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Surface Analysis under Ambient Conditions Using
Plasma-Assisted Desorption/Ionization Mass
Spectrometry
Lucy V. Ratcliffe,† Frank J. M. Rutten,†,# David A. Barrett,*,† Terry Whitmore,‡ David Seymour,‡
Claire Greenwood,‡ Yolanda Aranda-Gonzalvo,‡ Steven Robinson,§ and Martin McCoustra†,⊥
Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD,United Kingdom, Hiden Analytical Ltd., 420 Europa Boulevard, Warrington, Cheshire, WA5 7UN, United Kingdom, andForensic Science Service, Unit 2900, Solihull Parkway, Birmingham Business Park, Birmingham, B37 7YN, United Kingdom A novel plasma-assisted desorption/ionization (PADI)
DESI consists of directing a pneumatically assisted electrospray method that can be coupled with atmospheric pressure
onto an analyte surface, coupled with collection of the desorbed sampling mass spectrometry to yield mass spectral infor-
ions by the MS inlet.1 This ambient pressure ionization method mation under ambient conditions of pressure and humid-
has been applied to the analysis of a wide variety of compounds ity from a range of surfaces without the requirement for
including peptides,2 proteins,2,3 pharmaceuticals,4-6 explosives,7,8 sample preparation or additives is reported. PADI is
controlled substances,5,9 and others.2,10-12 DART is another carried out by generating a nonthermal plasma which
atmospheric pressure ionization technique capable of rapid surface interacts directly with the surface of the analyte. Desorp-
analysis.13 DART has been applied to the detection of pharma- tion and ionization then occur at the surface, and ions are
ceuticals, drugs of abuse, chemical warfare agents, and a multitude sampled by the mass spectrometer. The PADI technique
of other chemicals.13 This noncontact ion source consists of a is demonstrated and compared with desorption electro-
remote nonthermal plasma from which charged species are spray ionization (DESI) for the detection of active ingre-
rejected with a grid system and metastable species are directed dients in a range of over-the-counter and prescription
toward the surface of the analyte. Excited-state gas molecules have pharmaceutical formulations, including nonsterodial anti-
previously been used in ionization sources.14-18 For example, in inflammatory drugs (mefenamic acid, Ibugel, and ibupro-
the metastable atom bombardment (MAB) source a metastable fen), analgesics (paracetamol, Anadin Extra), and Bee-
ion beam is generated which interacts with neutral gas-phase cham's "all in one" cold and flu remedy. PADI has also
been successfully applied to the analysis of nicotine in
(1) Taka´ts, Z.; Wiseman, J. M.; Gologan, B.; Cooks, R. G. Science 2004, 306,
tobacco and thiosulfates in garlic. PADI experiments have
(2) Taka´ts, Z.; Wiseman, M.; Cooks, R. G. J. Mass Spectrom. 2005, 40, 1261-
been performed using a prototype source interfaced with
a Waters Platform LCZ single-quadrupole mass spectrom-
(3) Myung, S.; Wiseman, J. M.; Valentine, S. J.; Taka´ts, Z.; Cooks, R. G.; eter with limited modifications and a Hiden Analytical
Clemmer, D. E. J. Phys. Chem. B 2006, 110, 5045-5051.
(4) Williams, J. P.; Patel, V. J.; Holland, R.; Scrivens, J. H. Rapid Commun. Mass HPR-60 molecular beam mass spectrometer (MBMS).
Spectrom. 2006, 20, 1447-1459.
The ability of PADI to rapidly detect active ingredients in
(5) Leuthold, L. A.; Mandscheff, J. F.; Fathi, M.; Giroud, C.; Augsburger, M.; pharmaceuticals without the need for prior sample prepa-
Varesio, E.; Hopfgartner, G. Rapid Commun. Mass Spectrom. 2006, 20, 103-
110.
ration, solvents, or exposed high voltages demonstrates
(6) Kappulia, T. J.; Wiseman, J. M.; Ketola, R. A.; Kotiaho, T.; Cooks, R. G.; the potential of the technique for high-throughput screen-
Kostianen, R. Rapid Commun. Mass Spectrom. 2006, 20, 387-392.
ing in a pharmaceutical or forensic environment.
(7) Mulligan, C. C.; Talaty, N.; Cooks, R. G. Chem. Commun. 2006, 1709-
(8) Cotte-Rodriguez, I.; Chen, H.; Cooks, R. G. Chem. Commun. 2006, 953-
Desorption electrospray ionization (DESI) and direct analysis in real time (DART) are two recently introduced techniques which (9) Rodriguez-Cruz, S. E. Rapid Commun. Mass Spectrom. 2006, 20, 53-60.
(10) Nefliu, M.; Venter, A.; Cooks, R. G.
have successfully overcome the difficulties associated with vacuum- Chem. Commun. 2006, 888-890.
(11) Talaty, N.; Taka´ts, Z.; Cooks, R. G. Analyst 2005, 130, 1624-1633.
based analyses, such as the need for vacuum compatible samples.
(12) Van Berkel, G. J.; Ford, M. J.; Deibel, M. A. Anal. Chem. 2005, 77, 1207-
* Corresponding author. E-mail: [email protected]. Phone: (13) Cody, R. B.; Laramee, J. A.; Durst, H. D. Anal. Chem. 2005, 77, 2297-
+44(0)115-9515062. Fax: +44(0)115-9515102.
† University of Nottingham.
(14) Faubert, D.; Paul, G. J. C.; Giroux, J.; Bertrand, M. J. Int. J. Mass Spectrom. ‡ Hiden Analytical Ltd.
Ion Processes 1993, 124, 69-75.
§ Forensic Science Service.
(15) Tsuchiya, M.; Kuwabara, H. Anal. Chem. 1984, 56, 14-19.
# Present address: School of Pharmacy and iEPSAM, Keele University, Keele, (16) Tsuchiya, M. Mass Spectrom. Rev. 1998, 17, 51-69.
ST5 5BG, United Kingdom.
(17) McLuckey, S. A.; Glish, G. L.; Asano, K. G.; Grant, B. C. Anal. Chem. 1988,
⊥ Present address: Department of Chemistry, School of Engineering and Physical Sciences, Heriot-Watt University, Riccarton, Edinburgh, EH14 4AS, (18) Guzowski, J. P., Jr.; Broekaert, J. A. C.; Ray, S. J.; Hieftje, G. M. J. Anal. At. United Kingdom.
Spectrom. 1999, 14, 1121-1127.
10.1021/ac070109q CCC: $37.00 xxxx American Chemical Society Analytical Chemistry Published on Web 07/12/2007 analytes and ionization occurs via a Penning ionization process energetic species as in DART. The result is a simpler, more robust in vacuo.14 Other similar techniques include liquid surface Penning source. Second, unlike DART, the surface of the analyte is in direct ionization (LPI), where a liquid sample is deposited onto a needle contact with the active part of the plasma. This direct interaction tip held at a high potential and ionized by excited argon atoms.15,16 of the plasma with the sample results in surface interactions not In atmospheric sampling glow discharge ionization (ASGDI) only with metastable helium atoms, thought to be the dominant ionization occurs via Penning ionization when the sample is desorption/ionization mechanism in DART,13 but also with ener- exposed to an electrical discharge.17,18 Desorption atmospheric getic ions and radicals. Since electrons, ions, and radical species pressure chemical ionization (DAPCI)19 and the related technique interact with surfaces in chemically specific ways, this introduces atmospheric pressure solids analysis probe (ASAP)20 utilize corona the possibility of controlling specificity by exploiting the ability discharges and operate at ambient conditions.
to promote desired plasma-surface reactions. Selective etching Ambient sampling techniques, such as DESI and DART, offer of surfaces by promotion with certain radical groups is a technique significant potential benefits over current methods for the analysis long employed in low-pressure plasma processing in, e.g., the of pharmaceuticals and controlled substances which at present semiconductor industry.26 A direct consequence of this is the typically involves lengthy sample preparation. For example, solvent possibility of "cleaner" mass spectra, free from spectral interfer- extraction followed by filtration and analysis via liquid chroma- ences that might otherwise mask important information. Finally, tography mass spectrometry (LC/MS) or gas chromatography in contrast to DART and the corona discharge sources, PADI mass spectrometry (GC/MS) are commonly used to determine produces a visual plasma plume of submillimeter diameter that the presence of drugs.21-24 The ability to rapidly identify analytes terminates in a fine point. This has distinct advantages for without loss of quality of the data is an important analytical alignment issues.
challenge. The potential impact of ambient pressure ionization Herein, we describe the PADI technique and demonstrate its techniques capable of high-throughput analysis on the field of application for the analysis of active ingredients in a variety of pharmaceuticals is immense.
common pharmaceutical drugs, making a direct comparison with We have recently developed a new approach to ambient surface DESI analysis.
analysis, termed plasma-assisted desorption/ionization (PADI),which is distinct from and offers advantages over DESI, DART, and related techniques. PADI consists of generating a nonthermal The pharmaceutical preparations investigated are listed in radio frequency-driven atmospheric pressure plasma and directing Figure 1 along with the molecular weights and formulas of the it onto the surface of the analyte without charged particle active ingredients. Paracetamol (Sterwin Medicines), ibuprofen extraction. The PADI source is different from other direct (Galpharm Healthcare), Anadin Extra (Wyeth, U.K.), Ralgex ionization techniques, such as DART, DAPCI, and ASAP, in several cream (SSL International, U.K.), Ibugel (Dermal, U.K.), and ways. First, DART, DAPCI, and ASAP techniques utilize corona Beecham's "all in one" (GlaxoSmithKline, U.K.) were purchased discharges, typically formed by applying several kilovolts to the over the counter, and mefenamic acid tablets (Norton Healthcare, tip of a sharpened electrode. This class of discharge is character- U.K.) were obtained by prescription. HPLC grade methanol was ized by high-voltage/low-current characteristics which generate purchased from Fisher (Loughborough, Leicestershire, U.K.).
ions with energies extending to the full extent of the applied Sampling Preparation and Handling for PADI and DESI.
voltage. In contrast, the PADI source is a nonthermal atmospheric Uncoated tablets were used as supplied, whereas coated tablets glow discharge which is characterized by a lower operating voltage were carefully scraped with a scalpel blade prior to analysis to and higher current characteristics than corona discharges. The expose the underlying active materials. Cream formulations (ca.
PADI source operates over a lower voltage/power range (typically 10 mg) were deposited onto glass slides and spread into a thin 300 V peak to peak and less than 5 W total applied power). This layer using cotton-tipped safety swabs. A target plate was results in a truly nonthermal, or cold, plasma with an operating constructed for DESI analysis which consisted of a square of matt temperature close to that of the ambient surroundings.25 The glow finished card (2 cm × 2 cm) attached to a metal post placed in discharge is self-sustaining and results in relatively low ion close proximity to the mass spectrometer inlet. Samples (tablets energies, typically less than 5 eV and not exceeding 20 eV. In or creams on glass slides) were mounted onto the matt card with contrast to corona discharge and DESI techniques, the nonthermal double-sided tape and positioned approximately 45° to the solvent plasma of PADI is cold to the touch and does not heat the sample.
spray. For PADI analysis the sample was positioned at grazing This in turn allows direct interaction of the plasma with thermally incidence to the plasma with nonconducting tweezers typically at sensitive samples and does not require the removal of any highly a distance of 1-3 mm from the source sampling inlet.
PADI Instrumentation. The PADI source consisting of a
(19) Taka´ts, Z.; Cotte-Rodriguez, I.; Talaty, N.; Chen, H.; Cooks, R. G. Chem. nonthermal rf plasma "needle" operating at atmospheric pressure Commun. 2005, 15, 1950-1952.
was based upon the design of Stoffels et al.25 This consists of a (20) McEwan, C. N.; McKay, R. G.; Larsen, B. S. Anal. Chem. 2005, 77, 7826-
stainless steel wire, 190 mm long and 0.75 mm diameter, (21) Noggle, F. T., Jr.; Randall, C. C.; Deruiter, J. J. Liq. Chromatogr. 1990, 13,
sharpened into a needle-like point at one end. The wire serves as a powered electrode and is placed coaxially within a ceramic tube (22) Kumazawa, T.; Lee, X.-P.; Sato, K.; Suzuki, O. Anal. Chim. Acta 2003, 492,
(1.2 mm i.d., 2.5 mm o.d.) which is itself placed coaxially within (23) Ulrich, S. J. Chromatogr., A 2000, 902, 167-194.
a quartz tube (5 mm i.d., 7 mm o.d.). The ceramic and quartz (24) Drummer, O. H. J. Chromatogr., B: Biomed. Sci. Appl. 1998, 713, 201-
cylinders have independent gas feeds and may be filled with the (25) Stoffels, E.; Flikweert, A. J.; Stoffels, W. W.; Kroesen, G. M. W. Plasma Sources Sci. Technol. 2002, 11, 383-388.
(26) Booth, J.-P. Plasma Sources Sci. Technol. 1999, 8, 249-257.
Analytical Chemistry Figure 1. Structures and formulas of the analytes analyzed.
Figure 2. Schematic of the PADI probe with a photograph illustrating the source in operation.
same flowing gas, typically helium at several hundred milliliters Some PADI experiments were carried out on a Platform LCZ per minute, or with helium and a second gas or mixture of gases.
mass spectrometer (Waters, Manchester, U.K.) operating in A radio frequency (13.56 MHz) signal is applied to the unsharp- positive ion mode. For all experiments the ion source block was ened end of the needle via a matching network. The peak-to-peak maintained at 110 °C, and the cone voltage was set at 18 V. The rf voltage is typically 200-500 V, and powers are typically less Z-spray source of the instrument was removed, and the PADI than 5 W. Application of this rf signal generates a cold, nonthermal probe was positioned approximately 45° to the atmospheric plasma at the tip of the needle. The plasma is around 1 mm in pressure cone inlet of the MS.
diameter and may extend up to 10 mm from the tip. The plasma The PADI source was also interfaced to an HPR-60 molecular operates in ambient air and can be brought into direct contact beam mass spectrometer (MBMS) (Hiden Analytical Ltd., War- with any of the surfaces under study. The action of the plasma at rington, U.K.) which consists of a single-stage quadrupole mass the sample surface produces ions from the surface material which spectrometer (QMS) with a differentially pumped three-stage inlet enter the gas phase and are readily detected with a suitable mass system.27 The pressure reduction stages are separated by aligned spectrometer. A schematic illustration of the PADI source and skimmer cones and continuously pumped by separate turbomo- experimental setup are shown in Figure 2.
lecular pump sets. A free-jet expansion from atmospheric pressure Analytical Chemistry into the primary low-pressure stage is skimmed to produce a dimensions of the prototype PADI source. For PADI interfaced molecular beam in what is known as a Campargue source.28 The with the LCZ mass spectrometer these angles were found not to beam is then directed into the electron impact ion source of the be critical. However, PADI combined with the MBMS generated QMS. Ions generated via the ionization process enter the mass higher signal intensities when the angle of the plasma to MS inlet analyzer and are detected. PADI experiments were performed on was 0°. Overall, the setup and optimization of the PADI source the MBMS in both positive and negative modes of ionization.
was found to be considerably less time-consuming and critical than Optimum cone voltages were -30, 10, and -30 V on cones 1, 2, for the DESI source. The integration of the PADI source is and 3, respectively, in positive ion mode and 0, 0, and 2 V in therefore straightforward for mass spectrometers having an negative ion mode. The plasma beam was directly aligned with atmospheric pressure inlet, requiring minimal modification and the mass spectrometer inlet, and the sample was inserted into permitting control of voltages directly from vendor software. This the plasma using tweezers so that the beam grazed the tablet distinct advantage of PADI may be exploited for pharmaceutical and, potentially, forensic applications where rapid screening is DESI Instrumentation. For DESI analysis, the standard
Z-spray electrospray (ESI) probe of the platform LCZ (Waters, PADI with Molecular Beam Mass Spectrometry Detec-
Manchester, U.K.) was used to deliver the solvent spray to the tion. The objective of this work was to evaluate PADI as an
analyte surface. The only modification required to the instrument ambient pressure surface analysis technique. To achieve this PADI was the removal of the glass source cover to give access to the was combined with an MBMS for the analysis of a range of source region for positioning of the sample. The mass spectrom- pharmaceutical preparations. Figure 2b shows a photograph of eter was operated in positive ESI mode with a capillary voltage of the PADI source interfaced with the MBMS for the sampling of 4.7 kV. The nitrogen gas desolvation temperature was set to 325 a paracetamol tablet.
°C with a flow rate of 350 L/h supplied from a nitrogen generator Typical data obtained for the detection of active ingredients at 100 psi (Peak Scientific, Renfrew, U.K.). The ion source block of pharmaceuticals using PADI interfaced with the MBMS was maintained at 110 °C, and the cone voltage was set at 18 V.
operated in positive ion mode are shown in Figure 3a-c. All The sample (tablet or cream) was sprayed with a solution of spectra were acquired from approximately 1 s of experimental methanol/water (1:1) at a flow rate of 5 µL min-1 using a syringe data. Tablet and gel formulations were examined including pump (WPI, Stevenage, U.K.).
nonsterodial anti-inflammatory drugs such as mefenamic acid,ibuprofen tablets (data not shown), and Ibugel. For each of the RESULTS AND DISCUSSION
compounds the expected protonated molecules were observed Optimization of PADI Operational Parameters. Optimiza-
with high signal intensity. For example, the active ingredient of a tion of the PADI technique was carried out on both the MBMS generic mefenamic acid tablet (500 mg of mefenamic acid) was and LCZ mass spectrometers. The tip of the needle was aligned evident at m/z 242 (Figure 3a). Ibugel contains the active with the mass spectrometer inlet at a distance of a few millimeters component ibuprofen at the 5.0% level (w/w); this was observed (ca. 1-10), the plasma was ignited, and the sample was inserted as a protonated molecule at m/z 207 (Figure 3b). Simultaneous into the beam. Adjustment of the He gas flows controlled the detection of multiple ingredients was assessed by the rapid shape of the plasma jet; elongated plasma of about 4-5 mm was analysis of Beecham's "all in one", an "over-the-counter" cold and found to be optimum for PADI experimentation. This was typically flu remedy which contains the three actives paracetamol (250 mg), obtained with gas flows in the region of 300-500 mL min-1.
guaifenesin (100 mg), and phenylephrine hydrochloride (5 mg).
The main consideration with the PADI technique for the The two main active ingredients were observed as protonated analysis of pharmaceuticals was found to be the input power. In species, guaifenesin at general, the signal intensity of the protonated species of the active m/z 199 and paracetamol at m/z 152 ingredient increased as the power increased. However, at high (Figure 3c). The base peak at m/z 124 was due to fragmentation power (>7 W) surface erosion and charring of the tablet surface of guaifenesin.
were observed. Damage to the analyte surface was virtually The ability of the technique to operate in both negative and eliminated when the source was operated at low power (<3 W) positive ion modes is of particular importance to the pharmaceuti- at which setting high-quality mass spectra could readily be cal industry because many drug formulations may contain both basic and acidic molecules with a range of polar and nonpolar In contrast to PADI, there are several operational parameters properties. Paracetamol, ibuprofen, and aspirin tablets were related to the DESI source which need to be optimized in order selected as examples to demonstrate PADI for the detection of to effectively generate and detect ions. These include the high the active ingredients using the negative ion mode. The mass voltage applied to the ESI, solvent flow rate, and distances to the spectra generated are shown in Figure 3d-f. For all these MS inlet.1,2,6 The most critical variables for DESI analysis are the compounds the deprotonated ion of the active ingredient was angles between the sample, MS sampling cone, and the ESI spray.
observed with high signal intensities. For example, abundant Plasma to MS inlet angles over the range of 30-90° were peaks at m/z 150 and m/z 205 correspond to deprotonated investigated on the LCZ mass spectrometer. The scope of angles paracetamol and ibuprofen, respectively. The negative ion mass examined was limited by spatial parameters due to the physical spectrum obtained for aspirin using PADI is shown in Figure 3f.
As expected, the deprotonated molecule [M - H]- for the active (27) Aranda-Gonzalvo, Y.; Whitmore, T. D.; Rees, J. A.; Seymour, D. L.; Stoffels, ingredient at m/z 179 was observed. In-source CID of this ion E. J. Vac. Sci. Technol., A 2006, 24, 550.
resulted in the fragment at m/z 137, which is consistent with DESI (28) Scoles, G. Atomic and Molecular Beam Methods; Oxford Press: New York, 1988; Vol. 1, Chapter 2.
analysis of aspirin.29 DESI negative ion mass spectra were obtained Analytical Chemistry Figure 3. Typical positive ion mode PADI-MBMS spectra obtained for the rapid detection of active pharmaceutical ingredients in (a) a generic
mefenamic tablet (500 mg of mefenamic acid), (b) Ibugel (5% ibuprofen w/w), (c) "Beecham's all in one" (250 mg of paracetamol, 100 mg of
guaifenesin, and 5 mg of phenylephrine hydrochloride) and typical negative ion mode PADI-MBMS spectra obtained for (d) a paracetamol tablet
(500 mg of paracetamol), (e) a generic ibuprofen tablet (200 mg of ibuprofen), and (f) an aspirin tablet (300 mg of aspirin).
Figure 4. PADI-MBMS spectra obtained for the detection of (a) nicotine in tobacco, (b) allicin in freshly sliced garlic, and (c) propanethial-
S-oxide in freshly cut onion.
for paracetamol, ibuprofen, and aspirin (data not shown) which Allicin, the predominant thiosulfate in freshly cut garlic (3.2-4.8 were comparable with the PADI spectra.
mg g-1, <30 µmol)30 was detected with high abundance at m/z PADI was also applied to the analysis of naturally occurring 163, and propanethial-S-oxide was observed as a protonated plant alkaloids. One such example is nicotine which is present in species at m/z 91 for freshly cut onion. This unstable volatile tobacco. A small amount of dried tobacco was held in noncon- compound forms through the decomposition of sulfenic acids ductive tweezers and positioned in the plasma beam in the same generated by enzymes released when the onion tissue is damaged way as solid tablets. No detrimental effects were seen to the and is difficult to analyze by conventional mass spectrometric tobacco. Results were comparable to those reported for the analysis of nicotine via DESI and DART.4 The protonated A wide range of samples has thus far been analyzed using molecule of nicotine was observed at m/z 163 with high signal PADI, including a variety of over-the-counter drug formulations.
intensity, shown in Figure 4a. Other plant materials examined by Table 1 lists examples with the m/z values for the most prominent PADI MS have included the vegetable alliums, garlic and onion ions observed. Those shown in bold correspond to protonated (Figure 4, parts b and c). No sample preparation was required,apart from slicing the onion or garlic clove prior to analysis.
(30) Rybak, M. E.; Calvey, E. M.; Harnly, J. M. J. Agric. Food Chem. 2004, 52,
(29) Williams, J. P.; Scrivens, J. H. Rapid Commun. Mass Spectrom. 2005, 19,
(31) Block, E.; Putman, D.; Zhao, S.-H. J. Agric. Food Chem. 1992, 40, 2431-
Analytical Chemistry Table 1. Examples of Other Analytes Examined by
PADI MS with m/z Values Observeda
major m/z observed paracetamol and codeine dual active tablets Boots Paracetamol Extra 195, 152, 110
(paracetamol and caffeine) 181, 163, 139, 121
muscle rub ointment (menthol and methyl salicylate) 166, 138, 120
Benylin (guaifenesin and levomenthol) glucosamine sulfate Betnovate (betamethasone valerate) a Bold denotes protonated molecules of the active ingredients.
molecules of the active ingredients. Cough medicines, creams,and ointments were smeared onto a glass slides or foil prior toanalysis. In the case of the dual-active tablet paracetamol andcodeine the protonated molecule of paracetamol was detected atm/z 152 and the corresponding dimer [2M + H]+ at m/z 303.
This is consistent with results obtained for the DESI analysis ofa Solphadeine Max tablet, which contains the same activeingredients.4 Interestingly, the dimer was not observed for theanalysis of paracetamol and caffeine tablets. This difference inresults may be explained by the influence of excipients andirreproducible positioning of the sample in the plasma beam usingtweezers.
Figure 5. Analysis of the active ingredient of a generic paracetamol
tablet (500 mg of paracetamol) by (a) DESI and (b) PADI.
Comparison of PADI with DESI. A wide range of phar-
maceutical tablet drug formulations were successfully analyzedusing PADI-MBMS. However, further mass spectrometric experi- molecule of the active ingredient at m/z 207 was not observed ments were performed to compare PADI with DESI for the due to fragmentation of the molecule via in-source CID at 18 V analysis of a range of compounds including pharmaceutical cone voltage. The base peak at m/z 161 was due to the loss of a tablets, creams, and gels. PADI and DESI generated similar neutral fragment (HCOOH, formic acid) from m/z 207. However, data on a comparable time scale, and no significant carryover with PADI analysis the active ingredient was observed as a effects were observed. However, in general PADI spectra were protonated species with high signal intensity. Loss of the carboxyl cleaner, displaying less fragmentation than the DESI spectra, group from the protonated molecule was also observed in the and the active ingredients were observed with higher signal c. Anadin Extra. A solid Anadin Extra tablet containing aspirin
a. Paracetamol. A generic paracetamol tablet was analyzed
(300 mg), paracetamol (200 mg), and caffeine (45 mg) was by both PADI and DESI interfaced with a single-quadrupole mass analyzed by PADI and DESI. The resulting spectra are shown in spectrometer (Waters Platform LCZ). A comparison of the data Figure 7. All three active ingredients are evident as protonated obtained by each technique is shown in Figure 5. The base peak species in the resulting PADI spectrum, paracetamol at m/z 152, in both spectra corresponds to the protonated molecule of the aspirin at m/z 181, and caffeine at m/z 195. The protonated active ingredient at m/z 152. This was observed with higher signal molecule of aspirin was absent in the DESI mass spectrum, which intensity in the PADI spectrum. The fragment ion seen in the DESI is consistent with results obtained by Williams et al.33 The base spectrum at m/z 110 corresponds to the loss of ketene, and this peak in both spectra at m/z 121 corresponds to the loss of acetic is consistent with results observed by Chen et al.32 However, the acid from protonated aspirin. Further fragment ions indicating the fragment was not observed in the PADI spectrum indicating that loss of CH2CO and the loss of water from aspirin were seen in PADI is potentially a softer ionization technique for some the PADI spectra at m/z 139 and 163, respectively. Loss of water from aspirin has been previously reported for both DESI and b. Ibuprofen. Ibuprofen is a nonsterodial anti-inflammatory
drug used to relieve moderate pain and inflammation. PADI and d. Ralgex Cream. DESI and PADI have also been applied to
DESI mass spectra obtained for the analysis of this drug in tablet the analysis of ointments and creams. Ralgex, a cream used for form containing 200 mg of the active ingredient are shown in the treatment of muscular pain, is one such example. This contains Figure 6. In the DESI analysis, the expected protonated the active ingredients glycol monosalicylate 10% w/w, methyl (32) Chen, H.; Talaty, N. N.; Taka´ts, Z.; Cooks, R. G. Anal. Chem. 2005, 77,
(33) Williams, J. P.; Lock, R.; Patel, V. J.; Scrivens, J. H. Anal. Chem. 2006, 78,
Analytical Chemistry Figure 6. Rapid sampling of a generic ibuprofen tablet (ibuprofen
200 mg) by (a) DESI and (b) PADI.
nicotinate 1% w/w, and capsicum oleoresin 0.12% w/w. A thin layerof the cream was smeared onto a glass slide and positioned intothe source region of the mass spectrometer as previous de-scribed. Figure 8b shows the PADI spectrum which was generated Figure 7. Analysis of Anadin Extra (200 mg of paracetamol, 300
in ca. 3 s. Glycol monosalicylate and methyl nicotinate were mg of aspirin, and 45 mg of caffeine) by (a) DESI and (b) PADI mass detected as singly charged protonated molecules at m/z 183 and 138, respectively. The base peak at m/z 121 is formedby the cleavage of the carbonyl bond of glycol monosalicylate as direct electron impact ionization, metastable Penning ionization, indicated in Figure 8. Other ions observed in the spectra at low and ion-molecule reactions. The He(23S) metastable state has abundance are likely to be from additives in the cream. The an energy of 19.8 eV, and it is well-known that such species can resulting DESI spectrum for the analysis of Ralgex from a induce desorption from surfaces of either neutral molecules glass slide is shown in Figure 8a. Glycol monosalicylate and methyl nicotinate were again observed as protonated speciesalong with the fragment ion at m/z 121. Abundance of the ions in relation to each other was significantly different for DESI andPADI.
Mechanisms of Desorption and Ionization. The mecha-
The reaction of the helium(23S) state with water is very effi- nisms of desorption and ionization in the PADI method will be cient,35 and we suggest that analyte ionization mechanism the focus of further work, and we comment here only briefly on (34) Harada, Y.; Masuda, S.; Ozaki, H. Chem. Rev. 1997, 97, 1897-
what are likely to be the most important contributions. Positive ionization mechanisms are thought to include a combination of (35) Searcy, J. Q.; Fenn, J. B. J. Chem. Phys. 1974, 61, 5282-5288.
Analytical Chemistry Figure 8. Analysis of Ralgex cream (glycol monosalicylate 10% w/w, methyl nicotinate 1% w/w, capsicum oleoresin 0.12% w/w) from a glass
slide by (a) DESI and (b) PADI mass spectrometry.
in PADI proceeds via combination of ionized water cluster of this method for the rapid analysis of pharmaceuticals. Results formation and proton-transfer reactions: have shown that the coupling of PADI with the MBMS system iseffective for generating high-quality data from various pharma- He(23S) + nH O ceutical formulations, such as tablets and creams, and suggests + OH + He(11S), n > 1 (2) that the methodology has potential for future applications. The PADI source can be easily interfaced to mass spectrometers which + (n + 1)H O have an atmospheric pressure inlet. For the work presented here,no alterations were necessary to the MBMS instrument and the This mechanism is supported by observations of both M+ and only modification to the LCZ mass spectrometer was to remove MH+ fragments and also H the existing ESI source and override the source interlock to enable 3O+(H2O)n clusters from the PADI source (data not shown) and predicts that each mechanism plays control of the MS via the vendor software.
a part in the ionization of analytes in this technique. Negative ion As with DESI, PADI is an ionization technique which requires formation is thought to proceed via direct and dissociative electron no sample preparation prior to analysis. It is simple, fast, and attachment to oxygen species, producing, e.g., O - capable of high-throughput analysis. However, the main advan- react with analyte molecules to produce predominantly [M - H]- tages of the latter method is the ease of operation, minimal groups. These and other core negative ion species have been requirements for optimization of operating parameters, and the measured from the PADI source and previously in similar lack of need for solvents which is beneficial for pharmaceutical and forensics applications. PADI is less angle-dependent than Desorption processes are less well understood, but we believe DESI, in respect of the sample to the mass spectrometer inlet that a combination of energy transfer from metastable helium, and also the angle of the sample surface to the electrospray or ion impact, and radical-surface interactions contribute to the plasma probe. This enables faster setup and analysis with less mechanisms in the PADI technique. The action of radicals at dependence upon the sample under investigation. This initial study surfaces has long been exploited in low-pressure plasma tech- has shown that PADI has considerable potential as a valuable and niques and is known to be effective in similar high-pressure versatile tool for forensic, pharmaceutical, and biological applica- discharges.37 This is a clear advantage of PADI over other ambient tions. The technique is sensitive, tolerant to contaminants, and techniques since it presents the possibility of harnessing the cross-contamination is negligible.
selective reaction mechanisms long established and utilized in low-pressure plasma processing techniques.
The authors thank the Engineering and Physical Sciences Research Council (EPSRC) for financially supporting this work In conclusion, we have introduced PADI, a new technique for and Dr. Peter Milligan for his invaluable contributions especially surface chemical analysis, and have demonstrated the potential at the early stages of this project.
(36) Aranda Gonzalvo, Y.; Greenwood, C. L.; Whitmore, T. D.; Rees, J. A. Mass spectrometric investigation of an atmospheric dielectric barrier dischargein helium: positive and negative ions. 7th Workshop on Frontiers in Low Received for review January 18, 2007. Accepted June 4, Temperature Plasma Diagnostics, Beverley, U.K., April, 2007.
(37) Machala, Z.; Janda, M.; Hensel, K.; Jedlovsky, I.; Lestinska, L.; Foltin, V.; Martisovits, V.; Morvova, M. J. Mol. Spectrosc. 2007, 243, 230-237.
Analytical Chemistry

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