 <232> and <233> for the determination of metals in pharmaceutical products, the need has arisen for analysis of a wide variety of sample types, ranging from raw materials to final medications. Depending on how the medication is administered (oral, inhalation, or parenteral) and its daily dose, the maximum permissible exposure of the various elements changes. Although inductively coupled plasma–mass spectrometry (ICP-MS) is generally thought of as the preferred analytical method because of its ability to measure extremely low levels, ICP-optical emission spectroscopy (OES) can easily meet the requirements for many medications with low daily doses. With its advantages (compared to ICP-MS) in matrix tolerance, robustness, simplicity, and cost, ICP-OES is the technique of choice for the analysis of medications with low daily doses. This article will focus on sample preparation considerations and the analysis of a variety of medications with ICP-OES to meet the 

 <232> and <233> for the analysis of elemental impurities in finished drug products (1,2), it is important for manufacturers to monitor the metal content of the final products to be in compliance. The maximum permitted daily exposure (PDE) of different target elements is primarily defined in 

 <232>, and is based on the route of administration of the medications (1).

 <233> defines the analytical requirements, which are all based on the J values for each element. The J values are a function of the PDE, the maximum daily dose of the medication, and the dilution factor used in sample preparation. The four analytical criteria specified in the quantitative procedures for 

 <233> are accuracy, repeatability, ruggedness, and system suitability.

	Pharmaceutical tablets are complex mixtures that can contain a wide variety of excipients. Because of the variation and complexity, closed-vessel microwave digestion is the most efficient technique to get the tablets into solution without losing volatile elements, such as mercury (Hg). However, when tablets contain silica (SiO

) as excipients, digestion becomes more complex as hydrofluoric acid (HF) must be used. The presence of HF also requires the use of non-glass sample introduction components, unless the HF is dealt with during the digestion process.

	Inductively coupled plasma–optical emission spectroscopy (ICP-OES) can easily meet the requirements for many medications with daily doses of 1 g or less. With its advantages (compared to ICP-mass spectrometry [MS]) in matrix tolerance, robustness, simplicity, and cost, ICP-OES is the technique of choice for the analysis of medications with low daily doses.

	This article focuses on sample preparation considerations, and the analysis of a variety of medications with ICP-OES to meet the 

	A variety of medicines were purchased locally, as summarized in Table I. These samples represent common, over-the-counter medications that are popular among consumers, and include both tablets and nasal sprays. In addition, the acid reducers contained titanium dioxide, while the sleep aid and motion sickness medications had silica dioxide as an inactive ingredients. As a result, these medications required special treatment during sample preparation.

	Because of the variety of sample types and analytes, closed-vessel microwave digestion with a Titan MPS microwave preparation system was used for sample preparation. The high temperature and pressures easily broke down the medications while using a minimum amount of acid (1.5–3 mL HNO

 + 0.5–1.5 mL HCl, depending on the analytes), while the sealed vessels facilitated the recovery of volatile elements, such as mercury and selenium. Table II shows the microwave digestion program used. For each digestion, one tablet was used. For tablets containing SiO

, hydrofluoric acid was required, followed by a HF-complexation step (3 mL of saturated boric acid solution), which allowed a standard glass sample introduction system to be used for all medications.

	All analyses were performed on a PerkinElmer Avio ICP-OES system, using standard sample introduction components and plasma conditions. All measurements were made against external calibration curves prepared in a mixture of nitric and hydrochloric acids to match the acid composition of the samples after digestion. Yttrium (Y) and scandium (Sc) were added to all blanks, standards, and samples as internal standards.

	The digestion procedure was designed to minimize acid use and time. While most elements require nitric acid to be stable in solution, the platinum group elements (PGEs: Au, Ir, Pd, Pt, Rh, Ru) are only stable in hydrochloric acid. However, silver (Ag) precipitates in the presence of low HCl concentration, but remains stable at large excess HCl levels. Therefore, when measuring Group 2B elements, the challenge was to find appropriate HNO

 and HCl concentrations to maintain the stability of all elements in solution, which turned out to be 3% HNO

	Sample preparation time was further reduced by incorporating a cooling step in the microwave program. This step allowed the vessels to be handled 15 min after the digestion was complete, as opposed to 1–2 h if the cooling step were not used.

	Although a single tablet of each medication is required to meet the USP requirements, the digestion methodology was tested with multiple tablets of each medication in a single digestion vessel. It was found that the methodology could completely digest two of the SiO

-containing tablets (total mass = 0.86 g) and five of the allergy tablets (total mass = 0.5 g). Higher levels were not evaluated.

	One of the concerns with the analysis is that some analytes can interfere with other analytes. Consequently, it is possible to obtain results that meet the criteria of 

 <233> while actually measuring an interference on an analyte instead of the analyte itself. To address this situation, all analytes were run individually as single-element solutions at their 1.5J concentrations, and their spectra compared. Where interferences were observed, alternate interference-free wavelengths were chosen when available. For elements where they were not, the effects of the interferences were removed using the system's multicomponent spectral fitting (MSF) feature. Although interelement corrections (IECs) could also be used, MSF was found to be simpler to implement and more robust.

	The concentrations of all elements in each tablet analyzed were less than 0.3J, signifying that these medications do not pose a health risk.

 <233> defines four validation criteria that must be met when performing an analysis: suitability, accuracy, repeatability, and ruggedness. Each medication that was analyzed was subjected to these validation criteria.

	To meet the system suitability criterion, a 1.5J standard must be run at the beginning and end of each batch run, and the difference between the results must be less than 20%. Figure 1 demonstrates that each type of medication easily meets this criteria, with the largest variance being less than 6%.


	Figure 1: System suitability plot showing the drift over a batch analysis from 1.5J standards measured at the beginning and end of batch analyses for allergy tablets and TiO

	With the suitability of the system established, the accuracy of the methodology was evaluated. The accuracy criteria requires that spikes of 0.5J, 1J, and 1.5J be added to the microwave vessels before digestion and carried through the complete sample preparation scheme to determine if analytes are lost during sample preparation. The results are shown in Figure 2, indicating that all spike recoveries are less than 10% for all elements in all medications, significantly less than the method acceptance criteria of 70–150%.

	With the accuracy proven, the repeatability of the methodology was assessed. According to 

 <233>, the repeatability is evaluated through the preparation and analysis of six individual samples of the same medicine spiked at the J values. The RSD of the analysis of these six samples must be less than 20%. As shown in Figure 3, the RSDs are all less than 6%, easily surpassing the USP criterion.


	Figure 2: Accuracy plot showing 0.5J, 1J, and 1.5J predigestion spikes in allergy (green), TiO

-containing (pink) tablets. The black lines define the USP <233> limits.

	With the repeatability of the methodology demonstrated, the ruggedness was evaluated by analyzing the tablets in Figure 3 on a second day. According to USP <233>, the RSDs of the 12 measurements over two days must be less than 25%, which is easily met, as shown in Figure 4.


	Figure 3: Repeatability plot showing RSDs of six predigestion spikes of individual tablets containing TiO

	This article has demonstrated the ability of ICP-OES, in combination with closed-vessel microwave digestion, to meet the requirements of 

 <232> and <233> for allergy tablets and medicines containing TiO

 as excipients. With the inclusion of volatile elements and difficult matrices, high-pressure, high-temperature microwave digestion in sealed containers simplifies and speeds up sample preparation while preventing the loss of volatile elements. Although ICP-MS can also be used for these analyses, ICP-OES has the advantages of lower cost, higher matrix robustness, and ease of use for medicines with a daily dose of less than 1 g per day.


	Figure 4: Ruggedness plot showing RSDs of 12 measurements over 2 days of allergy medications and tablets containing TiO

, spiked at the J level for all analytes.

	(1) General Chapter <232> Elemental Impurities – Limits: Second Supplement of 

	(2) General Chapter <233> Elemental Impurities – Procedures: Second Supplement of 

 is a Product Line Leader at PerkinElmer in Seattle, Washington. Direct correspondence to: 

 is a Senior Application Specialist at PerkinElmer in Shelton, Connecticut. Direct correspondence to: 

Articles

With its advantages-compared to ICP-MS-in matrix tolerance, robustness, simplicity, and cost, ICP-OES may be the technique of choice for the analysis of medications with low daily doses. For such analyses, the use of high-pressure, high-temperature microwave digestion in sealed containers simplifies sample preparation and prevents the loss of volatile elements.

Meeting the USP  and  Guidelines with ICP-OES

In most cases, elements such as gold, platinum, rhodium, and iridium, generally considered noble metals and partly belonging to the so-called platinum group metals (PGMs), are considered interference free in inductively coupled plasma–mass spectrometry (ICP-MS). However, in cases where they need to be accurately quantified at low levels, for example, to determine if their concentration in an ore deposits is high enough to economically justify mining and processing the ore, other elements may easily interfere and cause significant bias. Even trace amounts of hafnium and tantalum severely affect the detection of Pt and Au as a result of interference from HfO, HfOH, and TaO, and negatively impact analysis results. Especially when very low amounts need to be detected, kinetic energy discrimination (KED), the primary tool applied to remove polyatomic interferences in single-quadrupole ICP-MS, is not sufficiently effective to eliminate all interferences at the level required for the accurate quantification of ultratrace amounts of Au, Pt, Rh, and Ir.

	The so-called platinum group metals (PGMs) strictly consist of six precious metals: ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium (Ir), and platinum (Pt). All of the metals possess unique characteristics and are important for applications such as catalysts, both in the chemical industry as well as in catalytic converters in cars, jewelry, and electronic components. Because of their use as catalysts in synthesis for core chemicals for polymerization, they may also be found in consumer products made from silicone or other plasticware. They are also mentioned as potentially occurring impurities in pharmaceutical products, and must be tested for if evidence for their presence in a particular product exists. Gold is another element of great interest. In nature, noble metals occur under certain geological conditions and in certain geographic regions (for example, South Africa, but also Russia or the northern area of the American continent, Canada, and Alaska). Noble metal ores may contain varying amounts and composition of metals at relatively low levels (up to 10 g per ton). Therefore, a careful characterization of all materials is required to make a final decision whether a source is viable to be explored. Because of their chemical nature, sample preparation is often lengthy and involves many different steps to reliably extract the noble metals into solution. Hence, their final concentration in a solution measurable with atomic spectroscopy techniques such as inductively coupled plasma–optical emission spectroscopy (ICP-OES) or ICP-mass spectrometry (MS) is low.

	Although higher mass regions in ICP-MS are not affected by the most abundant Ar-based polyatomic interferences, certain elements may be present in a sample that lead to significant false positive contributions on elements such as Rh or Pt. Whereas the detection of monoisotopic 

 or different polyatomic interferences such as 

, the interferences on the main isotopes of Pt and Au are mainly caused by the presence of Hf in a sample, forming HfO, HfOH, and TaO interfering ions.

	In this article, interference-free analysis of several noble metals will be demonstrated in two sample matrices. Method development was accomplished using a rock sample that did not contain the target elements, leading to excellent detection and quantification limits and quantitative spike recoveries. Finally, the method was applied to an ore sample containing the elements of interest, and the results demonstrate that interference-free analysis is achieved.

	All measurements were accomplished using a Thermo Scientific iCAP TQ ICP-MS system (Thermo Fisher Scientific). The selection of analytes, appropriate analysis mode (single quadrupole vs. triple quadrupole, choice of reactive gas) was accomplished using the Reaction Finder method development assistant software. Further analysis modes for particular isotopes were added manually for comparison. The mass selection in the first quadrupole was controlled using intelligent mass selection (iMS) in all cases. The instrument was tuned daily using the autotune routines supplied with the operating software. To compare the results obtained using different measurement modes, the ICP-MS system was configured to scan all samples in all measurement modes. An overview of the instrument´s settings can be found in Table I. Two certified reference materials were prepared for analysis, GSP 2 (United States Geological Survey), a granodiorite, and AMIS 0416 (African Mineral Standards), a platinum ore. All samples were prepared externally following a previously published protocol (1). Before analysis, all digests were diluted 20 times using a 3% hydrochloric acid, 1% nitric acid diluent and an internal standard solution (containing In and Bi at a concentration of 1 ng/mL

each) was added. After calibration using different multielement standard solutions (concentration range between 50 and 1000 ng/L, diluted in the same acid combination), an initial calibration verification (ICV) was performed (50 ng/L of different PGMs). During analysis, repeated continuing calibration verification checks (CCVs) were interspersed periodically at a concentration level of 500 ng/L. To verify the accuracy and precision of the proposed method, GSP 2 was spiked with trace amounts of different noble metals (10 and 25 ng/L) and analyzed as a quality control check repeatedly during analysis.

	In a first step, suitable measurement conditions involving different scan modes (single quadrupole vs. triple quadrupole) and reactive gases (no gas, KED, O

) were tested for the different PGMs and gold. To perform this study in a realistic sample matrix, containing typically interfering elements plus a considerable matrix load, the GSP 2 reference material provided by the United States Geological Survey (USGS) was chosen. This material represents a granodiorite rock collected in Silver Plume, Colorado. Most importantly for this study, GSP 2 does not contain significant amounts of any of the elements under scrutiny in this study, but plenty of interfering elements such as Hf (information value 14 ± 1 µg/g, interfering on Pt), Lu and Yb (0.23 ± 0.03 and 1.6 ± 0.2 µg/g respectively, interfering on Ir), Cu and Sr (43 ± 4 and 240 ± 10 µg/g respectively, interfering on Rh), among others. The major components (and hence the sample matrix) consists of SiO

	To eliminate the overlaps caused by the interfering elements and facilitate the detection of elements such as Rh, Pd, Ir, Pt, and Au at ultratrace levels, different measurement modes were applied. For example, Pt can be analyzed using two different reactive gases, O

. Figure 1 highlights the reaction pathways in the collision–reaction cell. Because no reaction occurs between Pt and O

, it will pass through the cell unaffected. In contrast, the interference, HfO, initially having the same mass-to-charge

 and hence eliminated in the analyzing quadrupole (Q3). At the same time, the first quadrupole (Q1) filters out all other ions with lower and higher mass, which could potentially react in a similar way, and hence create other interferences on the target ion mass. With ammonia, Pt undergoes different reactions forming Pt-NH

 clusters, the most abundant product ion being Pt(NH

, thus leading to a mass shift of 34 amu. Again, the HfO interferences will not react in the same way and will be eliminated in the analyzing quadrupole. Similar reaction schemes can also be applied for other PGMs, such as Rh, Pd, Ir and also Au. In most cases, they are not reactive toward O

, whereas their interferences can be efficiently eliminated.


	Figure 1: Schematic illustrating the analysis of platinum using triple-quadrupole ICP-MS operated with oxygen and ammonia as reaction gas.

	To prove the successful elimination of interferences and consistent quantification at ultratrace levels, GSP 2 was analyzed unspiked, but also with low-level spikes (10 and 25 ng/L). This approach allows determination of the blank equivalent concentration for each of the elements under study to ensure complete interference removal, and also verification of the capability to accurately detect at these concentration levels. In total, GSP 2 and both spiked samples were analyzed six times in an 11-h analysis. The results for 

Pt are summarized in Table II. The signal observed in the unspiked solution of GSP 2 was consistently found to be around 5 ng/L, so that probably a very low amount of Pt is indeed present in the material. Similar results were obtained for other elements (data not shown). Typical instrumental detection limits were observed to be between 0.1 and 2 ng/L for all elements investigated in this study.

	As can be seen from the results obtained for the unspiked samples, triple quadrupole–based modes allow complete removal of potential interferences. To additionally prove the effectiveness of the selected modes for interference removal the sample was spiked with the main interfering elements (Sr, Hf, Ta, and Lu) at the level equivalent to their initial concentration in the sample, and the increase of the background equivalent concentrations (BECs) for the noble metals was evaluated to be negligible. At the same time, all tested measurement modes accurately and precisely recovered the spiked amounts of both elements. Despite a lower detection sensitivity in comparison to typical measurement modes applied with single-quadrupole ICP-MS system (no gas or kinetic energy discrimination), the attainable limits of detection are still in the single digit nanogram-per-liter range, or even lower.

	In the same analysis sequence, another certified reference material, AMIS 0416, was analyzed to validate the method further. This material was derived from a platinum ore obtained in the Bushfeld complex in South Africa and is certified for its content of different noble metals. Its main composition is slightly different from GSP 2, containing much higher amounts of Fe

	Figure 2 shows the internal standard recovery for both internal standards in all measurement modes over the course of an 11-h analysis sequence, containing in total more than 100 samples. As can be seen, the different sample matrices (acid mixture used to dilute standards and QC checks, GSP 2 and AMIS 0416 reference materials) do not significantly affect the internal standard recovery over time, so that also the analysis of a high number of samples is feasible without interruptions through failed QCs or excessive signal suppression (less than ±30% as widely accepted in different regulatory guidelines).

	The results obtained for the analysis of AMIS 0416 are displayed in Table III. This table also contains all relevant information about the certified and provisional values as supplied by the certificate of analysis, as well as the method for collection (NiS vs. Pb collection), where applicable. Results are reported separately for the different measurement modes that were evaluated in this study. The given recoveries are either calculated for different measurement modes vs. available reference value when more than one result was available (for example, 

Rh), or relative to the reference values for different collection assays when more than one reference value was available (for example, 

Pd). In all cases, the concentrations in the finally measured solution were fairly low (between 20 to 350 ng/L), so that complete elimination of false positives was key to avoid large scaling errors when correcting for the dilution factor. As can be seen, the results for the platinum group elements Rh, Pd, Ir and Pt agree well with the certified values. However, only the result for Au falls short with respect to the reference value. Most likely, as results obtained with GSP 2 indicate excellent recoveries, this shortfall is related to an unresolved issue during sample preparation or handling, which may lead to a loss of Au in the analyzed samples. Gold is known to be ideally stabilized with higher concentrations of hydrochloric acid, typically above what was used as the acid diluent in this study.

	This study reveals the potential of triple-quadrupole ICP-MS for comprehensively eliminating interferences and subsequently allowing reliable quantification of noble metals at ultratrace levels, even in difficult matrices. The effective use of reactive gases for interference removal, complemented by mass filtration before the collision–reaction cell enables full elimination of interferences of different nature (polyatomic, isobaric, or doubly charged) and is therefore a significant improvement for challenging sample matrices such as rocks or ores. However, whereas controlling the analysis is one part of the story, a thorough and effective protocol for sample preparation and handling is equally important for successful ultratrace analysis of noble metals given their similar, yet slightly different chemical behaviors.

	(1) V.K. Karandashev, V. Khvostikov, S.V. Nosenko, and Zh.P. Burmii, 

Daniel Kutscher and Shona McSheehy Ducos 

 are with Thermo Fisher Scientific, Bremen, Germany. 

is with Intertech Corp., Moscow, Russia. 

is with Thermo Fisher Scientific, Hempstead, United Kingdom. Direct correspondence to: 

This study reveals the potential of triple-quadrupole ICP-MS for reliable quantification of noble metals at ultratrace levels even in difficult matrices.The
effective use of reactive gases for interference removal and a thorough and effective protocol for sample preparation and handling are essential.

ICP-MS Analysis of Noble Metals at Low Levels in Geological Reference Materials and Ores

Collision–reaction cell methods are now almost universally accepted in quadrupole inductively coupled plasma–mass spectrometry (ICP-MS) applications. Helium collision mode provides dramatic improvements in detection limits and accuracy of quantitation for many elements by reducing the relative transmission of polyatomic ions compared to the monatomic analyte ions that they overlap. However, spectral interferences that are not caused by polyatomic ions cannot be controlled effectively using helium collision mode. One important example is isobaric overlaps, where isotopes of two different elements occur at the same mass. Reactive cell gases can provide a solution to isobaric overlaps if a gas is selected that reacts quickly with one of the isobaric elements and slowly, or not at all, with the other. This approach, termed "chemical resolution," allows the target isotope to be resolved from the overlapping isobar. To control the reaction chemistry and to ensure that only the intended product ions are measured, an additional mass selection step (before the collision/reaction cell) is essential. This is achieved using a tandem mass spectrometry system (ICP-MS/MS), such as a triple-quadrupole configuration. In this work, we present application examples where ICP-MS/MS was used to separate isobaric overlaps, allowing accurate analysis to be performed.

	The development of collision–reaction cells in inductively coupled plasma–mass spectrometry (ICP-MS) around 20 years ago transformed the ability of analysts to address spectral interferences. In practical applications, the use of helium (He) collision cell gas and kinetic energy discrimination (KED) has been particularly effective to reduce polyatomic ion overlaps (1). Helium mode has improved the accuracy of ICP-MS results for many previously problematic analytes, such as the first-row transition elements, which suffer from multiple polyatomic overlaps in common sample types.

	However, while He mode may be viewed as a near universal approach to reducing polyatomic ion interferences in ICP-MS (2), it is not at all effective for certain other spectral overlaps. He mode cannot resolve the isobaric (same mass) interferences that occur when two (or more) different elements have an isotope at the same nominal mass (for example, 

 204). These isotopes are much too close to be mass-resolved using sector-field "high-resolution" ICP-MS. The resolution (

) required to separate the Hg/Pb isobars is almost 500,000, whereas sector-field ICP-MS instruments are limited to a resolution of about 10,000 (3). Direct interelement overlaps can also occur because of peak "tailing" from an adjacent mass; for example, boron analysis in organic solvents is affected by the low-mass tail from 

	All naturally occurring elements (except indium) have at least one isotope that is free from direct overlap from an isotope of another element, so isobaric overlaps should theoretically be avoidable. But the "free" isotope is not always the most abundant, and may be severely affected by other interferences, such as matrix-based polyatomic ions. Consequently, there may be analytical benefits to measuring an alternative isotope, even one that has an isobaric overlap, if a method can be devised to avoid or remove the overlapping isotope.

	Also, some applications require the measurement of more than one isotope, for example when isotope dilution is used for quantitative analysis, or where natural variations in isotopic abundances are studied. Isotopic dating (geochronology) studies require the analysis of two or more isotopes of an element to measure the degree of isotopic fractionation or radioactive decay over time. These applications require the accurate measurement of a second isotope, and such secondary isotopes often suffer overlap from isotopes of other elements.

Isobaric Overlaps on Natural and Radiogenic Isotopes

	Methods to address some isobaric overlaps are well-established, such as the use of cool plasma (4) or a reaction gas (5) to remove the interference from the major isotope of argon (

Ar, 99.6%) on the major isotope of calcium (

Ar allows the major Ca isotope to be measured, enabling trace level analysis of Ca in semiconductor process chemicals.

	Other isobaric overlaps are less well-known, but may impact ICP-MS performance for emerging applications. One example is the increasing need to monitor elements arising from high-technology industries and manufacturing. Elements including Ga, Ge, Nb, In, Te, and Ta may be important environmental contaminants, and their behavior and potential toxicological impact are not well understood (6). These elements can be measured using ICP-MS; indeed Ge, In, and Te are commonly used as internal standards. But some of these elements are difficult to measure at low levels and, because their natural background levels in the environment are extremely low, analytical methods must be carefully optimized.

	For example, Te detection limits are degraded by its relatively poor ionization. The first ionization potential of Te is 9.01 eV, similar to other poorly ionized elements, Be, Cd, and Zn, so Te is only about 25% ionized in a normal ICP. Also, the only Te isotope that is free from isobaric overlap is 

Te, so this is the preferred Te isotope for ICP-MS measurements. But 

Te has an isotopic abundance of only 7.07%, so the sensitivity is reduced by almost a factor of five compared to the most abundant Te isotope. To measure Te at low levels in environmental samples, it would be beneficial to be able to measure the more abundant isotopes, 

Te (34.08%). However, both these isotopes suffer isobaric overlaps from Xe (a common trace contaminant in high-purity argon gas), while 

Ba, which may be present at milligram-per-kilogram (part-per-million) levels in natural environmental samples. An ICP-MS/MS method that removes the Xe and Ba isobaric overlaps would significantly improve the trace determination of Te.

	Analysis of non-natural, radiogenic isotopes of interest in the nuclear industry can also be compromised by isobaric overlaps. These elements may need to be monitored following accidental release, or from decommissioning, waste disposal, or weapons testing activities. There is increasing interest in the potential of ICP-MS as a rapid technique for measuring radiogenic isotopes with long half-lives and therefore low specific activity (7). Radiogenic isotopes are frequently overlapped by isotopes of naturally occurring elements, which may be present at much higher concentration than the radiogenic isotope of interest. Examples include 

Eu) (11). Radiometric techniques are ideal for measuring the highly radioactive isotopes (such as 

Cs) that are monitored after an accidental release. But activity-based techniques are less suitable for the lower activity levels of the long-lived radioisotopes that persist in the environment long after the initial release. For these isotopes, the ability of ICP-MS/MS to resolve isobaric overlaps may offer a superior detection capability compared to traditional radiometric approaches.

	Theoretically, the reaction chemistry used to resolve isobaric interferences should be applicable to quadrupole ICP-MS instruments with a simple collision–reaction cell, or a bandpass filter before or in the cell. However, these configurations do not possess a true (1 u) mass filter upstream of the collision–reaction cell, so are unable to selectively pass only one precursor ion mass to the cell. As a result, the reaction chemistry is nonspecific, and the product ions formed are unpredictable, and vary with the sample composition. These errors are eliminated using MS/MS mode on a triple-quadrupole ICP-MS system.

	Isotopic overlaps from one element on another can also occur due to peak "tailing" from an adjacent mass. The efficiency with which a mass filter separates adjacent masses is called the abundance sensitivity (AS). This figure indicates the contribution that a peak makes to its neighbors, expressed as a ratio of the peak intensities.

	The mass spectrometer used in a typical quadrupole ICP-MS system operates with AS of about 10

 counts per second (cps) would contribute 1 cps to the masses 1 u above and below. If a trace analyte occurs next to an intense major element peak, accurate determination of the analyte can be difficult or impossible. Examples include the measurement of boron in organic solvents, and trace manganese analysis in an iron-rich matrix. The intense 

Mn peak, contributing to the background at 

 55 and affecting the accuracy of Mn results. In the nuclear industry, radiogenic isotopes that must be measured at extremely low levels can also be impacted by peak tailing, such as trace neptunium 237, measured next to the major isotope of U (238).

	Tandem mass spectrometry offers an interesting solution for these peak tailing overlaps, since the double mass selection of MS/MS improves the AS of the instrument. When both quadrupoles (before and after the cell) of a triple-quadrupole ICP-MS system are operated as true mass filters with a mass resolution of ~0.75 u (MS/MS mode), the overall AS of the instrument is the product of the AS of the two quadrupoles, so 10

. This dramatically improves the ability to separate a trace peak from an intense peak at an adjacent mass.

	An Agilent 8900 ICP-QQQ system (model 100, Advanced Applications Configuration) was used for all measurements. The instrument was fitted with a glass concentric nebulizer, quartz spray chamber, standard quartz torch with 2.5-mm injector, and standard nickel sampling and skimmer cones. Samples were introduced via the built-in peristaltic pump fitted with 1.02-mm i.d. pump tubing.

) was used to resolve the Xe and Ba overlaps on Te at 

 128 and 130. Helium was also added to the cell as a buffer gas. For 

) cell gas was used with mass-shift mode to resolve the isobaric interference from the 

U peak tail and the polyatomic overlaps from UHx that interfere with the trace determination of 

Np. The main operating conditions of the instrument are shown in Table I.


	Table I: ICP-MS/MS acquisition parameters used for measurement of Te in N

	Tellurium calibration standards and Ba matrix solutions were prepared from single-element stock solutions (Agilent Technologies). Ultrapure water was prepared in the laboratory using a Milli-Q Element system (Merck-Millipore), and nitric and hydrochloric acids used for sample stabilization were Ultrapure NORMATOM grade (VWR Chemicals).

	The U matrix for the Np determination was obtained from Agilent, and the trace 

Np standard was measured as part of an instrument evaluation by Springfields Fuels Ltd., UK (12).

 cell gases plus He buffer gas was used to resolve the isobaric interferences on the two most abundant isotopes of Te at 

 128 and 130. The improvement in trace detection of Te due to the removal of the Xe isobaric overlap is illustrated in the calibrations from 1 to 1000 ng/L (ppt) shown in Figure 1 (scales zoomed to ~200 ppt for clarity). The two major isotopes of Te, 

Te (right), are shown. The upper pair of calibration plots show the calibrations in no gas mode. The 

Xe contributing to the blank signal, giving background equivalent concentrations (BECs) of 16 ng/L for 

Te. The difference in the BECs is due to the ~2x higher abundance of 

 cell gas mode (lower pair of plots), the 

-axis offset is completely removed (background signals of 0.3 and 0.2 cps), leading to BECs of 0.029 ng/L and 0.017 ng/L for 

 mode reduced the BEC by a factor of more than 500 for 


	Figure 1: Zoom to show low level calibrations for 

Te (right) in no-gas mode (top) and MS/MS mode with N

	The mixed cell gas method allows the isobaric overlaps from both Xe and 

Te to be removed using the same cell conditions. This was tested using a series of Ba standards from 20 to 1000 µg/L (ppb). Each Ba standard was spiked with 500 ng/L Te, and measured in both no-gas mode and N

 cell gas mode. The measured Te concentrations are shown in the plot in Figure 2, and the recoveries are given in Table II. In no-gas mode, the lowest Ba concentration (20 ppb) gave around 50% error in the Te recovery. In 1000 ppb Ba, the 

Ba contribution led to a reported Te concentration almost 30x higher (2909% recovery) than the true Te concentration. In N

 mode, the Te recoveries were within ± 3% for all Ba concentrations.


	Table II: Recovery of 500 ng/L (ppt) Te spike 

Te in variable Ba matrix levels using MS/MS mode with N

Np was measured in a uranium matrix using MS/MS mass-shift mode with O

 cell gas. Mass shift refers to the mode of operation where Q1 (before the cell) is set to the precursor ion of interest (

Np in this case) and Q2 (after the cell) is set to the target product ion mass (NpO

 269 in this case). The mass transition for Np analysis is Np

 and less favorable for the potential polyatomic overlaps (

) that can affect ultratrace-level Np analysis when U is present. U

 ions are rejected by Q1. The abundance sensitivity of Q1 (10

 in the cell, the potentially interfering product ion 

 270) then undergoes a further mass filtering step in Q2. This reduces the contribution from 

Np is measured completely free from U overlap. This is illustrated in the spectrum in Figure 3, which shows overlaid 

Np standards from 0.19 to 9.5 ng/L (ppt), each prepared in a matrix of 10 mg/L (ppm) U. The calibration presented in Figure 4 shows that the BEC for 

Np in the 10 ppm U matrix was 0.32 pg/L (ppq), demonstrating the ability of triple-quadrupole ICP-MS to separate adjacent mass overlaps by utilizing the improved abundance sensitivity of MS/MS.


	Figure 2: Recovery of 500-ng/L (ppt) Te spike measured at 

Te in varying Ba matrix levels, in MS/MS mode with N

	Double mass selection (MS/MS) in a triple-quadrupole ICP-MS system has been applied to resolving direct, isobaric overlaps and peak tailing contributions from adjacent peaks. Isobaric overlaps can be chemically resolved using controlled, selective reaction chemistry in the collision–reaction cell of the ICP-MS/MS system. This approach allows normally inaccessible isotopes to be measured, providing improved analytical performance and enabling isotope ratio and isotope dilution measurements.

Np standards at 0, 0.19, 0.95, 1.9, and 9.5 ng/L (ppt) in U matrix of 10 mg/L (ppm), showing baseline separation of 

	The improved abundance sensitivity of MS/MS mode also offers analysts the possibility to measure trace elements using isotopes that would otherwise be affected by peak tailing from an adjacent major element. This approach is illustrated using the example of ultratrace 

Np in 10 ppm U matrix, showing BEC of 0.32 pg/L (ppq) and DL of 0.56 pg/L in MS/MS mass-shift mode with O

	(1) N. Yamada, J. Takahashi, and K. Sakata, 

	(3) N. Jakubowski, T. Prohaska, L. Rottmann, and F. Vanhaecke, 

	(5) S.D. Tanner, V.I. Baranov, and U. Vollkopf, 

	(6) M. Filiella and I. Rodushkin, 2018, 

	(7) I.W. Croudace, B.C. Russell, and P.W. Warwick, 

	(8) P. Petrov, B. Russell, D.N. Douglas, and H. Goenaga-Infante, 

	(10) G. Yang, Y. Kato, H. Tazoe, and M. Yamada, 

	(11) M. G. Miranda, B. Russell, and P. Ivanov, 

	(12) G. Duckworth and G. Woods, "Accurate Analysis of Neptunium 237 in a Uranium Matrix, Using ICP-QQQ with MS/MS," 2017, Agilent publication 5991-6905EN.

 are with Agilent Technologies LDA (UK) Ltd. Direct correspondence to: 

When using a triple-quadrupole ICP-MS system, the increased abundance sensitivity of MS/MS mode makes it possible to measure trace elements using isotopes that would otherwise be affected by peak tailing from an adjacent major element. This approach is illustrated using the example of ultratrace 237Np analysis in the presence of 10 ppm U.

Using Double Mass Selection and Reaction Cell Gases to Resolve Isobaric Spectral Overlaps in ICP-MS

Spectroscopy Applications of ICP and ICP-MS

Click the title above to open the Spectroscopy September 2018 Supplement, Applications of ICP & ICP-MS Techniques for Today's Spectroscopists in an interactive PDF format.

Special Issues-09-01-2018

Meeting the USP and Guidelines with ICP-OES

ICP-MS Analysis of Noble Metals at Low Levels in Geological Reference Materials and Ores

Using Double Mass Selection and Reaction Cell Gases to Resolve Isobaric Spectral Overlaps in ICP-MS

Spectroscopy September 2018 Applications of ICP & ICP-MS Techniques for Today's Spectroscopists