Screening Solution Using the Software Platform UNIFI: An Integrated

Chapter 9

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Screening Solution Using the Software Platform UNIFI: An Integrated Workflow by Waters Kenneth J. Rosnack,*,1 Malcolm J. Reid,2 Adam Ladak,1 and Gareth Cleland1 1Waters

Corporation, 34 Maple Street, Milford. Massachusetts 01757, United States 2Norwegian Institute for Water Research (NIVA), Gaustadaléen 21, NO-0349 Oslo, Norway *E-mail: [email protected].

Multi-analyte screening techniques are critical for monitoring environmental samples worldwide. Accuracy and timely information to confirm and quantify components of interest are vital. The method must meet the appropriate regulatory requirements and ideally be streamlined, rapid, and cost effective. To date, LC-MS/MS and GC-MS/MS tandem quadrupole systems are the “gold standard” for these analyses. However, an increasing number of analytes are constantly being added to methodologies creating very large target screening lists. Therefore, many laboratories are turning to high resolution mass spectrometry screening techniques that, in theory, can monitor an unlimited number of targets as well as providing information on unknown or transformation products of interest. Using a non-targeted, data independent approach to acquisition allows the user to collect a comprehensive dataset that can be used to screen for a large target list of targeted or suspect compounds, as well as unexpected, non-targeted compounds. This chapter will discuss the Waters approach to non-target screening analysis.

© 2016 American Chemical Society Drewes and Letzel; Assessing Transformation Products of Chemicals by Non-Target and Suspect Screening Strategies and ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Multi-analyte screening methodologies are essential for monitoring environmental samples across the globe. The goal of these methods is to provide accurate and timely information on confirmation and quantification of compounds of interest in the sample. Sensitivity must be in line with the relevant regulatory limits for residues in complex matrices. Also, a method must be validated in accordance with legislative requirements. This method would ideally be rapid, cost effective and a streamlined process, from sample preparation to reporting results. To date, LC-MS/MS or GC-MS/MS tandem quadrupole technologies meet the requirements above and currently exist as the de-facto technique used to perform these analyses. However, with a constantly increasing number of analytes being added to monitoring and watch lists, the scope of a typical screening method is being extended. In addition, requests to screen for compounds beyond a target list are becoming increasingly common. As a result, many laboratories are progressing towards high-resolution mass spectrometry (HRMS) screening techniques that, in theory, can monitor for an unlimited number of targets at the same time as providing information to help discover unknown compounds or metabolites of interest. With Tof MS the number of compounds that can be screened is not dependent on the duty cycle of the instrument, but on the chemical compatibility with the extraction and analysis methods. Using a non-targeted, data independent approach to data acquisition (MSE) (1) allows the user to collect a comprehensive dataset that can be used to screen for a large target list of targeted or suspect compounds, as well as unexpected, non-targeted compounds. The Waters® QTof systems have high mass accuracy, outperforming the criteria of 5 ppm specified in many regulatory guidelines. Using a scientific library that includes molecular formulae, compound structure, fragment ion and retention time information, one is able to confidently detect low concentrations of chemicals. The data can be interrogated at a later date for emerging compounds of interest that were not targeted in the initial suspect screen. The key to achieving the best possible results is to have robust and reproducible analyses. Although not discussed in detail here, critical to nearly all analyses is working with the sample (collection, preparation, etc.). See Figure 1 for a general workflow for sample analysis. Water analysis brings a wide range of analytical challenges, especially during sample preparation. This is mainly due to its matrix complexity, from drinking water quality to waste water. As such, the removal of interferences and isolation of target analytes usually requires some sort of extraction protocol. If an extraction protocol fails to address the removal of interferences, it will ultimately lead to a high level of matrix co-elution in the final extract. As a consequence, the quantification will show poor recoveries, and detection will be affected by matrix effects. An alternate to off-line sample preparation is using on-line 2D chromatography whereby compounds of interest can be trapped on a cartridge and then eluted onto the analytical column for analysis (2). Below, though, are examples of off-line sample cleanup.

156 Drewes and Letzel; Assessing Transformation Products of Chemicals by Non-Target and Suspect Screening Strategies and ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 1. General Analytical Method.

For example, in a targeted analysis of Estrogens in surface water (3), the samples were initially extracted utilizing an optimized method on an off-line Oasis® HLB Solid Phase Extraction (SPE) Cartridge. Crude influent and final effluent samples were first filtered, and then underwent the same Oasis HLB offline extraction step. This was followed by a second SPE step utilizing Sep-Pak® Silica Cartridges. These off-line SPE steps were critical to achieving lower limits of detection by providing the initial concentration step and cleaner extracts; thus reducing ion suppression within the mass spectrometer. This highly involved sample preparation is typical of many targeted analyses. A non-targeted approach would include a more generic sample preparation strategy. For example, F. Hernandez et. al. (4) used a simple Oasis HLB pass-through method using 250 mL of centrifuged water to load onto the cartridge and then wash with 10 mL of methanol. The effluent was divided into two portions and went through a drying / reconstitution process for use in both Ultra-Performance Liquid Chromatography (UPLC®)-HRMS & Atmospheric Pressure GC-HRMS on a Xevo® G2 QTof. The UPLC system is an advancement in LC instrumentation and column technology using sub-2 micro stationary phase particles that increases peak capacity, resolution, and sensitivity in chromatograpic separations. APGC is a soft ionization technique that uses chemical ionization at atmospheric pressure to create charged species that can be analyzed by a mass spectrometer. This technique produces more abundant precursor ions than traditional GC-MS ionization techniques. The samples were screened against a library of approximately 2000 compounds including pesticides and transformation products, pharmaceuticals, personal care products, and illicit drugs, among others. 157

Drewes and Letzel; Assessing Transformation Products of Chemicals by Non-Target and Suspect Screening Strategies and ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


As important as good sample preparation is to providing a robust and reproducible method, instrument system setup is critical to the success of consistent data. Once a sample extract has been produced, then the steps outlined in Figure 2 would be followed. In general, the system (UPLC, APGC, QTof) must be set up in a reproducible way so that the same sample measured on the same instrument but a different day or the same sample measured on different instruments, gives the exact same result. Traditionally the ability to achieve and maintain optimum performance from a high resolution analytical system, such as a QTof with UPLC and APGC capabilities, would require a level of knowledge and experience held only by expert users. The Waters QTof systems feature IntelliStart™ technology (5), an intuitive user interface that automates routine tasks and ensures reproducible data of the highest quality. This ensures the full capability of the system is accessible to everyone. IntelliStart enables essential functions on the QTof to be carried out including MS resolution and calibration checks, simple experiment setup, scheduled system checks and continuous system monitoring.

Figure 2. General Outline for the Waters Screening Application Solution using UNIFI Scientific Information System.



Fundamental to obtaining the best possible results on any MS is the chromatographic separation. The ACQUITY® UPLC I-Class System (6), is designed to produce accurate, reproducible separations, particularly when MS is the detection method (7), giving you the most information possible for ultimate laboratory performance. It improves peak capacity that helps chromatographically resolve background interferences with the compounds of interest, hence enhancing MS ionization efficiency. Selectivity in the analytical method is obtained through efficient chromatographic separation and through the use of high resolution accurate mass MS systems. As mentioned above, UltraPerformance LC® delivers the highest level of chromatographic separation and hence produces narrow chromatographic peaks (few seconds wide). In order to maintain that high analytical selectivity, a mass spectrometer must acquire data rapidly without compromising resolving power, sensitivity, isotope fidelity or in-spectrum dynamic range. Exact mass precursor and fragment ions acquired in the same run (MSE) permit automated software to propose a shortlist of found violations in the sample (8). The Waters QTof systems combine StepWave™ ion optics, XS Collision Cell, and QuanTof™ technologies (9) to provide a significant increase in sensitivity plus quantitative capabilities with no reduction in selectivity. After separation, the sample component peaks arrive at the mass analyzer in very narrow time windows so the mass spectrometer must be able to generate spectra rapidly. Since the identities of the arriving components are not known at the beginning of the analysis, data is acquired in an unbiased, independent way to avoid missing key information. Waters terms this functionality as MSE, a data-independent acquisition first coined in 2004 on the protein expression system (10). This technique was developed to overcome the short-coming of data directed analysis (DDA) such as reliance on pre-defined targets (e.g. include-list) or predefined parameters (e.g. thresholds). The MSE technique occurs in alternating scan functions collecting data up to 30 scans/sec (30 Hz). In the first scan all the ions are transmitted from the ion source through the collision cell, which is set to low collision energy so that no fragmentation occurs, to the mass analyzer and is recorded as a precursor ion spectrum. In the second scan all the ions are transmitted from the ion source through the collision cell, which is now run with a ramped collision energy to generate maximum information from fragment ions, to the mass analyzer and recorded as a fragment ion spectrum. The process of collecting precursor and fragment ions in alternating scans is then repeated throughout the run. Fragment ion spectra are then assigned to their associated precursor ion peaks using advanced software algorithms that profile each chromatographic peak and determine their corresponding retention times. Even when chromatographic peaks co-elute, the deconvolution algorithms are able to align the data and produce separate spectra for each component. This is illustrated in Figure 3 and details can be found in the MSE white paper (1).



Figure 3. MSE Precursor and Fragment Time Alignment Illustration.



Figure 4. Comparison of spectra generated from: A - An extracted ion chromatogram (XIC) from MSE data. The arrows point out unwanted interfering peaks. B - An Apex 3D time-aligned componentized spectrum from MSE data. Time alignment “cleans up” many of the unwanted peaks. C - A drift- and time-aligned spectrum observed from ion mobility IM-MSE data. Only the peak with the same drift- and time-alignment remains. 161 Drewes and Letzel; Assessing Transformation Products of Chemicals by Non-Target and Suspect Screening Strategies and ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


This non-target analysis technique was advanced with the introduction of an ion mobility separations device, first discussed at the 51st ASMS conference in 2003. This technique was commercially combined with MS technology by Waters in 2005 with the Waters Synapt® HDMS hybrid QTof system (11, 12). This IMS device uses a traveling wave ion optic device with a high efficiency ion mobility drift cell incorporated after the quadrupole but before the Tof region of a QTof instrument. Using IMS with drift time alignment provides an orthogonal separation of analyte from matrix ions and hence can be extremely important in the ability to clean up spectra (13) for an increased confidence of an ID. See Figure 4 for spectra with (C) and without (B) IMS drift time alignment. A measurement of the 3D confirmation known as CCS (collisional cross section) can be performed with mobility separation. The CCS calibration is performed automatically via IntelliStart. CCS is a physicochemical property of the molecule and can be used as an additional point of confirmation or criteria, during a screening experiment. Once the data is collected, the processing and review of the results can begin, see Figure 2. Perhaps the most crucial part of the analysis is how the user interfaces with the software in order to turn data into information. In the case of the Waters UNIFI Scientific Information System, raw data is processed once using a proprietary and powerful Apex Peak detection algorithm that transforms complex full scan data into components that can be subsequently queried as meta-data for targeted, suspect, and non-target (unknowns) analyses. Extracted Mass Chromatogram (EMC) or Extracted Ion Chromatogram (XIC or EIC) approach, utilized in other software, suffers as it includes noise and co-eluting peaks within the same retention window as the extracted ion of interest. The peak detection algorithm (14) locates the apex of each peak in a given mass chromatogram. Raw data are then organized into “candidate components” at narrow tolerances atop of the peak apex rather than combining entire extracted ion chromatogram peak widths. Given the wealth of information available in the precursor and fragment ions, isotopic distributions, and adducts, the componentization approach organizes and simplifies the data. The componentized data produces candidates that can be queried using workflows, views, and filters. See Figure 5 for the UNIFI data processing workflow. Most previous workflows and software were based on chromatographic extraction (at a pre-defined mass with pre-defined mass tolerance), followed by chromatographic peak integration (with pre-defined tolerances for area, shape and retention time) and finally the review and reporting. This method tends to be very hands-on and relies very much on pre-defined parameters before the processing takes place, and then again relies on chromatogram-by-chromatogram review by the analyst after initial processing. Peak detection and integration algorithms have improved significantly over the past 10-15 years and are now at a point where little or no human interaction is required. Unifi embodies this move as peak picking occurs automatically and in-line with data acquisition. It moves the point of human interaction to that of meta-data review. By this we mean reviewing individual chromatograms is rarely necessary and is, in most cases, completely unnecessary. Instead, the analyst reviews meta-data such as mass accuracy, isotope pattern match (often expressed as RMS error), retention time error, and the number of confirmed fragment ions 162



among others. This information is presented in a table/spreadsheet which allows for rapid review, filtering and reporting. This vastly improves the confidence in identifications made. For example, there may be 3 chromatographic peaks within 5 ppm and 0.5 minutes of an expected suspect analyte but only two have the expected isotopic pattern, and just one may have all the above together with a set of expected (or predicted) fragment ions visible in the high energy spectrum (MSE). This information is immediately obvious in the review panes within Unifi, meaning the correct identification is made instantly without further review. This is compared to traditional chromatogram-based methods which would necessitate analyst interaction and review of each peak, the calculation of isotope patterns, and review of fragment patterns before confirmation is made. Results review within UNIFI consists of interrogation of the componentized MSE or HDMSE data using filters, workflows, and views (15). This applies to all compound types whether target, non-target, or unknown. A filter is a question or a means to interrogate the componentized data generated in UNIFI. For example, “Show me the components identified with mass accuracy (±5 ppm), retention time (±0.5 min), and the presence of a high energy accurate mass fragment ion.” A second example could come from an unknown screening perspective such as “Show me components with a high probability of containing a halogen atom.” Another example for interrogation of unknown compounds of interest would be “Show me all components with a common accurate mass fragment.” A view is the combination of plots, chromatograms, spectra, tables, and columns that are displayed together on the screen. The view visually provides all the information required to answer the question in a filter. A workflow step is simply a saved view with a filter applied. A combination of these steps creates the workflow, which is designed to consistently, concisely and accurately answer a series of targeted, suspect, and/or unknown screening questions for each injection within an analysis. The workflow allows a supervisor, for example, to determine what information to extract from a non-targeted acquisition and customize how the review process is implemented. This ensures that the time from injection to report is minimized and that all users review data in a consistent and concise manner. Target analysis is the simplest of the three (target / suspect / unknown) for data acquisition and review. This mode is for analysis of 10s to the low 100s of compounds, typically. For laboratories focused exclusively on Questions 1 & 2 in Figure 6, a tandem quadrupole mass spectrometer operating in Multiple Reaction Monitoring (MRM) mode is considered the gold standard for multi-residue screening. The technique is fast, reliable, and robust and is deemed to have an established, efficient data review process. Reference standards are typically used to check ion ratios, retention times, and for precise quantitation (i.e. calibration curves) for each compound. The latest HRMS systems can also be operated in fully targeted mode with acquisition types such as Tof MRM, Selected Reaction Monitoring (SRM), and Selected Ion Recording (SIR) with excellent quantification accuracy for detected compounds. MRM, SRM, and SIR are all scan types used in tandam mass spectrometry whereby the precursor ion is selected in the first MS stage, fragmented in the collision cell, and then a specific fragment ion is monitored in the second stage. However, the same duty cycle 163



limitations exist when screening for a large list of compounds. These techniques are targeted acquisitions and provide limited information on unknown masses of interest.

Figure 5. UNIFI Data Processing Diagram. Raw Data is processed once and in parallel with acquisition. A component list is created using the Waters Apex Peak Detecting algorithm that takes into account isotopes, adducts, retention time for precursor and fragment ions. Meta-data is created (no raw data deleted or manipulated) and can be queried using UNIFI Workflows, Filters, and Views. 164 Drewes and Letzel; Assessing Transformation Products of Chemicals by Non-Target and Suspect Screening Strategies and ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 6. Fundamental Questions for Screening. If only the first two questions are to be answered, the Gold Standard is the Tandem Quadrupole MS. If all questions are needed, then HRMS may be the choice for the analysis. Using HRMS can allow you to screen for a theoretically unlimited number of compounds.

Laboratories wishing to answer all four questions in Figure 6, will need to utilize HRMS systems operating in “suspect, non-target, discovery, profile, or unknown screening” modes. Multiple workflows can be designed and used with componentized data and, for reference, some example workflows are shown in Figure 7. A qualitative non-targeted screening analysis is depicted in Figure 7A, and includes a workflow step to look for halogenated (i.e. Cl and Br) species. The workflow in Figure 7B adds a binary compare step to review; for example, differences between a reference standard and authentic sample. The workflow shown in Figure 7C contains steps that enhance the review of both qualitative and quantitative analysis in a non-targeted screen. For the analysis of metabolites and biotransformations of residues, the workflow shown in Figure 7D would be appropriate. Each of these workflows are a series of hyperlinks that employ user customizable views and filters and are easily constructed without the need to reprocess raw data. Suspect Screening uses a “suspect list” or database of hundreds of compounds with relevant information on each chemical species including structure, mass, retention time, CCS, etc. In this type of screening, reference standards may not be practical as in Target Screening. However, since UNIFI processing is based on componentized data (process raw data once), full information about a chromatographic peak (m/z, rt, isotopic pattern, etc.) is easily queried. All work at this point is based on using workflows, filters, and views. More importantly, no data is ever removed or even background subtracted as it is simply filtered away. Filters, views, and workflows can be modified or even removed depending on the analysis objective. Components can also be tagged with a classification such as a “GC marker”, or “reference” or “unknowns” to name a few. This allows for additional filters to be used in conjunction with the typical ones listed above. Suspect components are then queried against information in the database and 165



possible “hits” are displayed. The query is typically based on mass accuracy of the precursor ion and retention time, but is then further refined using isotope ratio / abundance, fragment ions, CCS, etc.

Figure 7. Example workflows used for A – Qualitative, non-targeted screening analysis. Includes Confident match IDs (i.e. Display the query of “Show me peaks that meet the Mass Accuracy, Retention Time, and Isotope Fidelity Criteria set forth.) vs. Tentative matches (i.e. Display those that meet some of the criteria); B. Quan-Qual non-targeted screening analysis (i.e. Include a Quantitative Step and calculate concentration based on a calibration curve using reference standards); and C - Unknown screening via binary compare (i.e. Include a step whereby a “Good” or “Blank” sample/matrix is compared to an “Unknown” sample and show me the differences between the two.); D - An unknown screening metabolite ID analysis (i.e. Display query steps to help find / elucidate possible metabolites within the sample.) 166



Once the samples have been reviewed for target and suspect screening, they can be subjected to non-targeted or unknown screening. This step is about finding out which peaks in the remaining “list” are important and which can be ignored (e.g. background, naturally occurring). UNIFI provides a number of possible tools to help with the unknown analysis. One of the simplest is the “Binary Compare” tool and appropriate filters. This tool simply compares two samples with each other. For example, one sample might be a “matrix blank” or “reference” while the other is the “contaminated” or “unknown sample.” A filter can be applied to only show components that are unique to the “unknown.” See Figure 8 for a binary compare example. For more involved analysis when sample sets are complex or when “references” are not available, multi-variate statistics are available also used for determining important components. These “unknowns” could then be investigated further using available tools in the “Elucidation Toolset.”

Figure 8. Binary Compare - Instant recognition of chromatography peaks of interest using Base Peak Intensity (BPI). Top trace is the blank (reference), middle trace is the spike (unknown) and the bottom trace plots the differences between the blank and unknown sample. The box highlights a region where there are large differences between the two samples. The “Elucidation Toolset” automates several aspect of identification of unknowns. Once a candidate of interest is found the low energy and associated high energy spectra can be taken into the discovery tool. The discovery tool is essentially a batch elucidation tool that combines elemental composition, database searching and fragment matching of the fragment ions into a one step process. First the unknown mass is subjected to an elemental composition search which searches the accurate mass within a mass tolerance (usually 3 ppm) against a user defined list of elements. A number of elemental compositions are generated and all subjected to the second stage which involves database searching. The scientific library can be searched or the entire ChemSpider database can be interrogated. All the matches from the database search that have structures associated with them are then subjected to fragment matching. In fragment matching the structure from the database is subjected to theoretical Insilco fragmentation and matched 167



within a mass tolerance (2 mDa). A score system is implemented by the software where the easier a bond is broken the lower the score is assigned to making that fragment. The results are then ranked and can be interrogated by the user. This is an advance in software that saves an enormous amount of time in data interpretation and opens up elucidation to all experiences of users. See Figure 9 for details.

Figure 9. Elucidation Toolkit Available Tools List in UNIFI. Each of these tools can be used in order to elucidate the identity of a candidate mass or to verify a target compound with more confidence.

There a number of other very useful investigation tools available in the elucidation toolset. One of those is a common fragment search. This allows the high energy fragments to be search across all candidate masses and can reveal compounds within the same class that may not have been present in the targeted list. As well as generating a list of these compounds an extraction chromatogram from the high energy function for the mass of the fragment is produced which aids in elucidation Figure 10. Halogen match can also be performed in the elucidation toolset. In Halogen match the software searches for spectra that contain specific bromine or chlorine isotopic distributions. This is particularly useful in pesticide analysis as often pesticides will contain these halogenated species. Figure 11 shows a halogen match search of a sample. Candidates that have halogens are potential pesticides and can be interrogated further with the discovery tool. In addition to these tools, it is important to have software capable of linking to external databases / libraries that are relevant to an application such as “STOFF-IDENT (16),” which is a database containing compounds found and confirmed in water samples. In that way, trace contaminants information that has been collected / uploaded can be provided to the analyst for a more focused search. 168



169 Figure 10. Common fragment Search. This view shows the common fragment search of the m/z 174 fragment in Atrazine. This common fragment is extracted from the high energy data and shows other possible compounds that have the same common fragment within a 2 mDa mass error.



170 Figure 11. Example of Halogen Match Filtering within the Discovery Toolkit. Listed in the table are possible halogen containing candidates which were not found in the target library.



In summary, high resolution mass spectrometers, such as the Waters QTof family of solutions, provide accurate mass determination of the precursor and product ions for compounds of interest at very low (ppb) levels. By utilizing a non-targeted data-independent acquisition in combination with a workflow-driven approach, specific and comprehensive qualitative and quantitative information can be obtained from complex screening data for simple visualization and interrogation versus a typical extracted ion chromatogram approach. The use of filters, views, and workflows greatly increases the rate of data review and reduces time from injection to report. Storing all data, methods, and libraries within a relational database provides easily accessible and quickly searchable information, which is most important for historical review.

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Screening Solution Using the Software Platform UNIFI: An Integrated

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