Appendix II G1. Inductively Coupled Plasma-Mass Spectrometry

(Ph. Eur. method 2.2.58)

Inductively coupled plasma-mass spectrometry (ICP-MS) is a mass spectrometry method that uses an inductively coupled plasma (ICP) as the ionisation source. The basic principles of ICP formation are described in chapter 2.2.57 on inductively coupled plasma-atomic emission spectrometry (ICP-AES).

ICP-MS utilises the ability of the ICP to generate charged ions from the element species within a sample. These ions are then directed into a mass spectrometer, which separates them according to their mass-to-charge ratio (m/z). Most mass spectrometers have a quadrupole system or a magnetic sector. Ions are transported from the plasma through 2 cones (sampler and skimmer cones, forming the interface region) to the ion optics. The ion optics consist of an electrostatic lens, which takes ions from an area at atmospheric pressure to the mass filter at a vacuum of 10^-8 Pa or less, maintained with a turbomolecular pump. After their filtration, ions of the selected mass/charge ratio are directed to a detector (channel electromultiplier, Faraday cup, dynodes), where ion currents are converted into electrical signals. The element is quantified according to the number of ions arriving and generating electrical pulses per unit time.

The sample-introduction system and data-handling techniques of an ICP-AES system are also used in ICP-MS.

apparatus

The apparatus consists essentially of the following elements:

— sample-introduction system, consisting of a peristaltic pump delivering the solution at constant flow rate into a nebuliser;

— radio-frequency (RF) generator;

— plasma torch;

— interface region including cones to transport ions to the ion optics;

— mass spectrometer;

— detector;

— data-acquisition unit.

Interference

Mass interference is the major problem, for example by isobaric species that significantly overlap the mass signal of the ions of interest, especially in the central part of the mass range (for example 40-80 a.m.u.). The combination of atomic ions leads to polyatomic or molecular interferences (i.e. ⁴⁰Ar¹⁶O with ⁵⁶Fe or ⁴⁰Ar⁴⁰Ar with ⁸⁰Se). Matrix interference may also occur with some analytes. Some samples have an impact on droplet formation or on the ionisation temperature in the plasma. These phenomena may lead to the suppression of analyte signals. Physical interference is to be circumvented by using the method of internal standardisation or by standard addition. The element used as internal standard depends on the element to be measured: ⁵⁹Co and ¹¹⁵In, for example, can be used as internal standards.

The prime characteristic of an ICP-MS instrument is its resolution, i.e. the efficiency of separation of 2 close masses. Quadrupole instruments are, from this point of view, inferior to magnetic-sector spectrometers.

procedure

sample preparations and sample introduction

The sample preparation usually involves a step of digestion of the matrix by a suitable method, for example in a microwave oven. Furthermore, it is important to ensure that the analyte concentration falls within the working range of the instrument through dilution or preconcentration, and that the sample-containing solution can be nebulised in a reproducible manner.

Several sample-introduction systems tolerate high acid concentrations, but the use of sulfuric and phosphoric acids can contribute to background emission. Therefore, nitric and hydrochloric acids are preferable. The availability of hydrofluoric acid-resistant (for example perfluoroalkoxy polymer) sample-introduction systems and torches also allows the use of hydrofluoric acid. In selecting a sample-introduction method, the requirements for sensitivity, stability, speed, sample size, corrosion resistance and resistance to clogging have to be considered. The use of a cross-flow nebuliser combined with a spray chamber and torch is suitable for most requirements. The peristaltic pumps usually deliver the standard and sample solutions at a rate of 20-1000 µL/min.

In the case of organic solvents being used, the introduction of oxygen must be considered to avoid organic layers.

Choice of operating conditions

The standard operating conditions prescribed by the manufacturer are to be followed. Usually, different sets of operating conditions are used for aqueous solutions and for organic solvents. Suitable operating parameters are to be properly chosen:

— selection of cones (material of sampler and skimmer);

— support-gas flow rates (outer, intermediate and inner tubes of the torch);

— RF power;

— pump speed;

— selection of one or more isotopes of the element to be measured (mass).

isotope selection

Isotope selection is made using several criteria. The most abundant isotope for a given element is selected to obtain maximum sensitivity. Furthermore, an isotope with the least interference from other species in the sample matrix and from the support gas should be selected. Information about isobaric interferences and interferences from polyatomic ions of various types, for example hydrides, oxides, chlorides, etc., is usually available in the software of ICP-MS instrument manufacturers.

control of instrument performance

System suitability

— Tuning of the instrument allows to monitor and adjust the measurement before running samples. ICP-MS mass accuracy is checked with a tuning solution containing several isotopes covering the whole range of masses, for example ⁹Be, ⁵⁹Co, ⁸⁹Y, ¹¹⁵In, ¹⁴⁰Ce and ²⁰⁹Bi.

— Sensitivity and short- and long-term stability are recorded. The instrument parameters (plasma condition, ion lenses and quadrupole parameter) are to be optimised to obtain the highest possible number of counts.

— Tuning for resolution and mass axis is to be done with a solution of Li, Y and Tl to ensure an acceptable response over a wide range of masses.

— Evaluation of the efficiency of the plasma to decompose oxides has to be performed in order to minimise these interferences. The ratio Ce/CeO and/or Ba/BaO is a good indicator, and a level less than about 3 per cent is required.

— Reduction of the formation of double-charged ions is made with Ba and Ce. The ratio of the signal for double-charged ions to the assigned element should be less than 2 per cent.

— Long-term stability is checked by running a standard first and at the end of the sample sequence, controlling whether salt deposits on the cones have reduced the signal throughout the run.

validation of the method

Satisfactory performance of methods prescribed in monographs is verified at suitable time intervals.

linearity

Prepare and analyse not fewer than 4 reference solutions over the calibration range plus a blank. Perform not fewer than 5 replicates.

The calibration curve is calculated by least-square regression from all measured data of the calibration test. The regression curve, the means, the measured data and the confidence interval of the calibration curve are plotted. The operating method is valid when:

— the correlation coefficient is at least 0.99;

— the residuals of each calibration level are randomly distributed around the calibration curve.

Calculate the mean and relative standard deviation for the lowest and for the highest calibration level.

When the ratio of the estimated standard deviations of the lowest and the highest calibration level is less than 0.5 or greater than 2.0, a more precise estimation of the calibration curve may be obtained using weighted linear regression. Both linear and quadratic weighting functions are applied to the data to find the most appropriate weighting function to be employed.

If the means compared to the calibration curve show a deviation from linearity, two-dimensional linear regression is used.

accuracy

Verify the accuracy preferably by using a certified reference material (CRM). Where this is not possible, perform a test for recovery.

Recovery

For assay determinations a recovery of 90 per cent to 110 per cent is to be obtained. The test is not valid if recovery, for example for trace-element determination, is outside the range 80 per cent to 120 per cent of the theoretical value. Recovery may be determined on a suitable reference solution (matrix solution) spiked with a known quantity of analyte (concentration range that is relevant to the samples to be determined).

repeatability

The repeatability is not greater than 3 per cent for an assay and not greater than 5 per cent for an impurity test.

limit of quantification

Verify that the limit of quantification (for example, determined using the 10 σ approach) is below the value to be measured.