Computational and design of experiment strategies to improve differentiation and quantitation of trace-level cannabinoids by copper cationization paper spray mass spectrometry

The medicinal and recreational use of cannabis products is quickly rising from increased worldwide legalization and decriminalization. Despite this, current analytical methods have compromises when analyzing common isobaric cannabinoids, such as cannabidiol (CBD) or (−)-trans-Δ9-tetrahydrocannabinol (THC). We report on the use of computational chemistry, combined with design of experiment (DoE), to optimize and develop a paper spray mass spectrometry (PS-MS) method with on-paper cationization to simplify workflow for trace level differentiation and quantitation of THC and CBD. Computational methods allowed for pre-screening of candidate metal ions prior to experimental measurements, with promising candidates then being evaluated by electrospray ionization high resolution mass spectrometry (ESI-HRMS). A direct mass spectrometry method using copper cationization with PS-MS was then developed and optimized using DoE. Copper cationization with both ESI and PS-MS tandem mass spectrometry demonstrated the best CBD/THC selectivity and sensitivity, with 1% interference between CBD and THC copper adduct product ions with ESI. DoE results increased the analytical performance of the PS-MS method for quantifying cannabinoids in methanol, acetonitrile/water, and saliva matrices. Methanolic detection limits were 10 ng mL−1 for CBD and 20 ng mL−1 for THC by PS-MS allowing rapid (one-minute measurement), direct mass spectrometry differentiation, whereas detection limits in both saliva and acetonitrile/water matrices were <2 ng mL−1 for THC and CBD. This work illustrates the advantages of using DoE and computational chemistry to develop PS-MS and ESI methods for the rapid differentiation and quantitation of isobaric cannabinoids.