Researchers have developed and validated an inductively coupled plasma–mass spectrometry (ICP-MS) method capable of simultaneously quantifying 24 elemental impurities in three widely prescribed anticoagulant tablets, and the analysis of commercially available samples found every targeted element below its detection limit. The study, published on 23 September 2026 in the open-access Future Journal of Pharmaceutical Sciences, was carried out by Shriram Pandurang Suryawanshi and Gayatri Barabde and aligned the method with the ICH Q3D guideline for elemental impurities as well as relevant United States Pharmacopeia general chapters.
The drug products in question were tablets containing apixaban, edoxaban, or rivaroxaban, three oral anticoagulants that belong to the therapeutic category of direct Factor Xa inhibitors. These medicines are prescribed for the preventive treatment of thromboembolic disorders and work quickly to interrupt blood clot formation, including prevention of clotting during hip or knee replacement surgery. Because they are often administered to vulnerable populations, the authors argue that controlling elemental impurity levels in these formulations is particularly important, since any deviation could lead to toxic effects, reduced therapeutic efficacy, or interactions with biological systems.
Elemental impurities in pharmaceutical products are a recognised patient-safety concern because of their potential toxicity. According to the study’s background, these impurities may arise from raw materials used in the process, the synthetic processes of drug substances, catalysts used in synthesis, manufacturing equipment, container-closure systems, and environmental factors. Even trace amounts can compromise drug safety and efficacy. The ICH Q3D guideline addresses this risk with a risk-based framework that defines permissible daily exposure limits and categorises elements by toxicity and likelihood of presence in pharmaceuticals.
Under that classification, the method targeted Class 1 elements, which are highly toxic and must be rigorously controlled regardless of source: arsenic, lead, mercury, and cadmium. Class 2A elements, which are highly probable to be abundant in pharmaceutical samples, comprised nickel, vanadium, and cobalt. Class 2B elements, less commonly observed but still requiring monitoring, included palladium, iridium, osmium, thallium, ruthenium, platinum, gold, selenium, silver, and rhodium. Class 3 elements, which have lower toxic potential but may still require control under certain conditions, were copper, molybdenum, lithium, tin, antimony, chromium, and barium.
The analytical work was performed on a quadrupole ICP-MS system, an Agilent 7850 instrument with MassHunter version 5.1 software for data acquisition and execution. The optimised configuration included a quartz Scott-type spray chamber, a MicroMist borosilicate glass concentric nebuliser with a 0.5 millimetre internal diameter, a quartz torch with a 2.5 millimetre internal diameter injector, and nickel-plated sampler and skimmer cones. The instrument’s octupole reaction system operated in standard helium gas mode to remove common polyatomic interferences and improve sensitivity for lower-concentration elements, with an autosampler delivering samples for analysis.
Sample preparation proved to be one of the more demanding parts of the development. The researchers evaluated several digestion reagent combinations, including 2 millilitres of concentrated nitric acid with 0.5 millilitres of 30 percent hydrogen peroxide, 3 millilitres of concentrated hydrochloric acid with 2 millilitres of water, and a mixture of concentrated nitric and hydrochloric acids. They noted that some acid mixtures are unsuitable because certain elemental impurities can become volatile during digestion, affecting analyte recovery. The combination of concentrated nitric acid and concentrated hydrochloric acid provided better digestion efficiency and satisfactory recovery, and the final method digested 0.2 grams of sample with 5 millilitres of 70 percent nitric acid and 1 millilitre of 37 percent hydrochloric acid in a microwave digester, followed by filtration through a 0.45 micron nylon syringe filter because the digests were turbid.
Validation followed USP General Chapters <233> and <730> alongside the ICH Q3D guideline, covering specificity, sensitivity, selectivity, precision, linearity, range, accuracy, and LOD–LOQ precision. For specificity, the average counts-per-second response of calibration blanks was required not to exceed 5 percent of the 100 percent level standard response, and observed blank readings ranged from 0.0 to 2.7 percent of that signal. Recovery of the LOQ-spiked samples fell within the 70 to 150 percent acceptance window, with reported results between 81.6 and 111.2 percent. The limit of detection was calculated from the standard deviation of ten aspirated blanks multiplied by three, and the limit of quantification by multiplying by ten, with the method required to quantify at least a 0.5 J value of the specification limit as per USP Chapter 730.
Across the performance parameters, the method met its acceptance criteria for all 24 elements. Linearity was assessed from the LOQ level, set at 30 percent of the specification limit, through 50, 100, 150, 200, and 250 percent levels, and every element produced a correlation coefficient greater than 0.99. Accuracy was demonstrated by spiking known quantities of impurities into test solutions in triplicate at the LOQ, 100 percent, and 200 percent levels, with mean recoveries required between 70 and 150 percent; the observed recovery range across the study was 81.3 to 111.2 percent. Method precision, evaluated with six individually prepared spiked samples at the working concentration, yielded %RSD values between 0.53 and 7.23 percent, all below the 20 percent limit. Ruggedness was tested by a different analyst on a different day, and the cumulative %RSD of combined method and intermediate precision data ranged from 1.03 to 6.53 percent, within the 25 percent acceptance limit. The %RSD at the LOD level ranged from 1.70 to 16.70 percent and at the LOQ level from 2.61 to 12.53 percent, both below 20 percent.
The validated method was then applied to commercially available samples of apixaban, edoxaban, and rivaroxaban tablets in an elemental impurity risk assessment. All 24 elements were found below the detection limit in all three products, and the results were below the control threshold defined by the ICH Q3D guideline, which the authors describe as below 30 percent of the specification limit. According to the paper, this indicates that routine monitoring of elemental impurities is not required for these samples and that the products pose minimal risk. The authors state that these findings confirm compliance with safety requirements and support the suitability of ICP-MS as a reliable technique for routine quality control of pharmaceutical formulations.
Based on their literature review, the authors report that no previously published method addressed the simultaneous determination of these elemental impurities in finished drug products of apixaban, edoxaban, and rivaroxaban, which they present as the novelty of the work. They conclude that the validated ICP-MS method is simple, highly sensitive, and accurate for determining elemental impurities in these anticoagulant drug products, and that it is well suited for routine analysis of trace-level toxic elements in such formulations, supporting regulatory compliance and product quality. The study’s scope is limited to the solid oral dosage forms tested, purchased from a commercial store, and the validation criteria applied were those of the ICH Q3D guideline and the cited USP general chapters; the sample analysis covered commercially obtained tablets rather than a broader market survey. All data and materials are stated to be available upon request.
Subject of Research: Development and validation of an ICP-MS method for quantifying 24 elemental impurities in anticoagulant tablets under ICH Q3D
Article Title: Simple sensitive ICP-MS method development and validation for quantitative evaluation and risk assessment of elemental impurities in anticoagulant drug product: study aligned with ICH Q3D guideline
Article References: Suryawanshi, S. P., & Barabde, G. (2026). Simple sensitive ICP-MS method development and validation for quantitative evaluation and risk assessment of elemental impurities in anticoagulant drug product: study aligned with ICH Q3D guideline. Future Journal of Pharmaceutical Sciences, 12(1), Article 90. https://doi.org/10.1186/s43094-026-01021-7
Image Credits: AI Generated
DOI: 10.1186/s43094-026-01021-7
Keywords: ICP-MS, elemental impurities, ICH Q3D, anticoagulants, apixaban, edoxaban, rivaroxaban, pharmaceutical quality control, method validation, USP, microwave digestion, trace elements
News Source: Ophelia Keating. (October 28, 2026). New ICP-MS Method Tracks 24 Toxic Elemental Impurities in Anticoagulant Tablets. Scienmag.
