Anal. Chem. 2007, 79, 7662-7668
Continuous Simultaneous Detection in Mass Spectrometry Gregory D. Schilling,† Francisco J. Andrade,† James H. Barnes IV,‡ Roger P. Sperline,§ M. Bonner Denton,§ Charles J. Barinaga,| David W. Koppenaal,| and Gary M. Hieftje*,†
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, Department of Chemistry, University of Arizona, Tucson, Arizona 85721, and Pacific Northwest National Laboratory, Richland, Washington 99352
In mass spectrometry, several advantages can be derived when multiple mass-to-charge values are detected simultaneously and continuously. One such advantage is an improved duty cycle, which leads to superior limits of detection, better precision, shorter analysis times, and reduced sample sizes. A second advantage is the ability to reduce correlated noise by taking the ratio of two or more simultaneously collected signals, enabling greatly enhanced isotope ratio data. A final advantage is the elimination of spectral skew, leading to more accurate transient signal analysis. Here, these advantages are demonstrated by means of a novel Faraday-strip array detector coupled to a Mattauch-Herzog mass spectrograph. The same system is used to monitor elemental fractionation phenomena in laser ablation inductively coupled plasma mass spectrometry. Mass spectrometry (MS) is one of the most widely used analytical tools, evidenced in part by the fact that there are at least eight scientific journals dedicated to the development and use of MS, and many other journals in which a large fraction of their content consists of MS-related articles.1 Furthermore, there are more than 10 instrument manufacturers who offer mass spectrometers commercially. These mass spectrometers are used in a wide range of fields including but not limited to forensics,2 geological dating,3 drug discovery/development,4 environmental monitoring,5 disease diagnosis,6 and food contamination control.7 In spite of this widespread use, the vast majority of MS instruments are limited in their capabilities because they require some portion of the instrument to be scanned or pulsed in order to acquire the desired information. Such instruments, based on quadrupole, time-of-flight, Fourier transform, or ion trap mass * Corresponding author. † Indiana University. ‡ Los Alamos National Laboratory. § University of Arizona. | Pacific Northwest National Laboratory. (1) Herbert, C. G.; Johnstone, R. A. W. Mass Spectrometry Basics; CRC Press: Boca Raton, FL, 2003. (2) Benson, S.; Lennard, C.; Maynard, P.; Roux, C. Forensic Sci. Int. 2006, 157, 1-22. (3) de Laeter, J. R. Mass Spectrom. Rev. 1998, 17, 97-125. (4) Hofstadler, S. A.; Sannes-Lowery, K. A. Nat. Rev. Drug Discovery 2006, 5, 585-595. (5) Muir, D.; Sverko, E. Anal. Bioanal. Chem. 2006, 386, 769-789. (6) Niwa, T. Mass Spectrom. Rev. 2006, 25, 685-685. (7) Careri, M.; Bianchi, F.; Corradini, C. J. Chromatogr., A 2002, 970, 3-64.
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analyzers, generally suffer from low duty cycle. Even sector-field instruments, which have the potential to continuously and simultaneously disperse and focus multiple mass-to-charge ratios (m/z), usually require scanning because they utilize only one or a few detectors. With these detection schemes, information is lost since only one or a few m/z values are detected at any one time. Therefore, a major advancement in MS technology is the development of instruments that allow the simultaneous and continuous monitoring of all m/z values. Several advantages can be achieved through simultaneous and continuous acquisition of multiple m/z values. One is a greatly improved duty cycle, arising from the continuous observation of all analyte species. In turn, improved duty cycle leads to lower limits of detection, better precision, smaller sample sizes, and reduced analysis times. A second advantage is the ability to reduce correlated noise between channels by taking the ratio of several detector responses. Fluctuations in the ion source often lead to correlated (multiplicative) noise, which affects all detector channels in the same manner at a given instant. Therefore, the effect of any common noise can be reduced by taking the ratio of responses from two or more independent detector channels. In elemental analysis, for example, isotope-ratio precision can be greatly improved by means of this strategy. A final advantage achieved through simultaneous detection is freedom from spectral skew. Spectral skew is an error in relative signal levels for several m/z values across a transient signal that arises from the need to scan a spectrum while the input sample concentration is changing. Of course, simultaneous detection is not new and was earlier achieved by devices such as the photographic plate and electrooptical imaging detector (EOID) coupled to sector-field instruments. However, these devices have serious limitations. For instance, they are inferior to modern single-channel devices in terms of key figures of merit such as sensitivity, spatial resolution, immediate readout, and dynamic range. In addition, these traditional detector arrays usually suffer from variations in detection efficiency across the array or from noise introduced through multiple conversion steps. These and other array-detector technologies have been recently reviewed by Koppenaal et al.8 and Barnes and Hieftje.9 (8) Koppenaal, D. W.; Barinaga, C. J.; Denton, M. B.; Sperline, R. P.; Hieftje, G. M.; Schilling, G. D.; Andrade, F. J.; Barnes, J. H., IV Anal. Chem. 2005, 77, 418A-427A. (9) Barnes, J. H., IV; Hieftje, G. M. Int. J. Mass Spectrom. 2004, 238, 33-46. 10.1021/ac070785s CCC: $37.00
© 2007 American Chemical Society Published on Web 09/19/2007
In addition to using array detectors on sector-field instruments, simultaneous detection can be mimicked by sampling a packet of ions from the ionization source and then detecting all m/z values of interest from the sampled packet. This is the case with timeof-flight mass spectrometers (TOFMS), ion trap mass spectrometers (ITMS), and Fourier transform ion cyclotron resonance mass spectrometers (FTICRMS). However, due to the nature of sampling an ion packet and waiting a period of time for the mass analysis, the duty cycle of such instruments is often quite low. On the other hand, recent advances have allowed greatly enhanced duty cycles on such instruments by utilizing Hadamard transforms10 and external ion accumulation cells to hold an ion packet while the previous packet is analyzed by the mass analyzer.11-13 With these techniques, duty cycles using these mass analyzers have been reported to be 100%.10,14 The potentially deleterious effect of the multiplex disadvantage on Hadamardtransform TOFMS has not, to our knowledge, yet been thoroughly evaluated. In the present article, the advantages of continuous simultaneous detection are verified experimentally and illustrated through use of a novel Faraday-strip array detector that has been developed in a collaborative project involving the University of Arizona, Pacific Northwest National Laboratory, and Indiana University. The array detector, coupled with suitable electronics in a package termed the focal plane camera (FPC), has been paired with an inductively coupled plasma (ICP) Mattauch-Herzog mass spectrograph (MHMS) for the simultaneous detection of a range of m/z values. Presented here are experimental results illustrating the improved figures of merit in mass-spectrometric measurements achieved with such a simultaneous, continuous detection system. EXPERIMENTAL SECTION Focal Plane Camera. The FPC has been described previously8,15-21 so only a brief overview will be included here. The (10) Yoon, O. K.; Zuleta, I. A.; Kimmel, J. R.; Robbins, M. D.; Zare, R. N. J. Am. Soc. Mass Spectrom. 2005, 16, 1888-1901. (11) Senko, M. W.; Hendrickson, C. L.; Emmett, M. R.; Shi, S. D. H.; Marshall, A. G. J. Am. Soc. Mass Spectrom. 1997, 8, 970-976. (12) Hashimoto, Y.; Hasegawa, H.; Satake, H.; Baba, T.; Waki, I. J. Am. Soc. Mass Spectrom. 2006, 17, 1669-1674. (13) Belov, M. E.; Nikolaev, E. N.; Anderson, G. A.; Udseth, H. R.; Conrads, T. P.; Veenstra, T. D.; Masselon, C. D.; Gorshkov, M. V.; Smith, R. D. Anal. Chem. 2001, 73, 253-261. (14) Quenzer, T. L.; Emmett, M. R.; Hendrickson, C. L.; Kelly, P. H.; Marshall, A. G. Anal. Chem. 2001, 73, 1721-1725. (15) Schilling, G. D.; Andrade, F. J.; Barnes, J. H.; Sperline, R. P.; Denton, M. B.; Barinaga, C. J.; Koppenaal, D. W.; Hieftje, G. M. Anal. Chem. 2006, 78, 4319-4325. (16) Barnes, J. H.; Schilling, G. D.; Sperline, R.; Denton, M. B.; Young, E. T.; Barinaga, C. J.; Koppenaal, D. W.; Hieftje, G. M. Anal. Chem. 2004, 76, 2531-2536. (17) Barnes, J. H., IV; Schilling, G. D.; Hieftje, G. M.; Sperline, R. P.; Denton, M. B.; Barinaga, C. J.; Koppenaal, D. W. J. Am. Soc. Mass Spectrom. 2004, 15, 769-776. (18) Barnes, J. H., IV; Schilling, G. D.; Sperline, R. P.; Denton, M. B.; Young, E. T.; Barinaga, C. J.; Koppenaal, D. W.; Hieftje, G. M. J. Anal. At. Spectrom. 2004, 19, 751-756. (19) Barnes, J. H., IV; Schilling, G. D.; Stone, S. F.; Sperline, R. P.; Denton, M. B.; Young, E. T.; Barinaga, C. J.; Koppenaal, D. W.; Hieftje, G. M. Anal. Bioanal. Chem. 2004, 380, 227-234. (20) Barnes, J. H., IV; Sperline, R.; Denton, M. B.; Barinaga, C. J.; Koppenaal, D.; Young, E. T.; Hieftje, G. M. Anal. Chem. 2002, 74, 5327-5332. (21) Knight, A. K.; Sperline, R. P.; Hieftje, G. M.; Young, E.; Barinaga, C. J.; Koppenaal, D. W.; Denton, M. B. Int. J. Mass Spectrom. 2002, 215, 131139.
ion-detection component of the FPC consists of an array of 45 µm wide gold Faraday strips. The strips are set on 50 µm centers, which translates to a fill factor of 90% across the array. Each Faraday strip is wire-bonded to its own integrating operational amplifier (OA). Capacitors in the feedback loops of these OAs are on the order of 10 fF, so an output voltage in the 16 µV range is generated for each collected ion. In addition, there are two selectable parallel capacitors in each OA circuit, thereby allowing the gain of each detecting element to be individually controlled. Furthermore, the charge at the output of the OA can be read multiple times in a nondestructive manner in order to reduce read noise associated with the measurement. This characteristic was utilized in all of the following measurements except for the spectral-skew data since the signal was not constant. ICP-MHMS. The ICP-MHMS was used for all experiments. This instrument has been described previously16,22 so only the pertinent operating conditions will be listed here. The ICP was operated with a forward power of 1.25 kW, and argon (99.998%, Airgas, Inc., Radnor, PA) gas flows were maintained at 17.0, 1-1.5, and 0.7-1.5 L/min for the outer, intermediate, and aerosol channels, respectively. Ions were extracted into the MHMS by means of a 0.75 mm sampling orifice, a 0.5 mm skimmer cone, and a 1.0 mm third-stage aperture. The ions were accelerated through the mass analyzing portion of the MHMS by maintaining the sampler and skimmer cones at a voltage of 1-1.2 kV. For simultaneous m/z measurements, the magnet was maintained at constant field strength, while for the scanning measurements, the magnetic field was swept at a rate between 0.4 and 7 mT/s. The scan rate was chosen in order to cover the same m/z window as in simultaneous mode while maintaining the same overall integration time. For example, if a window corresponding to 5 m/z values was monitored for 5 s in the simultaneous mode, the scan rate was chosen to cover the same 5 m/z values within 5 s in the scanning mode. Sample Introduction. For the duty-cycle and elemental fractionation studies, a LSX-200 laser ablation (LA) system (Cetac Technologies, Inc., Omaha, NE) was used to introduce samples into the ICP. For all experiments, the laser was operated at 20 Hz to obtain a pseudo-steady-state signal. The laser energy and spot sizes were set to maximum values of ∼7 mJ and 300 µm, respectively. Ablated material was swept from the specially designed fast-washout ablation cell23 by means of a 0.7-1.0 L/min flow of He (99.999%, Airgas, Inc., Radnor, PA). Directly following the ablation cell, a glass Y-connector was used to add a supplemental flow of argon (0.7-1.0 L/min). For the correlated noise studies, an ultrasonic nebulizer (USN) with membrane desolvator (U-6000AT+, Cetac Technologies, Inc., Omaha, NE) was used. Sample flow to and waste from the USN were regulated via a four-head peristaltic pump (RP-1, Rainin, Emeryville, CA). The heating and cooling sections of the USN desolvator were maintained at temperatures of 160 °C and 5-10 °C, respectively. A counter argon gas flow of 4 L/min was used for the membrane desolvator with a heater temperature of 160 °C. Heating tape was used around the transfer tube between the USN and the membrane desolvator in order to keep sample vapor from condensing between the two. (22) Burgoyne, T. W.; Hieftje, G. M.; Hites, R. A. J. Am. Soc. Mass Spectrom. 1997, 8, 307-318. (23) Leach, A. M.; Hieftje, G. M. Appl. Spectrosc. 2002, 56, 62-69.
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Figure 1. Spectra showing the simultaneous (top plot) and sequentially scanned spectrum (bottom plot) of Cu and Zn obtained from steadystate laser ablation of a brass sample. The signal and S/N are much larger in the simultaneously acquired spectrum due to the increased duty cycle, which allows all isotopes to be monitored for a longer time period.
Figure 2. Spectra obtained by simultaneous (top plot) and scanned (bottom plot) data collection methods for the Cu and Zn isotopes during a flow-injection transient. Notice the different vertical scales. Cu and Zn were present in the sample at the same concentration. The scanned spectrum shows a skewed result in the relative intensity of Cu to Zn and the lower-abundance isotopes of both elements are not observed because of the reduced signal-to-noise ratio. The naturally occurring abundances for Cu and Zn are: 63Cu, 69.2%; 65Cu, 30.8%; 64Zn, 48.6%; 66Zn, 27.9%; 67Zn, 4.1%; and 68Zn, 18.8%.
To further emphasize the system’s ability to circumvent correlated noise, the LA system was used in the single-shot ablation mode. In this case, the same laser parameters as above were used except only single laser pulses were employed. This mode was used in order to introduce even more correlated noise into the system. For the spectral-skew measurements a six-port mediumpressure injection valve (V-451, Upchurch Scientific, Oak Harbor, WA) was placed between the peristaltic pump and the USN. A 100 µL sample loop was used to reproducibly introduce the sample solution. Although the USN adds significant peak broadening, this was not a concern since the main goal of these experiments was 7664 Analytical Chemistry, Vol. 79, No. 20, October 15, 2007
to show the difference between simultaneous and scan-based detection techniques. Standards. Reagent-grade nitric acid (70%., Mallinckrodt Baker, Inc., Philipsburg, NJ) was purified by means of sub-boiling distillation in a Teflon still (SBS-108, Savillex, Minnetonka, MN). This purified nitric acid was diluted with deionized water to achieve a 0.1 M HNO3 solution which was used to prepare all solution samples. For the correlated noise studies, a 1 µg/mL solution of Ag was prepared from an atomic absorption standard (Johnson Matthey Electronics, Ward Hill, MA). For the spectralskew measurements, an ∼0.1 µg/mL multielemental solution (SPEX Certiprep, Metuchen, NJ) containing Cu and Zn was used.
Figure 3. (a) Traces for Ag isotope signals collected at different times (top plot) and in synchrony (bottom plot). Each trace shows a precision of 0.45% RSD. (b) Ag isotope ratio for 10 repetitions. When the isotopes are measured simultaneously, a precision of 0.015% RSD is achieved, whereas a precision of 0.65% RSD is obtained when the isotope signals are collected at different times.
All data involving solution samples were background-subtracted by using the 0.1 M HNO3 blank. For the studies involving LA, a nonstandard brass sample was used. RESULTS AND DISCUSSION Improvement of Duty Cycle. When a continuously operating ion source is employed, duty cycle (dc) in mass spectrometry can be defined as the ratio of the length of time during which ions are detected (Td) to the total time of analysis (Ta),24 eq 1. When
dc )
Td Ta
(1)
an instrument requires scanning, as does a quadrupole mass filter, for example, the duty cycle must be divided by the number of
analytes (n) that are desired because only a single analyte is detected at any given time. This is shown by eq 2; typical dc values
dc )
Td 1 Ta n
(2)
under these conditions are generally on the order of 0.1-10%, depending on the number of analytes of interest. Of course, this simple analysis assumes that the same dwell time is used for each (24) Barshick, C. M., Duckworth, D. C., Smith, D. H., Eds. Inorganic Mass Spectrometry: Fundamentals and Applications; Marcel Dekker, Inc.: New York, 2000.
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Figure 4. Detector response for two isotopes of Mo (bottom two traces, left axis), when single-shot laser ablation is employed with an ICP source and the array-detector mass spectrometer. The two traces track each other, indicating that correlated noise is dominant in the system. This correlated noise is effectively removed by taking the ratio of the two signals, shown by the top trace (right axis).
analyte species. When pulsed instruments such as TOFMS or ITMS are used, the dc depends on the frequency at which a full spectrum can be obtained. In this case, the dc is defined by the length of time required to fill the extraction region in TOFMS or the ion trap in ITMS (Tfill) divided by the length of time required to obtain the mass spectrum (Ta), cf. eq 3. Typical dc values for
dc )
Tfill Ta
(3)
TOFMS and ITMS are on the order of 10% or less.25 However, as stated before, special techniques have been developed in order to greatly enhance the duty cycle in such mass analyzers. Sector-field mass spectrometers (SFMS) generally fall into the category of scanned instruments along with quadrupole mass filters because they typically operate by scanning an accelerating potential or magnetic field. Some SFMS utilize multiple detectors, thereby increasing the dc. However, these multiple-detector instruments are ordinarily used for specific applications such as isotope-ratio measurements and are rarely used to obtain full spectra. An improvement in SFMS instruments would be to use a detector array in which the entire mass spectrum, or the entire range of m/z values of interest, can be acquired simultaneously as is the case with the MHMS-FPC. With this detection scheme, the dc can reach 100% since ions of every desired m/z are detected throughout the entire analysis time. A comparison of spectra obtained simultaneously and sequentially (scanned), shown in Figure 1, illustrates the power of simultaneous, continuous detection. The laser ablation system was operated in a pseudo-steady-state fashion to obtain a relatively constant signal level. A brass sample was ablated and the Cu and Zn isotopes were monitored. For the simultaneous measurement, 124 Faraday strips of the FPC were used to obtain the spectrum whereas in the sequential case only a single Faraday strip was (25) Mahoney, P. P.; Ray, S. J.; Hieftje, G. M. Appl. Spectrosc. 1997, 51, A16A28.
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used and the magnetic field was scanned to produce the spectrum. In both cases, the total acquisition time (the time interval used for the analysis) is the same. However, in the simultaneous mode, each isotope is constantly monitored so the signal level is dramatically enhanced and the signal-to-noise ratio (S/N) is correspondingly greater. For example, ∼1.5 × 108 charges were collected for 63Cu during the 5.5 s integration period in the simultaneous mode, whereas only ∼1.6 × 106 charges were accumulated in the scanning mode. This corresponds to about a 90 times reduction in integration time per m/z value in the scanning mode as opposed to the simultaneous mode. Elimination of Spectral Skew. Spectral skew is the error in relative signals from several analytes that occurs when the analyte peaks are sequentially scanned at the same time their concentration is changing. Analyte peaks measured at lower instantaneous concentrations then appear artificially small. Spectral skew is a significant problem in mass spectrometry because most MS instruments are operated in a scanned or peak-hopping mode, even when transient sample introduction schemes are employed. Examples of such transient introduction approaches are chromatographic separations, laser ablation, flow injection, and electrothermal vaporization. Spectral skew can be lessened when one uses a very fast scanning instrument so each analyte of interest is sampled several times during the transient peak. However, as an increasing number of analytes must be determined or transient peaks become ultrashort (
