Ed McCurdy is an Agilent ICP-MS Applications Engineer; article from Spectroscopy Magazine, Vol. 37, No. 2.
Inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) is a relatively new technology, with the world’s first ICP-MS/MS (Agilent 8800) being commercially available in 2012. However, the technology is rapidly gaining acceptance and is used in a variety of industries including industrial manufacturing, third party testing, government, research and universities. In this article we will explain the key steps in the development of an ICP-MS/MS method and clarify some common misconceptions surrounding the technology.
Key advantages of ICP-MS/MS over conventional single quadrupole inductively coupled plasma mass spectrometry (ICP-MS) include: the ability to eliminate mass spectral interference using controlled chemical reactions in a collision reaction cell (CRC); two mass filters for better separation of ‘peak trailing’ from adjacent masses; higher sensitivity and lower background for improved detection limits.
The flexibility of ICP-MS/MS has led some users to believe that method development for ICP-MS/MS must be more difficult than in single quadrupole ICP-MS. However, existing single quadrupole methods can often be transferred directly to ICP-MS/MS without major modifications. In addition, the reaction mode is more stable, the method is more versatile and the operation is simpler when run on ICP-MS/MS compared to single-rod. The following six steps can help guide the method development setup for ICP-MS/MS (Figure 1):
Step 1: Getting the basics right
When developing an ICP-MS/MS method, the user may first focus on how specific mass spectral interferences need to be resolved. However, as with conventional ICP-MS, the starting point for ICP-MS/MS method development should be to prioritise the wider analytical needs. These needs include several factors that are easily overlooked.
Firstly, can the instrument tolerate the sample matrix? Matrix tolerance is very important for many ICP-MS applications. Optimising the plasma to provide low CeO+/Ce+ (<1.5%) ensures that the instrument can easily tolerate common sample matrix levels. Low CeO/Ce indicates better matrix breakdown and thus less deposition on the interface, resulting in better stability and less maintenance. Low CeO/Ce conditions also increase ionisation of the elements to be measured, improving sensitivity to difficult to ionise elements such as beryllium, arsenic, cadmium and mercury. Low CeO/Ce indicates a more complete dissociation of the molecular state, which would otherwise form polyatomic ions interfering.
Secondly, are the sample components unknown or in transformation? Major element concentrations and inter-sample variability can be important influencing factors. Changing sample matrices can cause unexpected polyatomic ion interference that may not be effectively removed by a fixed reaction mode. In such cases, the helium (He) collision mode can provide a simpler, more versatile and reliable solution.
Thirdly, which elements are analysed and at what concentration levels?He mode has been used successfully in most ICP-MS applications, but lower elemental concentrations may require reaction mode methods to further reduce background and increase detection limits. Similarly, analysis of higher elemental concentrations may require manual tuning or dilution of the sample if the detector does not cover the entire concentration range.
Finally, how many samples to analyse? Many parameters affect the speed of analysis of large batches of samples. ICP-MS/MS is compatible with discrete injection systems and can reduce sample analysis time. However, the number of cell gases and the time taken to switch between modes can also affect the analytical throughput.
Step 2: Identify Critical Method Needs—Why is ICP-MS/MS Needed?
Once the basic needs of the analysis have been addressed, critical needs should be considered. This stage usually focuses on difficult sample types, specific elements to be analysed or very low concentration levels. In the context of ICP-MS/MS method development, this step should focus preferentially on elements that are affected by mass spectral interferences.
Step 3: Apply the Simplest Approach to Address Interferences
ICP-MS/MS offers performance advantages due to the addition of the quadrupole Q1 prior to CRC, which allows control of the reaction process in the cell. The reaction mode can be very effective in removing interferences, for example for the analysis of high purity reagents. However, reaction mode methods may be specific for different interferences and therefore multi-element methods often require multiple pool conditions. These conditions may not be fully applicable to all sample types.
As mentioned above, most ICP-MS interferences can usually be resolved using the He mode. the main mass spectral interferences in ICP-MS are generated by polyatomic (molecular) ions. For example, 40Ar35Cl+ overlaps with 75As+ at m/z 75. The He mode uses kinetic energy discrimination (KED) to reduce polyatomic ion transport to avoid them interfering with monoatomic ions. The He model therefore supports multi-element analysis and is compatible with secondary (confirmatory) isotopes of many elements, while also reducing the need for unreliable mathematical correction equations.
The main attraction of the He mode is that the same cell conditions can be used for multiple elements with different sample types, making method development simple and consistent. he mode is the default mode for single quadrupole ICP-MS methods and can be used in the same way on ICP-MS/MS. The use of He mode for most elements also makes method development relatively simple for reaction modes for only a few elements.
Step 4: Identify Analytes or Overlaps that Cannot Be Addressed Using He Mode
Many users use ICP-MS/MS precisely because they are unable to meet their analytical requirements in single quadrupole ICP-MS, even with an optimised He mode. Often, these requirements involve specific mass spectral interferences or adjacent mass number interferences that can only be resolved using reaction gas or two mass screens (MS/MS).
ICP-MS/MS can use reaction modes to eliminate strong mass spectral interferences, such as 14N2 on 28Si, 14N16O1H on 31P and 16O2 on 32S, allowing analysis of these previously difficult-to-measure elements at low concentration levels. The reaction mode also reduces matrix-derived mass spectral interferences to low levels, enabling trace analysis.
The He mode cannot resolve homogeneous isotopic interferences such as 48Ca on 48Ti, 40Ar on 40Ca, 204Hg on 204Pb, etc. In conventional ICP-MS analysis, these interferences can be avoided by measuring alternative mass numbers (47Ti, 44Ca and 206/207/208Pb in the example above). However, for some applications the measurement of the interfered isotope is necessary or there are performance advantages in some applications, such as higher sensitivity. In these cases, the reaction mode can resolve the above-mentioned interferences.
Double-charged ion interference is formed when an atom loses two electrons in the plasma and forms a double-charged (M2+) ion. Quadrupole mass filters separate ions according to the mass-to-charge ratio (m/z), so that M2+ ions present half of their true mass. Most elements form insignificant concentrations of M2+ ions, but some elements, such as rare earth elements (REEs), do form a small fraction of M2+ ions. These REE2+ ions can cause interference. For example, 150Nd2+ and 150Sm2+ overlap with 75As+. Single quadrupole ICP-MS can correct for routine levels of M2+ interference, but this method is not effective at high concentrations of interference. For the analysis of trace arsenic and selenium in rare earth minerals, for example, the reaction mode is more effective.
Major element peaks trailing off can strongly affect the trace elements measured next to them. An example is the analysis of trace manganese (m/z 55) in an iron or steel matrix (iron major isotopes at m/z 54 and 56). A dual mass number filter for MS/MS is used to resolve peak trailing, as the abundance sensitivity (AS) of a tandem mass spectrum is the product of the two mass filters AS, thus in the case of ICP-MS/MS Q1 AS x Q2 AS.
Step 5: Select the Preferred Reaction Gas Mode
Selecting the appropriate reaction mode for mass spectral interferences that cannot be resolved using He mode is not as difficult as new users often believe, as ICP-MS/MS ion-molecular chemistry reactions are well known and documented. Agilent applications can usually be run using the pre-defined method settings provided by the instrument software. More established application methods are documented in the manufacturer’s application notes and user publications.
ICP-MS/MS users also benefit from unique method development tools, including product ion and pre-stage ion scans. These are useful for identifying suitable analyte product ions and potential matrix-derived product ion interferences.
Step 6: Ensure Control of Cell-Formed Reaction Product Ions
When the reaction gas is used in ICP-MS, new product ions can be formed in the CRC. The generation of potentially interfering product ions is a major disadvantage of the reaction mode compared to the He mode, but the control of product ion formation is a key advantage of the tandem mass spectrometry configuration. Prior to CRC, the Q1 mass filter ensures that only ions of the target mass (i.e. the element to be measured and corresponding interferences of the same mass number) enter the CRC. Q1 therefore prevents the formation of product ions from other mass numbers of analytes or matrix elements. However, product ions can still be generated from the reaction gas itself. For example, when measuring 52Cr+ in an organic matrix, Q1 is set to m/z 52, allowing 52Cr+ and 40Ar12C+ to enter the cell. NH3 gas removes 40Ar12C+ by charge transfer reactions:
However, the NH4+ product ion can further react with the NH3 pool gas to form a new NH4(NH3)2+ cluster ion at m/z 52:
Depending on the configuration and conditions of the ICP-MS/MS collisional reaction cell, either mass discrimination or energy discrimination can be used to prevent the formation of sequential reactions of NH4(NH3)2+ product ions. One of the energy discrimination methods is effective because the product ions produced from the cell gas only have the kinetic energy they have gained from the collision. These low-energy product ions do not have enough energy to pass through the gas-filled reaction cell, so they do not appear in the mass spectra (Figure 2).
Figure 2: (a) Superimposed ICP-MS/MS mass spectra (blank and 1 ppb chromium (Cr) in 1% methanol). Background equivalent concentrations <1 ppt confirm that the NH4(NH3)2+ product ions formed in the cell can be removed using energy discrimination (m/z 52).