Investigation of an artificial solution degradant of linagliptin: An undesired linagliptin urea derivative generates in sample preparation of linagliptin tablet treated by sonication in acetonitrile containing diluent.

During the related substances testing method development for linagliptin tablet, an unknown peak was observed in HPLC chromatograms with a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MS with mechanism-based stress studies, the unknown peak was rapidly identified as linagliptin urea, a solution degradant that is caused by the reaction between the API and hydrocyanic acid with sonication treatment to accelerate dissolution of the drug substance in sample preparation of linagliptin tablets, and hydrocyanic acid is a known impurity in HPLC grade acetonitrile and acetonitrile is used as part of diluent. The mechanism of the solution degradation chemistry was verified by stressing linagliptin API with trimethylsilyl cyanide (TMSCN, which can give off HCN slowly in the presence of water) treated with sonication in the sample preparation. Further investigation found that when the sonication treatment was replaced by vortex vibration in the process of the sample preparation, the RRT 1.28 species was decreased to below the level of the detection limit (0.02%). The structure of this impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the presence of trace amount of HCN in HPLC grade acetonitrile, these types of solution degradation would likely occur in analysis of pharmaceutical finished products containing APIs with primary and secondary amine moieties drug product during sample preparations, particularly when sonication treatment is used to accelerate dissolution of drug substance from the finished drug product. In the GMP quality control laboratories, such events may trigger undesirable out-of-specification (OOS) events. Hence, the results of this paper can help to prevent these events from happening in the first place or resolve these OOS events in GMP laboratories.