Radiant energy – Ionic separation or analysis – Ion beam pulsing means with detector synchronizing means
Reexamination Certificate
2000-06-09
2003-03-18
Berman, Jack (Department: 2881)
Radiant energy
Ionic separation or analysis
Ion beam pulsing means with detector synchronizing means
C250S282000, C250S288000
Reexamination Certificate
active
06534764
ABSTRACT:
FIELD OF INVENTION
The invention generally relates to mass spectrometers and specifically to tandem mass spectrometers. More specifically, the invention provides an effective coupling of a first time-of-flight mass spectrometer to a second mass spectrometer of any one of various types, including a time-of-flight mass spectrometer with orthogonal acceleration, through use of a collision cell with collisional damping.
BACKGROUND OF INVENTION
Mass spectrometer (MS) instruments analyze compounds and their mixtures by measuring the mass to charge ratio (M/Z) of ionized molecules generated at a source. Time-of-flight (TOF) mass spectrometers accelerate a pulsed ion beam across a nearly constant potential and measure the flight time of ions from their origination at the source to a detector. Since the kinetic energy per charge of an ion is nearly constant, heavier ions move more slowly and arrive at the detector later in time than lighter ions. Using the flight times of ions with known M/Z values, the TOF spectrometer is calibrated and the flight time of an unknown ion is converted into an M/Z value.
Historically, TOF mass spectrometers have been primarily used with pulsed sources thereby generating a discrete burst of ions. Typical examples of mass spectrometers with pulsed sources include plasma desorption mass spectrometers and secondary ionization mass spectrometers. Recently TOF mass spectrometers have become widely accepted, particularly for analysis of labile biomolecules and other applications requiring wide mass range and high speed, sensitivity, resolution and mass accuracy. New ionization methods such as matrix assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) have greatly extended applications of TOF mass spectrometry. TOF mass spectrometers have become one of the most preferred instrumentation platforms for both of these new ionization methods.
The pulsed nature of the MALDI ion source naturally complements the pulsed operation of a time-of-flight analyzer, and thus TOF has been the mass spectrometer of choice from the earliest applications of the MALDI method. However, early MALDI implementation suffered from extreme sensitivity to laser energy. Recently, the resolution of MALDI/TOF MS instruments has been significantly improved by using a delayed ion extraction (DE) method, as described in U.S. Pat. Nos. 5,625,184; 5,627,369; and 5,760,393. In this method, a plume of ions and neutral molecules is allowed to expand after desorption by a laser shot and then the ions are accelerated after application of a delayed electric pulse. As a result, ions are no longer dragged through the dense plume by a high electric field. This technique reduces the energy spread of the ions and the amount of fragmentation. The delayed ion extraction method is much less sensitive to laser energy, and much higher resolution and mass accuracy are routinely available with MALDI-TOF mass spectrometers.
While pulsed sources are readily adapted to TOF mass spectrometers, it is more difficult to apply TOF to intrinsically continuous sources, like ESI. The problem was resolved with the introduction of an orthogonal extraction scheme, as described in Russian Patent SU1681340A1 and corresponding Published PCT application W091/03071, entitled “Method of time-of-flight analysis of continuous ion beam”. In orthogonal TOF (o-TOF) MS instruments, a continuous, slow-moving ion beam is converted into ion pulses by means of an orthogonal pulsed electric field. Ion pulses are accelerated in a direction orthogonal to the ion beam path to a much higher energy and are focused onto an intermediate focusing plane, which serves as an object plane of a reflecting TOF MS. The orthogonal pulser/accelerator serves as a high repetition rate (typically 10 kHz) pulsed ion source for the o-TOF mass spectrometer. The efficiency of conversion, referred to as the “pulser duty cycle”, is usually in the order of 10 to 20%. The conversion losses are well compensated by the ability of TOF mass spectrometers to detect all ions in a given pulse. As a result, the orthogonal TOF scheme provides a significant improvement in sensitivity compared to traditionally used scanning instruments, such as quadrupole and magnet sector spectrometers, which transmit only one narrow M/Z component at a time and discard the rest of the ion beam. The acquisition duty cycle of scanning instruments (i.e., the portion of the ion beam used for analysis considering that only a single component is passed at a time) is inversely proportional to mass resolution and is in the order of 10
−4
to 10
−3
%, compared to an acquisition duty cycle of ~10% for o-TOF MS instruments. In addition to high sensitivity, the o-TOF scheme provides greater mass range, exceptional speed, medium to high resolution and high mass accuracy.
While ESI-TOF MS and DE MALDI-TOF MS provide excellent data on the molecular weight of samples, one disadvantage to these instruments is that they provide little information on molecular structure. Traditionally tandem mass spectrometers (MS-MS) have been employed to provide structural information. In MS-MS instruments, a first mass spectrometer is used to select a primary ion (or ions) of interest, for example, a molecular ion of a particular compound, and that ion is caused to fragment by increasing its internal energy, for example, by colliding the ion with neutral molecules. A second mass spectrometer then analyzes the spectrum of the fragment ions, and often the structure of the primary ion can be determined by interpreting mass spectra of fragment ions. The MS-MS technique improves recognition of a known compound with a known pattern of fragmentation and also improves specificity of detection in complex mixtures, where different components give overlapping peaks in the first MS instrument. In the majority of applications, such as drug metabolism studies and protein recognition in proteome studies, the detection level is limited by chemical noise. Frequently, the MS-MS technique improves the detection limit in such applications.
In MALDI-TOF MS, the technique known as post-source decay (PSD) can be employed in a single MS instrument to provide information on molecular structure. The primary ions are separated in space in a linear TOF mass spectrometer and are selected by a timed ion selector. Ions are excited during the ion formation process and partially fragment in a field-free region (referred to as metastable fragmentation). Fragment ions continue to fly with the about the same velocity and, hence, with energy proportional to their mass (known as the energy partitioning effect). Subsequently, the ion fragments can be time separated in an electrostatic mirror (reflector). The PSD method, although involving a single mass spectrometer, is referred as a pseudo MS-MS scheme. Fragmentation spectra are often weak and difficult to interpret. Adding a collision cell where ions may undergo collision induced dissociation (CID) improves fragmentation efficiency. Still, the performance of both PSD and CID spectra is strongly affected by energy partitioning and, in the CID case, by an additional collisional energy spread. Parent ions and fragment ions have different energies and thus can not be simultaneously focused in a reflecting TOF mass spectrometer with an electrostatic ion mirror. To resolve the problem the mirror voltage is stepped and the spectrum is composed of stitches, a practice which hurts sensitivity, acquisition speed and mass accuracy.
Nowadays, the most common form of tandem mass spectrometer is a triple quadrupole (Triple Q), where both mass spectrometers are quadrupoles and the collision cell uses a radio frequency (RF)-only quadrupole to enhance ion transport. Because of its low scanning speed the Triple Q instrument employs continuous ion sources such as ESI and atmospheric pressure chemical ionization (APCI) sources. Since scanning of the second mass spectrometer would cause additional losses, the most effective way of using a Triple Q instrument is in monitoring selected reactions. Drug me
Hayden Kevin M.
Verentchikov Anatoli N.
Vestal Marvin L.
Berman Jack
Karnakis Andrew T.
PerSeptive Biosystems
Smith II Johnnie L
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