Targeted and untargeted impurity profiling by means of high resolution mass spectrometry and ball milling experiments

The analysis of losartan API samples from different suppliers revealed various impurity profiles. Remarkable was the detection and identification of reprotoxic residual solvent, N-methyl-2-pyrrolidone (NMP), in one sample. The untargeted screening had highlighted a corresponding signal. Based on the exact mass, MS/HRMS data and a spiking experiment, the related structural formula could be elucidated and identified. In a subsequent study, losartan medicinal products and combination products were investigated. Interestingly, it was found that some of the samples on the market in 2018 were already contaminated with the synthesis by-product losartan azide. The contamination of losartan-containing medicinal products with this impurity was not published by authorities until 2021 and consequently led to recalls. The applied HRMS technique was also valuable for the investigation of mechanochemically stressed APIs and drug products. Therefore, it was crucial to characterize the untreated APIs regarding their impurity profile. In this way it was possible to assess which degradation products were already present before mechanochemical stressing and which were formed exclusively by the forced degradation. The investigation of clopidogrel hydrogensulfate and medicinal products revealed previously unknown degradation products. In a further study, five different sartans were stressed in the ball mill under different experimental parameters and the residues obtained were analysed by means of LC-MS/HRMS. In addition to degradation products not yet known in the literature, many known impurities could be generated and identified. Overall, this work demonstrates several applications for the combination of targeted and untargeted screening approaches using advanced HRMS technology. Studies like this are important to enable the establishment of such technical facilities in the pharmaceutical quality control and drug stability testing.