International Journal of Drug Development and Research

Key words

Inductively coupled plasma mass spectroscopy; sample introduction, element speciation, separation technique.

INTRODUCTION

Inductively coupled plasma mass spectrometry (ICPMS) is an analytical technique that performs elemental analysis with excellent sensitivity. The ICP-MS instrument employs argon plasma (ICP) as the ionization source and a mass spectrometer (MS), usually with a quadrupole mass filter, to separate the ions produced.

It can simultaneously measure most elements in the periodic table and determine analyte concentrations down to the sub nanogram per litre or parts per trillion (ppt), level. It can perform qualitative, semi quantitative, and quantitative analysis, and compute isotopic ratios on water samples, and in waste extracts and digest In an ICP-MS instrument, liquid samples are introduced by a peristaltic pump to the nebulizer where a sample aerosol is formed.

A double-pass spray chamber ensures that a consistent aerosol is introduced to the plasma. Argon gas is introduced through a series of concentric quartz tubes, known as the ICP torch. The torch is located in the Se centre of a RF coil. A Tesla coil ionizes the argon gas and free electrons are accelerated by a 27 MHz radio frequency field. Collisions between the accelerated electrons and the argon gas generate high temperature plasma. The sample aerosol is instantaneously decomposed in the plasma to form analyte atoms, some of which are ionized.

The ions produced are extracted from the plasma into the mass spectrometer region, which is maintained at a high vacuum (typically 10-6torr) using differential pumping. The analyte ions are extracted through a pair of orifices, approximately 1 mm in diameter, known as the sampling cone and the skimmer cone. The analyte ions are then focused by a series of lenses into a quadrupole mass analyzer which separates the ions based on their mass-tocharge ratio (m/z). Finally, ions are detected using an electron multiplier, and data at all masses are collected and stored through a computer interface. The mass spectrum generated is extremely simple[1].

PRINCIPLE OF ICP-MS

Using ICP-MS, all kinds of materials can be measured. Solutions are vaporized using a nebulizer, while solids can be sampled using laser ablation. Gasses can be sampled directly. The sampled material is introduced into high-energy argon plasma that consists of electrons and positively charged argon ion. In the plasma, the material is split into individual atoms. These atoms will lose electrons and become (singly) charged positive ions. Most elements ionize very efficiently (>90) in the hot plasma.

The layout of an ICP-MS is shown in (fig.1).To allow their identification, the elemental ions produced in the plasma (ICP)must be transferred from 7000K to room temperature and from atmospheric pressure to high vacuum. To do so, the ions are extracted through a number of apertures. Besides ions also photons are produced in the plasma. Photons also pass through the apertures. They are not removed by vacuum and produce high background signal when they reach the detector. To minimize this background, also called photon stop is present this is a small metal plate placed in the centre of the ion beam, which reflects the photons away from the detector.

The positive ions are not stopped by the photon stop because a positively charged cylinder lens guides them around it. Subsequently, the ion beam enters the quadrupole mass analyser. In the quadrupole the ions are separated on the basis of their mass-tocharge ratio. Each element has its own characteristic isotopes and masses and will therefore produce its own mass spectrum. After passing the quadrupole the ions hit a special detector .It contains two stages to allow simultaneous measurements of high and low signals. This allows simultaneous detection of main components and ultra trace elements in single run, the ICP-MS a perfect tool for survey analysis of totally unknown samples[2].

ICP-MS ANALYSIS

An ICP-MS consists of the following component.

•Sample introduction system – composed of a nebulizer and spray chamber and provides the means of getting samples into the instrument

•ICP torch and RF coil–generates the argon plasma, which serves as the ion source of the ICP-MS

•Interface – links the atmospheric pressure ICP ion source to the high vacuum mass spectrometer

•Vacuum system – provides high vacuum for ion optics, quadrupole, and detector

•Collision/reaction cell – precedes the mass spectrometer and is used to remove interferences that can degrade the detection limits achieved. It is possible to have a cell that can be caused both in the collision cell and reaction cell modes, which is referred to as a universal cell

•Ion optics – guides the desired ions into the quadrupole while assuring that neutral species and photons are discarded from the ion beam

•Mass spectrometer – acts as a mass filter to sort ions by their mass-to-charge ratio (m/z)

•Detector – counts individual ions exiting the quadrupole

•Data handling and system controller- controls all aspects of instrument control and data handling to obtain final concentration results.

Now it is time to take a closer look at each of these components.

SAMPLE INTRODUCTION

The first step in analysis is the introduction of the sample. This has been achieved in ICP-MS through a variety of means. The most common method is the use of a nebulizer. This is a device which converts liquids into an aerosol, and that aerosol can then be swept into the plasma to create the ions. Nebulizers work best with simple liquid samples (i.e. solutions). However, there have been instances of their use with more complex materials like slurry. Many varieties of nebulizers have been coupled to ICP-MS, including pneumatic, cross-flow, Babington, ultrasonic, and desolvating types. The aerosol generated is often treated to limit it to only smallest droplets, commonly by means of a double pass or cyclonic spray chamber. Use of auto samplers makes this easier and faster.

Less commonly, the laser ablation has been used as a means of sample introduction. In this method, a laser is focused on the sample and creates a plume of ablated material which can be swept into the plasma. This is particularly useful for solid samples, though can be difficult to create standards for leading the challenges in quantitative analysis.

Other methods of sample introduction are also utilized. Electro thermal vaporization (ETV) and in torch vaporization (ITV) use hot surfaces (graphite or metal, generally) to vaporize samples for introduction. These can use very small amounts of liquids, solids, or slurries. Other methods like vapor generation are also known.

THE ICP TORCH MAKING IONS

The plasma used in an ICP-MS is made by partially ionizing argon gas (Ar Ar+ +e). The energy required for this reaction is obtained by pulsing an electrical current in wires that surround the argon. After the sample is injected, the plasma's extreme temperature causes the sample to separate into individual atoms (atomization). Next, the plasma ionizes these atoms (M M+ + e−) so that they can be detected by the mass spectrometer. Inductively coupled plasma (ICP) for spectrometry is sustained in a torch that consists of three concentric tubes, usually made of quartz. The end of this torch is placed inside an induction coil supplied with a radiofrequency electric current. A flow of argon gas (usually 14 to 18 litres per minute) is introduced between the two outermost tubes of the torch and an electrical spark is applied for a short time to introduce free electronsintothe gas stream. These electrons interact with the radio-frequency magnetic field of the induction coil and are accelerated first in one direction, then the other, as the field changes at high frequency (usually 27.12 MHz). The accelerated electrons collide with argon atoms, and sometimes a collision causes an argon atom to part with one of its electrons. The released electron is in turn accelerated by the rapidly changing magnetic field. The process continues until the rate of release of new electrons in collisions is balanced by the rate of recombination of electrons with argon ions (atoms that have lost an electron). This produces a ‘fireball’ that consists mostly of argon atoms with a rather small fraction of free electrons and argon ions

INTERFACE SAMPLING IONS

Placing a plasma, operating at 6000 °C, near an ion focusing device operating near room temperature is a bit like placing the earth about a half-mile away from the sun. In addition to a large temperature difference, the plasma operates at a pressure that is much higher than the vacuum required by the ion lens and allows mass spectrometer portions of the instrument. The interface the plasma and the ion lens system to coexist and the ions generated by the plasma to pass into the ion lens region. The interface consists of two or three inverted funnel-like devices called cones.

Until recently, all commercially available ICP-MS systems used the two-cone design. Such a design requires down-stream focusing of the beam that exits the interface region.

This focusing has been achieved through the use of a single or a series of charged devices called ion lenses. The need for these ion lenses can be explained in fig no 2 . A mentioned earlier, the plasma (located to the left of the sampler cone) operates at atmospheric pressure, while the filtering quadrupole (located to the right of the skimmer cone) operates at a very low pressure. With a two-cone design, there can only be a two-step reduction in the pressure between the plasma and filtering quadrupole.

A recent innovation has introduced a third cone into the interface which greatly reduces the divergence of the ion beam as it exits the interface region. The third cone, called the hyper-skimmer, provides a threestep reduction in pressure between the plasma and the filtering quadrupole, resulting in a substantial reduction in the divergence of the emerging ion beam. With the three-cone design, conventional ion lenses can be completely eliminated from the instrument, resulting in greater ion transmission, improved long-term stability, and reduced instrument maintenance. In the three-cone design, none of the cones has a voltage applied such as may exist on an extraction lens. Since the cones are electrically neutral, any build up of material on their surfaces will not significantly impact their function. In addition, experience has shown that the threecone design requires no more maintenance than a conventional two-cone design. Cones are most often produced from nickel or platinum. While nickel cones have a lower purchase price, platinum cones provide longer life, are more resistant to some acids, and provide a small improvement in instrument performance. The orifice openings of the cones should be large enough to allow for the passage of the ion beam while, at the same time, not allow so much gas to enter the instrument that the instrument’s vacuum system is taxed. Experience has shown that orifice openings of approximately 1 mm are ideal[3].

TRANSFER OF IONS INTO VACUUM

The carrier gas is sent through the central channel and into the very hot plasma. The sample is then exposed to radio frequency which converts the gas into a plasma. The high temperature of the plasma is sufficient to cause a very large portion of the sample to form ions. This fraction of ionization can approach 100% for some elements (e.g. sodium), but this is dependent on the ionization potential. A fraction of the formed ions passes through a ~1 mm hole (sampler cone) and then a ~0.4 mm hole (skimmer cone). The purpose of which is to allow a vacuum that is required by themass spectrometer.

The vacuum is created and maintained by a series of pumps. The first stage is usually based on a roughing pump, most commonly a standard rotary vane pump. This removes most of the gas and typically reaches a pressure of around 133 Pa. Later stages have their vacuum generated by more powerful vacuum systems, most often turbo molecular pumps. Older instruments may have used oil diffusion pumps for high vacuum regions.

COLLISION REACTION CELL

The collision reaction cell is used to remove interfering ions through ion/neutral reactionsCollision/reaction cells are known under several trade names. The dynamic reaction cell was introduced by Perkin-Elmer on their Elan DRC (followed by Elan DRC II and Elan DRC-e) instrument and is located before the quadrupolein the ICP-MS device[4],[5]. The chamber has a quadrupole and can be filled-up with reaction (or collision) gases (ammonia, methane, oxygen or hydrogen), with one gas type at a time or a mixture of two of them, which reacts with the introduced sample, eliminating some of the interference. The collisional reaction interface (CRI) technology used in the Bruker(former Varian) ICP-MS is another effective approach to removing ions.

Axial field technology (AFT) is a DRC modification by Perkin-Elmer, which consists in two supplementary rods placed in the DRC cell that move the ions faster through the cell and improving analysis speed. Thermo Scientific's XSeries2 instrument utilizes a collision/reaction cell for interference removal, consisting of a non-consumable hexapole and chicane ion deflector, which takes the ion beam offaxis. The Agilent octopole reaction system (ORS)) uses only helium or hydrogen and the volume of the cell is smaller than that of a DRC, but is based only on collision reactions and not on chemical reactions

COLLISIONAL REACTION INTERFACE (CRI)

The proprietary collisional reaction interface (CRI)[6] used in the Bruker ICP-MS destroying interfering ions. These ions are removed by injecting a collisional gas (He), or a reactive gas (H2), or a mixture of the two, directly into the plasma as it flows through the skimmer cone and/or the samplercone.

Supplying the reactive/collisional gas into the tip of the skimmer cone and/or into the tip of the sampler cone induces extra collisions and reactions that destroy polyatomic ions in the passing plasma. Fundamentally, CRI is a micro Collision/Reaction Cell (mCRC) destroying ICP-MS interferences using a collisional Kinetic Energy Discrimination (KED) phenomenon and chemical reactions with interfering ions similarly to traditionally used larger Collision

ION OPTICS

Before mass separation, a beam of positive ions has to be extracted from the plasma and focused into the mass-analyzer. It is important to separate the ions from UV photons, energetic neutrals and from any solid particles that may have been carried into the instrument from the ICP. Traditionally,ICP-MS instruments have used transmitting ion lens arrangements for this purpose. Examples include the Einzel lens,the Barrel lens, Agilent's Omega Lens [7] and Perkin-Elmer's Shadow stop.

Another approach is to use ion guides (quadrupoles, hexapoles, or octopoles) to guide the ions into mass analyzer along a path away from the trajectory of photons or neutral particles. Yet another approach is Varian patented used by Bruker[8] 90 degrees reflecting "Ion Mirror" optics, which are claimed to provide more efficient ion transport into the massanalyzer, resulting in better sensitivity and reduced background[9].

THE MASS SPECTROMETER-SEPERATING ION

The mass spectrometer separates the singly charged ions from each other by mass, serving as a mass filter. Three main types of mass spectrometers are used in commercial ICP-MS systems: quadrupole, time-of-flight, and magnetic sector. For overall performance and economic value, most laboratories choose an ICP-MS with a quadrupole mass spectrometer. A quadrupole works by setting voltages and radio frequencies to allow ions of a given mass-to-charge ratio to remain stable within the rods and pass through to the detector. Ions with different mass to charge ratios are unstable in the cell and are ejected.

To cover the full mass range, the electronics rapidly change the conditions of the quadrupole to allow different mass-to-charge ratio ions to pass through. Under the control of the instrument software, the mass spectrometer can move to any m/z needed to measure the elements of interest in the sample analyse.

DATA HANDLING AND SYSTEM CONTROLLER

All ICP-MS instruments require computers and sophisticated software to control the mass spectrometer as well as perform calculations on the data collected. Additionally, the operating parameters of the spectrometer, including proper ignition of the plasma, pressure within the high vacuum region, and the voltage applied to the detector, are to be constantly monitored by the controller, and the operator is to be alerted if any parameter falls outside of the proper working range and mass response of the instrument. All in all, the controller should monitor more than 100 separate parameters of the spectrometer.

DATA HANDLING AND CALCULATION

The software translates he ion counts measured by the detector into information that may be more useful to the operator. The ICP-MS instrument can provide data in one of four ways – semi-quantitative analysis, quantitative analysis, isotope dilution analysis, and isotope ratio. Results can be generated using customized report formats or easily transferred to a laboratory information management system (LIMS) or other data handling system

ICPMS SPECTRUM

Is a plot of ion intensity (y-axis) versus mass to charge ratio (x-axis).In an argon plasma, predominantly singly charged ions are produced .This means in practice that the mass-to-charge ratio can be replaced by mass in the spectrum (fig. 4).Most elements have more than one isotope and each isotope has a specific mass. Copper(Cu) ,or example, has two isotopes: 63 Cu with 34neutrons and 65 Cu with 36neutrons in the nucleus .thus, the mass spectrum of copper consists of two peaks, mass 63 and mass 65.The natural ratio of the different isotopes of an element is constant in nature. Therefore it is not difficult to correct for overlap of isotopes of different elements. In addition, a noninterfered isotope is present for almost all elements. Remaining interfering signals are removed by “inhouse” software. This approach makes fast overview analysis of the total elemental composition (10)

INTERFERENCES

Although interferences do occur in ICP-MS, they are relatively few in number (when compared to some other analytical techniques such as for example inductively coupled plasma atomic emission spectrometry, ICP-AES), generally predictable and can often be corrected for, may be minimized by optimizing instrument operating conditions, or are relatively insignificant. The three types of interferences that occur are isobaric, molecular (or polyatomic) and doubly-charged ion interferences.

ISOBARIC INTERFERENCES

Occur for equal mass isotopes of different elements. Examples include the following: 58Fe on 58Ni,64Ni on 64Zn,48Ca on 48Ti. They are best avoided by choosing alternative, noninterfered analyte isotopes, if available. Given acknowledge of the natural abundances of the isotopes of all elements, isobaric interferences are easily corrected by measuring the intensity of another isotope of the interfering element and subtracting the appropriate correction factor from the intensity of the interfered isotope.

MOLECULAR INTERFERENCES

Are due to the recombination of sample and matrix ions with Ar or other matrix components (e.g. O, N, Cl, etc.) in the cooler regions of the plasma. Examples include the following:

40Ar16O on 56Fe,47Ti16O on 63Cu,40Ar35Cl on 75As ,40Ar2 on 80Se.

Most molecular ions formed by matrix components are predictable and may be corrected for by applying correction factors determined by analysing interference solutions. Molecular interferences may also be avoided by using alternative, non-interfered analyte isotopes. In some cases they can be reduced in severity or even eliminated completely by using more appropriate sample introduction systems or optimizing instrument operating conditions

DOUBLY-CHARGED ION INTERFERENCES

Are due to relatively rare doubly-charged matrix or sample ions with twice the mass of the analyte and hence the same mass/charge ratio. The following is an example:

90Zr++ on 45Sc.

The formation of doubly-charged species can generally be minimized by optimizing instrument operating conditions. Luckily, the first ionisation potential of Ar, although high enough to efficiently ionise most elements once, is not high enough to produce doubly-charged ions of most elements, thus limiting their numbers in Ar plasmas.

MATRIX EFFECTS

Clogging of the orifices in either or both of the interface cones may be a problem when samples with high total dissolved solid (TDS) contents are analysed. The high salt content of seawater samples represents a common example of this type of matrixdependent effect. The problem may be overcome by sample dilution or by avoiding solutions with TDS concentrations above 0.1 wt.%. Alternatively, a sample introduction system capable of removing dissolved salts may be used (e.g. an ultrasonic nebuliser with a desolvation unit).

The presence of abundant, easily ionised matrix components such as Na in seawater may lead to a suppression in the ionisation efficiency of analytes. Once again, this effect may be reduced by sample dilution or by removal of the easily ionised matrix component.

Mass-charge effectsbetween abundant heavy matrix ions (e.g. Pb, U) with high kinetic energies and lighter analyte ions may also result in decreased analyte signal intensities[11].

LAB CAUTIONS FOR ICP - MS

•Make sure that all samples are well mixed prior to analysis.

•Label all sample tubes and caps.

•Calculate the exact added standard concentration in each sample.

•After completion of the experiment, remove all sample tubes and caps from the ICP-MS instrument area[12].

CURRENT ICP-MS OFFERS

There are several ICP-MS systems that are presently promoted for various application markets. Although quadrupole ICP-MS is the vast majority of ICP-MS instruments produced and sold ,the other two types of ICP-MS instruments available include sector field and time-of-flight (TOF). “In terms of the numbers produced, you can think of quadrupole ICP-MS as being like gasoline engine cars, sector field ICP-MS as diesel cars, and TOF-ICP-MS as being like hybrid cars,”according to Steven Beres, Perkin Elmer ICPMS Specialist/Expert. Asseen, PerkinElmer’s ICP-MS system is continually evolving. The current ICP-MS instruments offered include the ELAN 9000, ELAN DRC-e, and ELAN DRC II.

Agilent Technologies currently markets the 7500 series2, including the 7500cx, which is a wide-range sampler, whereas the 7500csis specifically for the semiconductor industry. ICP-MS systems from Thermo Fisher Scientific include the XSERIES 2, ELEMENT GD, ELEMENT XR, and ELEMENT2 HRICP- MS. The ELEMENT models are sector field ICPMS units. In July 2008, Thermo Fisher published a poster demonstrating the capability of collision cellbased ICP-MS to analyze multi elemental environmental and geological samples with the use of the XSERIES 2 collision cell-based ICP-MS analyzer. Varian currently offers the 810-MS, for trace and elemental analysis, and the 820-MS, which uses a collision reaction interface system to overcome spectroscopic interferences.

GBC Scientific (Dandenong, Victoria, Australia) offers the GBC OptiMass 9500 ICP-TOF-MS, a second-generation time-of-flight mass spectrometer. Its main areas of application include both environmental and forensic analysis[13].

EXPANDING MARKETS

The market size for the number of ICP-MS units sold, including both quadrupole and high-resolution systems, is currently 900–1000 per year. ICP-MS has been widely used for testing drinking water, wastewater, soil and other parts of the environment, body fluids, tissues, and the materials that make electronic chips. ICP-MS technology has revolutionized many industries, including the semiconductor and environmental industries, by enabling laboratories to run more precise, sensitive analyses, more economically and more quickly. In fact, today’s three major applications served by ICPMS technology include environmental monitoring, biomonitoring, and elemental analysis in the semiconductor industry.

Environmental monitoring and biomonitoring go somewhat hand-in-hand, since both involve testing for chemicals in the environment. Environmental monitoring is of fundamental importance because it provides the basis on which we make our assessments of the quality of our environment. Biomonitoring is an important application on a personal level since it involves testing human blood, urine, and other body fluids and tissue samples to assess the degree of exposure and absorption of natural, synthetic, and toxic chemicals in the environment.

The semiconductor industry is another important application market for ICP-MS. Over the past several decades, computer chips have been introduced into the majority of electronic devices manufactured in the world today— mobile phones, TVs, DVD players, and more. Throughout the years, the application of ICP-MS to test the materials that make electronic chips has allowed semiconductor chips to become more powerful, smaller, and affordable. “ICP-MS has allowed them to achieve greater densities with fewer defects per wafer so that the cost per chip could decrease,” noted Steven Beres.

ICP-MS is influencing new ways of thinking in other markets. One market involves the observation of life science and biological applications. Cells and other intracellular components interact with elements and metals for signaling, function, and maintenance. As a result, ICP-MS would be a potential tool to analyze molecular interactions occurring within the cells, which includes binding interactions between proteins and other metals

APPLICATIONS QUANTITATIVE ANALYSIS

The ICP-MS accurately determines how much of a specific element is in the material analyzed. In a typical quantitative analysis, the concentration of each element is determined by comparing the counts measured for a selected isotope to an external calibration curve that was generated for that element. Liquid calibration standards are prepared in the same manner as used in AA and ICP-OES analysis. These standards are analyzed to establish the calibration curve. The unknown samples are then run, and the signal intensities are compared to the calibration curve to determine the concentration of the unknown.

ISOTOPE RATIO

Since ICP-MS instruments measure specific isotopes of an element, the ratio of two or more isotopes can readily be determined. Isotope-ratio determinations are used in a variety of applications, including geological dating of rocks, nuclear applications, determining the source of a contaminant, and biological tracer studies.

ISOTOPE DILUTION

Isotope dilution experiments can also be performed by ICP-MS. In isotope dilution, the sample is spiked with an enriched isotope of the element of interest. The enriched isotope acts as both a calibration standard and an internal standard. Because the enriched isotope has the same chemical and physical properties as the analyte element, it is the best possible internal standard. For this reason, isotope dilution is recognized as being the most accurate type of all analyses and is often used to certify standard reference materials.

SEMI-QUANTITATIVE ANALYSIS

For some analyses, it is not necessary to calibrate the ICP-MS for each element. After the instrument has been calibrated using a single solution containing as few as three elements, a high-quality semiquantitative analysis for 82 elements can be performed in just a few minutes. Semi-quantitative analysis provides a fingerprint of the elements present in a sample and the approximate concentrations of each element. This information can help determine what standards are necessary for quantitative analysis. Additionally, semi- quantitative analysis can provide valuable information on what other elements are present in a sample that could cause interferences and potentially affect the results. The software does this by comparing the measured spectrum of the unknown sample to the known isotopic fingerprints for each element and mass response of the instrument. When a match is obtained, the element is identified and the concentration estimated by comparing the measured signal to a stored response file for that element.

This technique is routinely used to analyse trace and ultra-trace levels of most metals and some nonmetals in:

•digests of rocks, minerals and organic materials

•waters

Elements routinely determined by ICP-MS:

Li, Be, Sc, V, Cr, Co, Ni, Cu, Zn, Ga, Rb, Y, Zr, Nb, Mo, Cd, Sn, Sb, Cs, Ba, rare earth elements, Hf, Ta, W, Re, Tl, Pb, Th, U

Examples

•chemical analysis of meteorites and lunar rocks(10)

•high-precision determination of ultra-trace levels of rare earth elements in a wide range of rocks, minerals and natural waters

•determination of rare earth and other trace elements in peat samples as tracers of climate change

•biomonitoring using rare earth and other trace elements in lichens

•detection of ultra-trace levels of metals using diffusive gradients in thin films (DGT)

•detection of titanium and silver in experimental solutions

•study of elemental tracers in biological samples - gadolinium in cell lysates, for example

•survey analysis of main and ultratrace elements in both organic and inorganic samples.

•Depth profiles of elements in solids by using laser abalation as a sampling technique, Trace element analysis of fresh, saline and sediment pore waters.

Conflict of Interest

NIL

Source of Support

NONE

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4

References

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