Building a Bridge Between Ambient MS and LC‐MS by Non‐Exhaustive Microdesorption

Ambient mass spectrometry (AMS) offers rapid screening but faces challenges in analyzing complex samples due to high matrix effects and limited selectivity. The absence of a separation step can also lead to false positives due to the isomers or isobars. In this study, a sequential analysis strategy which combines ambient MS and LC‐MS was developed for the first time based on the non‐exhaustive microdesorption in solid‐phase microextraction (SPME). This strategy was demonstrated by combining coated blade spray (CBS)‐MS with LC‐MS. In the first step, a few microliters of solvent was used for non‐exhaustive desorption with high enrichment factor for rapid screening by CBS‐MS. For the suspicious samples, the remaining analytes on the SPME coating undergo exhaustive desorption, then followed by LC‐MS confirmation. The matrix‐compatible coating used in the SPME device significantly reduces matrix effects while enhancing sensitivity through analyte enrichment. This method is environmentally friendly, utilizing only a few microliters of organic solvents for screening. The approach was rigorously validated, both theoretically and experimentally, and successfully applied to anti‐doping testing, enabling detection of 53 prohibited substances in urine samples by integrating CBS‐MS with LC‐MS.