Quadrupole accurate mass measurement

A simple mass spectrometer of low resolution (many quadrupoles, magnetic sectors, time-of-flight) cannot easily be used for accurate mass measurement and, usually, a double-focusing magnetic/electric-sector or Fourier-transform ion cyclotron resonance instrument is needed. 

This is not always the case, and the ability to use accurate mass measurements to confirm that certain ions do, or do not, have the same atomic composition would certainly be an advantage. As discussed earlier in Chapter 3, the instruments most widely used for MS-MS studies, i.e. the triple-quadrupole and the ion-trap, do not routinely have accurate mass capability for product ions. 

Various analyzers have been used to analyze phenolic compounds. The choice of the MS analyzer is influenced by the main objective of the study. The triple quadrupole (QqQ) has been used to quantify, applying multiple reaction monitoring experiments, whereas the ion trap has been used for both identification and structure elucidation of phenolic compounds. Moreover, time-of-flight (TOF) and Fourier-transform ion cyclotron resonance (FT-ICR) are mainly recommended for studies focused on obtaining accurate mass measurements with errors below 5 ppm and sub-ppm errors, respectively (Werner and others 2008). Nowadays, hybrid equipment also exists, including different ionization sources with different analyzers, for instance electrospray or atmospheric pressure chemical ionization with triple quadrupole and time-of-flight (Waridel and others 2001). 

Geometries composing of an oaTOF as MS2 bear the advantage that advanced TOFs offer accurate mass measurements close the the accuracy of magnetic sector instruments. Currently, QqTOF systems can be regarded as the commercially most successful hybrid. While the linear quadrupole serves as MSI in MS/MS experiments, it is operated in RF-only mode when tandem MS is not intended, because... 

In tandem MS mode, because the product ions are recorded with the same TOF mass analyzers as in full scan mode, the same high resolution and mass accuracy is obtained. Isolation of the precursor ion can be performed either at unit mass resolution or at 2-3 m/z units for multiply charged ions. Accurate mass measurements of the elemental composition of product ions greatly facilitate spectra interpretation and the main applications are peptide analysis and metabolite identification using electrospray iomzation [68]. In TOF mass analyzers accurate mass determination can be affected by various parameters such as (i) ion intensities, (ii) room temperature or (iii) detector dead time. Interestingly, the mass spectrum can be recalibrated post-acquisition using the mass of a known ion (lock mass). The lock mass can be a cluster ion in full scan mode or the residual precursor ion in the product ion mode. For LC-MS analysis a dual spray (LockSpray) source has been described, which allows the continuous introduction of a reference analyte into the mass spectrometer for improved accurate mass measurements [69]. The versatile precursor ion scan, another specific feature of the triple quadrupole, is maintained in the QqTOF instrument. However, in pre-... 

The TOF mass analyzer has a low duty cycle, and the combination with an ion accumulation device such as an ion trap is therefore very advantageous. It offers also MS capabilities with accurate mass measurement. In all acquisition modes, the ions are accelerated into the time of flight for mass analysis. Various other hybrid mass spectrometers with TOF have been described, including quadrupole ion trap [70] and linear ion trap [58]. High energy tandem mass spectrometry can be performed on TOF-TOF mass spectrometers [71, 72]. 

Hopfgartner, G. Vdbois, F. The impact of accurate mass measurements using quadrupole/time-of-flight mass spectrometry on the characterisation and screening of drug metabolites. Analusis 2000, 28, 906-914. 

A Q-TOF spectrometer is similar to a triple quadrupole but Q3 is replaced by an orthogonal TOF mass spectrometer. Using a Q-TOF instrument only the product ion scan mode can be collected, but because of its high resolving power, accurate masses for both the precursor ion and product ions can be obtained. (See the section below on accurate mass measurements.)... 

Recently, Quintela et al. [58] have determined THC and the carboxy metabolite in oral fluid using HPLC coupled to a quadrupole-TOF mass spectrometer. Extreme selectivity of detection and LLOQs of 0.1 and 0.5ng/mL, respectively, were achieved through accurate mass measurement. None of the real positive samples examined was found to contain THC-COOH. 

Paul, G., Winnik, W., Hughes, N., Schweingruber, H., Heller, R., and Schoen, A. (2003). Accurate mass measurement at enhanced mass-resolution on a triple quadrupole mass-spectrometer for the identification of a reaction impurity and colfisionally-induced fragment ions of cabergoline. Rapid Commun. Mass Spectrom. 17 561-568. 

Similar experiments have previously been performed separately using a triple-quadrupole or an ion trap mass spectrometer for quantitation followed by accurate mass measurements with a Q-TOF mass spectrometer. With the introduction of the LTQ-FTMS instruments, all the data can be gathered quickly and easily with one experimental setup, and the variations in observed metabolic profiles introduced by... 

Superior sensitivity, efficiency, and specificity have made high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS), the predominant analytical technique for characterization and quantitative analysis of metabolites (Kostiainen et al., 2003 Ma et al., 2006 Prakash et al., 2007). Ion trap, triple-quadrupole, and quadmpole time-of-flight (Q-TOF) mass spectrometers are routinely used to profile and characterize metabolites in plasma and excreta (Ma et al., 2006). The combination of scan types and features available on mass spectrometers of different design (product ion, MS", neutral loss, precursor ion scans, accurate mass measurements) allows identification and characterization of putative and unexpected metabolites with or without little prior knowledge of biotransformation pathways of a given dmg molecule. 

By examining this brief history of the development of instrumentation and methods, it should be clear what parameters define the instrument of choice for analysis of pharmaceutically important molecules. Such an instrument is one capable of performing LC-MS, typically using a reverse-phase HPLC separation and one of the API techniques. MS-MS capability is desirable—using an ion trap, a triple quadrupole, or other tandem mass analyzer instrument. Accurate mass measurement capability is also desirable. These attributes make up a prioritized list of capabilities for the ideal full-purpose instrument to be used in a pharmaceutical research environment. As one progresses through this list, the expense of the instrument increases, the sophistication of the instrument increases, and the intellectual and technological commitment required to do these experiments increases. 

Nielen, M.W., Vissers, J.P., Fuchs, R.E., van Velde, J.W. and Lommen, A. (2001). Screening for anabolic steroids and related compounds in illegal cocktails by liquid chromatography/time-of-flight mass spectrometry and liquid chromatography/quadrupole time-of-flight tandem mass spectrometry with accurate mass measurement. Rapid Commun. Mass Spectrom., 15, 1577-1585. 

Most FTICR mass spectrometers use superconducting magnets, which provide a stable calibration over a long period of time. Although some mass accuracy can be obtained without internal calibrant, mass accuracy and resolution are inversely proportional to m/z, and the best accurate mass measurements require an internal calibrant. Unlike the quadrupole ion trap, the FTICR mass spectrometer is not operated as a scanning device. 

Combinations of magnetic and electrostatic analyzers have been used to make instruments with high resolution capable (with appropriate calibration) of accurate mass measurements. Because they are scanning instruments, magnetic sector analyzers suffer from duty cycle limitations, as do quadrupole analyzers. Furthermore, because the scan speed of the magnetic field is proportional to resolution, additional time is required to obtain a spectrum as resolution is increased. Scanning the... 

While the development of ESI and MALDI provided techniques that ionize polar compounds effectively the spectra provide little or no structural information because molecular species are the only ions formed. The need to investigate not only the mass but also the structure of ions was an important factor in the development of multianalyzer mass spectrometers. There are several formats of MS/MS systems based on combinations of quadrupole, ion trap (Q and FT), and TOF analyzers. Combinations that use the same type of analyzers are tandem instruments, whereas different separation methods are used in sequence in hybrid systems. In MS/MS instruments, the first analyzer is used (usually) to select an ion of interest that is then passed, with or without fragmentation, into a second analyzer, which is often of higher resolving power and can be used for accurate mass measurement. 

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