Analytical Methods for Elemental Impurities in Pharmaceuticals

Medicines may contain elemental impurities through catalysts or reagents used in the synthesis of active substances and excipients; without any therapeutic benefit but with potential toxic effects, these impurities threaten the product quality, efficacy and consumer safety, and it is necessary to control the concentration of impurities in pharmaceuticals within acceptable limits. Regulations issued by United States Pharmacopeia (USP), European Pharmacopeia (EP) and International Conference on Harmonization (ICH) on the limitation of elemental impurities such as heavy metals and catalyst residues require an urgent need for robust and efficient instrumental methods. The most common methods for analyzing elemental impurities in drugs are MIP OES, WDXRF, ICP-OES, ICP-MS, and etc.

Inductively Coupled Plasma Mass Spectrometry (ICP-MS) Analysis

Currently, a number of methods using ICP for elemental impurity analysis in the pharmaceutical field have been proposed. ICP-MS is a new method based on flow injection that rapidly and accurately analyzes many elements in a drug by prior dilution, dissolution or microwave assisted closed vessel digestion according to the regulations. This method has an unprecedented high sample throughput compared to obtaining continuous signals because the total analysis time is approximately 30 s and the low sample consumption is less than 50 μL, while meeting the strict USP requirements on detection/quantification limits, precision and accuracy. Wang et al. had established a semi-quantitative ICP-MS method covering target elements in the USP and EMA regulations. However, this method solely covers the analysis of the drug substance leaving the analysis of the excipients, some of which are expected to be more troublesome. Moreover, when using ICP-MS techniques, some elements such as Pd, Pt and Ir need concentrated acid mixtures of nitric acid and hydrochloric acid to guarantee a suitable solubilization, which may cause interference due to residual carbon content in final sample and consequent suppression or enhancement of analytical signal for some elements.

Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) Method

The ability to simultaneously determine multiple elements is one of the major advantages of ICP-based methods, especially when compared to atomic absorption spectrometry (AAS). In general, ICP-OES and ICP-MS automatically analyze multiple sample solutions and multiple elements in minutes. The above ICP-MS method is used for analysis of drug substances and excipients respectively and doesn't cover all USP target elements. The relevance of an ICP-OES method for analysis of a drug product is evident. ICP-OES generally provides higher LODs compared to ICP-MS. It also has sufficient sensitivity to quantify elemental impurities corresponding to the USP target limits. In the past work of Stoving, C., et al., a ICP-OES method for quantitation of As, Cd, Cu, Cr, Fe, Hg, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru, V and Zn in tablets according to the new USP chapters was developed. A potential limitation for ICP OES and ICP-MS is associated with their relatively high acquisition and running costs when compared with AAS methods.

Fig.1 ICP-OES quantify the trace elements ⁸

Feasibility of wavelength dispersive X-ray fluorescence spectrometry (WDXRF)

An analytical procedure based on Wavelength Dispersive X-ray Fluorescence spectrometry (WDXRF) was validated and applied for the determination of Zn, Fe, Ni in API, showing that the API matrix significantly influences the determination of metals by WDXRF spectrometry. More work is necessary before establishing WDXRF as a good alternative method because if the broader metal set listed by EMA and USP may be present in the API, then the observed matrix effects need to be considered. Figueiredo, A., et al.’s work has also shown that the WDXRF method has the good degree of linearity, sensitivity, precision and accuracy necessary for the determination of Zn, Fe and Cr in pelletized samples of medicines. Following the guidelines of EMA ICH, WDXRF's strength lies in its specifications, which require little sample preparation compared with ICP and AAS.

Fig.2 WDXRF monitor the elemental impurities ²

From a consumer’s perspective, the safety and therapeutic efficacy of the final drug products is vital, which may incorporate residues of metal elements throughout the above mentioned routes.Therefore, it is important to investigate the feasibility of the different analytical methodologies for the process of sale and public consumption.

References

• Althoff, A. G., C. B. Williams, T. McSweeney, D. A. Goncalves and G. L. Donati (2017). ‘Microwave-Induced Plasma Optical Emission Spectrometry (MIP OES) and Standard Dilution Analysis to Determine Trace Elements in Pharmaceutical Samples.’ Appl Spectrosc 71(12): 2692-2698.

• Figueiredo, A., T. Fernandes, I. M. Costa, L. Goncalves and J. Brito (2016). ‘Feasibility of wavelength dispersive X-ray fluorescence spectrometry for the determination of metal impurities in pharmaceutical products and dietary supplements in view of regulatory guidelines.’ J Pharm Biomed Anal 122: 52-58.

• Fischer, L., B. Zipfel, G. Koellensperger, J. Kovac, S. Bilz, A. Kunkel, C. Venzago and S. Hann (2014). ‘Flow injection combined with ICP-MS for accurate high throughput analysis of elemental impurities in pharmaceutical products according to USP<232>/<233>.’ J Pharm Biomed Anal 95: 121-129.

• Lewen, N. (2011). ‘The use of atomic spectroscopy in the pharmaceutical industry for the determination of trace elements in pharmaceuticals.’ J Pharm Biomed Anal 55(4): 653-661.

• Muller, A. L., J. S. Oliveira, P. A. Mello, E. I. Muller and E. M. Flores (2015).‘Study and determination of elemental impurities by ICP-MS in active pharmaceutical ingredients using single reaction chamber digestion in compliance with USP requirements.’ Talanta 136: 161-169.

• Nageswara Rao, R. and M. V. Talluri (2007). ‘An overview of recent applications of inductively coupled plasma-mass spectrometry (ICP-MS) in determination of inorganic impurities in drugs and pharmaceuticals.’ J Pharm Biomed Anal 43(1): 1-13.

• Raghuram, P., I. V. Soma Raju and J. Sriramulu (2010). ‘Heavy metals testing in active pharmaceutical ingredients: an alternate approach.’ Pharmazie 65(1): 15-18.

• Stoving, C., H. Jensen, B. Gammelgaard and S. Sturup (2013). ‘Development and validation of an ICP-OES method for quantitation of elemental impurities in tablets according to coming US pharmacopeia chapters.’ J Pharm Biomed Anal 84: 209-214.

• Wang, T., J. Wu, R. Hartman, X. Jia and R. S. Egan (2000). ‘A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials.’J Pharm Biomed Anal 23(5): 867-890.

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