Patent Application: US-59819405-A

Abstract:
a tandem linear ion trap and time - of - flight mass spectrometer , where the ion trap has a straight central axis orthogonal to the flight path of the mass spectrometer . the ion trap comprises a set of electrodes , at least one of the electrodes has a slit for ejecting ions towards the mass spectrometer ; a set of dc voltage supplies to provide discrete dc levels and a number of fast electronic switches for connecting / disconnecting the dc supplies to at least two of the electrodes ; a neutral gas filling the ion trap and a digital controller to provide a switching procedure of ion trapping , manipulation with ions , cooling and including a state at which all ions are ejected from the ion trap towards the mass spectrometer .

Description:
referring to fig1 there is a block diagram of a tandem it - tof mass spectrometer including the ion source , means to transmit ions into the ion trap and time - of - flight mass spectrometer . the ion source is positioned external to the ion trap . ions can be generated in the ion source by any of the methods known in the art . in particular the electrospray ion source and maldi are most commonly used for ionisation of molecules of biological nature . ion source can operate at elevated pressure and ions are collected from ion source and transmitted through regions of differential pumping into the ion trap with the help of rf ion guides . ions are manipulated inside the trap and prepared for mass analysis using tof . it - tof tandem can be built on the basis of 3d trap . configuration of such instrument with ejection of ions out of the trap directly into the tof flight path is presented on fig2 . however , such configuration suffers from low introduction efficiency mass discrimination and low charge capacity of a 3d trap . preferred embodiments are based on the use of linear ion traps ( lit ). electrode geometry arrangement of the quadrupole lit is shown in fig3 a . such ion trap is created by 4 main trapping electrodes elongated parallel to the central axis of the trap ( z - axis ). the electrodes have preferably hyperbolical cross section that corresponds to the shape of equipotential surfaces for 2d quadrupole field ( fig3 . d ). all 4 electrodes are arranged symmetrically with respect to each other and at the same distance from z - axis . such electrode configuration is capable of creating electrical field , which is most close to quadrupole field . shape and position of electrodes can be modified in order to create distortions of quadrupole fields for some applications , and this included in the scope of current invention . ions of certain mass range can be trapped within such electrode arrangement if a periodic trapping potential is applied to the electrodes . at the same time ions can leave the trapping volume along the axis . in order to prevent this from happening lit have additional electrodes for creating potential barrier at the entrance and the exit of the trap . in the simplest case diaphragm electrodes at the entrance and the exit of the ion trap can create the dc barrier to prevent ions from leaving the trap along z - axis ( fig3 b ). alternatively linear ion trap can be designed using segmented structure with 3 quadrupole segments arranged inline one after another ( fig3 c ). in this case the barrier is created by the dc voltage offset on the entrance and exit sections ( with respect to the middle section ). in both cases ion cloud is confined within the middle section of quadrupole and for further discussion the motion of ions along the z - axis is irrelevant . referring to fig4 there is a cross - sectional view of a lit - tof tandem with ejection of ions out of the trap into pulsar volume , from which ions are accelerated into the tof flight - path . the ion trap is created by 4 elongated electrodes 401 , 403 ( x electrodes ) and 402 , 404 ( y electrodes ) with hyperbolic cross - section . one of the electrodes 401 has a slit for ejecting ions into a pulsar region . the pulsar is created by flat plate 405 and semitransparent flat mesh 406 . high voltage switches 407 and 408 are connected to these electrodes and capable of producing a fast raising voltage pulses at appropriate time . ion trap is operated by a set of electronic switches 409 under control of digital signal generator ( dsg ). these switches are capable of connecting and disconnecting a set of dc power supplies + v , − v , v 1 , v 2 to the electrodes of the ion trap within 10 - 50 ns . digital signal generator is capable of calculating a implementing and arbitrary switching sequence according with requirements . the instrument is operated as follows . ions are formed in the ion source and injected into the ion trap along the z - axis near the centre of the trap . ions are trapped within the trap by periodic disconnecting and connecting + v and − v voltage supply from electrodes of the trap in such way , that at any given time y electrodes of the trap have the same polarity and x electrodes have also the same polarity but opposite sign with respect to y electrodes . the durations of positive voltage and negative voltage are equal . ions are cooled down by collisions with buffer gas down to the centre of the trap . at appropriate time both + v and − v power supply are disconnected from x electrodes . at the same time power supplies v 1 and v 2 are connected to electrodes 401 and 403 correspondingly . these voltage supplies are not disconnected from electrodes until all ions of interest will leave the ion trap in x direction towards pulsar as well as voltage supply for y electrodes , which is preferably positive + v voltage supply ( for positively charged ions ). time of voltage switching on x electrodes is controlled by dsg and can be adjusted in order to achieve the best performance . electrodes of pulsar are connected to the same voltage v 4 , which is slightly lower than the voltage of the trap centre on application of the extraction voltages , so that on arrival into the pulsar ions will continue to drift along x axis and expand in y direction . a high voltage power supplies v 5 and v 6 , are connected to the electrodes of pulsar simultaneously at appropriate time and ions are accelerated into the flight path of tof . in the ion mirror ( reflectron ) ions are reversed back and focused in the plane of detector in such a way , that ions of the same mass - to - charge ratio arrive as close to each other as possible in time . a fast digitiser is used to record a signal from detector thus producing a mass spectrum . fig5 shows the cross - sectional view of the second preferred embodiment : a lit - tof tandem with ejection of ions out of the trap directly into the tof flight path . this configuration do not have pulsar and hence it requires high voltage supply v 1 and v 2 to be connected to electrodes of the trap for ejection of ions . the electronics include additional switches in order to protect the trapping circuit from high voltage . instrument is operated similar to previous case with the following modifications . after sufficient cooling of the ion cloud the voltage supply on extraction x electrodes is disconnected from + v and − v power supplies and connected to high voltage supplies v 1 and v 2 . the voltage supply on y electrodes prior to extraction is preferably negative ( for positively charged ions ). the positive voltage supply + v is connected to the y electrodes before extraction and stay connected for a time sufficient for ions to leave the trap . the time elapsed from the last voltage switching on y electrodes and start of high voltage pulse on x electrodes is controlled by dsg and adjusted in order to achieve best performance of the instrument in terms of tof resolution , mass accuracy or sensitivity . for further discussion of preferred embodiments the preparation of the ion cloud within the ion trap is of importance . modern ion traps operate under elevated pressure conditions ( 1 - 0 . 1 mtorr ). typically he buffer gas is used in order to provide momentum - dissipating collisions for ions . such collisions assists with removing of excess kinetic energy during ion introduction process and provide means for cooling of the ion cloud . in some configurations a pulsed introduction of heavy gases ( ar , xe , . . . ) is used in order to provide more energetic collisions during ion fragmentation step . preparation steps can include several stages of ion cooling , selection of the ions of interest by removing ions of other mass - to - charge ratio out from the trap and fragmentation of selected ions . isolation and fragmentation can be implemented by several methods known in the art . all the way of preparation of the ion cloud the ion trap operation can be very complicated . the trapping waveform ( voltage or / and frequency ) can be modified many times including slow scan and application of additional low voltage ac signals to the electrodes of the trap . finally , ions are cooled down within the ion trap and prepared for extraction into tof . resolution and mass accuracy of final mass analysis is determined by tof properties itself , but the process of ion ejection out of the trap is the most important factor in this . the core of invention is to create optimum conditions of ion ejection out of the trap , so that with any given tof mass spectrometer the resolution can reach maximum possible value . this is achieved by creating conditions of electrostatic field inside the trap all the way during ejection , which is possible using “ digital drive ” for ion trap . such driving method is described in patent application [ 9 ] the entire content of which is included here by reference . unlike in conventional sinusoidal rf supply the voltages on the electrodes of the ion trap with digital drive are switched between discreet dc levels . in the simplest case the voltages are switched between two levels — positive and equal negative with the same duration of each level ( square waveform with 50 % duty cycle ). a precise control of the period can be achieved with the help of digital controller . using this method the period of waveform can be switched at any given time to a longer period . fig6 shows the time dependence of voltage on one of the electrodes of the ion trap , which is driven by switching every 500 ns between two levels + 1000v and − 1000v giving a total period of 1 μs . at certain time , which is equal to 10 μs on fig6 , the period of square wave is changed to 10 μs . the voltage level on the electrode reaches constant value within less than 10 - 50 ns , and it is maintained for another 5 μs . during this time the extraction of ions into tof can be performed . voltages on the electrodes of the ion trap remain constant with high precision apart from raising edge of the extraction pulse , which can be made shorter than 10 ns . ejection process happens in conditions of pure electrostatic field within the trap (“ frozen field ”). this provides means for optimising the ejection process for receiving best conditions for further processing . such optimisation for tof mass analysis of two preferred embodiments is provided later in this section . fig7 shows a table of voltages on the electrodes of lit of the preferred embodiments , which are used for ion trapping and extraction . during the ion trapping mode the voltage on x pair of electrodes is switched from positive + v to negative − v value every cycle . the voltage of y pair of electrodes is simultaneously switched to opposite sigh with respect to x electrodes . voltage supply on the electrodes of lit for ion trapping shown in fig7 as “ trap +” and “ trap −”. by using this simple trapping method a wide range of ions can be trapped . a more complicated trapping waveforms can be implemented by using a digital switch with several dc levels to drive each of the electrodes of the lit and / or by introducing delay between waveforms in each electrode . such methods of ion trapping are included in the scope of current invention . extraction voltages v 1 and v 2 are applied to the x electrodes ( different voltage on left and right electrodes ) at appropriate time . for direct ejection into tof flight path these voltages are preferably high ( over 5 kv ) in order to reduce turn - around time . for ejection into pulsar these voltages can be of the same order of magnitude as trapping voltage ( from 200v to 2000v ). voltage supply on the electrodes of lit during ejection is shown at fig7 as “ eject ” configuration . further discussion of preferred embodiments is based on optimisation of the ejection process . for this the distribution of ion positions and velocity was investigated in detail . after sufficient cooling time ions are collected near the centre of the ion trap along the axis in a cigar - like cloud . due to inherent nature of rf trapping , the energy spread of the ions in radial direction is phase dependant . this phenomena was investigated by using simulations of a big population of ions trapped in presence of he buffer gas at temperature 323 k . fig8 shows the dependence of the average kinetic energy for singly charged ions of mass 1000 da in a linear ion trap with inscribed radius ro = 5 mm driven by square waveform at frequency 1 mhz and voltage levels +/− 1000v . for convenience the voltage on y electrodes over the cycle is shown on the upper graph of fig8 . it follows that the energy spread for radial direction is phase dependant and has two minima — at the middle of positive and negative phases of the voltage waveform . thermal energy spread at 323 k equals kt / 2 = 0 . 0139 ev . this value of energy spread is reached at phase 0 . 75 ( middle of negative voltage on y electrodes ) for x motion and at phase 0 . 25 ( middle of positive voltage on y electrodes ) for y motion . qualitatively the phase dependence of average kinetic energy is universal for ions of a different mass - to - charge ratio differing slightly in the actual values of minimum and maximum energy . for minimising the velocity spread of the ions prior to ejection into tof the extraction pulse should be applied when the energy spread is minimal . for example for it - tof with extraction into a pulsar ( fig4 ) the optimum phase should be 0 . 25 , because it gives smallest spread in y direction ( direction of acceleration from pulsar into tof ). phase space distribution of ion cloud for y direction at phase 0 . 75 is presented in fig9 . it was used as an initial condition for simulations of ion ejection into pulsar . ejection process was simulated with voltages on the electrodes of the ion trap as presented in fig1 . the switching period for y electrode is changed from 1 μs to 10 μs . the time when it happens corresponds to t = 0 in fig1 . preferably positive voltage on y electrodes should be used for ejection of positively charged ions . voltages on x electrodes are switched to a negative dc level as in trapping mode . some time δt after this a negative power supply is disconnected from x electrodes and a different voltage supply v 1 and v 2 is connected to left and right x electrodes respectively . in fig1 these voltages are equal to 500v and 0v . time duration δt can be adjusted in order to achieve best performance . for smallest velocity spread of ions in y direction ( direction of further acceleration into tof ) it is useful to take δt equal to the quarter of the switching period just before extraction . in example of fig1 this time equals 250 ns . time of connecting v 1 and v 2 to x electrodes is referred further as start of ejection . fig1 shows the cross - section of a lit and a pulsar region of first preferred embodiment . position of the ion cloud of singly charged ions of mass 600 da at different time from the start of ejection is shown . during ejection the ion cloud experiences several compressions and decompressions in y and x direction . upon arrival into pulsar ( after 7 μs ) the ion cloud starts to spread in both directions ( as in field free region ). ions of different mass - to - charge ratio arrive into the pulsar at different time . this is a usual problem of methods based on extraction into external pulsar . only a limited mass range of ions can be present within the pulsar upon application of the extraction pulse . for current geometry the positions of singly charged ions of mass 300 da , 600 da and 1200 da upon arrival into the pulsar ( 10 μs after start of ejection ) is shown in fig1 . this is the right time for applying another extraction pulse ( high - voltage ) to the opposite electrodes of the pulsar in order to accelerate ions into the flight path of tof . the phase space distribution of ions in pulsar region at 10 μs is presented in fig1 . velocity spread of 600 da ions is below 300 m / s . with acceleration voltage of 10 kv the turn - around time is estimated to be 6 . 2 ns . with a typical flight time of 100 μs this gives a maximum resolution of tof spectra of 16 . 000 . although it was not attempted here , further optimisation of velocity spread and tof resolution is possible by using different extraction voltages on the electrodes of the trap and by traditional ion optics between ion trap and pulsar . for a configuration with ejection directly into the tof flight path ( x direction ) the moment of applying extraction pulse should be close to 0 . 75 phase as it provides minimum velocity spread of ions in x direction . phase space distribution of initial positions of ions in x phase space at phase 0 . 75 ( middle of negative voltage on y electrodes ) is presented in fig1 . in this particular example the extraction voltages should be applied 250 ns ( quarter of the period ) from the beginning of negative pulse on y electrodes . just before ejection the period of square wave is switched from 1 μs ( frequency 1 mhz ) to 10 μs ( frequency 100 khz ). negative voltage on y electrodes is kept for another 5 μs , which is enough to eject all ions out of the trap . the actual waveforms on each of the electrodes of the linear ion trap are similar to presented in fig1 with a following differences : just before the start of ejection voltage on y electrodes is negative , voltage on x electrodes is positive and extraction voltages are much higher . position of the ion cloud of 600 da ions at different time from the beginning of extraction is presented in fig1 . at the distance of 22 . 85 mm from the trap centre ( 550 ns after start of ejection ) the ion cloud has a first order focus . distribution of ion positions in the first order focus is presented in fig1 . the width of the ion cloud in first order focus is 60 μm and average velocity is 54 km / s . this focusing point of the cloud can be considered as a virtual source for tof mass spectrometer . after passing the focus point the ion cloud starts to spread again , but in the ion mirror of tof ( reflectron ) ions are reversed back and focused into detector . assuming that reflectron is built in such a way , that it focuses the ion cloud to a size which is at least not worse than the size of the virtual source , the resolution of mass spectra with typical flight path of 3 m equals 3 m /( 2 * 60 μm )= 25 . 000 . such resolution is considered as high for tof mass analysis . hence the proposed method allows for receiving tof mass spectrum of high resolution . mass accuracy of tof mass spectrum is believed to be of the same order because ions of different mass - to - charge ratio are ejected at the same electrostatic “ frozen field ” conditions and hence have essentially equal energy apart from thermal energy spread . it worth mentioning that the resolution can be further optimised by the adjusting of the extraction voltages and by using traditional ion optics on the flight path of ions from ion trap into tof . such methods are known in the art and are included within the scope of current invention . fig1 shows a cross section of a linear ion trap and voltage supply using digital switching method , which are used in 3 - d preferred embodiment . in this case trapping of ions is achieved by switching between two discreet dc levels on the y electrodes of trap only . high voltage power supplies for extraction are connected to x electrodes of the trap through electronic switch , which is controlled by dsg and connected only for ejection . during normal trapping and cooling the voltages on x electrodes are constant ( zero ). an additional ac power supply for generating excitation waveforms is shown on fig1 . this power supply is required for ion isolation and activation during preparation of the ion cloud before ejecting into tof . an advantage of this configuration is isolation of trapping switches from high voltage switch . thus such configuration does not require additional switches to protect trapping circuitry from high voltage . such configuration is a most simple practical implementation of the proposed method . l . he , y .- h . liu , y . zhu and d . m . lubman , detection of oligonucletides by external injection into ion trap storage / reflectron time - 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