Abstract:
Apparatus for delivering ions to the mass analyzer. The apparatus includes a time of flight ion guide, a pulsing device for receiving a continuous ion stream containing ions of different atomic mass and for delivering pulses of ions to the ion guide wherein ions in each of the pulses of ions exit the ion guide in ascending order of their atomic mass, and a gating device at the exit end of the ion guide for allowing ions of a predetermined atomic mass to pass to the mass analyzer.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     Not applicable  
       STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT  
       [0002]     This invention has been created without the sponsorship or funding of any federally sponsored research or development program.  
       FIELD OF THE INVENTION  
       [0003]     This invention relates to the field of mass spectrometry. More particularly, it relates to the field of tandem mass spectrometry.  
       BACKGROUND OF THE INVENTION  
       [0004]     In the field of tandem mass spectrometry, it is common to use different kinds of mass analyzers and mass filters in series to improve analytical performance of the combined system. However, coupling between different mass analyzers is not always technically easy or even possible. The most common combinations of the mass analyzers are triple quadrupole instruments, where two linear quadrupole filters are connected by a collision cell positioned in-between. An efficient way to couple linear quadrupole, collision cell and a time of flight (TOF) analyzer is disclosed in EP1006559. Magnetic and electric sector analyzers are also commonly used in tandem. These instruments are typically expensive, free standing instruments. Several systems have been recently developed to couple an ion trap with a time of flight mass analyzer. For example, U.S. Pat. No. 5,569,917 describes a combination of an ion trap followed by time of flight mass analyzer. However, the resulting combination is characterized by substantially increased cost and the necessity to operate time of flight at very high energy to obtain reasonable accuracy and resolution of analysis readings.  
         [0005]     In another tandem mass spectrometry system, the time of flight mass analyzer was coupled with a quadrupole collision cell followed by a second time of flight analyzer, see WO 0077823 and WO 0077822. In this configuration, it was possible to achieve fragmentation information for the molecule of interest using two time of flight mass analyzers. Like previous systems the final configuration is somewhat expensive and bulky.  
         [0006]     In still another tandem mass spectrometry system, two linear quadrupoles were connected by a placing ion trap mass analyzer in-between (Kofel, P.; Peinhard, H.; Schlunegger, U.; Org. Mass Spectrum., 1991, 26, 463). This mass spectrometer system contained two precisionly machined quadrupoles. This results in a complex and expensive system with moderate performance, with the difficulty of coupling an ion beam from a quadrupole mass filter to an ion trap mass analyzer. These and other difficulties experienced with the prior art tandem mass spectrometry systems may be obviated by the present invention.  
         [0007]     What is needed is an economical and efficient way to select ions of a specific mass range that can be injected into a mass analyzer from a continuous ion source to improve selectivity and sensitivity from the mass spectrometer system.  
       SUMMARY OF THE INVENTION  
       [0008]     Apparatus for and method of delivering ions to the mass analyzer. The apparatus includes a time of flight ion guide, a pulsing device for receiving a continuous ion stream containing ions of different atomic mass and for delivering pulses of ions from the continuous stream of ions into the entrance end of the ion guide so that ions in each pulse reach the exit end of the ion guide in ascending order of their atomic mass, and a gating device at the exit end of the ion guide operating in timed sequence with the pulsing device for allowing only ions of a predetermined atomic mass in each pulse to pass through the gating device to the mass analyzer. The invention also includes a mass spectrometer that includes the apparatus for delivering ions described above. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0009]     The character of the invention, however, may be best understood by reference to one of its structural forms, as illustrated in the accompanying drawings, in which:  
         [0010]      FIG. 1  is a diagrammatic view of a example of an ion delivery system of the present invention applied to an ion trap mass spectrometer;  
         [0011]      FIG. 2  is an example of a timing diagram for the present invention;  
         [0012]      FIG. 3  is an isometric view of a two part ion lens which serves as the ion gating device portion of the present invention;  
         [0013]      FIGS. 4-7  are mass spectra obtained from an ion trap mass spectrometer, utilizing an ion delivery system of the present invention; and  
         [0014]      FIG. 8  is an example of a timing diagram for the selection of two mass ranges of ions for injection into the mass spectrometer system. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0015]     Referring to  FIG. 1 , an example is shown of a mass spectrometer system incorporating the present invention including of an ion source, generally indicated by the reference numeral  26 , a linear time of flight mass separator, generally indicated by the reference numeral  1  and a quadrupole ion trap mass analyzer, generally indicated by the reference numeral  6 . The time of flight mass separator  1  comprises a first or preliminary ion guide, generally indicated by the reference numeral  2 , a second ion guide, generally indicated by the reference numeral  4 , a gating device, generally indicated by the reference numeral  5 , and an ion trap entrance lens, generally indicated by the reference numeral  30 . A pulsing device, generally indicated by the reference numeral  11 , is located between ion guides  2  and  4  and defines an ion pulse region, generally indicated by the reference numeral  3 . The first ion guide  2  may be a radio frequency (RF) ion guide, or it may be any other type of ion guide, such as, by way of example and not limitation, a direct current (DC) ion guide, a stacked ring ion guide or an ion lens system. If it is an RF or DC guide, it may comprise a multipole structure. Similarly, the second ion guide  4  may be any type of ion guide, with examples similar to those given for ion guide  2 . In some exemplary systems incorporating the invention, first ion guide  2  may be omitted.  
         [0016]     The ion source  26  may be any ion source known in the art that can be used for generating ions from an analyte sample and delivering them to a mass spectrometer system. Examples include atmospheric pressure ionization (API) sources, such as electrospray (ESI), atmospheric pressure chemical ionization (ACPI) and atmospheric pressure photoionization (APPI) sources. The analyte sample may be in liquid or gas form, for example, and is introduced into the ion source  26  by means well known in the art. The ion source  26  communicates with an interface  9  that comprises functions of transmitting ions from the ion source  26  to the mass spectrometer system and, optionally, allowing a reduction of gas pressure from that of the ion source  26  to that of the mass spectrometer system. Interface  9  may be an orifice, a capillary, a tube, a passageway or any other such device for ion transport and, optionally, pressure reduction.  
         [0017]     The exemplary mass spectrometer system comprises one or more vacuum chambers, for example chambers  15 ,  16  and  25  shown in  FIG. 1 , that may optionally be separately pumped by vacuum pumps (not shown). In  FIG. 1 , an optional skimmer  14  is shown dividing chamber  15  and  16 , the first ion guide  2  is shown within chamber  16 , and second ion guide  4  is shown as located within chamber  25 . The quadrupole ion trap mass analyzer  6  comprises a quadrupole ion trap, generally indicated by the reference number  23 , and an ion detector  7 . The quadrupole ion trap comprises end cap electrodes  17  and  18  and a ring electrode  24 .  
         [0018]     The various components of the mass spectrometer system shown in  FIG. 1 , such as the interface  9 , skimmer  14 , ions guide  2  and  4 , pulsing device  11 , and lens  30 , gating device  5  and ion trap  23  are connected to conventional electrical power sources and controls in a manner well known in the art of mass spectrometers to produce the electrical potential, voltages, and timing described in example of systems described in this application.  
         [0019]     The power supplies for each of the electrical components of the exemplary mass spectrometer system of the present invention are shown diagrammatically in  FIG. 1 . The power to interface  9  is indicated by block  54 . The power supply to skimmer  14  and first ion guide  2  are represented by blocks  55  and  56 , respectively. The power supply to lenses  10  and  20  are represented by block  57 . The power supply to the split lens  27  is represented by block  58 . Power supplies  57  and  58  are connected to a master clock represented by block  59  to ensure that the lens  27  operates in timed sequence with the operation of the lenses  10  and  20 . The power supply, i.e. radio frequency generator, to the second ion guide  4  is represented by block  60 . The power supply to the quadrupole ion trap  28  is represented by block  61 .  
         [0020]     According to the present example of the invention, a continuous beam of ions  8  from the interface  9  pass through the skimmer  14  and enter the first or preliminary ion guide  2 . The ions travel along a preliminary ion path through the ion guide  2  and accumulate in the ion pulse region  3 . After accumulation, ions are pulsed out into the second ion guide  4 , that serves as the free flight region for the time of flight mass separator  1 . All of the pulsed ions have substantially the same energy. Therefore, the flight time of ions through the second ion guide  4  depends only on their m/z. The gating device  5  at the exit of the second ion guide operates with a controlled time delay, synchronized with the ion pulse and stays open also for a predetermined period of time. This allows only ions having masses within a selected m/z range to enter the ion trap mass analyzer  23 .  
         [0021]     A typical timing diagram for the control pulses is shown in  FIG. 2 . Ions are typically stored in the ion pulse region during D 1  and P 2  time intervals, then ions are pulsed out of the region  3  during P 1  time interval and the process continues in cycles. During the D 1  time interval, the pulsed out ions separate in their positions along the longitudinal axis of the second ion guide  4  according their m/z values, while the new portion of ions is accumulated in the ion pulse region  3 . The typical time for the pulses P 1  is 10 microseconds, while the whole cycle (P 1 +D 1 +P 2 ) is 100 microseconds, thus resulting in 10 kH z  repetition rate.  
         [0022]     in an example, the first ion guide  2  is an octapole ion guide 25 mm long with 3 mm inscribed diameter. The second ion guide  4  is 260 mm long with the same inscribed diameter as the first ion guide. Both ion guides  2  and  4  operated at 2.2 Mhz, 150 V peak-to-peak radio frequency voltage applied in the unusual manner for an octapole RF ion guide. Pulsing device  11  comprises two lenses  10  and  20 . Lens  20  has a 3.5 mm ID aperture  22 . Lens  10  has an aperture  21  that is substantially larger than aperture  22 . The pressure in the pulse region  3  is the range of about 10 to about 10 −1  mTorr, due to the neutral gas accompanying the ion beam  8  into first ion guide  2 . The presence of the neutral gas is useful for the efficient ion accumulation in the pulse region  3 . Several DC voltages are applied to the ion optical elements to produce continuous cycles of ion accumulation in the pulse region  3 . ion guide  2  is maintained typically at 1.8V DC, lens  10  at 1V DC, lens  20  is pulsed from 30V DC during ion accumulation to 0V DC during ion pulse out (P 1 ), the second ion guide  4  is maintained at −21V.  
         [0023]     The gating device  5  is a split lens, generally indicated by the reference numeral  27 , shown also in  FIG. 3 . The split lens  27  is an electric lens comprising a first element  40  and a second element  50 . The lens  27  has an aperture  41 . A first portion  42  of the aperture  41  is located in the element  40 . A second portion  52  of the aperture  41  is located in the element  50 . Both lens elements  40  and  50  for the gating device  5  are maintained at the same potential of −5V during (P 2 ) pulse to provide ion transmission for the ions of selected mass range. During the rest of the time, the lens element  50  is switched to −100V to deflect the ion beam. The ion lens  30  serves as a refocusing element to direct the ion beam into the ion trap  23  and is maintained at −70V for the experiments. Refocusing can be accomplished by any number of ion lenses known in the art for example, an aperture lens, a system of aperture lenses, one or more einzle lenses, a dc quadrapole lens system, a cylinder lens or system thereof, or any combinations of the above lenses.  
         [0024]     Tests with the system of the present invention were performed on a modified ion Trap MSD instrument from Agilent Technologies, wherein the standard ion optics in the third vacuum chamber were replaced with TOF ion optics as described in the above described example. The standard calibration mix sample from Agilent Technologies (part# G2431A) was introduced through a standard electrospray nebulizer. This sample has several ion species across the complete range of the mass analyzer; with m/z of 118, 322, 622, 922, 1522, and 2122 Da.  
         [0025]      FIG. 4  shows a mass spectrum obtained with P 1 =10 microseconds, D 1 =19 microseconds and P 2 =15 microseconds. Only masses within the mass range from 70 to 250 are selectively injected into the ion trap with the main peak at mass 118 Da.  
         [0026]      FIG. 5  shows the spectrum obtained at P 1 =10 microseconds, D 1 =30 microseconds and P 2 =15 microseconds. As expected, the increase in the delay time D 1  between pulses P 1  and P 2  shifts the transmitted mass range to the higher m/z values.  
         [0027]      FIG. 6  shows a spectrum with maximum of the transmission window positioned around the m/z 1522 Da peak, which is obtained with P 1 =10 microseconds, D 1 =6 microseconds and P 2 =15 microseconds.  
         [0028]      FIG. 7  shows the transmission window positioned around the m/z 2122 Da microseconds peak with P 1 =10 microseconds, D 1 =76 microseconds and P 2 =15 microseconds. All the spectra were obtained with total of 10 time of flight cycles with 100 microseconds duration time for each cycle. For the analytical applications, the optimum number of time of flight cycles injected into the ion trap can be calculated based on the previous scan information. Alternatively, a special short scan can be used to evaluate the number of cycles that are needed during the following main scan to target the same number of ions injected into in ion trap. This short scan can have a small fixed number of ions from time-of-flight cycles injected into an ion trap, with fast scanning of the trap analyzer to evaluate the intensity of the injected beam for the main scan. It is recognized, that it is also beneficial to synchronize the pulse P 1  with the phase of the main radio frequency voltage of the ion trap mass analyzer in a way that ions of interest arrive at the ion trap entrance at the most favorable phase for the injection, thus further improving sensitivity for the tandem system. It is also recognized that two or more mass ranges can be selected to transmit ions from within those ranges into an ion trap and to reject ions outside of the selected ranges.  
         [0029]      FIG. 8  shows the timing diagram for the selection of two mass ranges for the injection into the ion trap. Ions are pulsed out from the storage region  3  during the pulse P 1 . during D 1 , a new portion of ions are accumulated in the storage region  3 , while pulsed out ions are separated in a second ion guide according to their m/z values. The gating device  5  opens twice. In the first opening, the ions in the first mass region first pass during the P 21  pulse. After time delay D 2 , gating device  5  opens a second time to pass ions for the second mass region during the time P 22 . This mode can be of particular benefit when rejection of a single matrix ion is desired.  
         [0030]     Although examples of the invention are described, the invention is not limited to any particular implementation. For example, the radio frequency ion guide can be a quadrupole, hexapole or other multipole device, as well as a structure of rings or a multipole sliced into several segments as is well known in the art. The gating device can be of different geometry and design as well known in the prior art. The ion delivery system of the present invention can be used with different ionization techniques including electrospray, electron impact, etc. The ion delivery system of the present invention operates at relatively low energy and only allows ions within a predetermined mass range to enter the ion trap of quadrupole ion trap mass analyzer. This also may result in improved sensitivity, selectively and signal-to-noise ratio for the mass analyzer.  
         [0031]     According to the present invention the time of flight mass separator can operate at unusually low accelerating energy (below several hundred volts), since ions are guided in free flight region by an ion guide (otherwise the ions would disperse). low ion energy simplifies the design, and also results in small, portable instruments. Another advantage of the device may be high duty cycle (close to 100%), since ions can be accumulated in the ion pulse region for about the same period of time that it takes for the heavier mass of interest to reach the exit of the second ion guide. Also, since virtually no ions are lost during accumulation in the pulsed region, the ion transmission in the selected mass window may be close to 100%. Therefore, the tandem combination of a linear time of flight mass analyzer and an ion trap mass analyzer allows selecting a predetermined mass range to be injected into an ion trap without appreciable losses in the ion intensities. This results in filing the ion trap to capacity only with ions of interest within a specified mass range and rejecting the interfering matrix ions outside of the transmission window, thus improving sensitivity, selectivity and signal to noise ratio for the ion trap mass analyzer.