Liquid samples are typically digested and then reconstituted in an aqueous matrix to stabilize elements as an ionic solution. The matrix typically contains 2% nitric acid, and may have 0.5% hydrochloric acid added to stabilize certain elements. The final composition of any matrix is highly dependent on the nature of the analytes being measured.

Liquids can be analyzed directly without dissolution using a standard ICP-MS introduction kit—provided the TDS (total dissolved solids) level is below ~0.5%. Above this level, the TDS may precipitate in the nebulizer or overload the plasma, either of which alter the way the sample is processed in the plasma. This can result in a data collection issue called drift. Specialized nebulizers and spray chambers may be required to counteract drift; more commonly, sample dilution is performed. Organic liquid samples can be analyzed in the sample with minor modifications to the ICP-MS system. Usually, a smaller injector and platinum tipped cones are used, and oxygen is added to the plasma to prevent carbon deposition and signal drift.

With solid samples, digestion in strong and hot acids is the typical protocol. The acids themselves range from simple nitric acid (for relatively simple matrices) to hydrofluoric acid (for samples containing high silicon dioxide content). Samples containing organic matter may also have hydrogen peroxide added to them during the digestion step because H2O2 breaks down organic matter efficiently. Solid samples can also be directly turned into aerosols several different ways, the most common being laser ablation (LA), spark ablation, or electrothermal vaporization (ETV). In all of these methods, the samples are converted to an aerosol and transported to the plasma with inert gas.

ETV is a bulk analysis method that interacts with the entire sample and is useful for combustible samples. Spark ablation is a semi-bulk analysis tool and is useful for sampling large spots (1–3 mm diameter) of a conducting sample. LA is a microanalysis technique using high irradiance (UV) lasers to analyze very small spots (2–750 µm in diameter) on virtually all solid samples. Because of the small spot sizes, LA is also useful for tracking element distribution in a sample.

Internal standards can be added into the sample to monitor and correct for a range of parameters during the experiment, from sample viscosity to analyte precipitation to instrument drift. The amount of dissolved solid in the sample also has an effect on the analysis. Typically, the maximum percentage of total dissolved solid (TDS) that will allow robust data to be produced is 0.2%, but this also depends on the instrument setup (nebulizer used, cones, and interface setup) and the constituents of the matrix. Heavier elements have a much stronger effect on the ion beam than lighter elements, so a 0.5% TDS for a sodium or calcium-based matrix can be tolerated, whereas only 0.1% of a tungsten or lead-based matrix is possible.

Specialized sample introduction systems can be coupled to an ICP-MS, including spark- or laser-ablation systems, hydride generators, and chromatography systems (GC, IC, HPLC, and UPLC systems). In these cases, sample preparation protocols will vary depending on the sample introduction system being used.

When complete precision is not required, and analyte standards are not readily available, semi-quantitative calibration can be used to generate concentration data. Semi-quantitative calibrations are typically based on the sensitivities of elements surrounding the analyte signal, and the response from this range of elements is already known. These sensitivities are corrected for isotope abundance and a curve is fitted to them. Sensitivity for the analyte is then measured from that curve, and a concentration is calculated.

The response curve is usually a polynomial fit, and therefore requires at least three other elements for effective semi-quantitative analysis to be performed. When elements with similar masses to the analyte are used, semi-quantitative concentration data offer good accuracy.

External calibration uses a range of separate (external) standards of known concentration of the analyte to generate a calibration curve of instrument response. The calibration curve, which is usually a linear regression, is then used to back-calculate the concentration of analyte in unknown samples based on their instrument response. Pure elemental standards generate highly accurate calibration curves; however, they do not account for matrix-induced effects, such as signal suppression, or instrument drift that can arise due to the matrix present in the sample.

Drift can be corrected by recalibrating throughout the assay, but this can add significant time and expense to most routine assays. Matrix effects can be compensated for by using matrix-matched calibration standards, which means adjusting the matrix of the standards to match that of the samples. Accomplishing this task successfully depends entirely on how well the sample matrix is understood and characterized.

A good way to compensate for matrix effects and instrument drift is to combine external calibration with internal standardization. This is the most widely used method of calibration in ICP-MS and involves adding the same amount of one or more elements to all measured solutions (blanks, calibration standards, quality control standards, unknown samples, etc.). The response from this element is expected to be the same throughout the assay, so that any variation is assumed to be derived from either matrix effects or instrument drift.

A mathematical correction factor is calculated from the relative internal standard response that is then applied to the analytes to correct for both matrix and drift effects. The ideal internal standard for any given analyte is not already present in the sample, has a similar mass and ionization potential as the analyte, and behaves similarly to the analyte, both in solution and the plasma.

In cases where the samples have a very high percentage of total dissolved solids (e.g., 0.3% or higher), internal standardization may not be sufficient to correct for matrix-induced effects and drift. The sample is then divided into several aliquots in order to generate a calibration curve (e.g., three aliquots for a blank and two standards). Into each of these aliquots, external calibration solutions are spiked directly. This yields an ‘offset’ calibration curve, and the negative x-intercept is the analyte concentration.

While the method of standard additions is more robust and reliable than typical calibration, it is costly and time-consuming. Ideally, one might use just one sample to generate a calibration curve, then use that curve to quantify many other samples, provided they all have the same matrix.

The radio frequency (RF) generator provides a constant source of energy to maintain the plasma. It does this by sending a high power (~1.5 kW) RF signal through a load coil wrapped around the ICP torch. The plasma itself is formed when seed electrons from a spark source, such as a Tesla coil, cause argon atoms to ionize within the torch gas flows. When these ions collide with other argon atoms, they cause a cascade of ionization that forms the plasma. The constant RF electrical energy provided by the RF generator then maintains the plasma. The plasma itself generates a magnetic field that directly opposes the RF generator. For a stable plasma, the RF generator and plasma frequencies are synchronized (or ‘matched’) so the magnetic field coming from the plasma has minimal effect and the plasma can be sustained more easily. When samples are introduced, the plasma frequency changes, so the RF generator may become mismatched to the plasma.

Due to this phenomenon, an RF generator must be capable of coping with fluctuations in the plasma by either returning the plasma frequency to the RF generator frequency (performed in frequency-locked generators), or by adjusting the RF generator frequency so that it matches that of the plasma (performed in free-running generators). Free-running RF generators are capable of coping with wider variations in the sample matrix as well, and can therefore sustain the plasma for longer time periods. In so doing, they enable longer analyses because a more robust plasma is possible.

Once they pass through the high vacuum region, elemental masses of the sample are separated using a mass analyzer. There are two types of mass analyzer typically used in ICP-MS, namely quadrupole and magnetic sector. Quadrupole mass analyzers are sequential, so each element is measured in sequence. Magnetic sector analyzers can be either sequential or simultaneous depending on the geometry of the instrument components.

Quadrupole instruments are typically used in routine labs since they are relatively easy to operate and maintain. Magnetic sector instruments are inherently more sensitive than quadrupole instruments because they use higher ion extraction potentials. As a result, they are used in more specialized applications, or when higher sensitivity is needed.

A quadrupole mass analyzer works by combining a radio frequency (RF) alternating current (AC) potential with a direct current (DC) potential over four electrodes, or poles, to create the electric field that sample ions pass through. As the ions pass through this electric field, they gain energy and accelerate. Two of the oppositely placed poles have a positive potential applied to them, and the other two have a negative potential applied. So, the quadrupole actually generates two overlapping electric fields: one in the horizontal plane and the other in the vertical plane.

The DC component of the electric field produces a constant force on the ions while they travel through the quadrupole. Because the ions are positively charged from the plasma, the positive poles repel the ions into the center of the mass analyzer, while the negative poles attract the ions away from the center of the quadrupole. The AC component counteracts the effect of the DC component depending on the ion’s mass. Because the ions gain energy as they pass through the quadrupole, the degree to which the AC component affects the ion flight path increases along the length of the quadrupole.

Lighter ions are more easily affected by the AC field than heavier ions and they follow the oscillations of the RF driving circuit. Heavier ions are significantly less responsive to the AC field, tending to follow the DC field instead. This means that for the positive pair of poles, lighter ions are pushed out of the quadrupole along its length by oscillations. For the negative pair of poles, the lighter ions are held in the quadrupole by oscillations

For both the vertical and horizontal electric fields, only specific combinations of AC and DC potential result in a stable flight path through the quadrupole for any given mass. Plotted on a stability diagram, there is overlap in the stability regions, so the ion can pass through the quadrupole mass filter.

The size of this stability region is different for each ion mass, so individual masses can be resolved with specific AC/DC potential combinations. Mass resolution is controlled by the ratio of DC against AC potential, and unit mass resolution is easily achieved. Keeping the ratio constant and increasing the potentials allows each mass in the spectrum to be scanned individually.

Mass resolution can be controlled by increasing the DC offset of this line, but this does come with an associated loss in sensitivity. Also, the practical resolution limit depends on the overall sensitivity of the instrument. Typically, this is 0.7–0.85u in ‘normal’ resolution. However, in most quadrupole mass spectrometers, resolution can be switched to ‘high’ resolution at 0.3–0.4u. Such a switch helps attenuate very high signals of, for example, matrix components.

A magnetic sector mass analyzer works by applying a force on charged ions as they pass through a magnetic field. This force is perpendicular to the ion flight path and is directly proportional to the momentum of the ions. As such, the ions are deflected, with the radius of their deflection proportional to the force being applied as well as the momentum of those ions.

The electromagnets used in mass spectrometers are also curved and contain a central channel through which particular ions can pass unhindered. Varying the magnetic field strength ultimately controls the momentum of the ion that can pass through the center of the electromagnet, and into the following section of the mass spectrometer.

Momentum is the product of an ion’s mass and velocity, which is in turn governed by the amount of kinetic energy it contains. Because a plasma produces ions with a wide range of kinetic energies, ions of slightly varying mass could have the same momentum. It is therefore possible for two ions of different mass to have the same radius of curvature through the magnet.

To compensate for this effect, an electric sector analyzer (ESA) is used to separate ions by their kinetic energy. The ESA focuses ions of the same mass yet slightly varying kinetic energies onto the same point in space, so that any remaining ions of slightly varying mass can be rejected from the ion beam.

Correcting ion energies allows the magnetic sector to separate ions into different points in space. Placing separate detectors at these points allows ions to be detected simultaneously, and these so-called ‘multicollector’ systems are capable of measuring isotope ratios with much greater precision than can be achieved with sequential quadrupole or magnetic sector mass analyzers. In this case, the ESA and magnet are reversed to provide better spatial resolution and stability.

Some analytes have other elements or polyatomic species that overlap with their signal, resulting in the analyte signal becoming higher than normal. These species are called interferences. One type of interference occurs when argon, sample matrix, and solvent-based ions enter the collision cell and generate new product ions. These product ions can affect data quality by reducing detection capability.

Interferences must be corrected if the final analyte signal is to be accurate. This is completed either during the analysis or following data acquisition. Reducing interferences is a key challenge in ICP-MS, but it can be achieved in several ways. One of the simplest methods is using alternative sample introduction, including aerosol desolvation, to minimize the population of unwanted precursor ions in the plasma itself. This serves to reduce molecular species entering the mass spectrometer. Cold plasma techniques take this effect into account; in plasma generation, the plasma power is reduced, which also reduces the formation of polyatomic species. This method, however, assumes consistent matrix effects; any significant changes in matrix from one sample to the next could have a significant effect on interference generation that cannot be accounted for by internal standardization.

Isobaric interferences can be addressed by measuring another intereference isotope and, after correcting for natural isotope abundance differences, using those counts to estimate the proportion of signal in the analyte channel that is derived from the interference. This can then be subtracted before further data processing to give a more accurate result. This method assumes no isotope fractionation, so it cannot be used for isotope dilution or any method intended for geological process analysis.

The methods mentioned above are not always successful in addressing interferences; therefore, collision reaction cell (CRC) technology has emerged as a comprehensive solution to this issue. In CRC, the cell is a multipole system like the mass analyzer, but only operates with RF voltage. This means it can transmit a range of masses, but each ion mass has an optimum transmission at a different AC voltage.

In quadrupole CRCs, there is a minimum mass that will pass through the cell, or a ‘low mass cutoff’ (LMCO), that is tunable with AC voltage. An AC voltage for optimum transmission of the analyte mass is selected (i.e., final mass analyzer mass), which means quadrupole CRCs have the added advantage of being able to reject small ‘precursor’ ions and reduce polyatomic ion formation in the cell itself. This inherently reduces interferences by design, even when not in active use. The CRC can be set to kinetic energy discrimination (KED) mode, which is the most universal mode for interference removal. This mode utilizes helium as the cell gas because it is inert and does not react with the analyte. Helium also has low mass, so it does not degrade signal sensitivity very much.

KED creates a potential energy barrier at the CRC exit using ion lenses. Because the exit of the CRC is more positive than the entrance, this slightly repels ions back into the cell. As the sample ions pass through the CRC, they encounter neutral helium atoms and collide. These collisions slow the ions down, so their kinetic energy is reduced. As the ions progress through the cell and collide with additional upstream helium atoms, their kinetic energy is reduced to the point where the potential energy barrier prevents them from leaving the cell as part of the ion beam, resulting in their ejection from the cell.

Polyatomic ions are larger than sample ions because they are made up of multiple atoms by definition. Because of this, they encounter more collisions than the analyte ions, and so lose energy faster. By altering the amount of helium in the cell, it is possible to reduce the kinetic energy of the polyatomic interferences to the point where they are ejected by the potential energy barrier set up in the cell, but not the analyte ion.

When combined with KED, the LMCO collision/reaction cell is capable of filtering out unwanted polyatomic interferences based on differences in analyte and polyatomic intererence cross-sectional sizes. Such “Q Cell” technology effectively removes unwanted precursor ions, preventing them from recombining later on in the selection quadrupole.

After mass separation, ions must be detected and amplified in order to determine their intensities. Two types of detector are typically used: Faraday cups and electron multipliers.

Faraday cups are simple devices: When high-velocity ions hit the Faraday cup, they transfer their charge to the metal inside the cup. This induces a current that is sent to an amplifier circuit leading to detection. Faraday cups require a relatively large number of ions to produce a measurable signal, and so cannot be used to detect single ion events. However, they are extremely stable and are suited to precision isotope ratio measurements, especially in multicollector instruments where the necessary ion currents are easily achievable.

Electron multipliers (also known as secondary electron multiplier, or SEM, detectors) can detect extremely small ion currents, including even single ions, coming from the mass analyzer. They operate on the principle of secondary electron emission, in which charged particles with sufficient energy incident on a ‘dynode’ stimulate the emission of electrons from the surface. By setting up a series of discrete dynodes, gain amplification that allows for single ion detection can be easily achieved. Modern SEM detectors are capable of count rates in the range of single ions, to more than 109 ions per second.