LC-MS/MS-based impurity profiling of high-purity methamphetamine for precursor identification and regional comparison

Methamphetamine (MA) is a widely abused illicit drug synthesized primarily using either ephedrine/pseudoephedrine or 1-phenyl-2-propanone (P2P) as precursors. These processes generate precursor-derived impurities that can provide valuable forensic intelligence. However, recent advances in purification techniques have resulted in refined MA samples containing impurities at ultra-trace levels, thereby posing analytical challenges for conventional gas chromatography-based methods. In this study, a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the targeted detection of MA precursor-associated impurities at ultra-trace levels. A total of 19 impurities, including markers associated with the P2P and ephedrine/pseudoephedrine precursor classes, were analyzed using multiple reaction monitoring (MRM) mode. Chromatographic and mass spectrometric conditions were optimized to achieve high sensitivity and selectivity. The developed method demonstrated limits of detection ranging from 0.008 to 2.500 ng/mg and showed satisfactory selectivity and repeatability for qualitative identification. The method was applied to 33 high-purity seized MA samples to evaluate precursor-associated impurity profiles and regional differences based on documented geographical origins. Differences in impurity patterns were observed between samples from North America and Southeast Asia, reflecting regional variation in these profiles. P2P-related impurities were detected in North American samples, whereas Southeast Asian samples exhibited more variable profiles, including both P2P- and ephedrine/pseudoephedrine-related markers. These results demonstrate that the proposed LC-MS/MS method enables reliable detection of ultra-trace level impurities and provides a valuable analytical tool for impurity profiling and forensic intelligence applications, particularly for highly purified MA samples.