spectrometer orspectrometry.

ICP-QQQ

Abbreviation for triple quadrupole ICP-MS.

IDA, ID, ID-MS

Isotope Dilution Analysis or Isotope Dilution Mass
Spectrometry is a highly accurate method to quantify
elements based on the change in isotope ratio that resultsfrom the spiking of an unknown sample with a spike enrichedin one isotope of the target analyte. Because each sample
result is based on the measurement of the change in ratio inthat sample, rather than relative to a response in a separate
calibration standard, IDMS results are also directly traceable
to certified standards, which reduces uncertainty.

Inert Sample
Introduction kit

O-ring-free and manufactured from PFA for the lowest
contamination levels. Demountable torch with Pt or sapphire
injector options. HF resistant, and suitable for high-purity
reagents.

Interferences– spectral

Direct overlap from a different element with an isotope at thesame nominal mass (isobar), or overlap from a polyatomic
ion, or doubly-charged ions resulting from the loss of twoelectrons instead of just one. Because the quadrupole
separates ions based on m/z (mass over charge ratio),a doubly-charged ion (M2+) will appear at mass M/2.

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Ion guide

Operation of an ion lens where no mass rejection is
performed. Applies to simple electrostatic ion lenses, and also
to multipole ion guides operated with no low- or high-mass
cut-off.

IP, Ionization
Potential

The first ionization potential of the element is the energy
required to remove one electron from a neutral atom and isspecific for each element. Most elements are largely
converted (>90%) to singly-charged ions in an argon plasma.
Elements with a low second IP will also form some doublycharged ions.

IR, Isotope Ratio

Ratio of abundance of two isotopes of an element.

Isobar

Refers to isotopes of different elements that appear at thesame nominal mass. These overlaps occur when atoms oftwo different elements (i.e. different number of protons in the
nucleus, so different atomic number) each have an isotope
with the same atomic weight (same total number of protons
plus neutrons in the nucleus, e.g. 204Pb and 204Hg).

Isobaric
interferences

Overlaps that occur at the same mass (see isobar).
These overlaps/interferences can be resolved by reaction
chemistry (e.g. NH3 is used to separate Pb from the Hg
overlap), but cannot be separated by high-resolution ICP-MS;
separation of 204Pb from 204Hg would require a resolutionof around 500,000 (50x higher than can be achieved by any
commercial high-resolution ICP-MS).

IsotopeA specific form (atomic weight) of an element. Many elements
have atoms with different atomic weights, such as Pb 204,
206, 207 and 208; these are called isotopes. The different
isotopes of Pb all have 82 protons in the nucleus (Pb has
atomic number 82) but a different number of neutrons, so theatomic weight is different for each isotope.

ISTD, internal
standard

Internal standards are commonly used in ICP-MS, particularly
where samples vary in composition from the calibration
standards. Changes in sample transport, nebulization
efficiency and signal intensity (long-term drift) would all leadto errors, which may be corrected if an ISTD element withsimilar behavior is used as a reference.

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K
KED, Kinetic Energy KED is used to discriminate the analyte ion of interest from
Discriminationinterfering ion(s) by the difference of kinetic energy. Refer tocollision mode. KED is also used as a tuning parameter of
CRC conditions: KED = (Q2 bias voltage) - (octopole bias
voltage).

L
LA, Laser Ablation

Method used for the direct analysis of solid samples
using a laser to vaporize the sample before introduction to
the plasma.

LC speciation kits

Sample introduction kits to facilitate LC coupling and provide
turn-key methods for common speciation applications.
A Capillary-LC connection kit is also available.

M
MUGS,
Make-up gas

Make-up gas refers to Ar gas applied to the spray chamber toincrease/adjust total injector gas flow rate. It is a tuning
parameter of the plasma.

MS/MS mode

Acquisition mode unique to Agilent ICP-QQQ. MS/MS mode
operates Q1 as a unit (1 amu window) mass filter and Q2 isalso set to the single mass of the target ion or reaction
product ion.

Mass balance

Balance between the amount of a substance introduced into
the system and excreted from the system.

Mass pair

MS/MS mode requires a mass setting for Q1 and Q2.
The selected mass settings for Q1 and Q2 are known as themass pair. For example when As is measured in O2 mode,
Q1 is set to the precursor ion (As+) at m/z 75 and Q2 is set tothe product ion (AsO+) at m/z 91. 75 --> 91 is the mass pairfor As in O2 mode.

Mass filter

Generic term for any mass analyzer capable of unit mass
resolution. Note that the ion guide used in the CRC of somequadrupole mass spectrometers appears physically similar toa quadrupole mass filter. However, these ion guides cannot
provide unit mass resolution because of the ion scattering
effect at the higher pressures present in the CRC.

Mass spectrum

See spectrum.

Mass-shift method A method where the analyte ion is reactive and is moved toa new mass free from the original interference. Sometimes
referred to as “indirect” measurement, e.g. Se+ reacts with
O2 in the cell and is converted to SeO+. It can then be detected
free from the original interference of ArAr+.
MH, MassHunter
software

Software package that provides comprehensive instrument
control for the Agilent ICP-QQQ and accessories, andintegrated data processing.
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> Return to table of contents> Search entire documentm-lensAn optional lens of the Agilent 8900. It provides a low BEC foralkaline elements like K and Na under hot plasma conditions.

Monoclonal
antibody, mAb

Antibody produced by identical antibody-forming cell, whichbinds to a certain antigen.

A calibration solution is spiked at multiple levels directly into
MSA, Method ofStandard Additions the unknown sample, giving a calibration of response against
added concentration. MSA eliminates matrix effects by(also known ascalibrating in the sample matrix.
StdAdd)Multiquad ICP-MS, Any ICP-MS instrument that incorporates more than one
quadrupole. This can apply to a triple quadrupole ICP-MS thatMulti-quadrupole
uses two quadrupole analyzer mass filters (Q1 and Q2), for
ICP-MS.
example. It can also apply to a single quadrupole ICP-MS thatuses a quadrupole ion guide in the collision reaction cell.

N
Nanoparticle, NP

Sub-microscale particles with at least one dimension in thesize range from 1 to 100 nm.

Neutral Gain Scan

Q1 and Q2 scan together, a fixed mass-shift apart.
For example, Q2 scans at Q1 + 16 amu for O-atom addition
reactions.

O470

O2, oxygen

A reaction gas used with the Agilent ICP-QQQ. A number of
elements can be measured in mass-shift method using O2,e.g. Se+ can be measured as SeO+ using O2 cell gas. O2 is also
added to the plasma carrier gas to decompose the carbon
matrix when organic solvents are analyzed.

Octopole bias
(OctP Bias)

A CRC parameter. It is the bias voltage applied to the octopole
ion guide, which determines the collision energy of analyteions with cell gas molecules.

OIDA, on-line
isotope dilution
analysis

A very powerful and useful development of traditional
isotope dilution, using on-line addition of the isotope spike.
Removes the time consuming step of spiking enrichedisotope standards into each separate sample.

On-mass method

A method where reactive interferences are removed to allow
an unreactive analyte to be measured at its original mass.
Sometimes referred to as “direct” measurement, e.g., theinterference of GdO+ on Yb+ can be removed by the reactionof GdO+ with NH3.

Organics kit

Contains the sample introduction parts needed to run volatileorganic solvents. Includes organics torch, solvent-resistantdrain kit and uptake tubing.

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ORS

Agilent’s CRC design is known as the Octopole Reaction
System. It is a temperature-controlled collision/reaction cellwith octopole ion guide and four cell gas lines as standard on
the Agilent ICP-QQQ. Provides maximum flexibility in collisionand reaction modes, and uses a small internal volume cell toensure rapid cell gas switching and high ion transmission.

ORS4

Fourth generation Octopole Reaction System.

Oxygen atom
abstraction or
oxygen atomtransfer

Reaction mechanism associated with the use of oxygen in thecollision reaction cell.

P
Preset method

Preset methods are provided in the ICP-MS MH software.
These built-in methods cover a range of predefined operating
conditions to suit different applications. Using a preset
method, a user can create a new batch with minimum or no
customization.

Preset plasma

Preset plasma conditions are a function of ICP-MS MH
software. The software provides several predefined plasma
conditions that users can select according to the application.
This greatly simplifies system optimization by automaticallytuning and calibrating the plasma parameters, rather than theuser having to set a number of individual plasma tuning
parameters. There are three preset plasma conditions thatcan be selected depending on the sample matrix: Low matrix,
general purpose and HMI/UHMI.

Polyatomic,
polyatomic ion

A molecular ion (an ion composed of more than one atom)that arises in the plasma or during ion extraction, and canappear at the same nominal mass as analyte ions.
Polyatomics are usually interferences (such as ArO+).

Precursor ion scan Q1 scans a user set mass range, while Q2 is set to a single
fixed mass, measuring all the reaction product ions at thatmass, formed from the different ions entering the cell as Q1
scans the mass range.
Product ion scan

Q1 is set to a fixed precursor ion mass, while Q2 scans a user
set mass range measuring all reaction product ions formed
from that single precursor ion.

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Q
Quadrupole bias
(QP Bias or Qpole
Bias)

Bias voltage applied to the Q2 rods. Used in conjunction
with the Octopole bias to provide a bias voltage “step” at thecell exit, usually to reject unwanted low energy ions from theion beam.

Quantitation orquantification

Quantitative results are produced by comparing signal
intensities of elements in the sample to those generated bycalibration standards.

Q1

First quadrupole in the configuration of the Agilent ICP-QQQ.
Q1 is positioned in front of the ORS, to control the ions thatare passed to the cell and enable MS/MS operation.

Q2

Second quadrupole in the configuration of the Agilent
ICP-QQQ. Q2 filters the ions that emerge from the cell exit,
passing only the target analyte ions to the detector.

R
Rare EarthElements, REEs

Comprise 17 elements: Sc, Y, La, Ce, Pr, Nd, (Pm), Sm, Eu, Gd,
Tb, Dy, Ho, Er, Tm, Yb, and Lu.

Resolution

The ability of a mass filter to separate adjacent masses.
Defined as M/ΔM; the mass of the target peak/the massdifference to the nearest adjacent peak that can be separated.
Sometimes also quoted as the width of the peak at a given
peak height (e.g. 0.75 u at 10% peak height).

S
SEMI

Semiconductor Equipment and Materials International
standards are international standards for materials,
chemicals and manufacturing devices used in
microelectronics industries.

Single particle (sp) In this handbook, spICP-MS analysis refers to particle size
analysismeasurement using the signal generated from a single
particle.
Single Quadrupole
MS, ICP-QMS

Conventional ICP-MS containing a single quadrupole
mass filter.

Single Quad mode, Q1 operates as a wide band mass filter. SQ mode emulates
SQ modeconventional quadrupole ICP-MS.
Speciation
measurement

472

Combination of chromatographic techniques with ICP-MS
as a detector to determine the chemical form of elementsin the sample.

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Spectrum(mass spectrum)

After separation by the final mass filter (Q2), the ions aredetected by an electron multiplier. The detector electronics
count and store the total signal for each mass (m/z), creating
a mass spectrum. The spectrum that is produced provides asimple and accurate qualitative representation of the sample.
The magnitude of each peak is directly proportional to theconcentration of an element in a sample.

STS, ShieldTorch
System

A technique to eliminate capacitive coupling between the RF
coil and plasma, keeping the plasma potential low and energy
distribution of ions narrow. The technique is crucial for cool
plasma and collision mode.

T
TDS, total
dissolved solids

The total summed concentration of all non-volatile, dissolved
inorganic and organic substances in a liquid. The nominal
matrix tolerance of ICP-MS instruments is 0.2 % TDS. On
Agilent ICP-MS system, this can be extended to approximately
3% TDS with HDMI, and up to approximately 25% with UHDMI.

Triple quadrupole
ICP-MS

ICP-MS with a tandem MS configuration, featuring aquadrupole mass filter (Q1) in front of the collision/reaction
cell (CRC), which is followed by a second quadrupole massfilter (Q2).

U
Unified atomic
mass unit (u)Equivalent to Dalton (Da) and the obsolete but still widelyused atomic mass unit (amu). All are used to indicate theatomic mass of ions, atoms or molecules, based on the
carbon 12 standard.

UPW

Ultra Pure Water, purified by ion exchange to remove tracecontaminants. Used for preparation of standards and forsample dilution for ultratrace analysis

V
Venomics

The study of venoms via genomic, proteomic, andtransciptomic approaches.

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DE71430128
This information is subject to change without notice.
© Agilent Technologies, Inc. 2022
Published in the USA, July 4, 2022
5991-2802EN