Venturi Easy Ambient Sonic-Spray Ionization - Analytical Chemistry

Jan 14, 2011 - The development and illustrative applications of an ambient ionization technique termed Venturi easy ambient sonic-spray ionization (V-...
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Venturi Easy Ambient Sonic-Spray Ionization Vanessa G. Santos,† Thaís Regiani,†,‡ Fernanda F. G. Dias,† Wanderson Rom~ao,† Jose Luis Paz Jara,† Clecio F. Klitzke,† Fernando Coelho,‡ and Marcos N. Eberlin*,† † ‡

ThoMSon Mass Spectrometry Laboratory, Institute of Chemistry, University of Campinas;UNICAMP, Campinas, SP, Brazil Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas;UNICAMP, Campinas, SP, Brazil ABSTRACT:

The development and illustrative applications of an ambient ionization technique termed Venturi easy ambient sonic-spray ionization (V-EASI) is described. Its dual mode of operation with Venturi self-pumping makes V-EASI applicable to the direct mass spectrometric analysis of both liquid (VL-EASI) and solid (VS-EASI) samples. V-EASI is simple and easy to assemble, operating solely via the assistance of a sonic stream of nitrogen or air. The sonic gas stream causes two beneficial and integrated effects: (a) the self-pumping of solutions via the Venturi effect and (b) sonic-spray ionization (SSI) of analytes either in solution or resting on solid surfaces. In its liquid mode, VL-EASI is applicable to analytes in solution, forming negatively and/or positively charged intact molecular species in a soft fashion with little or no fragmentation. In its solid mode, VS-EASI relies on Venturi self-pumping of a proper SSI solvent solution in combination with SSI to form a stream of bipolar charged droplets that bombard the sample surface, causing desorption and ionization of the analyte molecules. As for its precursor technique (EASI), V-EASI generates bipolar droplets with considerably lower average charging, which increases selectivity for ionization with high signal-to-noise ratios and clean spectra dominated by single molecular species with minimal solvent ions. V-EASI also operates in a voltage-, heat-, and radiation-free fashion and is therefore free of thermal, electrical, or discharge interferences.

ass spectrometry (MS) is now firmly established as one of the most powerful and wide-ranging analytical techniques, but despite this success and mature state, MS is still experiencing an explosive growth in the development of new concepts of mass analysis and ionization. The effectiveness of MS comes mainly from its unique combination of high sensitivity, selectivity, and speed (“the 3 S trademark of MS”). Ease or simplicity, however, have not been common attributes of MS due to intricate instrumentation and ionization techniques performed in “inhospitable” high-vacuum environments. Extraction, derivatization, and preseparation steps were also often required, particularly for complex mixtures and matrixes. Ionization techniques performed outside the mass spectrometer at atmospheric pressure such as electrospray ionization (ESI)1 have, however, been developed, thus greatly simplifying

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MS analysis. Recently, the need for sample preparation has been eliminated (or greatly minimized) with the development of desorption/ionization techniques performed directly for analytes in their natural environment or matrixes. This field, known as ambient mass spectrometry,2-4 was triggered by desorption electrospray ionization (DESI)5 and direct analysis in real time (DART).6 We have also recently introduced an ambient technique termed easy ambient sonic-spray ionization (EASI).7 Being based on sonic-spray ionization (SSI),8 EASI requires no assistance of voltages, radiation, or heating and operates with the sole assistance of a high-velocity (sonic) nebulizing gas. EASI is Received: October 20, 2010 Accepted: December 13, 2010 Published: January 14, 2011 1375

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Analytical Chemistry based on the unique SSI mechanism8,9 by which the sonic spray of an ionic solution forms very minute droplets with limited capacity of accommodating ions,10 hence with a statistically imbalanced distribution of charges. EASI forms, therefore, from an ionic solution, a dense bipolar cloud of droplets with either positive or negative net charges. This bipolar droplet stream promotes desorption and ionization of molecules typically as either [M þ H]þ or [M - H]- ions or as both. Bipolar EASI(() also deposits very little energy into the gaseous ions, causing little or no fragmentation,11 whereas the low charge concentration on the minute (()-droplets has been shown to be beneficial for analytical performance: absolute signal intensities are normally not that high (normally on the same order of magnitude),9 but solvent and chemical noise are greatly reduced, thus increasing sensitivity by increasing signal-to-noise ratios.8 The beneficial signal-tonoise ratio of EASI(() (or SSI) has been demonstrated for drugs,12 peptides,13 and zopiclone drug tablets.9 EASI is also free of thermal, electrochemical, or discharge interferences14 that may cause redox interferences or competitive different ionization mechanisms with diverse ionic forms. Ambient ionization techniques15 have been applied mainly to solid samples16,17,7 or viscous liquids.18 Liquid solutions needed to be frozen or subjected to solvent evaporation.19 To deal with solutions directly, some strategies have been tested. We, for instance, have coupled EASI to membrane introduction mass spectrometry (MIMS)20 using a cellulose dialysis membrane as a solid surface interface for the analysis of solution constituents. In neutral desorption extractive ESI (ND-EESI),21 solutions are handled via a distant microejecting process by which an aerosol of microdroplets of the solutions is created and transported to an ESI source. For DESI,10 capillaries were used to hold the analyte solutions which were driven out by the DESI nebulizing gas.22 Solutions have also been spread on a solid surface, and then normal DESI has been performed.23 Analyzing molecules already dissolved in proper solvents is beneficial for ambient MS since the required dissolution of the analyte is already achieved,10 particularly for less soluble analytes such as large proteins.10 More than two centuries ago, the Italian physicist Giovanni Battista Venturi discovered the Venturi effect.24 Such a useful siphon effect has since been widely used in many devices. In MS, a few self-aspirating but relatively complex devices based on Venturi self-pumping for conventional ESI-MS have been proposed.25-28 The Venturi effect occurs when a high-velocity fluid flows through a constricted section of pipe, causing a reduction in fluid pressure and a self-pumping effect (Figure 1A). Since EASI uses a sonic nebulizing gas, we rationalized that this high-velocity fluid could be used to concomitantly perform two important tasks: (a) SSI and (b) Venturi self-pumping of either analyte or solvent solutions (Figure 1B). This Venturi self-pumping would make an EASI apparatus even easier to assemble and operate and able to handle either solid or liquid samples without the assistance of electrical pumping. A simple and flexible dualmode EASI source (Figure 2) could therefore be constructed from common laboratory parts. Herein we describe the development and illustrative applications of a dual-mode Venturi easy ambient sonic-spray ionization (V-EASI) technique for the analysis of either liquid or solid samples.

’ EXPERIMENTAL METHODS Chemicals. HPLC-grade methanol and toluene used as solvents were purchased from Burdick & Jackson (Honeywell),

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Figure 1. Schematic of (A) the Venturi effect and (B) the V-EASI effect for combined Venturi self-pumping and sonic-spray ionization.

Figure 2. Actual picture of the V-EASI apparatus made by using common laboratory parts: a simple Swagelok T-element with appropriate ferrules, a 53 mm long stainless steel needle for the gas flow (i.d. = 400 μm and o.d. = 728 μm), and a fused-silica capillary (i.d. = 100 μm and o.d. = 125 μm) at the sonic-spray exit for the liquid flow.

formic acid was purchased from Acros, and ammonium hydroxide was purchased from Fluka. A sample of Brazilian crude oil available in our laboratory was used as received. The Brazilian artisan cachac-a (Seleta) aged in amburana casks was purchased at a local distributor. The cocaine standard was obtained from Radian (Austin, TX), and PEG 600 was available in our laboratory from a local producer. Commercially available myoglobin and cytochrome c from horse heart were purchased from Sigma-Aldrich, and the synthetic peptide sample was kindly supplied by Dr. Robson L. Melo (Center for Applied Toxinology-CAT/CEPID, Butantan Institute). For the Morita-Baylis-Hillman (MBH) reaction, methyl acrylate and 1,4-diazobicyclo[2.2.2]octane (DABCO) were purchased from Acros and 2-pyridinecarboxaldelyde was purchased from SigmaAldrich. All reagents were used as received without further purification. Deionized water was obtained from a Milli-Q (Millipore, Billerica, MA) purification unit. Mass Spectrometry. Experiments were performed on an LCMS-2010 EV single-quadrupole mass spectrometer (Shimadzu) using a homemade V-EASI ionization source. In general, the design of the V-EASI source is similar to that described for EASI.7 1376

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Analytical Chemistry The sonic-spray ionization was assisted only by compressed N2 at ca. 10 bar and a flow of 3.5 L min-1. The V-EASI source used a simple Swagelok T-element with appropriate ferrules and a 53 mm long stainless steel needle for the gas flow (i.d. = 400 μm and o.d. = 728 μm) and a fused-silica capillary (i.d. = 100 μm and o.d. = 125 μm) at the sonic-spray exit for the liquid flow. V-EASI uses, however, no electrical syringe pumping, since pumping of the analyte or spray solution is caused by the Venturi effect. For pure methanol, the solvent is suctioned at ∼20 μL min-1, for aqueous solutions at ∼5-10 μL min-1. Mass spectra were acquired over the 50-2000 m/z range.

’ RESULTS Figure 1A shows a classical schematic for the Venturi effect. The self-pumping effect, which is indicated for the green liquid, is caused by the passing of higher gas velocity (v2 > v1) through the restriction point. Figure 1B shows the Venturi effect operating in V-EASI in which the forces of the sonic gas perform two simultaneous, perfectly integrated and fundamental tasks for mass spectrometric ionization: (1) Venturi self-pumping of either the analyte or SSI solvent solution and (2) SSI that forms the dense cloud of very minute bipolar droplets. Figure 2 shows an actual picture of the V-EASI(() source constructed using common laboratory parts. Note its simplicity and ease of use. Optimization of V-EASI(() Parameters . Tube Diameters. In V-EASI (Figure 2), Venturi self-pumping can be finely tuned by using tube lines with varying internal/external diameters. In our prototype system, by using tubes with different diameters commonly available in analytical laboratories, a quite stable solution flow rate of ca. 15 μL min-1 was attained, which is typical for spray techniques such as ESI.1 We expect, however, that tube diameters and lengths can still be subjected to further improvements for the best V-EASI performance. Gas Flow. Different flows of compressed N2 (or air) were tested to find reference values, and on average the best results were observed for compressed N2 at ca. 10 bar and a flow of 3.5 L min-1. We also expected that much reduced gas flows could be used in optimized V-EASI sources using inner and outer tubes both with reduced diameters. Ideally (as we noted for the molecules tested herein), the gas flow should be finely tuned (via analyte ion monitoring) using a standard solution of the target molecule(s) for improved sensitivity and signal-to-noise ratio. Analyte-dependent tuning is recommended since the response is the overall result of several combined effects such as (a) SSI, (b) the spray shape, and (c) the solution flow rate during Venturi self-pumping that will depend on both analyte and solvent properties. Sensitivity. In this study, after tuning for the best ESI and V-EASI performance of the commercial ESI source of the mass spectrometer and our prototype V-EASI source, the absolute intensity of all analyte ions for V-EASI was on average 2-3 times lower than that for ESI, 29 but V-EASI always displayed superior signal-to-noise ratios, reduced chemical noise and fragmentation, and much less tendency to form adducts and dimers, with the response mostly concentrated on a single species. Although sensitivity varied considerably for the range of analytes tested, the limit of detection (LOD) for cocaine in acidic methanol was estimated to be around 0.2 ng mL-1. Angles. Two spray solvents (acidified methanol or acetonitrile9) were tested. Via self-pumping by VS-EASI, the resulting spray was directed to the surface of a sildenaphil tablet at different angles. In our prototype system, the best performance was achieved with angles close to 40°.

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Figure 3. Signal profile of VL-EASI(þ)-MS as measured by the TIC for a 30 μg mL-1 solution of cocaine in acidified methanol.

Signal Profile. After the optimization of all major parameters for V-EASI((), the signal profile in VL-EASI(þ)-MS (Figure 3) was monitored using a 30 ng mL-1 solution of cocaine in acidified methanol as a test solution. Initially, pure acidified methanol is sprayed, and a baseline signal (a) arises from background and chemical noise produced mainly from solvent ions and residual impurities. In (b), the solution line is moved from pure acidified methanol to the cocaine solution (c). A total ion current (TIC) spike is observed, from (b) to (c), due to the concomitant selfpumping of air, which greatly speeds the flow of the remaining solution, hence increasing the VL-EASI response. The signal is now close to zero in (c) since only air is being self-pumped. In (d), the cocaine solution is continuously self-pumped and TIC is abundant and quite stable, with the spectra now dominated by [M þ H]þ ions. Note that in (d) much reduced solvent ions and chemical noise are observed due to preferential SSI of cocaine in detriment to solvent molecules and impurities. The solution line is then returned back to the pure acidified methanol for cleaning. A spike is again observed at the end of (d) due to concomitant self-pumping of air. From (e) to (f), TIC decreases back to the baseline in ca. 2-3 min due to solvent cleaning. VL-EASI and VS-EASI. Figure 4 illustrates, for sildenaphil, the dual mode of operation of V-EASI. In VL-EASI(þ) (Figure 4A), Venturi self-pumping of a sildenaphil solution (30 ng mL-1 in acidified methanol) with a quite stable solution flow rate of ca. 15 μL min-1 produces a clean spectrum nearly free of chemical noise (from solvent ions and adducts and dimers) and a good signal-to-noise ratio. For VS-EASI (Figure 4B), acidified methanol is then self-pumped by the Venturi effect and the bipolar stream of charged droplets carrying solvent ions produced by SSI is directed to the surface of a sildenaphil tablet at an angle of ca. 40°. Note again the clean spectrum nearly free of chemical noise. Note also the nearly exclusive formation of [M þ H]þ of m/z 475 with very few Naþ and Kþ adducts, in contrast to ambient MS data for sildenaphil tablets in which dimers, adducts, ion fragmentation, and/or substantial solvent noise has been normally observed. Assorted Samples. Figure 5 shows data for some representative analytes in solution. VL-EASI(þ)-MS for a cocaine solution (Figure 5A) results again in a clean spectrum with an analyte response mostly concentrated on [M þ H]þ of m/z 304. Note the absence of solvent ions, fragments, dimers, or adducts. This feature should benefit the analysis of multidrug compositions and illicit drugs with unknown and variable compositions. For PEG 600 (Figure 5B), VL-EASI(þ)-MS also produces a clean spectrum with a correct average mass of ∼600 Da and a proper oligomeric distribution of PEG oligomers detected mainly as their [M þ K]þ adducts.30 Fruit juices and alcoholic beverages can be directly analyzed by VL-EASI(()-MS, as Figure 5C illustrates for 1377

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Analytical Chemistry

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Figure 4. Illustration of the V-EASI dual mode of operation: (A) VLEASI(þ) performed for a 30 ng mL-1 sildenaphil solution in acidified methanol and (B) VS-EASI(þ) performed for a commercial sildenaphil tablet using acidified methanol as the spray solvent.

Figure 6. VL-EASI(þ)-MS spectra of biological molecules in acidified aqueous solutions: (A) synthetic peptide FSDGLK at 150 μg mL-1, (B) myoglobin from horse heart at 1 mg mL-1, (C) cytochrome c from horse heart at 1 mg mL-1. Deconvoluted spectra are shown as insets.

Figure 5. Typical VL-EASI-MS spectra: (A) VL-EASI(þ)-MS spectrum of a 30 μg mL-1 solution of cocaine in acidified methanol, (B) VL-EASI(þ)MS spectrum of a 50 μg mL-1 solution of PEG 600 in acidified methanol, (C) VL-EASI(-)-MS spectrum of cachac-a diluted 1:100 in acidified methanol, (D) VL-EASI(þ)-MS spectrum of a 100 μg mL-1 solution of crude oil in an acidified methanol/toluene (5:1) solution.

cachac- a, a typical Brazilian alcoholic beverage. The ions of m/z 271, 313, and 377 are characteristic of cachac- a aged in amburana casks (Amburana cearensis).31 The VL-EASI(-)-MS of Figure 5C matches closely that produced by direct infusion ESI(-)-MS.30 For a sample of crude oil (Figure 5D), VL-EASI(þ) was also able

to efficiently ionize its myriad of polar components with data comparable to those of ESI(þ)-MS32 and EASI(þ)-MS.33 Biomolecules. Figure 6 illustrates the use of VL-EASI for biomolecules. Interestingly, for the biomolecules tested herein, an improved response (ca. 5-10 times better absolute intensity with reduced chemical noise) was observed for VL-EASI(þ) in pure water as compared to 1:1 water/methanol solutions. Spraybased techniques normally use 1:1 water/methanol solutions for reduced surface tension.34 The improved performance of liquid V-EASI in pure water for biomolecules, perhaps due to the reduced effect of surface tension on the formation of the very minute droplets during sonic spraying, in contrast to ESI, seems promising for the analysis of peptides and proteins in undisturbed physiological solutions. Figure 6A shows the spectrum of an aqueous solution of the synthetic FSDGLK peptide, with the dominance of the [M þ H]þ and [M þ 2H]2þ ions of m/z 666 and 333, respectively. Figure 6B shows the spectrum of an aqueous solution of the horse heart myoglobin (16.9 kDa). Note the characteristic and well-balanced cluster of multiply protonated molecules [M þ nH]nþ centered at 17þ of m/z 998 but ranging all the way from 25þ (m/z 679) to 12þ (m/z 1413).35 Figure 6C shows the spectrum for an acidified aqueous solution of cytochrome c (12.3 kDa), with the typical [M þ nH]nþ cluster ranging from 7þ (m/z 1766) to 19þ (m/z 651) and centered at about 15þ (m/z 825).36 Spectra deconvolution to the singly protonated molecules gave the correct masses for both proteins. Reaction Monitoring. The development of atmospheric pressure ionization techniques, most particularly ESI, has allowed online and continuous MS monitoring of reaction solutions.37-39 This monitoring provides representative snapshots of the ionic composition of the reaction solutions and therefore key information on the mechanisms.40 Low-temperature plasma (LTP),41 an 1378

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Figure 7. Representative VL-EASI(þ)-MS at different reaction times of the reaction solution for the nearly continuous (3 s min-1) monitoring of an MBH reaction between methyl acrylate (2) and 2-pyridinecarboxyaldehyde (4) catalyzed by DABCO (1): (A) 0 min, (B) 30 min, and C) 2 h.

Scheme 1. Catalytic Cycle of the MBH Reaction

ambient ionization technique that preferentially detects more volatile molecules, was also recently employed to monitor the progress of reactions from the surface of reaction solutions. We have employed direct infusion ESI-MS(/MS) monitoring42 to investigate different mechanistic aspects of the Morita-Baylis-Hillman reaction43 and have successfully characterized its intermediates.44 Figure 7 illustrates the VL-EASI(þ)-MS monitoring of an MBH reaction solution. Self-pumping was continuous, but the spray was directed intermittently to the MS skimmer (3 s min-1). During the remaining 57 s, the spray was deviated from the MS skinner to minimize source contamination. Reaction solutions should also be diluted as much as possible. For the MBH reaction tested (Scheme 1), the first intermediate 3 in its protonated form [3 þ H]þ of m/z 199 and the catalyst

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Figure 8. Kinetic curve (polynominal fitting) from nearly continuous (3 s min-1) VL-EASI(þ)-MS monitoring of the reaction solution for the MBH reaction of methyl acrylate (2), DABCO (1), and 2-pyridinecarboxyaldehyde (4). For the ion structures see Scheme 1.

DABCO as [1 þ H]þ of m/z 113 were both intercepted at the very beginning (Figure 7A). After 30 min (Figure 7B), a second and key MBH intermediate was detected as the prominent [5 þ H]þ ion of m/z 306. After 2 h (Figure 7C), the final MBH product was detected as both [6 þ H]þ of m/z 194 and [6 þ Na]þ of m/z 216. Two additional ions can be assigned as follows: [4 þ H]þ of m/z 108 and [4 þ MeOH þ H]þ of m/z 140. Figure 8 summarizes the MBH reaction monitoring via a kinetic curve for ions arising from reactants, intermediates, and the final product.

’ CONCLUSIONS A simple, easy to assemble and operate, dual-mode ionization technique for ambient mass spectrometry applicable to both liquid and solid samples with Venturi self-pumping has been developed, and some illustrative applications have been demonstrated. Bipolar V-EASI(() uses the combined effects of a high-velocity sonic stream of nitrogen or air that integrates two fundamental steps of ionization: (i) self-pumping of the analyte or spray solution via the Venturi effect and (ii) ionization via SSI. Since V-EASI uses no voltages, heating, or radiation, its ionization process is inherently free of thermal, electrical, and discharge interferences. V-EASI is also a very soft45 ionization process; hence, fragmentation is minimized or, most often, completely eliminated. Although the absolute intensity of analyte ions in the voltagefree V-EASI seems to be lower than that from high-voltage spray techniques, V-EASI benefits from reduced chemical noise and therefore improved signal-to-noise ratios, leading to clean spectra with little or no competitive dimers, adducts or fragments and with the analytical signal concentrated on a single ionic species with reduced ion suppression effects.14 The dual mode of operation in both (() ion modes due to its bipolar stream as well as via VL-EASI or VS-EASI modes for liquid or solid samples should also contribute to the flexibility and broad range of applications of V-EASI. The improved performance of V-EASI for biomolecules in pure water also seems attractive for the analysis of proteins and peptides in undisturbed physiological solutions and biological fluids. We are currently testing V-EASI(() for urine analysis. Ambient mass spectrometry has, as its fundamental promise, the delivery of a much easier way to perform mass spectrometry. 1379

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Analytical Chemistry Although there is currently an explosive growth in the arrival of new ambient ionization techniques,2-4 few of them have simplicity among their figures of merit. Among those currently available,4 we consider that LTP,39 paper spray,46 and EASI7 (and now V-EASI) form a concise set of efficient, yet simple, and easy (to assemble and operate) ambient ionization techniques for easier than ever mass spectrometry.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT We thank the Brazilian science foundations FAPESP, CNPq, and CAPES for financial assistance. ’ REFERENCES (1) Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse, C. M. Science 1989, 246, 64–71. (2) Harris, G. A.; Nyadong, L.; Fernandez, F. M. Analyst 2008, 133, 1297–1301. (3) Ifa, D. R.; Wu, C. P.; Ouyang, Z.; Cooks, R. G. Analyst 2010, 135, 669–681. (4) Alberici, R. M.; Simas, R. C.; Sanvido, G. S.; Rom~ao, W.; Lalli, P. M.; Benassi, M.; Cunha, I. B. S.; Eberlin, M. N. Anal. Bioanal. Chem. 2010, 398, 265–294. (5) Takats, Z.; Wiseman, J. M.; Gologan, B.; Cooks, R. G. Science 2004, 306, 471–473. (6) Cody, R. B.; Laramee, J. A.; Durst, H. D. Anal. Chem. 2005, 77, 2297–2302. (7) Haddad, R.; Milagre, H. M. S.; Catharino, R. R.; Eberlin, M. N. Anal. Chem. 2008, 80, 2744–2750. (8) Hirabayashi, A.; Sakairi, M.; Koizumi, H. Anal. Chem. 1994, 66, 4557–4559. (9) Zivolic, F.; Zancarano, F.; Favretto, D.; Ferrara, S. D.; Seraglia, R.; Traldi, P. J. Mass Spectrom. 2010, 45, 411–420. (10) On the basis of calculations performed for ESI droplets, and the very minute droplets expected for SSI, it is also likely that EASI and V-EASI droplets containing the analyte carry on average a single molecule, having therefore reduced ion suppression effects; see: Wilm, M. S.; Mann, M. Int. J. Mass Spectrom. 1994, 136, 167–180. (11) Takats, Z.; Nanita, S. C.; Cooks, R. G.; Schlosser, G.; Vekey, K. Anal. Chem. 2003, 75, 1514–1523. (12) Haddad, R.; Sparrapan, R.; Eberlin, M. N. Rapid Commun. Mass Spectrom. 2006, 20, 2901–2905. (13) Sorensen, M. B.; Aaslo, P.; Egsgaard, H.; Lund, T. Rapid Commun. Mass Spectrom. 2008, 22, 455–461. (14) Pasilis, S. P.; Kertesz, V.; Van Berkel, G. J. Anal. Chem. 2008, 80, 1208–1214. (15) Chen, H.; Gamez, G.; Zenobi, R. J. Am. Soc. Mass. Spectrom. 2009, 20, 1947–1963. (16) Figueiredo, E. C.; Sanvido, G. B.; Arruda, M. A. Z.; Eberlin, M. N. Analyst 2010, 135, 726–730. (17) Eberlin, L. S.; Abdelnur, P. V.; Passero, A.; de Sa, G. F.; Daroda, R. J.; Souza, V.; Eberlin, M. N. Analyst 2009, 134, 1652–1657. (18) Simas, R. C.; Catharino, R. R.; Cunha, I. B. S.; Cabral, E. C.; Barrera-Arellano, D.; Eberlin, M. N.; Alberici, R. M. Analyst 2010, 135, 738–744. (19) Alberici, R. M.; Simas, R. C.; de Sa, G. F.; Daroda, R. J.; Souza, V.; Eberlin, M. N. Anal. Chim. Acta 2010, 659, 15–22. (20) Haddad, R.; Sparrapan, R.; Kotiaho, T.; Eberlin, M. N. Anal. Chem. 2008, 80, 898–903. (21) Law, W. S.; Chen, H. W.; Balabin, R.; Berchtold, C.; Meier, L.; Zenobi, R. Analyst 2010, 135, 773–778.

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(22) Ma, X.; Zhao, M.; Lin, Z.; Zhang, S.; Yang, C.; Zhang, X. Anal. Chem. 2008, 80, 6131–6136. (23) Miao, Z. X.; Chen, H. J. Am. Soc. Mass Spectrom. 2009, 20, 10–19. (24) Geankoplis, C. J. Transport Processes and Unit Operations, 3rd ed.; Prentice-Hall: Englewood Cliffs, NJ, 1993. (25) Wachs, T.; Henion, J. Anal. Chem. 2001, 73, 632–638. (26) Asano, K. G.; Ford, M. J.; Tomkins, B. A.; Van Berkel, G. J. Rapid Commun. Mass Spectrom. 2005, 19, 2305–2312. (27) Geromanos, S.; Philip, J.; Freckleton, G.; Tempst, P. Rapid Commun. Mass Spectrom. 1998, 12, 551–556. (28) Geromanos, S.; Freckleton, G.; Tempst, P. Anal. Chem. 2000, 72, 777–790. (29) A recent study9 also reported EASI and DESI responses on the same order of magnitude, with a 2-3 times lower absolute intensity of EASI as compared to DESI. We note, however, that source geometry and gas flow seemed not to have been optimized for the best EASI performance. We have also compared EASI and DESI responses for a variety of drug tablets11 with, on average, comparable performances. (30) Harris, J. M.; Zalipsky, S. Poly(ethylene glycol): Chemistry and Biological Applications; American Chemical Society: Washington, DC, 1997. (31) de Souza, P. P.; Siebald, H. G. L.; Augusti, D. V.; Neto, W. B.; Amorim, V. M.; Catharino, R. R.; Eberlin, M. N.; Augusti, R. J. Agric. Food Chem. 2007, 55, 2094–2102. (32) Marshall, A. G.; Rodgers, R. P. Acc. Chem. Res. 2004, 37, 53–59. (33) Corilo, Y. E.; Vaz, B. G.; Simas, R. C.; Nascimento, H. D. L.; Klitzke, C. F.; Pereira, R. C. L.; Bastos, W. L.; Santos Neto, E. V.; Rodgers, R. P.; Eberlin, M. N. Anal. Chem. 2010, 82, 3969–4304. (34) Neto, B. A. D.; Santos, L. S.; Nachtigall, F. M.; Eberlin, M. N.; Dupont, J. Angew. Chem., Int. Ed. 2006, 45, 7251–7254. (35) Katta, V.; Chait, B. T. J. Am. Chem. Soc. 1991, 113, 8534–8535. (36) Chowdhury, S. K.; Katta, V.; Chait, B. T. J. Am. Chem. Soc. 1990, 112, 9012–9013. (37) Svennebring, A.; Sjoberg, P. J.; Larhed, M.; Nilsson, P. Tetrahedron 2008, 64, 1808–1812. (38) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 34, 4389–4389. (39) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 19, 2514–2518. (40) Santos, L. S. Eur. J. Org. Chem. 2008, 2, 235–253. (41) Harper, J. D.; Charipar, N. A.; Mulligan, C. C.; Zhang, X.; Cooks, R. G.; Ouyang, Z. Anal. Chem. 2008, 80, 9097–9104. (42) Amarante, G. W.; Benassi, M.; Milagre, H. M. S.; Braga, A. A. C.; Maseras, F.; Eberlin, M. N.; Coelho, F. Chem.;Eur. J. 2009, 15, 12460– 12469. (43) Coelho, F.; Veronese, D.; Pavam, C. H.; de Paula, V. I.; Buffon, R. Tetrahedron 2006, 62, 4563–4572. (44) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 43, 4330–4333. (45) Takats, Z.; Nanita, S. C.; Schlosser, G.; Vekey, K.; Cooks, R. G. Anal. Chem. 2003, 75, 6147–6154. (46) Wang, H.; Liu, J.; Cooks, R. G.; Ouyang, Z. Angew. Chem., Int. Ed. 2010, 49, 877–880.

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