Workhorses of the Chromatography Lab: Quadrupoles and Ion Traps

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1 Workhorses of the Chromatography Lab: Quadrupoles and Ion Traps Hans-Joachim Huebschmann, Thermo Fisher Scientific, Singapore White Paper We called it, almost from the beginning, a workhorse instrument. It really, to this day, is that and more. With real advantages in scan speed, sensitivity, ease of use, a linear output, and workhorse capability it really caught on in a hurry. Bob Finnigan 2001 With the Chinese New Year in 2014, the year of the horse has arrived a perfect time to look back at the workhorses of modern chromatography labs, especially in GC-MS and LC-MS. Today, quadrupole mass spectrometers are the undisputed workhorses of every analytical lab, whether their studies involve trace analysis, quality control, quantitative or qualitative, organic or inorganic analysis. What made quadrupole mass spectrometers so successful? Here, we look back on the advent of the quadrupole mass spectrometer as analytical tool for chromatography and examine the unique and compelling operational benefits that made this technology so successful. We will also look at the latest developments in one of today s most-used analytical instruments. Can atomic particles be stored in a cage without material walls? This question is already quite old. The physicist Lichtenberg from Göttingen wrote in his notebook at the end of the 18th century: I think it is a sad situation that in the whole area of chemistry we cannot freely suspend the individual components of matter. This situation lasted until At that time we succeeded, in Bonn, in freely suspending electrically charged atoms, i. e. ions, and electrons using high frequency electric fields, so-called multipole fields. We called such an arrangement an ion cage. Prof. Wolfgang Paul ( ) in a lecture at the Cologne Lindenthal Institute in The Success Story In the early 1950s, Wolfgang Paul s research group at the University of Bonn, Germany, was working on the analysis of ions, specifically on keeping ions stored for further spectroscopic investigation. The resulting ion storage device was called QUISTOR, the quadrupole ion storage device 2. Erhard Fischer, one of Paul s postgraduate students, built the first functioning ion cage in A mechanical model of the Paul Ion Trap is on display today in the German Museum Bonn 3. While the Paul ion trap storage solution is a three-dimensional device, the quadrupole filter with its four parallel rods is a special twodimensional solution in general ion trap theory 4. Figure 1 shows its first mention in publication in It was not until 1989 that Paul was recognized for his discoveries with the Nobel Prize in Physics.

2 2 The great potential of GC was obvious to many analytical chemists who had never heard of mass spectrometry, and this prediction has been amply borne out by the widespread GC applications today. Rüdiger Gohlke, Figure 1. Paul and Steinwedel first quadrupole publication 1953 about A New Mass Spectrometer without Magnetic Field. A quadrupole device, based upon early QUISTOR developments, eventually emerged for commercial mass spectrometers as a scanning mass filter 4. Soon afterwards, in the early 1960s, Robert Finnigan, a senior research engineer at the Stanford Research Institute in the United States made further developments for ion analysis in process control. Finnigan joined Electronic Associates Incorporated (EAI) to start a process-systems group there 5. The first successful quadrupole applications were in residual gas analysis (RGA), with the EAI Quad 150, a device that still had a limited mass range, but included mass-scanning capabilities. The RGA market at that time was dominated by magnetic sector instruments, detecting only fixed masses using Faraday cup detection. Meanwhile, gas chromatography was being used as a high potential separation tool for organic compounds in process control, particularly in the semiconductor industry. Later, it also became valuable in crude oil exploration. It did not take long to bring both analytical techniques together and connect chromatography separation with mass spectrometry detection. Having recently purchased F&M Scientific Corporation, a company that produced gas chromatographs, Hewlett Packard ordered a Quad 300 mass spectrometer from EAI. Bill Hewlett and Dave Packard asked about the approach we were taking with the quadrupole, and recognized that it was a better approach for what they wanted to do at HP than the magnetic MS, Finnigan said. 5 The demand for quadrupole solutions in GC-MS grew steadily, not only from petrochemical applications, but also from life science researchers, including Carl Djerassi, known for the steroid research that resulted in the advent of oral contraceptives. In 1967, Finnigan resigned from EAI when the company rejected his proposal to venture into the GC-MS market. Later that same year he founded the Finnigan Corporation. A Difficult Start to GC-MS The Finnigan Model 1015 was launched in 1967 as the first routine laboratory quadrupole mass spectrometer. It was optionally equipped with a Varian Aerograph or Hewlett Packard GC, which was coupled via a glass jet separator (Ryhage/Stenhagen separator 1966) for packed column GC 6, and featured data system control. It became the first routine GC-MS manufactured in high numbers. The U.S. Environmental Protection Agency (EPA) introduced the 1015 quadrupole GC-MS as the standard measurement procedure in environmental control for priority pollutants (Fig. 2). Figure 2. Finnigan Model 1015 GC-MS system from 1964 with full data system control At that time, quadrupole instruments were competing with time-of-flight (TOF) and magnetic sector mass spectrometers. In 1955, Rüdiger Gohlke, of Dow Chemical, had already implemented the first GC- MS coupling with a Bendix time-of-flight instrument using a split inlet from the packed columns 7, 8. The fast scanning capabilities (2000 spectra/s) and magneticsector-compatible spectra quality set the expectations in GC-MS. In 1966, LKB introduced the model 9000, a magnetic sector instrument for GC-MS in Stockholm, Sweden 9. Gohlke joined Finnigan in 1968, developing the 3000 series GC-MS, which was marketed as the GC Peak Identifier. Today, the initial poor spectral quality of quadrupole systems has been forgotten. GC-MS systems have a longer ion flight time to the detector compared to TOF and sector instruments, allowing less stable (metastable) ions to fragment during the quadrupole flight time. This effect is visible with the abundance of molecular ions in long chain hydrocarbons. Commercial libraries contain replicates of both types of spectra from the early magnetic sector and have recently added quadrupole and ion trap type mass spectra. Search algorithms have improved significantly over the years to handle potential intensity variations from different tuning or instrument conditions. As a result, today s quadrupole-based mass spectrometers produce significantly more spectra than any other MS type.

3 3 Compelling Analytical Benefits Quadrupole and Ion Trap Operation The primary benefits of quadrupole mass spectrometers are their compact size, fast scan rate, and high sensitivity for trace analyses. The small ion source and the short distance to the detector allow for very small benchtop instruments, even smaller in footprint than a typical GC. Electron impact ionization (EI) is standard in GC-MS. Also, there is the option of using chemical ionization for positive and negative ion generation. On the LC-MS side, the standard ion source is electrospray ionization (ESI), with options for atmospheric pressure chemical ionization (APCI) or photo ionization (APPI). The vacuum requirements are lower for quadrupoles and ion traps than for magnetic sector instruments, so smaller pump sizes can be used. With some exceptions, turbomolecular pumps are used today for a clean vacuum and quick maintenance shutdown and power-up cycles. Quadrupoles consist of a set of four electrodes of a particular length in a radial array, as shown in Figure 3. The opposing rods are electrically connected. Quadrupole analyzers are mass filters with variable mass resolution settings. Ions are filtered from their flight path on the basis of their mass-to-charge ratio, m/z. The filter effect is obtained by applying a combination of high radio frequency (RF) and direct current (DC) with opposite polarity to the rods. The trajectory of charged particles (ions) entering the quadrupole assembly in the axial direction is affected in that only ions of a certain massto-charge ratio (m/z) are able to pass the quadrupole assembly without hitting the rods, and reach the detector. By variation of the applied voltages, ions of different keep m/z together ratios (e.g., the next mass ion) can pass the filter while ions of different m/z are discharged by collision with the rods, preventing their detection. The mechanical simplicity of GC-MS and LC-MS coupling allows an affordable price range, and hence, wide distribution. From their early days, the high scan speeds made quadrupole analyzers the ideal MS detectors for fused silica capillary chromatography separations (the so called HRGC, high resolution gas chromatography, in contrast to packed column applications). Current scan speeds up to Da/s also made quadrupoles compatible with ultra-fast GC, and comprehensive GCxGC applications. Today, most quadrupole rods are round for a good reason. In 1971, Denison showed the best performance of round rods to the hyperbolic force lines inside the quadrupole assembly if the ratio of the rod radius, r, to the quadrupole field radius, r0, is In practice, a large entrance cross-section for high ion transmission comes with large diameter rods. Additionally, hyperbolic rods with particularly high surface quality and length, as shown in Figure 4, provide the ideal quadrupole curvature for improved mass separation capabilities. Figure 2. Quadrupole mass filters with round rods. An initial early Figure 2. Quadrupole massand filterscurrent with round rods. An initial early design (left) technology, (right). design (left) and current technology, (right). Figure 3. Front view of hyperbolic quadrupole assemblies Figure 3. Quadrupole mass filters with round rods. An initial early design (left) and current technology, (right) (courtesy Thermo Fisher Scientific). Figure 4. Front view of hyperbolic quadrupole assemblies (U.S. patent number 5,389,785 Thermo Fisher Scientific).

4 4 Tunable Mass Resolution The mass resolution is adjusted electrically by changing the ratio of the applied RF and DC voltages to the rods. The sophisticated mechanical slit devices used in magnetic sector instruments are not necessary. The mass resolution of quadrupole mass filters is controlled by the applied RF/DC ratio operating as a narrow band pass filter, which at a certain point in the scan, eliminates all ions below and above of the desired m/z value from detection. The known stability diagram gives a visual simplification of the parameter changes during operation of the quadrupole as a mass filter 11. Increasing the voltages, while keeping the ratio constant, provides the typical mass scan necessary to register complete mass spectra (full scan operation mode). Constant mass resolution over the complete mass range is typical for the quadrupole analyzer. The standard factory setting is the nominal mass resolution with a peak width of 0.7 Da at half peak height (FWHM). Increasing the mass resolution improves the selectivity of the analyzer. In contrast, opening the quadrupole to wider peak widths increases sensitivity with increased ion transmission, but at the expense of selectivity with matrix samples. Current technologies allow improved mass resolutions settings with round rods to approx. 0.4 Da, and with specially designed hyperbolic rods down to 0.1 Da (Fig. 5). A variable resolution setting is common with triple quadrupole mass spectrometers with, for instance, normal (0.7 Da), wide (1.5 Da) and widest (2.5 Da) resolution settings. Mass range For use in GC-MS, the mass range is typically limited to the working range in GC, up to 1100 Da. For DC, the operating voltages are in the range of 300 V and RF 1500 V for this mass range. Quadrupole instruments used for LC-MS use a significantly higher mass range of up to 3000 Da or more. Sensitivity Quadrupole sensitivity is primarily dependent on ion dwell time. This is the time it takes for a certain ion species of a selected m/z ratio to reach the detector and have its ion flux measured. The set mass resolution has strong impact on the ion transmission. In full scan, the dwell time per ion is limited by the overall cycle time (data points per second). High scan speeds for fast chromatography even further reduce the dwell time per ion and hence the sensitivity. Full scan mode is typically reserved for generating complete mass spectra for a library search to identify unknowns. For trace target compound quantitation, scan mode often does not provide enough sensitivity. Typically, the quadrupole is operated in the selected ion monitoring mode (SIM), detecting only the known molecular or fragment ions of the target analytes at their retention time. This reduction of detection to only a few ions increases the dwell time for each ion significantly, resulting in high sensitivity, at the expense of the complete mass spectrum. Figure 5. Increased peak resolution of hyperbolic quadrupoles. Note the decrease in peak height of a factor 2 at 0.1 Da peak width compared to unit mass resolution (courtesy Thermo Fisher Scientific).

5 5 Three ions per target compound are typically required, allowing an additional ion ratio confirmation on top of the retention time for confirmation 12. In the European Union (E.U.) regulatory system, the identification point (IP) system was put in place as a requirement for the identification of banned and limited organic residues and contaminants in food 13. As close three-dimensional relatives to quadrupoles, ion traps may provide a solution. The ion trap analyzer consists of three basic components the ring electrode and two end caps, all of them hyperbolic. Quadrupole ion traps work using similar ion control by electromagnetic fields with applied RF and DC voltages. George Stafford at Finnigan Corp. in Sunnyvale, CA, USA, revisited the Paul trap and developed a scanning solution for the QUISTOR, which until then had been used only as trapping device 14. Ions can be generated inside or outside of the ion trap. Current ion trap MS systems use the same ion sources as quadrupole mass spectrometers for spectrum compatibility, except that the quadrupole device is replaced by the ion trap analyzer. In contrast to the quadrupole as ion filter, the ion trap is a three dimensional device, and, as the name implies, it can act as a trap for ions. The beauty of the ion trap analyzer is its ability to store ions. Weak ion beams can be integrated until the trap has reached the maximum storage capacity. This unique ability enables two important features. First, the registration of full scan spectra at very low concentration levels. Hence, one strength of the ion traps is the high full scan sensitivity, where quadrupoles need to switch to the SIM mode and cannot register a spectrum anymore. This feature is used to confirm compounds using the complete spectra, as is common, for example, in the confirmation of positive anabolic steroid tests. MS/MS Analysis Stored ions can also be manipulated in the ion trap such that storage occurs only for a certain mass range or particular ion species. This manipulation is the basis of the generation of MS/MS product ion spectra. While stored in the trap, the selected precursor ions are accelerated and undergo collision-induced fragmentation (CID). The high efficiency of RF-only isolation of the parent ion combined with the high efficiency of CID, results in the ion trap having a much higher overall MS/ MS efficiency than a quadrupole system 15. As a result the product ion mass spectra from ion trap systems are rich in fragmentation ions compared to quadrupole MS/MS. These mass spectra are also achievable at low ion concentrations, making ion traps the ideal analyzers for selective trace target compound analysis. The high sensitivity of the ion trap analyzer has made LC-MS electrospray ionization (ESI) very successful for trace analysis and it has become best known within other applications for the analysis of polar pesticides. The accumulation of low intensity ion beams from the ESI source, together with the high efficiency of the ion trap MS/MS fragmentation processes, made ion traps the ideal analyzer in LC-MS trace analysis. Target analysis can be combined with untargeted screening and the identification of unknowns. Multiple MS/MS stages made ion traps especially interesting for structure elucidation of unknowns. Ion traps can be operated in up to 10 MS/MS stages, in case there is still sufficient ion signal trapped. Data dependent control of the analyzer MS/MS stages facilitates the exploration work. This finally leads to ion fragmentation trees revealing the complete structural details of an unknown compound. The powerful mass spectrum interpretation software, HyperChem MassFrontier TM pulls all the encoded information into one annotated spectrum, providing the most suitable hypothesis for the unknown structure 16,17. Ion Trap Analyzer Limitations The significant benefits of ion traps can become limitations when operated outside of the optimum working range. As with all storage devices, ion traps have limited storage capacity. This limitation is handled using dynamic ion injection timing (automatic gain control, AGC) providing a high dynamic range of more than six orders of magnitude. High matrix concentrations in the sample lead to less efficiency for analytes, as the storage capacity is covered by both types of ions those from both the matrix and the analytes. As demonstrated in many publications, increased sensitivity and selectivity in matrix samples requires the use of MS/MS. Another tradeoff for the benefit of ion accumulation and storage can be seen on the time axis. Time is required to fill the trap, collect, store and manipulate the ions for detection. Time is also required to achieve fragmentation during the MS/MS CID process. In a beam instrument like a quadrupole analyzer, the MS/MS steps are realized in different components of the analyzer. This discrepancy led to the terms MS/MS in time and MS/MS in space, coined by Yost in 1983 when launching the first triple quadrupole instruments in collaboration with the R&D team of former Finnigan Corp. Triple quadrupole mass spectrometers quickly became valuable research tools, especially for using MS/MS to elucidate structures 15,18.

6 6 Single Quadrupole GC-MS MS Ion Source Ion Transfer Optics Quadrupole EM Detector Triple Quadrupole GC-MS/MS MS MS Ion Source Ion Transfer Optics Quadrupole 1 (Q1) Quadrupole 2 (Q2) Collision Cell Quadrupole 3 (Q3) EM Detector Figure 6. Single Quadrupole vs. Triple Quadrupole Analyzer. The Breakthrough of Triple Quadrupole MS/MS Gradually, MS/MS technology began to make inroads with the regulatory requirements for food safety analyses such as those outlined by the Codex Alimentarius Commission. This support of the technology created a strong demand for multi-methods in trace residue analysis and sample preparation and detection to comply with international regulations. Advances in pesticide analysis in recent years are prime examples of the success of MS/MS methods. Optimized, class-specific extraction, clean-up, and analysis were increasingly replaced by one-step methods created for pesticide compounds of different compound classes and chemical nature. Additionally, in replacement of liquid/ liquid extractions (Luke and mini-luke methods) the dispersive SPE methods (QuEChERS) became increasingly popular. Ease-of-use and low cost, combined with high recoveries for hundreds of pesticides, and even for other analyte groups like POPs, PAHs, or drugs from different types of matrices, were the compelling reasons for the wide success of these methods. QuEChERS became standardized with AOAC method and the European method EN The compatibility of QuEChERS with GC-MS and LC-MS further increased productivity. Both detection systems can use extracts right away, so can cover a wide range from lipophilic to highly polar compounds in one workflow. One significant drawback in GC-MS arose with multimethods. The clean-up process was less efficient, requiring a delicate balance of good clean-up effect and low recoveries for some compound classes. Finally, reasonably high recoveries were achieved at the expense of a high matrix load of the extracts. The classic element-specific detectors and the highly successful single quadrupole MS systems were increasingly challenged. The specific masses of analytes were masked by background signal from the matrix. The single quadrupole system cannot distinguish between a mass signal generated by the analyte and one generated by the matrix. Although sensitive with well-cleaned extracts, the selectivity appeared to be limited by the number of extracts with a higher matrix background. Peak detection and integration from QuEChERS extract analyses became increasingly difficult at low signal to noise ratios. The use of triple quadrupole MS brought the solution for multi-methods. The triple quadrupole analyzer is perfectly suited for target compound quantitation. The selected reaction monitoring mode (SRM) delivers high analyte selectivity and sensitivity, even in dirty matrix samples. Due to the fast electrical control of the quadrupoles, analytical methods could be created to detect many hundreds of compounds in a single run, commonly called multi reaction monitoring methods (MRM). The operation of the triple quadrupole can be derived from the single quadrupole analyzer in SIM mode. This generally allows extending known SIM methods to triple quadrupole instruments. While the first quadrupole still works in SIM mode, the selected target ions are not detected, but get fragmented in the collision cell, followed by a second mass analyzing quadrupole, as shown in Figure 6. Out of the all fragment ions generated, only

7 7 the ions generated by the structure of the target analyte are selected by the third quadrupole and finally detected. As the analyte and the matrix are of different chemical structures, they generate different product ions. In fact, the triple quadrupole analyzer works this way as a structure-selective detector, able to pick the analyte out of an intense matrix. Setting up a multi-residue method for triple quads can be tedious. For every analyte in the method, a new set of parameters is required. These parameters include retention time, precursor masses (typically the SIM masses), optimum collision energy in the collision cell, and the most intense product ions. For ion ratio confirmation, two precursor ions are monitored for each analyte. Usually, this procedure starts with the information from a given SIM method. Each analyte needs to be measured individually in one or more standard cocktails, avoiding coelution with an appropriate GC method. After acquiring the full scan spectrum, the retention time is determined and the two most intense precursor ions are chosen. In many cases, the chromatogram also needs to be cut into suitable retention time segments in which the SRM transitions of a number of analytes are monitored together. A next analysis uses the chosen precursor masses in the set retention time segments and acquires the complete product ion spectra using medium-high collision energy. All of these spectra must be manually inspected for selection of the most intense product ions of the analytes. In the next steps, a couple of additional injections are required with different collision energy settings, typically in the range of 5 to 35 V. Four injections are required, with a 10 V increase for each one. A step width of keep together 5 V results in seven runs. These analyses determine the most suitable collision energies and the method setup is complete. There are two different approaches to facilitate this complex MRM method setup. For a set of known analytes, comprehensive compound databases are available, restricted to a certain GC column type and oven temperature program. The other method involves AutoSRM, an automated procedure performing the above sequence of analysis and evaluation with direct analyzer access (Figure 7), providing more flexibility for new compounds. Even SIM tables from single quadrupole MS systems can be used as the starting point for the extension to a MRM method. This automated method setup controls the required injection via autosampler and allows a complex standard mix with coelution. The result is a ready-to-use MRM acquisition method for an unlimited number of compounds. 1. Full Scan Precursor Ion Selection 2. Selectivity Optimization by Product Ion Selection 3. Sensitivity Optimization by Collision Energy Ramp Figure 7. The AutoSRM three-step procedure for automated GC-MS/MS method setup.

8 8 Current Performance Examples 2. High Sensitivity and Precision Currently, there is a wide range of quadrupole MS applications for gas and liquid chromatography. The following selection, from actual lab work, includes compelling examples of current applications, demonstrating the high level of quadrupole technology development achieved over the last decades. The analysis of dioxins (polychlorinated dibenzodioxins, -furans, and -biphenyls) creates one of the biggest challenges for GC-MS because legal regulations require great sensitivity and precision in detection and quantification of these chemicals. 1. Impact of Quadrupole Mass Resolution The chromatogram in Figure 7 shows the ROSH analysis for brominated flame retardants, demonstrating the impact of an increased quadrupole mass resolution on target analyte selectivity. The analyzed samples are solvent extracts from children s plastic toys. For MRM analysis, the selected compounds were the tris(dibromopropyl)-phosphate flame retardant contained in commercial products like Bromkal PTM, or FiremasterTM. SRM mass transitions: Precursor ion > Product ion: Previously, high mass resolving magnetic sector instruments were the international standard for control of the maximum regulated levels of dioxins in food and feed. However, recent developments in quadrupole technology have increased sensitivity and precision (Fig. 9). Good concordance with the data of magnetic sector instruments has been demonstrated in several instances. As a result, the European Commission has amended the EU directive for the control of dioxins (PCDD/Fs) and dioxin-like and non-dioxin-like PCBs (dl-/ndl-pcbs) to allow triple quadrupole GC-MS/MS instrumentation for the maximum residue level control (MRL) in food and feed. m/z > m/z > Mass resolution (set peak width for acquisition): Chromatograms A & B: 0.7 Da Chromatograms C, D, & E: 0.2 Da Figure 9. Dioxin quantification in animal fat tissues by GC-MS/MS. Concentration determined as 0.13 pg TEQ/g fat, precision 12.5%, n=5. (courtesy EURL for Dioxins (EU Reference Laboratory), Freiburg, Germany). 3. Multi-Compound Analysis of Pesticides Figure 8. ROSH analysis for brominated flame retardants in children s toys: Impact of quadrupole mass resolution (J. Gummersbach, Dreieich, Germany). Comprehensive analysis of pesticides is extremely complex due to the vast number of compounds to be screened for. The chemical nature of pesticides ranges from lipophilic, such as highly chlorinated hydrocarbons, to readily water-soluble acids. Accordingly, it is a task for both GC-MS and LC-MS, with a wide, overlapping range of compounds amenable to both techniques. Multi-methods today cover more than 600 compounds in GC-MS/MS and LC-MS/MS methods. Today s highly developed triple quadrupole technology achieves complete coverage of these 600 compounds, providing the required sensitivity independent of the number of compounds screened. At the same time, it provides spectacularly high selectivity in dirty matrix samples, such as those from the popular QuEChERS multi-compound extraction method.

9 9 Figure 10 shows the analysis of 600 pesticides screened in a single run for MRL level control in food. The blue trace shows the limits of detection (LOD) achieved. For comparison, the red trace shows the LODs when using a method with only 50 compounds in the run. Current maximum concentration limits for residues based upon the current European MRL regulations are represented by the purple area above those traces. Figure 10. Multi-compound pesticide analysis with GC-MS/MS compared to current EU MRL levels. Both the method including 50 compounds and the one with 600 compounds are well within compliance of the most strict European pesticide regulations. The chromatogram in Figure 11 shows the analysis of a quality control standard comprising 437 pesticides in a single LC-MS/MS run, spiked to an orange extract at 2 µg/kg, confirming that both methods are efficient at accomplishing the routine food safety control of more than 1000 pesticide compounds. Outlook Quadrupole mass spectrometry technology has a successful history in organic as well as inorganic applications. Even today, technological advances are further improving the performance and application range of this technology. Ion sources have become smaller for improved sensitivity, implementation of easy exchangeable source cartridges facilitates maintenance, and the introduction of matrix pre-filters has improved robustness. We expect to see progress with regard to ionization efficiency with further improved ion yield for higher sensitivity and ion statistics. Single quadrupole mass spectrometers today are undoubtedly the real workhorses of the chromatography laboratory, with many thousands of installations for innumerable GC-MS and LC-MS applications. Triple quadrupole systems are on a strong growth path, making inroads into routine labs for multi-class multicompound trace-level quantitation with the potential to replace many aging single quadrupole systems and take routine target compound trace analysis to a new level of performance. Today, quadrupole technology is mature, having reached an apex in technical development. Advances, if any, are expected on the ion source side for increased ion yields, detector technology, or signal processing. According to the Kondratiev waves of innovation, it is time for another leap in analytical technology 19. But, technology itself does not determine change. Change is driven by the steadily increasing demands of chemical analysis, especially in food and product safety. Pesticide analysis provides a good example of constant progress. At first, only single compound classes were analyzed, using specialized sample preparation methods and selective detectors. But these days, efficient control of the large number of compounds for analysis requires multi-methods. Discussions about how keep pace to cover those compounds not yet on regulatory target lists is ongoing. The success of the targeted approach for analysis creates the expectation that we will also be able to detect of unknown contamination, a non-targeted approach. New analytical technologies are giving notice that their innovative capabilities better meet these new requirements. Determination of accurate mass is key to providing access to the elemental formulae of unknown compounds. Figure 11. Multi-compound pesticide analyis using LC-MS/MS. Quadrupoles and ion traps will likely remain the undisputed chromatography workhorses for target compound quantitation over the coming decades. Already, hyphenated instrumentation, such as combinations of quadrupole with time-of-flight (Q-TOF) and Thermo Scientific TM Orbitrap TM analyzer systems, offer unique capabilities for identification of unknowns by determination of the compound sum formula. The rapid development of Orbitrap analyzers into affordable, highperforming benchtop detectors portends an upcoming

10 leap in technology that merges targeted and non-targeted analysis for routine analytical tasks, overcoming the inherent limitations of the present-day chromatography workhorses 20,21. References 1. Paul, W., A Cage for Atomic Particles a basis for precision measurements in navigation, geophysics and chemistry, Frankfurter Allgemeine Zeitung, Dec 15, 1993, (291) p. N4. 2. Paul W., Steinwedel H., Ein Neues Massenspektrometer Ohne Magnetfeld, Z. Naturforschg. 1953, 8a: Deutsches Museum, Der Paulsche Ionenkäfig, Information leaflet for QUISTOR exhibit, Bonn, Paul W., Reinhard, H. P., von Zahn, U., Das Elektrische Massenfilter als Massenspektrometer und Isotopentrenner, Zeitschrift für Physik 1958, 152: Finnigan, R.E., interview by David C. Brock at Los Altos, California, December 4, 2001 (Philadelphia: Chemical Heritage Foundation, Oral History, Transcript #0227). 6. Ryhage, R., Use of a Mass Spectrometer as a Detector and Analyzer for Effluents Emerging from High Temperature Gas Liquid Chromatography Columns, Anal. Chem. 1964, 36(4): Gohlke, R. S., Time-of-Flight Mass Spectrometry and Gas- Liquid Partition Chromatography. Anal. Chem (4): Gohlke, R. S., and F. W. McLafferty, Early Gas Chromatography/Mass Spectrometry, J. Am. Soc. Mass Spectrom. 1993, 4.5: LKB, LKB 9000 GC-MS Advertisement, Anal. Chem. 1966, 38.2: 28A 28A. 10. Denison, D.R., Operating parameters of a quadrupole in a grounded cylindrical housing, J. Vac. Technol : Miller, P.E., Denton, M.B., The Quadrupole Mass Filter: Basic Operation Concepts, J. Chem. Educ. 1986, 63 (7): J.A. Sphon, Use of mass spectrometry for confirmation of animal drug residues, J.- Assoc. Off. Anal. Chem. 1978, 61: COMMISSION DECISION of 12 August 2002 implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results, Off. J. Eur. Communities: Legis 2002 L221: Stafford, G., Ion trap mass spectrometry: A personal perspective, J. Am. Soc. Mass Spectrom. 2002, 13(6): Johnson, J.V., Yost, R. A., Kelley, P. E., Bradford, D. C., Tandem-in-Space and Tandem-in-Time Mass Spectrometry: Triple Quadrupoles and Quadrupole Ion Traps, Anal. Chem. 1990, 62: Mass Frontier 7.0 Spectral Interpretation Software. (accessed Sept 3, 2014). 17. HighChem Mass Frontier Page. index.php/massfrontier (accessed Sept 3, 2014). 18. Yost, R.A., MS/MS: Tandem Mass Spectrometry, Spectra (4): Šmihula, D., The waves of the technological innovations, Studia Politica Slovaca (Studia Politica Slovaca), : Makarov, A., Orbitrap Against All Odds, Analytical Scientist, Nov 10, 2013, p Zubarev, R.A., Makarov, A., Orbitrap Mass Spectrometry, Anal. Chem. 2013, 85(11): White Paper Thermo Fisher Scientific Inc. All rights reserved. ISO is a trademark of the International Standards Organization. All other trademarks are the property of Thermo Fisher Scientific and its subsidiaries. This information is presented as an example of the capabilities of Thermo Fisher Scientific products. It is not intended to encourage use of these products in any manners that might infringe the intellectual property rights of others. Specifications, terms and pricing are subject to change. Not all products are available in all countries. Please consult your local sales representative for details. Thermo Fisher Scientific, Austin, TX USA is ISO 9001:2008 Certified. Africa Australia Austria Belgium Canada China (free call domestic) Denmark Europe-Other Finland France Germany India Italy Japan Korea Latin America Middle East Netherlands New Zealand Norway Russia/CIS Singapore Spain Sweden Switzerland UK USA WP10427-EN 1214ZH