Journal of Chromatography Open (Nov 2021)
Impurity profiling of bisoprolol fumarate by liquid chromatography-high-resolution mass spectrometry: A combination of targeted and untargeted approaches using a synthesis reaction matrix and general unknown comparative screening
Abstract
Several examples of the emergence of unexpected impurities in medicinal products in the past, e.g. the 2018 valsartan scandal, disclosed the need for sophisticated approaches in impurity profiling. Advanced techniques in mass spectrometry offer the possibility to detect impurities in untargeted approaches complementing the targeted search for potential impurities. In this study, a combination of targeted and untargeted approaches using LC-MS/HRMS was applied in creating an impurity profile of bisoprolol fumarate. In the targeted approach, a reaction matrix was used to predict potential impurities, which were searched for in addition to the related substances stated in the European Pharmacopoeia. For the untargeted analytics, general unknown comparative screening was performed to detect unexpected impurities. To cover a maximum range of detectable analytes, two complementary mobile phases, i.e. buffered to acidic and basic pH, were combined with four mass spectrometric ionization conditions, i.e. electrospray ionization and atmospheric pressure chemical ionization in both positive and negative mode. Information-dependent acquisition was used to generate MS and MS/MS data in a single run. The targeted and the untargeted approach revealed the presence of 18 and 17 impurities, respectively. The plausibility of proposed/elucidated structural formulae was checked by in silico fragmentation and assignment of characteristic fragments/neutral losses. Quantification of the impurities was performed with respect to the internal standard metoprolol. The analyzed batches showed contents of up to 0.05% of single impurities. A thorough procedure for the development of a complete impurity profile for drug substances was demonstrated. To ensure a maximum of patient safety, the described approach is prototypical and should be implemented during drug development and after relevant changes in manufacturing processes.
