Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS² fingerprinting from collision‐induced decomposition of protonated ions

Abstract

Rationale The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high‐resolution tandem mass spectrometry (LC/HRMS2) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. Methods Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2. Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one‐ and two‐dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. Results The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2H3O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. Conclusions The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.

Structural elucidation of two novel degradants of lurasidone and their formation mechanisms under free radical‐mediated oxidative and photolytic conditions via liquid chromatography‐photodiode array/ultraviolet‐tandem mass spectrometry and one‐dimensional/two‐dimensional nuclear magnetic resonance spectroscopy

“…Two novel degradation products were observed under free radical‐mediated oxidative (via AIBN) and solution photolytic conditions. The two previously unknown degradants were investigated via an approach combining LC‐PDA/UV‐MS n ( n = 1, 2), mechanism‐based stress studies, and NMR, a strategy that has been successfully utilized in our laboratories for rapidly identifying degradant structures and elucidating their plausible formation mechanisms 7–19 …”

“…The two previously unknown degradants were investigated via an approach combining LC-PDA/UV-MS n (n = 1, 2), mechanism-based stress studies, and NMR, a strategy that has been successfully utilized in our laboratories for rapidly identifying degradant structures and elucidating their plausible formation mechanisms. [7][8][9][10][11][12][13][14][15][16][17][18][19] We now report the process of identifying the structures of the two novel degradants, and propose their possible formation mechanisms. At the same time, the different oxidative degradation behaviors under the free radical-mediated oxidative condition and nucleophilic oxidative condition are compared and the implication is discussed.…”