Identification, isolation, characterization, and UHPLC quantification of potential genotoxic impurities in linagliptin

Abstract

During the stress testing of linagliptin, one unknown degradation product (impurity I) on acidic conditions was detected by using high-performance liquid chromatography and subsequently isolated, identified, and characterized by the spectral data (MS, MS/MS, 1D and 2D NMR spectroscopy, and IR spectroscopy) and finally subjected for mechanism analysis. The degradation product (impurity I) and another process-related impurity (impurity II) of linagliptin were found to contain the structural alerts of N-acylated aminoaryl and alkyl halide, respectively, which were both potential genotoxic substances. Hence, a rapid and facile ultra high performance liquid chromatography method was developed for the simultaneous determination of these two potential genotoxic impurities at ppm levels in linagliptin. The factors involved in the method development were discussed and this method was fully validated as per International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, which proved the method sensitive, selective, and robust. The presented method has been successfully applied to the analysis of real samples from multiple batches. This study will help to risk management of possible genotoxic impurities present in linagliptin.

Application of online liquid chromatography/quadrupole time‐of‐flight electrospray ionization tandem mass spectrometry for structural characterization of linagliptin degradation products and related impurities

“…In addition, some bioanalytical methods were reported for LIN ‐ related to its pharmacology, kinetics and drug interactions 13–16 . There have been a few studies on the stability of LIN alone and in combination with other antidiabetic drugs in formulations using HPLC 17–19 and two reports on the impurity analysis of LIN 20,21 . However, there is no information available on the degradation behavior of LIN.…”

Recent Advances in Chromatography for Pharmaceutical Analysis

“…Finally, 2D-LC(-MS) can be helpful when all of the other approaches do not meet the required selectivity and sensitivity. 229,230 A comprehensive example of method development for PGI identification and characterization was recently published by Huang et al 233…”

Development and validation of an analytical method for quantitative determination of three potentially genotoxic impurities in vildagliptin drug material using HPLC‐MS

“…Also Huang et al. reported an analytical method for the analysis of two GTIs in linagliptin using LC‐MS/MS [24]. These papers did not study any of PGIs that were studied in this research.…”