Desorption Electrospray/Metastable-Induced Ionization: A Flexible Multimode Ambient Ion Generation Technique Leonard Nyadong, Asiri S. Galhena, and Facundo M. Ferna ´ ndez* School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive Northwest, Atlanta, Georgia 30332 Presented here is a novel multimode ambient ion source termed desorption electrospray/metastable-induced ion- ization (DEMI), which integrates the beneﬁts and circum- vents some of the limitations of desorption electrospray ionization (DESI, polarity range limited) and direct analy- sis in real time (DART)-type metastable-induced chemical ionization (MICI, molecular weight limited). This ion source allows three unique operation modes, each with unique capabilities, including spray (DESI-like)-only, MICI-only, and DEMI (multimode), and can be thus operated in each of these modes allowing the detection of a wider range of analytes of interest. Ion source operation in the MICI-only mode is particularly well suited for the analysis of low-polarity, low-molecular weight compounds in powdered, solid, or dissolved samples. Operation of the ion source in spray-only mode shows superior performance for the analysis of high-molecular weight, high-polarity compounds over the MICI-only mode. Heating the nebulizer gas in spray-only mode allows improved analyte solubility in the spray solvent, enabling up to an order of magnitude improvement in sensitivity. Perhaps the most appealing mode of operation of the ion source is the DEMI mode which allows the simultaneous detection of compounds within a much broader range of polarities and molecular weights than each of the individual modes. For drug quality screening and counterfeit detection applications, operation in the DEMI mode results in the generation of both protonated and sodiated analytes. The observation of such comple- mentary ionic species facilitates compound identiﬁcation when investigating unknowns. The pursuit of enabling technologies for high-throughput analysis remains the cornerstone of analytical instrumentation development. In this sense, a recurrent theme in mass spectro- metry (MS) has been the deployment of hybrid ion generation techniques based on multiple and complementary physicochemical mechanisms, allowing the simultaneous detection of a broader range of analyte chemistries. 1 Multimode ionization sources combining electrospray ionization with atmospheric pressure chemical ionization (ESI/APCI) 1,2 and electrospray ionization with atmospheric pressure photoionization (ESI/APPI) 3,4 for probing high complexity samples by liquid chromatography-mass spec- trometry (LC-MS) 5 have been reported and are now com- mercially available. Recently introduced methods for direct ionization without sample preparation under ambient conditions 6-8 have also shown great promise for high-throughput analysis. 9 These methods are particularly attractive for investigating samples of odd shapes and sizes, while preserving their intrinsic chemical information content. Two of the most popular ambient ionization techniques are desorption electrospray ionization (DESI) 10 and direct analysis in real time (DART). 11 In DESI, a continuous pneumatically assisted electrospray jet is directed onto the sample, resulting in a thin solvent ﬁlm where surface molecules are extracted. The solvent ﬂow from the spray dynamically dislodges the surface ﬁlm resulting in the generation of analyte-containing secondary drop- lets, sampled downstream by the mass spectrometer inlet. 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Chem. 2009, 81, 7788–7794 10.1021/ac9014098 CCC: $40.75  2009 American Chemical Society 7788 Analytical Chemistry, Vol. 81, No. 18, September 15, 2009 Published on Web 08/18/2009