A novel microextraction method for further elemental impurity determination in oily pharmaceutical excipients by ICP-MS

Abstract

In this study, a reversed-phase dispersive liquid-liquid microextraction (RP-DLLME) method was proposed for the subsequent determination of elemental impurities of class 1 (As, Cd, Hg, and Pb) and class 2 A (Co, Ni, and V) in oily pharmaceutical excipients, as recommended by the International Council for Harmonisation (ICH) guideline Q3D. Analyte determination was carried out by inductively coupled plasma mass spectrometry (ICP-MS). Operational parameters were evaluated, including dispersant and extractant solvents, total volume and proportion of the extraction solution, sample mass, temperature, heating time, centrifugation, and stirring. Suitable results were obtained using a high sample mass (5 g), 2 mL of 50:50 % (v/v) of n-propanol:HNO₃ (3 mol L⁻¹ HNO₃ for all analytes and 6 mol L⁻¹ HCl only for Hg), heating at 85 °C for 20 min, stirring for 1 min, and centrifugation for 10 min. Accuracy was assessed using certified reference materials (CRMs) of mineral oil, comparison with a reference method (microwave-assisted wet digestion), and analyte recovery experiments at three concentration levels, following ICH Q3D recommendations and the United States Pharmacopeia (USP) guidelines for injectable drugs. No statistical differences were observed in any of the accuracy assessments. The method achieved low quantification limits (LOQs) of 0.045, 0.006, 0.006, 0.009, 0.040, 0.020, and 0.102 µg g⁻¹ for As, Cd, Co, Hg, Ni, Pb, and V, respectively, all of which were below the maximum levels allowed by the ICH guideline. The proposed method presented several advantages for routine analysis, including simplicity, high throughput, the use of diluted solutions, and minimal laboratory waste generation.