Mass spectrometers that use different types of analyzers for the first and second stages of mass analysis in tandem mass spectrometry (MS/MS) experiments are often referred to as "hybrid" mass spectrometers. The general goal in the design of a hybrid instrument is to combine different performance characteristics offered by various types of analyzers into one mass spectrometer. These performance characteristics may include mass resolving power, the ion kinetic energy for collision-induced dissociation, and speed of analysis. This paper provides a review of the development of hybrid instruments over the last 30 years for analytical applications. (J Am Soc Mass Spectrom 2008, 19, 161-172) © 2008 American Society for Mass Spectrometry T andem mass spectrometry (MS/MS), in a very generic description, is a process in which an ion formed in an ion source is mass-selected in the first stage of analysis, reacted, and then the charged products from the reaction are analyzed in the second stage of analysis. The type and quality of data that is obtained can vary greatly depending upon the type of analyzer used in the first and second stages of analysis, and the type of reaction performed between the stages of analysis. The reactions that can be done also can depend upon the type of analyzer. Over the years there have been a variety of means developed to measure the mass-to-charge ratio of gas-phase ions. The most common methods involve: dispersion based on ion momentum or kinetic energy (magnetic and electric sector instruments); separation in time based on ion velocity (time-of-flight); transmission through an electrodynamic field (quadrupole mass filter); and periodic motion in a magnetic or electrodynamic field (ion traps). There are differences in the experimental parameters associated with these various analysis methods that are pertinent to the MS/MS experiment. Some parameters are obvious, typically related to the performance of the mass analyzer while others are more subtle, related to the reactions/chemistry occurring between the stages of analysis. Many times these different parameters are used to categorize MS/MS experiments.One parameter is the ion kinetic energy. Sector and time-of-flight (TOF) instruments typically operate at "high" ion kinetic energies (5-20 keV), whereas "low" ion kinetic energies (Ͻ50 eV) are typical in quadrupole mass filters and ion traps. The ion kinetic energy is an important parameter in MS/MS experiments because the most common reaction involves colliding the ion of interest with a target gas atom or molecule. When performing ion-neutral collision experiments, the possible reactions that can be accessed (e.g., collisioninduced dissociation, collisional cooling, charge permutation, ion/molecule reaction) depends upon the ion kinetic energy. The appearance of the MS/MS spectrum can change drastically as a function of the collision (ion kinetic) energy. A related factor that is equally important, but often not considered, is the time frame of the experiment, that is, the elapsed time bet...

Collision induced dissociation (CID) in a quadrupole ion trap mass spectrometer using the conventional 30 ms activation time is compared with high amplitude short time excitation (HASTE) CID using 2 ms and 1 ms activation times. As a result of the shorter activation times, dissociation of the parent ions using the HASTE CID technique requires resonance excitation voltages greater than conventional CID. After activation, the rf trapping voltage is lowered to allow product ions below the low mass cut-off to be trapped. The HASTE CID spectra are notably different from those obtained using conventional CID and can include product ions below the low mass cut-off for the parent ions of interest. . During CID, the internal energy of a parent ion is increased through inelastic collision(s) with a target gas, resulting in the dissociation of parent ions. CID is the result of two distinct events; parent ion activation (collisional activation) and parent ion dissociation [3]. The appearance of an MS/MS spectrum, both product ion formation and abundance, is a function of the amount of energy deposited into the parent ion during the activation period [4,5]. Activation times for CID in rf trapping instruments typically range between 10 and 50 ms; however, CID can be accomplished using much shorter activation times in these instruments [6].For rf trapping instruments, the Mathieu parameters q z , (proportional to the applied fundamental ac rf voltage), and a z , (proportional to the applied dc voltage) determine if ions of a given mass-to-charge will be trapped. Typically, and in these experiments, rf trapping instruments are operated at a z ϭ 0, so theoretically ions with q z values from 0 to 0.908 are trapped. As the mass-to-charge value of an ion increases, its q z value decreases. Thus, the mass-to-charge value corresponding to a q z value of 0.908 is the minimum mass-to-charge value of ions trapped and is termed the low mass cut-off (LMCO).Each ion held by the trapping field exists in a pseudo potential well with the well depth proportional to the q z for each mass-to-charge value. Hence, smaller mass-tocharge ions, which have larger q z values, exist in deeper wells than larger mass-to-charge ions, which have smaller q z values [7]. To implement CID, a q z value is selected that allows the kinetic energy of the parent ion to increase via power absorption from a supplementary resonance excitation voltage without exceeding the pseudo potential well depth. Typical q z values for CID in quadrupole ion traps range from 0.2 to 0.3 and supplementary resonance excitation voltages with amplitudes greater than 1 V are not generally utilized [8]. A trade-off in the selection of the q z value for CID is that product ions with mass-to-charge values below the LMCO will not be trapped. This means that product ions with mass-to-charge values less than ϳ25-30% of the parent ion mass-to-charge are not observed in the MS/MS spectrum.Previous research conducted using "fast excitation" CID has shown that collisional activation can be accom-

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