Simultaneous detection of nitrosamines and other sartan-related impurities in active pharmaceutical ingredients by supercritical fluid chromatography

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 174; pp. 151 - 160
• Main Authors: Schmidtsdorff, Sebastian, Schmidt, Alexander H.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 10.09.2019
• Subjects: Angiotensin II Type 1 Receptor Blockers - analysis; Chromatography, Supercritical Fluid; Diethylnitrosamine - analysis; Dimethylnitrosamine - analysis; Drug Contamination; Limit of Detection; Losartan - analysis; Nitrosamines; Nitrosamines - analysis; Propylamines - analysis; Quality Control; Quality-by-Design (QbD); Reference Standards; Risk Assessment; Sartans; Supercritical fluid chromatography (SFC); Valsartan - analysis; Nitrosamines; Sartans; Quality-by-Design (QbD); Supercritical fluid chromatography (SFC)
• ISSN: 0731-7085; 1873-264X; 1873-264X
• DOI: 10.1016/j.jpba.2019.04.049

•Simultaneous detection of nitrosamines and monographed impurities in sartans•Novel SFC approach for large group of nitrosamines•High sensitivity and selectivity within extreme short analysis time•Improved reliability and deep understanding by QbD development approach•Both NDMA and NDEA detected in Losartan API Since July 2018, the pharmacological class of “sartans” has been the subject of considerable media and analytical interest, as it became known that they are contaminated with nitrosamines such as N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosodiisopropylamine (NDiPA). Previous compendial methods are not able to detect these new contaminants. Using the latest and innovative Quality-by-Design (QbD) approach, it has now been possible to develop an analytical method that enables to investigate sartans, such as valsartan and losartan. Also a large class of different nitrosamines in the ppb range and sartan-related impurities can thus be determined simultaneously in a single analysis using supercritical fluid chromatography (SFC). By using SFC, a broad spectrum of nonpolar and very polar impurities can be separated and analyzed in under 20 min. The analytical method developed is validated for limit testing according to ICH Q2(R1) and fulfills default thresholds of EMA and FDA for testing of drug substances and genotoxic impurities. Additionally, it can also be adapted to other pharmaceuticals that may be contaminated with nitrosamines, since tetrazole synthesis as the underlying cause of nitrosamine contamination is important for a set of other non-sartan drug substances.