Inductively coupled plasma mass spectrometry (ICP-MS) is a highly sensitive analytical technique used to identify and quantify elements in nanoparticle formulations, biological samples, environmental matrices, and other materials. For nanoparticle characterization, ICP-MS is particularly useful for measuring elemental mass concentration, evaluating purity, quantifying dissolved material, and determining nanoparticle content in complex samples.
ICP-MS can detect many elements at very low concentrations, but accurate results depend on appropriate sample preparation, calibration, interference control, and a clear definition of what the measurement is intended to quantify.
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On this page
- What ICP-MS Measures
- How ICP-MS Works
- ICP-MS vs. Single-Particle ICP-MS
- Sample Preparation
- Nanoparticle Dissolution Studies
- Measuring Nanoparticle Concentration
- Interpreting ICP-MS Data and Data Quality
- Troubleshooting ICP-MS Analysis
What Does ICP-MS Measure?
ICP-MS measures elements based on the mass-to-charge ratio of ions generated from a sample. The primary quantitative result is the concentration of a selected element or isotope.
For nanoparticle applications, conventional ICP-MS can be used to measure:
- Total elemental concentration: Quantify the total mass of an element present after complete sample digestion.
- Nanoparticle mass concentration: Determine the elemental mass associated with a purified nanoparticle formulation.
- Dissolved elemental concentration: Quantify an element in a particle-depleted fraction after an appropriate separation step.
- Elemental composition: Measure multiple elements in materials such as alloys, core-shell nanoparticles, or complex samples.
- Nanoparticle content in biological or environmental samples: Quantify a target element after appropriate digestion and matrix control.
- Trace impurities: Detect selected elemental contaminants when the analytical method provides sufficient sensitivity and selectivity.
ICP-MS Does Not Directly Determine Chemical Speciation
Conventional ICP-MS identifies elements and isotopes, but it generally does not determine their oxidation state, molecular form, or chemical species.
For example, measuring silver by conventional ICP-MS does not by itself distinguish Ag+ from soluble silver complexes or nanoparticulate silver. Chemical or physical separation before analysis, hyphenated separation techniques, or single-particle ICP-MS may be needed when distinguishing different forms of an element is important.
How Does ICP-MS Work?
In conventional ICP-MS, a liquid sample is introduced into a nebulizer, which converts the sample into a fine aerosol. The aerosol enters a high-temperature argon plasma, where the solvent is removed and the sample components are atomized and ionized.
The ions then enter the mass spectrometer under vacuum. In a quadrupole ICP-MS, combinations of radiofrequency and direct-current electrical fields allow ions with selected mass-to-charge ratios to pass through the quadrupole and reach the detector while other ions are filtered out.
Calibration and Quantification
Elemental concentration is determined by comparing the measured ion signal from the sample with signals from standards containing known concentrations of the target element.
A calibration curve should span the concentration range of the analyzed samples. Samples that exceed the calibrated range are diluted appropriately and remeasured rather than extrapolated beyond the validated range.
Internal standards are commonly used to monitor changes in sample introduction, plasma conditions, and instrument response. Blanks, calibration-verification standards, replicates, and appropriate quality-control samples help establish confidence in the reported concentration.
Spectral Interferences
ICP-MS measurements can be affected by ions that overlap with the mass of the target isotope. These can include atomic ions, polyatomic ions formed from the plasma or sample matrix, and doubly charged ions.
Modern ICP-MS instruments may use collision or reaction cell technology, alternative isotopes, interference equations, or other strategies to reduce these effects. The appropriate approach depends on the target element and sample matrix.
Conventional ICP-MS vs. Single-Particle ICP-MS
Conventional ICP-MS and single-particle ICP-MS (sp-ICP-MS) use the same underlying elemental detection principle but answer different analytical questions.
| Measurement | Conventional ICP-MS | Single-Particle ICP-MS |
|---|---|---|
| Primary measurement | Elemental concentration in a bulk sample | Time-resolved elemental signals from individual particles |
| Total elemental mass concentration | Yes | Can be determined within appropriate methods |
| Particle number concentration | No, not directly | Yes |
| Element mass per particle | No | Yes |
| Equivalent particle size | No | Can be calculated when particle composition, geometry, and density are known |
| Dissolved elemental fraction | Requires physical separation before analysis | Can be estimated from the continuous dissolved-element background under appropriate conditions |
| Particle morphology | No | No |
| Chemical oxidation state | No | No |
How Single-Particle ICP-MS Works
In sp-ICP-MS, an appropriately dilute nanoparticle suspension is analyzed using rapid time-resolved acquisition. Individual nanoparticles entering the plasma generate short bursts of ions that appear as discrete signal events above the dissolved-element background.
The frequency of these events can be used to calculate particle number concentration, while the signal associated with each event can provide the mass of the measured element per particle. For spherical nanoparticles of known composition and density, elemental mass can be converted to an equivalent particle diameter.
Accurate sp-ICP-MS analysis requires additional parameters and controls, including transport efficiency, acquisition time, particle dilution, elemental response calibration, and appropriate reference materials. ISO/TS 19590:2024 provides current guidance for reliable detection, characterization, and quantification of nano-objects using sp-ICP-MS.
nanoComposix also provides nanoparticle reference materials designed for applications including single-particle ICP-MS.
Sample Preparation for ICP-MS
Sample preparation is often the most important part of an ICP-MS measurement. The appropriate method depends on whether the objective is to measure total elemental concentration, dissolved material, individual nanoparticles, trace impurities, or elemental content in a complex matrix.
Define the Measurand Before Preparing the Sample
Processing a sample can change what is ultimately measured. Before filtering, centrifuging, digesting, washing, or diluting a sample, define the analytical question.
| Analytical Goal | General Sample Preparation Strategy |
|---|---|
| Total elemental concentration | Digest the complete representative sample without intentionally removing the target element. |
| Elemental concentration of a nanoparticle stock | Digest an accurately measured aliquot of the representative nanoparticle dispersion. |
| Dissolved elemental fraction | Separate particles from the surrounding medium using a validated separation method, then analyze the particle-depleted fraction. |
| Elemental content in tissue or another complex matrix | Use a digestion method capable of recovering the target element from the complete matrix. |
| Single-particle analysis | Keep the nanoparticles intact and dilute them to an appropriate particle number concentration rather than digesting them. |
Digestion for Total Elemental Analysis
Solid particles and complex matrices commonly require digestion before conventional total-element ICP-MS analysis. Digestion converts the target element into a form compatible with sample introduction and helps produce a homogeneous solution for quantitative measurement.
The appropriate digestion chemistry depends on nanoparticle composition, coatings, surrounding matrix, and target element. Some refractory materials, oxides, biological tissues, or highly organic samples require more extensive digestion than simple aqueous metal nanoparticle formulations.
Incomplete digestion can lead to poor analyte recovery, nonrepresentative sampling, or inconsistent results. A clear solution alone does not necessarily demonstrate complete elemental recovery, so appropriate controls and recovery assessments are important for difficult matrices.
For submitted samples, nanoComposix can perform sample preparation including microwave-assisted acid digestion where appropriate. Refer to the ICP-MS analysis service for current capabilities and sample requirements.
Dilution
ICP-MS is highly sensitive, so nanoparticle formulations frequently require substantial dilution before analysis. The final target-element concentration should fall within the calibrated measurement range while maintaining an appropriate sample matrix.
Dilution factors should be recorded accurately and propagated into the final reported concentration. When large dilution factors are required, gravimetric dilution can help reduce volumetric error.
Dilution can also reduce matrix effects, but simply diluting a difficult sample does not guarantee that all analytical interferences have been eliminated.
Matrix Effects
High concentrations of salts, acids, dissolved solids, organic material, or other sample components can affect aerosol formation, ionization, ion transmission, and detector response.
Biological tissues, environmental samples, concentrated buffers, polymer-rich formulations, and samples containing multiple inorganic components can therefore require additional method development compared with simple aqueous nanoparticle dispersions.
Strategies for controlling matrix effects may include appropriate dilution, internal standards, matrix-matched calibration, standard addition, digestion, interference-control methods, or other sample-specific approaches.
Avoid Unintentional Loss of the Target Analyte
Filtration, centrifugation, washing, and other purification methods should not automatically be used to make a sample "cleaner" for ICP-MS. These steps can remove part of the target analyte and bias the result.
If the goal is total elemental concentration, the preparation method should retain the complete target-element inventory. If the goal is to measure a specific fraction, such as dissolved material, the separation step should be validated for both particle removal and analyte recovery.
Using ICP-MS for Nanoparticle Dissolution Studies
Some nanoparticles release dissolved elemental species when exposed to water, biological media, environmental matrices, or other solutions. Silver nanoparticles are a common example where dissolution can be important for understanding particle stability, environmental fate, and biological response.
A typical dissolution study separates the remaining nanoparticle fraction from the surrounding liquid at selected time points and measures the target element in the particle-depleted fraction by ICP-MS.
Potential separation approaches include:
- Centrifugation or ultracentrifugation
- Centrifugal ultrafiltration
- Membrane filtration
- Dialysis
- Chromatographic or field-flow separation methods
No separation method is universally appropriate. Nanoparticles may pass through a membrane, dissolved species may adsorb to a membrane or tube, or centrifugation may fail to completely pellet very small particles. Separation performance should therefore be evaluated for the specific nanoparticle and medium.
Dissolved Element Is Not Necessarily Free Ion
ICP-MS measures the elemental concentration of the analyzed fraction. If silver nanoparticles are removed and the supernatant is analyzed, the result represents silver that remains in that fraction.
It should generally be described as dissolved silver rather than automatically interpreted as free Ag+. The sample may contain free ions, soluble complexes, or other silver-containing species that conventional ICP-MS does not distinguish.
For more detail, see Silver Nanoparticle Dissolution and Ion Release.
Control the Experimental Conditions
Dissolution can depend on temperature, pH, dissolved oxygen, light exposure, ionic strength, ligands, particle concentration, surface chemistry, and other properties of the medium.
Use consistent experimental conditions and sampling times when comparing materials. Include appropriate blanks and controls for possible contamination, adsorption, or elemental background from the medium.
Using ICP-MS to Measure Nanoparticle Concentration
For a purified nanoparticle formulation with known composition, ICP-MS can provide the elemental mass concentration needed to calculate other concentration units.
For a homogeneous particle composed entirely of the measured element:
N = Cm / mp
where N is particle number concentration, Cm is the measured elemental mass concentration, and mp is the mass of the measured element in one particle.
For a spherical solid nanoparticle:
mp = (4/3)πr3ρ
where r is particle radius and ρ is material density.
This calculation assumes that particle dimensions, composition, density, and elemental mass fraction are known and representative of the population. Core-shell, porous, alloyed, or irregular particles require an appropriate particle-mass model.
Learn more in Nanoparticle Volume, Mass and Concentration.
Mass Concentration Is Not the Same as Particle Number Concentration
Two nanoparticle dispersions can contain the same mass concentration but very different numbers of particles. Because particle mass scales strongly with particle dimensions, smaller nanoparticles produce far more particles per unit mass than larger particles of the same composition.
Conventional ICP-MS provides the elemental mass concentration. Particle number concentration calculated from that result therefore depends on independent knowledge of particle size and composition. Single-particle ICP-MS can provide particle-number information more directly under appropriate measurement conditions.
Interpreting ICP-MS Results and Data Quality
An ICP-MS result should be interpreted together with the preparation method, calibration range, dilution, matrix, quality controls, and analytical uncertainty. A reported concentration alone does not demonstrate that the measurement captured the intended fraction of the sample.
Calibration
Calibration standards should bracket the concentration of the measured sample. The analytical response should demonstrate appropriate performance across the calibration range, and independent calibration-verification standards can be used to confirm instrument response.
Blanks
Method blanks help identify elemental contamination introduced by reagents, labware, digestion vessels, filters, or sample handling. Blank contributions become especially important when measuring elements near the method detection limit.
Internal Standards
Internal standards can compensate for changes in sample introduction and instrument sensitivity during an analytical run. The selected internal standard should behave appropriately under the measurement conditions without interfering with the analyte.
Replicates and Duplicates
Replicate measurements evaluate instrumental repeatability, while independently prepared duplicate samples can provide information about sample preparation and sample homogeneity. For heterogeneous biological or environmental materials, preparation variability may be substantially larger than instrumental variability.
Spike Recovery and Reference Materials
Spike-recovery studies can help determine whether the sample matrix suppresses or enhances analyte response or whether analyte is lost during preparation. Certified reference materials or other well-characterized controls can provide additional confidence when suitable materials are available.
Detection and Quantification Limits
ICP-MS can achieve very low elemental detection limits, but there is no single detection limit that applies to every element or sample. Practical detection and quantification limits depend on isotope abundance, background signal, interferences, dilution, matrix, sample preparation, and instrument configuration.
Claims such as "ppt sensitivity" should therefore be understood as element- and method-dependent rather than as a universal performance level for every sample.
What Should an ICP-MS Result Report?
For reproducible elemental analysis, report relevant information such as:
- Element and isotope analyzed
- Reported elemental concentration and units
- Sample preparation and digestion approach
- Sample dilution factor
- Calibration range and calibration strategy
- Relevant blank or background correction
- Internal standard when applicable
- Replicate or duplicate results
- Relevant interference-control approach
- Detection or quantification limit when important to interpretation
- Whether the result represents total, dissolved, particulate, or another operationally defined fraction
Troubleshooting ICP-MS Analysis
| Observation | Possible Causes and Next Steps |
|---|---|
| Measured concentration is below expectation | Consider incomplete digestion, adsorption to sample containers or filters, analyte loss during preparation, incorrect dilution, poor recovery, or matrix suppression. |
| Measured concentration is unexpectedly high | Check blanks, reagents, labware, carryover, calculation factors, sample contamination, and spectral interferences. |
| Poor replicate precision | Evaluate sample homogeneity, incomplete digestion, particulate material, pipetting or dilution error, sample introduction stability, or instrument drift. |
| Sample exceeds the calibration range | Dilute the sample appropriately and remeasure within the validated calibration range. |
| High background at the target mass | Investigate blank contamination, matrix-derived polyatomic ions, isotope selection, and appropriate collision/reaction cell or interference-correction strategies. |
| Poor spike recovery | Matrix suppression or enhancement, incomplete preparation, analyte adsorption, or spectral interference may be affecting the measurement. |
| Dissolved fraction appears unexpectedly high | Confirm that nanoparticles were not passing through the separation step and evaluate contamination or particle transformation during sample handling. |
| Dissolved fraction appears unexpectedly low | Evaluate adsorption of dissolved analyte to membranes, containers, or other surfaces and confirm recovery of the separation method. |
| Core-shell composition appears inconsistent | Confirm complete digestion, select appropriate isotopes for both elements, evaluate interference and recovery independently, and consider particle-to-particle heterogeneity. |
When an ICP-MS result does not match expectations, troubleshooting should begin with the analytical question and sample preparation. The most precise instrument result is not useful if the preparation step altered or failed to recover the fraction that was intended to be measured.
Have questions about ICP-MS analysis for your nanoparticles or samples?
Talk with our technical team about elemental concentration, sample preparation, dissolution studies, complex matrices, or the most appropriate characterization strategy for your material.
Selected References
- Meermann, B. and Nischwitz, V. ICP-MS for the analysis at the nanoscale - a tutorial review. Journal of Analytical Atomic Spectrometry. 2018;33:1432-1468.
- Montaño, M.D., Olesik, J.W., Barber, A.G., Challis, K., and Ranville, J.F. Single Particle ICP-MS: Advances toward routine analysis of nanomaterials. Analytical and Bioanalytical Chemistry. 2016;408:5053-5074.
- Pace, H.E., Rogers, N.J., Jarolimek, C., Coleman, V.A., Higgins, C.P., and Ranville, J.F. Determining transport efficiency for the purpose of counting and sizing nanoparticles via single particle inductively coupled plasma mass spectrometry. Analytical Chemistry. 2011;83(24):9361-9369.
- Laborda, F., Abad-Álvaro, I., Jiménez, M.S., and Bolea, E. Catching particles by atomic spectrometry: Benefits and limitations of single particle-inductively coupled plasma mass spectrometry. Spectrochimica Acta Part B: Atomic Spectroscopy. 2023;199:106570.
- ISO/TS 19590:2024: Nanotechnologies - Characterization of nano-objects using single particle inductively coupled plasma mass spectrometry. International Organization for Standardization.
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