Evaluation of the effects of residual carbon content matrix on the determination of pharmaceutically regulated elemental impurities by ICP-MS

In recent years, several changes to elemental impurities control strategy in active pharmaceutical ingredients (APIs), drug products (DPs) and excipients were proposed by the United States Pharmacopoeia (USP), European Pharmacopoeia/European Medicine Agency (EP/EMA) and the International Conference on Harmonisation (ICH). The wet chemistry colorimetric tests for heavy metals such as USP<231> and EP 2.4.8 have been replaced with instrumental methods, one of which being inductively coupled plasma mass spectrometry (ICP-MS) that provides fast, specific and quantitative determination of individual elemental impurities. ICP-MS has the capability to quantify the 24 regulated elemental impurities using a single method, whether present at ultra-trace levels or high concentrations, due to the instruments’ wide dynamic range (up to 11 orders).

USP <233> defines different methods for sample preparation prior to ICP-MS analysis. The majority of pharmaceutical materials, including the most commonly used excipients, can be digested using either closed-vessel microwave digestion or room temperature digestion in concentrated acids. The choice of concentrated acid depends on the sample matrix, however the most used reagent for organic matrix decomposition is nitric acid. Only a limited number of pharmaceutical samples, such as polymers and heavy organic chemicals, cannot be digested directly in nitric acid and these require an initial char step with sulfuric acid.

Acid solutions combined with different additives (e.g. thiourea, d-mannitol) can cause matrix effects in ICP-MS analysis. Furthermore, direct dissolution of pharmaceutical samples can lead to relatively high residual carbon content (RCC) which may cause matrix effects as well. The chemical structure of the pharmaceutical samples contains elements other than C and H, such as N, O, S, P and Cl. The presence of these elements in digests can result in spectral interferences in ICP-MS due to the formation of polyatomic ions. In general, matrix effects in ICP-MS may be divided into two basic categories; matrix induced spectral overlap problems (due to polyatomic interferences) and matrix induced signal intensity changes. It is not unusual that both effects are present simultaneously and both of them can significantly impact the accuracy of the analytical data.

The RCC matrix effects on the regulated elements were assessed in this study. Two Case study quantitative methods (external calibration and standard addition) were compared by analysing elemental impurities in sucrose, as a source of residual carbon content, to investigate the RCC induced bias and the efficiency of the two techniques in reducing it.