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Hybrid Mass Spectrometers


Spectroscopy
Volume 26, Issue 3, pp. 16-21

Hybrid automobiles combine both electric- and combustion-based systems to achieve better performance in terms of mileage. How their mileage should be measured has become a matter of some debate, but better performance drives their sales success. Hybrid mass spectrometers combine several mass-analyzer components in a similar quest to achieve higher performance and similarly have been a sales success. Performance for hybrid mass spectrometers can be measured as higher sensitivity (and lower limits of detection), higher resolving power, or even other metrics such as speed of data production or data-set richness. A marketing approach used for hybrid automobiles is that "they drive just like a regular car," touting the seamless transition between propulsion modes. For hybrid mass spectrometers, they too can be "driven" just like regular mass spectrometers, and because of their high throughput, they add millions of mass spectra daily to the database. This column takes a two-stage tour, reviewing first some of the earlier ventures into hybrid mass spectrometers, and second, discussing the new metric of data-set production rate and richness for hybrid mass spectrometers.


Table I: Acronyms that describe generic hybrid mass spectrometers
Hybrid mass spectrometers are instruments constructed with at least two component "mass" analyzers (selectors) of different types arranged in sequence from ion source to ion detector. Table I lists the common acronyms used to describe components used in hybrid mass spectrometry (MS) systems. The difference between "q" and "Q" is important. The "q" component acts as an ion containment or focusing device; a "Q" component is a quadrupole mass filter that performs a mass analysis. The listed sequence of acronyms reflects the instrumental sequence of the physical components of the mass spectrometer, reading from ion source to the ion detector, and reflecting the flight path of ions through the instrument. Therefore, an EB/qQ and a Q/TOF are both hybrid instruments comprising the components in the sequence shown, with "q" acting as the ion activation component in the first instrument and "Q" acting as a mass-analyzing component in the second. The solidus (/) emphasizes an interface (accomplishing processes of ion activation, ion focus, and ion transport) between instrument components of different types that must be designed to accommodate substantial differences in beam shapes, fluxes, or energies, and may also need to mold a continuous ion beam into discrete packets ("packetize" the ions). Many hybrid mass spectrometers are used for MS-MS. An MS-MS analysis is predicated on at least one, and possibly several, sequential changes in an ion's mass, charge, or reactivity. A hybrid mass spectrometer must therefore perform three basic functions: it must complete an analysis of ions (one mass, a selection of masses, or all masses with the selected mass range) before the change, it must complete an analysis of ions (same suite of options) after the change, and it must provide a means to cause the change in ion mass, charge, or reactivity. Hybrid mass spectrometers can be composed of beam components (an ion beam moves through the component) or trap components (a packet of ions resides within the component). The details of these components and how they are joined in a single instrument is a focus of a forthcoming overview (1). Hybrid mass spectrometers have also been the subject of two earlier reviews (2,3).

Three metrics (sensitivity, resolving power, and production rate and richness of the data set) can be used to sketch out performance for modern hybrid mass spectrometers. When introducing these metrics, consider that the modern hybrid automobile provides a mileage gain of 2–3 times the usual vehicle (and not even a hypermile champion can eke out any greater performance). But mass spectrometry sometimes advances on a much grander scale. As noted in reference 1, "The practical attainable sensitivity (expressed as a limit of detection) progressed from micrograms to nanograms from 1950 to 1960, from nanograms to picograms by 1970, to femtograms by 1980, to attograms now. The past twenty years evidenced a factor of 1000 increase in performance associated with sensitivity." In the same period of time, practical attainable resolving power has similarly advanced from 102–103 in 1950–1960 to 105–106 today. For the classical performance metrics of sensitivity and resolving power, there are ample applications for hybrid mass spectrometers, and the first-generation hybrid instruments provided modest but consequential increases in performance.


Figure 1: A mixture of perfume sample components in the ionization source provides overlapped mass spectra. Data on the left represent ion signals measured at a resolving power of about 4000 for ions at m/z 177 and m/z 178. Two of the precursor ions at m/z 178 selected with higher resolving power to yield product ions indicative of a dialkyl phthalate (right top) and methyl eugenol (right bottom). (Reproduced from reference 1.)
Other than specialized instruments, the first commercial hybrid mass spectrometers (the EB/qQ and the BE/qQ) were the result of a combination of the double-focusing sector-based instruments and two-thirds of the triple-quadrupole instrument (QqQ), then in its first generation on the market. The double-focusing instruments were combined with two-thirds of the triple-quad instrument. How did such instruments impact sensitivity or resolving power in the MS-MS analyses that formed their typical applications? Clearly, a predictable performance attribute is the attainable resolving power in parent ion selection in a product ion scan (4). Otherwise isobaric ions could be mass-separated, separately selected, and one or the other passed through the qQ section for MS-MS. A few examples of such isobaric overlap and selection of one parent ion or the other appeared in the early research and sales literature of the time. Figure 1 (reproduced from reference 1), represents an example derived from the then-current sales literature for a commercial EB/qQ instrument. The left side of Figure 1 represents data measured at a resolving power of about 4000 for ions at m/z 177 and m/z 178, with the sample derived from a perfume mixture. Two of the precursor ions at m/z 178 selected with higher resolving power to yield product ions indicative of a dialkyl phthalate (right top) and methyl eugenol (right bottom).

With increased mass-resolving power, confidence in the analytical results was enhanced concomitantly, because interfering compounds could be discerned and mixtures could be more accurately deconvoluted. In some instances, limits of detection also could be lowered despite the lowered flux of ions transported through a physically larger hybrid instrument. Remember that at about the same time as these first-generation hybrid mass spectrometers became available, a number of novel ionization methods were also being introduced, including fast atom bombardment (FAB), liquid secondary ion mass spectrometry (LSIMS), and matrix-assisted laser desorption ionization (MALDI). These ionization methods were inherently "noisy," in that they often provided some level of signal at every integral ion mass, and this background level could constrain the lower limit of detection. Even a modest increase in resolving power for the parent ion could separate the true analytical signal from the noise. It is significant to remember also that these new ionization methods shifted our ability to create molecular ions into a higher mass range, first into the 1000–5000 Da range, and later even higher. The sector-based components of a hybrid instrument deal with ions moving at higher kinetic energies than the quadrupole-based components. Transmission losses are relatively lower at higher kinetic energies, so the higher flux of higher-mass ions through these components supported better overall instrument sensitivity. However, instrument refinements that led to better sensitivity paled in comparison as electrospray ionization was developed and was shown to provide higher performance through a far more efficient ionization process. The ultimate sensitivity of a mass spectrometer is of course related to both initial ion flux into the mass spectrometer and ion transmission through the components and the performance of the detector. The most consequential ion loss occurs in sample introduction (often outside of our direct control), sample ionization, the extraction of ions from the source, and the manipulation of the ion beam for the very first stage of mass analysis. The benefits derived from the optimization of electrospray ionization far outweighed the other more iterative developments.


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