WO2017042665A1 - Resonance mass separator - Google Patents

Abstract

Disclosed is a resonant mass separator (RMS) and method of resonant mass separation are based on passing of continuous or gently modulated ion beams through electric field of an isochronous open trap so that ions isochronously oscillate (reflect or turn) in one plane and slowly progress in the orthogonal direction. Spatially localized excitation electric field is energized periodically, preferably at much higher frequencies compared to ion oscillations. Spatially local AC excitation within isochronous open traps is found to produce an effect of resonant stabilization and effective transmission of selected narrow mass bands, while deflecting or defocusing other ionic components. The open trap may employ a dipolar RF filter, or electrostatic sector multi-turn analyzer, or multi-reflecting analyzerbased on ion mirrors. Preferably, continuous ion beams are pulsed modulated to reach near unity transmission at high (for separators) resolving power of 10,000. Tandem MS-MS is the most preferred application of RMS. In one method, multiple parent ion windows are passed through the RMS for tandem analysis, thus reaching higher throughput of MS and MS-MS analyses.

Description

Resonance Mass Separator

Field of the Invention The invention relates to the field of mass spectrometry and in particular to resonant mass spectrometers and tandem mass spectrometers, and methods of mass separation for use therewith.

Background to the Invention

Nowadays, tandem mass spectrometers (MS-MS) are widely used for routine trace analyses within complex mixtures and matrices, like food and biological extracts. Between tandems, triple quadrupoles (3Q) are most popular for their sensitivity and speed. Triple quadrupoles operate as follows. Ion source, say, Electrospray (ESI) or electron impact (EI) ion source, generates continuous ion beams of parent ions of different compositions and of different m/z ratios. First analytical quadrupole (called Ql or MSI) is used to select parent ions, i.e. to transfer the parent ions of a target m/z (Ml), while discarding other m/z species, however, still with probability of passing through a number of species of the same nominal mass, where close m/z isobars correspond to different compositions and structures, commonly presenting compounds of different chemical classes. A collisional cell with radio-frequency RF ion confinement (CID) is used for parent ion fragmentation to differentiate between parent isobars and isomers by presence of unique characteristic fragments. Finally, the second analytical quadrupole (MS2) is used to filter and detect fragment ions of the second target m/z (M2). Both quadrupole analyzers do filter and pass one m/z specie in a time. Both parent and characteristic fragment ion masses (Ml and M2) are determined in prior calibration experiments when injecting standards. The target pair of Ml and M2 is called "reaction" or "channel". Since detected compounds generate multiple fragment species, the M1-M2 pair is selected to minimize interference with M1-M2 channels of the matrix. The reliability of compound detection may be improved by detecting several fragment ions at proper intensity ratio.

In a simplest strategy, called single reaction monitoring (SRM), the M1-M2 pair remains constant during the analysis time. SRM signal profile at chromatographic (LC or GC) separation provides selective detection within complex matrices (food extracts, blood, urine) at part per billion (ppb) levels. To detect multiple compounds in a single LC or GC run, in so-called strategy of Multiple Reaction Monitoring (MRM), the M1-M2 channels are mapped per chromatographic retention time RT. Rapid development and continuous additions of new libraries extend the area of 3Q application.

There still remains an issue of analysis selectivity in triple quadrupoles, affecting their limits of detection (LOD) within complex matrices. Choice of M1-M2 pair depends on matrix composition, which complicates development of analytical methods and reduces the analyses reliability. The selectivity may be strongly enhanced at higher 10,000-30,000 resolving power of MSI and MS2 to distinguish between close isobars. However, quadrupoles provide nearly full ion transmission at the resolving power equal to ion mass (R=M) and the transmission drops drastically at attempts of improving the resolving power.

Magnetic sector mass spectrometers are capable of providing high resolution in excess of 30,000 and large dynamic range of the analysis, but they are bulky, slow, expensive and introduce significant ion losses. To obtain resolution above 10,000, magnetic sectors operate with narrow (tens of microns) slits while accepting about one percent of ion beams.

Linear ion traps mass spectrometers are capable of MS-MS analysis at higher resolutions up to 10,000-30,000, but at a cost of very slow analysis and at significant compromises in the dynamic range, primarily caused by space charge effects at prolonged ion trapping.

In so called, resonant mass spectrometers exampled by Omegatrons of US2958774, radio-frequency (RF) signals are used for resonant excitation of ion orbital motion within magnetic fields, this way bringing ions of selected m/z to higher orbits. Resolution of those analyzers is low. Their successors -ICR FTMS mass spectrometers obtain resolving power in the order of millions, but they are slow for coupling with chromatography and are prohibitively expensive for routine analysis.

In so-called radiofrequency mass spectrometers, the RF signals are used to excite oscillations of ions of interest between mesh electrodes. However, resonant mass spectrometers were never implemented into mass product for their low mass resolution and poor transmission.

Time-of-flight mass spectrometers (TOF MS), and in particularly multi-reflecting MR- TOF MS do provide high resolving power but they are not yet adopted for parent ion selection out of continuous ion beams at high ion currents in nA range.

Thus, for enhancing specificity of routinely used tandem MS-MS, it is desirable improving mass resolution of mass selectors, while operating with continuous ion beams at high nA range currents, without dramatic losses of ion transmission and at moderate instrument cost. It is also desirable providing parallel detection of fragment ions for (a) yet higher sensitivity and speed and for (b) simplifying MRM method development for new applications.

SUMMARY OF THE INVENTION

Inventors realized that an effective mass separation may be achieved with the novel method of resonant stabilization at spatially local and high frequency excitation of ions moving within electric fields of isochronous open traps.

The resonant mass separator (RMS) of the present invention employs open isochronous ion traps with two-dimensional electric field in the X-Y-plane, substantially extended in the third orthogonal Z-direction. There are provided several examples of such isochronous open traps: an RF quadrupole with local dipole field; a multi-turn electrostatic sector analyzer; and a multi- reflecting electrostatic analyzer built of ion mirrors. Multiple ion species in a range of ion m/z are injected into one of such open traps to induce multiple ionic oscillations in the X-Y plane. The exemplar open traps are known to provide for isochronous ion oscillations, with oscillation period independent on ion spatial and energy spreads at least to the first order of aberrations, while the oscillation period is m/z dependent.

Two-dimensional electric field of open traps does not have Z-component, which allows ion propagation through the open trap in the third, drift Z-direction. Alternatively, as described for electrostatic open traps with sectors or ion mirrors, the ion propagation in the Z-direction may be controlled by either local spatial modulation of X-Y field of the open trap along the Z- direction, or by a set of periodic einzel lens, or by a set of quadrupolar lens. The mean ion trajectory become spiral (in case sectors) or zigzag (in case of ion mirrors), characterized by a fixed z-advance per turn and a fixed number of ion oscillations through the open trap.

To arrange resonant mass selection, there is arranged at least one excitation electrode, inducing excitation electric field within at least one spatially local excitation region, whereto ions get periodically in time. In multiple described examples, there are formed multiple excitation regions lying spatially periodic along the mean ion path. In all cases, isochronously oscillating ions get into the excitation region/regions periodically in time. A time periodic excitation signal is then applied to said at lest one excitation electrode. Excitation signal may be either harmonic or pulsed or of an arbitrary shape. The excitation field may be deflecting ions off the mean path, focusing/defocusing ion beams or accelerating/decelerating ions along the mean ion path. According to SIMION simulations, quadrupolar focusing appeared the most effective excitation. If no excitation signal is applied, ions of all mass follow the mean ion trajectory and pass through the open trap. To induce mass selective transmission of target m/z species, which have the oscillation period T and oscillation frequency f=l/T, the excitation signal is applied at frequency F being substantially higher than oscillation frequency f and being either an integer N or half integer N+l/2 harmonics of frequency f, so that multiple excitations are mutually compensated for the target m/z specie. The choice between N and N+l/2 harmonics depends on presence or absence of excitation inversion per single oscillation, which in turn depends on electrodes shape and tuning of electric fields of open traps. Other ion species (out of resonant stabilization) are exposed to variety of phases of the excitation field, accumulate notably higher excitation, get off the mean ion path and eventually are lost onto electrodes or stops.

Novel principle of resonant stabilization is strong departure from conventionally used principle of resonant excitation of target m/z species, commonly employed in RF ion traps.

The invention proposes another two novel features, not typical for ion traps: (a) spatially local excitation fields and (b) high harmonics of the excitation signal. The combination of the two allow for substantial acceleration of ion separation in fewer oscillation cycles. Below are provided examples of achieving R=10,000 resolution within 10-20 oscillation cycles, wherein conventional resonant separation (such as analytical quadrupoles or RF ion traps) requires approximately 300-1000 oscillation cycles for reaching this level of resolution. As a result, the resonant separator now can be constructed within an open trap of reasonably compact size, which has been unthinkable before. As an example, analytical quadrupole with 1000 RF cycles shall be several meters long, which would ruin the required micron precision of electrodes.

Using higher harmonics provide another novel feature - the proposed RMS transmits multiple m/z bands: m/z= (m/z)₀*K²/N² or m/z= (m/z)₀*(K+0.5)²/(N+0.5)², where (m/z)₀ is the target m/z, N is harmonics number and K is an integer number. Single desired mass band can be selected by a crude mass filter (such as quadrupole mass analyzer) placed upstream or downstream of the RMS, or by applying a second excitation signal of a second frequency, e.g. two signals corresponding to N and N-l, N and N+l, N-l and N+l harmonics, etc. Alternatively, multiple ion beam signals can be acquired at AC frequency scan (steps), or multiple parent mass bands could be admitted into a fragmentation cell, and MS or MS-MS spectra may be recovered by spectral decoding after frequency AC scan, smooth or stepped. The method of admitting multiple bands is expected to improve the MS and MS-MS throughput.

The method of resonant stabilization is demonstrated to work for continuous ion beams. However, a moderate enhancement is expected if gently modulating continuous ion beams at the same frequency as the excitation signal. According to the first aspect of the invention, there is provided a method of mass separation, comprising the following steps:

(a) Passing continuous ion beam of multiple ion species through a two-dimensional electric field of an open trap along a folded mean ion path, so that ions experience multiple oscillations (reflections or turns) in said two-dimensional field while drifting in the third orthogonal drift direction;

(b) Arranging said open trap being isochronous between time focus points periodically located along the ion mean path, so that the period T and frequency f=l/T of said oscillations are dependent on ion m/z ratio, but independent on ion spatial, angular and energy spreads to at least first order approximation;

(c) Arranging spatially local regions of excitation electric field around said time focus points along the mean ion trajectory; said excitation field affecting ion trajectories by either deflecting ions off the mean path, or by focusing/defocusing of ion beam, or by accelerating/decelerating the ion beam along the mean ion path;

(d) Energizing said local excitation electric fields with time periodic AC excitation signal at frequency F being higher integer N or half-integer N+l/2 harmonics of the ion oscillation frequency f;

(e) Choosing regime of spatial focusing between said focal points of said open trap, choosing said harmonics N or N+l/2 of the excitation field, and an amplitude of said excitation AC signal so that multiple AC excitations are minimal or mutually canceling and so produce only limited excitation for ions of a particular m/z of interest, leaving them in close vicinity of said mean ion path, while ions of different m/z with oscillation frequency being off resonance with said excitation signal do accumulate larger displacement off mean ion trajectory and get removed by electrodes or stops; and (f) Receiving ion beam along the mean ion path.

Preferably, said excitation frequency may substantially exceed the ion oscillation frequency corresponding to N»l . This improves the resolution of mass separation per ion path, space charge throughput, and the transmission of continuous ion beams. Preferably, said ion beam may be time modulated to provide temporary and spatially compressed ion packets in said regions of spatially local AC excitation field.

Preferably, said step of arranging electric fields for isochronous oscillating motion may comprise one step of the group: (i) arranging an RF dipolar trap with substantially quadrupolar RF fields; (ii) arranging electrostatic field of multi-turn sector analyzers with spiral ion trajectories; and (iii) arranging electrostatic fields of mirror based multi-reflecting TOF mass analyzers with zigzag ion trajectories.

Preferably, said ion drift motion in the Z-direction may be one of the group: (i) free propagation at variable number of oscillation cycles; (ii) a controlled Z-motion defined by spatially-periodic electric fields in the Z-direction to provide fixed number of oscillations through the open trap; and (iii) temporal ion entrapment in the Z-direction with subsequent release of mass separated species.

Preferably, the method may be applied to tandem mass spectrometry analysis, where said resonance separation is employed in at least one stage of mass selection. Preferably, the method may further comprise a step of transmitting a set of multiple mass windows and a step of scanning the frequency of said AC excitation for scanning said set of multiple mass windows. Preferably, said two dimensional electric field of open trap may be either of planar or cylindrical topology with corresponding straight or bent at constant radius axes Z.

According to the second aspect of the invention, there is provided a resonant mass separator, comprising:

(a) An ion source, generating continuous ion beam of multiple ion species;

(b) An isochronous multi-pass open trap built of gridless electrodes, extended along a Z- axis to form two-dimensional electric fields in X-Y plane being orthogonal to said Z-axis; shape and potentials of said open trap are arranged to provide periodic and isochronous ion oscillations (turns or reflections) along a mean ion path P in said X-Y plane; wherein the oscillation period along said ion path and between spatially periodic focusing points is at least first-order independent on ion spatial and energy spreads, but is dependent on ion mass to charge ratio m/z;

(c) Means for injecting said ion beam into said isochronous open trap to provide energetic ion motion along said ion path in said X-Y plane, combined with relatively slower ion drift in said Z-direction;

(d) At least one AC excitation electrode, arranged for providing multiple substantially local regions of excitation electric field around said focal points, deviating said ion beam off the mean ion path;

(e) A generator of a periodic AC excitation signal, applied to said at least one electrode at excitation period being substantially shorter compared to said oscillation period; and

(f) A receiver of mass selected ions.

Preferably, said excitation frequency substantially exceeds the ion oscillation frequency.

Preferably, said open trap may be one of the group: (a) an RF dipolar trap with substantially quadrupolar RF fields; (b) a multi-turn electrostatic sector analyzer with spiral ion trajectories; and (c) a mirror based electrostatic multi-reflecting TOF mass analyzers with zigzag ion trajectories. Preferably, said open trap may further comprise one set of means for spatial ion confinement in the drift Z-direction of the group: (i) local spatial modulation in the Z-direction of electrodes of said open trap; (ii) a set of spatially periodic einzel lens in a field free region of said open trap; (iii) a set of quadrupolar lens in field free region of said open trap; and (iv) an Z- end deflector for trapping ions for a fixed time period.

Preferably, the mass separator may further comprise a pulsed accelerating modulator after said ion source for temporary ion packet compression in said AC excitation regions. Preferably, the mass separator may further comprise an additional crude mass selector between said ion source and said ion receiver. Preferably, said at least one AC excitation electrode may comprise one of the group: (i) a pair of deflecting electrodes extended along said Z-axis; (ii) a set of deflectors; (iii) a set of periodic einzel lens; (iv) a set of quadrupolar lens.

Preferably, the method and apparatus may be applied within a tandem mass spectrometer for at least one stage of mass selection.

The proposed resonant mass selectors (RMS) are expected to provide an improved combination of resolution and sensitivity compared to prior art continuous beam separators, like quadrupoles and magnet sectors, and are expected to provide much higher dynamic range compared to prior art ion trap mass spectrometers and TOF MS. The RMS may be used as a single stage mass spectrometer or may be used in tandem MS-MS, like RMS-RMS, Q-RMS; RMS-Q and RMS-TOF.

Disclosed is a method of mass separation, comprising the following steps:

(a) passing ion beams or ion packets through static (DC) or dynamic (RF) electric fields of a multi-pass open trap built of gridless electrodes;

(b) arranging electric fields of said trap and arranging ion injection into said trap to provide periodic and isochronous ion oscillations with the oscillation period being at least first-order independent on ion spatial and energy spreads, but being m/z dependent;

(c) forming a time-periodic and spatially local deflecting electric field, deflecting ions in a substantially orthogonal direction to the ion path by applying a periodic AC excitation signal to at least one electrode of said open trap;

(d) arranging said deflection fields at minimal distortion onto the isochronicity of ion motion; and

(e) choosing the frequency and the amplitude of said AC excitation signal to pass ions with m/z of interest (target ions) while destabilizing ion motion and removing other ionic components from the ion path.

The excitation frequency may substantially exceed the ion oscillation frequency in order to increase the separation per ion path and this way reducing the vacuum requirements.

The continuous ion beams may be time modulated to provide temporary and spatially compressed ion packet in the region of spatially local AC deflection field.

The said step of arranging electric fields for isochronous oscillating motion may comprise one step of the group: (a) arranging an RF dipolar trap with substantially quadrupolar RF fields; (b) arranging electrostatic field of multi-turn sector analyzers with spiral ion trajectories; and (c) arranging electrostatic fields of mirror based multi-reflecting TOF mass analyzers with zigzag ion trajectories. Ion motion in the drift Z-direction may in some embodiments be either free propagation at variable number of oscillation cycles, or a controlled Z-motion defined by spatially-periodic electric fields in the drift direction to provide fixed number of oscillations through the open trap; or a trap is arranged for temporal ion entrapment in the Z-direction with subsequent release of mass separated species.

The method of mass separation may be used for at least one stage of mass selection in a tandem mass spectrometry analysis. The method of mass separation may further comprise a step of transmitting a set of multiple mass windows and a step of scanning the frequency of said AC excitation for scanning said set of multiple mass windows.

Alternatively, or in addition, the method may comprise a step of crude mass selection with resolution to distinguish between multiple transmitted mass window at high AC harmonics for the purpose of selecting a single m/z specie. Also disclosed herein is a resonant mass separator, comprising:

(a) an ion source, generating continuous ion beam of multiple ion species;

(b) an isochronous multi-pass open trap built of gridless electrodes to provide periodic and isochronous ion oscillations in the first X-direction with the oscillation period being independent on ion spatial and energy spreads, but being m/z dependent;

(c) said open trap is arranged for ion confinement in the second orthogonal Y-direction;

(d) said open trap is arranged for ion propagation through the trap in the third orthogonal Z-direction;

(e) at least one electrode of said trap is arranged for providing a substantially local region of deflecting electric field, being substantially orthogonal to the X-direction;

(e) a generator of a periodic AC excitation signal, applied to said at least one electrode to form a time-periodic deflecting electric field, primarily deflecting ions in the Y or Z directions, being orthogonal to the first X-direction of the mean ion path for minimal distortion onto the isochronicity of ion oscillations; and

(f) a receiver of mass selected ions.

The open trap may be selected from one of the group: (a) an RF dipolar trap with substantially quadrupolar RF fields; (b) a multi-turn electrostatic sector analyzer with spiral ion trajectories; and (c) a mirror based electrostatic multi-reflecting TOF mass analyzers with zigzag ion trajectories.

The mass spectrometer may have an open trap comprising means for spatial modulation of electric fields to provide the spatial confining of the ion Z-motion in the drift direction, thus, providing a fixed number of oscillations per ion passage through said open trap. The mass spectrometer may comprise a pulsed accelerating modulator after said ion source for temporary ion packet compression in said AC deflection zone.

The mass spectrometer may comprise an additional crude mass selector between said open trap and said ion receiver.

The open trap may employ RF fields and wherein said open trap is wrapped into a circle or a spiral.

The mass spectrometer may be used for at least at least one stage of mass selection in a tandem mass spectrometer.

DESCRIPTION OF THE FIGURES Various embodiments of the present invention will now be described, by way of example only, and with reference to the accompanying drawings in which:

Fig.l schematically depicts a resonant mass separator based on radio-frequency dipole; Fig.2 schematically depicts a radio-frequency mass separator with extended separation paths and times;

Fig.3 schematically depicts a tandem mass spectrometer employing the resonant mass separator of Fig.1;

Fig.4 schematically depicts an electrostatic resonant mass separator using multi-turn isochronous analyzer based on electric sectors;

Fig.5 schematically depicts an electrostatic resonant mass separator using multi- reflecting isochronous analyzer based on gridless ion mirrors;

Fig.6 schematically depicts an electrostatic resonant mass separator with axial bunching of continuous ion beams;

Fig.7 depicts a model of resonant separator used for subsequent numerical simulations;

Fig.8 presents a simulated graph for vertical ion packet displacement Y Vs number of oscillations for odd (n=100) and even (n=101) high harmonics of oscillations for exact resonant mass m/z and for close in mass specie with m/z*(1.0001), simulated at longer focal distance F=150mm and for model parameters shown in the grey icon;

Fig.9 presents a simulated graph for vertical ion packet displacement Y Vs number of oscillations for odd (n=100) and even (n=101) high harmonics of oscillations for exact resonant mass m/z and for close in mass specie with m/z*(1.0001), simulated at shorter focal distance F=l 13mm and for model parameters shown in the grey icon, matching parameters of Fig.8;

Fig.10 presents a simulated graph of ion transmission Vs square root of m/z for soft bunched ion beam at shown simulation parameters; the graph illustrates that RMS normally provides multiplicity of transmitted mass bands; the graph also illustrates the principle of resonant stabilization for narrow mass band;

Fig.ll shows the peak shape for simulations of Fig.10; peak shape has narrow wings and mass resolving power is over 10,000 at 92% transmission, which exceeds resolution of convention quadrupole separators by factor of 100;

Fig.12 shows mass resolution and total angular deflection Vs transmission in RMS for continuous ion beams (i.e. without bunching); In case of continuous ion beams, even at optimal RMS parameters, the transmission drops to approximately 30% when reaching R=10,000, which is still beyond the reach for conventional quadrupoles;

Fig.13 shows a SINION model and spiral ion trajectories in a resonance mass separator, constructed of cylindrical sectors and sets of periodic einzel and quadrupolar lens;

Fig.14 shows the shape of one transmitted band at m/z=1000 at AC frequency scan in the vicinity of N=10.5 harmonics; Figure illustrates two cases - of pulsed ion packets in graph 141 and of continuous ion beams in graph 144;

Fig.15 illustrates the principle of parallel MS-MS analysis employing RMS of the present invention for parent separator; AC frequency is scanned to admit multiple m/z species simultaneously, from which normal MS-MS spectra may be recovered after data decoding while improving the MS-MS throughput.

DETAILED DESCRIPTION

Definitions

Multi-pass open traps are defined as analyzers, trapping ions within a two-dimensional electric (DC or RF) field in an X-Y plane, while passing ions in the third Z-direction. Ion trapping in the X-Y plane is arranged by moving ions along a generally curved mean ion path P, composed of multiple oscillations (turns or reflections), while passing ions through the trap in the generally curved third - drift direction Z, being locally orthogonal to the X-Y plane. The invention proposes using either electrostatic open traps, trapping moving ions within DC electric fields, or electro-dynamic open traps, trapping ions in radiofrequency RF fields. Exemplar multipass traps comprise: (a) RF dipolar trap with substantially quadrupolar RF fields; (b) multi-turn electrostatic sector analyzers with spiral ion trajectories; and (c) mirror based multi-reflecting TOF mass analyzers with zigzag ion trajectories. It is of principal importance that the invention employs open traps passing ion beams through in 0.1-lms time scale without prolonged ion trapping, thus avoiding space charge effects which are present in ion traps of prior art.

To account for various topologies of the proposed open traps (RF quadrupolar, sector based, or mirror based), the axes are defined consistently through the entire application. X and Y axes define the plane of the two-dimensional electric field in planar or cylindrical topologies. Generally curved Z axis is defined being locally orthogonal to X-Y plane, which accounts for examples of cylindrical topology, shown in Fig.2. Two-dimensional electric field does not induce any field in the Z-direction and allows free ion propagation (drift) in the Z-direction, also called as drift direction.

To keep general annotation of axes, we define a separate set of axes, where P axis corresponds to projection of isochronous mean ion path onto the X-Y plane and N-axis is defined being locally orthogonal to the P-axis within the X-Y plane. In some cases, the P-axis is arranged along the X-direction, as shown in Figs. 1-3, 5, 6 and 13. In case of sector based analyzers, the mean ion trajectory is curved and a set of P and N axis rotate in the X-Y plane to follow the curvature of the mean ion trajectory.

Within open traps, the ion motion in the drift Z-direction may be either free or controlled. Free ion propagation at non determined number of oscillations through the trap occurs at zero field in the Z-direction. The ion motion may be confined along a mean ion trajectory by electric fields, thus, providing fixed number of oscillations per ion passage through the open trap. Alternatively, ions may be temporarily trapped in the Z-direction for fixed (though limited to 0.1-lms) trapping time.

In isochronous traps, the period T of ion oscillations (turns or reflections) in the X-Y plane and between time-focal points stays independent on spatial angular and energy spreads of ion beams or packets at least to the first order of corresponding time aberrations. Quadrupolar RF fields are parabolic and thus provide isochronicity for a wide range of ion beam spreads. Multi-turn sector open traps are known to be first-order isochronous relative to spatial, angular and energy spreads. Multi-reflecting ion mirror analyzers are known to be isochronous to high (second and third) order of aberration limits.

Regardless of the field type, the proposed resonant mass separators use the same method of ion selection. Continuous, or time modulated ion beam propagates through a multi-pass open trap analyzer. The analyzer is isochronous, i.e. ions of any particular m/z oscillate in X-Y plane at fixed period T, and such period is mass dependent: in RF fields, T is proportional to first power of m/z: TRF=C*m/z; and in electrostatic fields, T is proportional to square root of ion m/z: TDC=C(m/z)° ⁵. A periodic excitation signal is applied to at least one AC excitation electrode for side deflecting, focusing or defocusing, arranged spatially periodic, say, at symmetry plane of the analyzer. Multiple examples are provided for various AC excitation set of electrodes, like deflectors, periodic einzel lens, or periodic quadrupolar lens. The excitation signal appears in resonance with periodic oscillation for ions of some particular m/z, thus providing an opportunity for various schemes of resonance ion selection, either by removal of unwanted resonant ions or by stabilizing motion of wanted resonant ion species.

It is of principal importance, that the proposed method and apparatus of mass selection employs the effect of resonant (anti-resonant) mutual compensation of adjacent excitations, where the choice of resonant F=N/T or F= (N+0.5)/T frequency depends on type of excitation field. In case of using lens excitation (periodic einzel lens and quadrupolar lens), F=(N+0.5)/T always. In case of using deflectors, the choice between N and N+0.5 depends on ion trajectory inversions in the transverse direction and thus, depends on spatial focusing of a chosen analyzer.

It is of principal importance that the proposed methods and apparatuses employ local regions of excitation AC field and high harmonics (N»l) of the excitation frequency compared to ion oscillation frequency. Both means allow much higher resolution of mass selection at limited ion passage time and ion path. The method would work similarly to gated TOF with rarely pulsed ion packets, but at a cost of very limited duty cycle, space charge effects at higher ion currents, and dynamic range limitations. It is of principal importance that the proposed method is suitable and employs either continuous ion beams or quasi-continuous beams, e.g. gently modulated with frequent axial bunching usually at MHz frequency range.

RMS based on RF dipoles

Referring to Fig.l, one preferred embodiment of resonant mass selector 10 comprises a pair of back to back monopoles 11, each monopole 11 being composed of circular rod placed against the 90 corner electrodes, having slits for ion passage between monopoles. To reduce the distortions of the "ideal" quadrupolar potential distribution V=Vo*(X²-Y²), shown by equipotential lines, the improved embodiment 12 may be a dipole with purely quadrupolar field, composed by two pairs of hyperbolic electrodes 14 and 15, where electrodes 14 have much larger distance to the center relative to one of electrodes 15. The hyperbolic rods of the embodiment 12 may be reasonably approximated with wedge electrodes having circular tips, as shown in the drawing. Generally, the electrode system may be energized by RF and DC signals to form quadrupolar fields. Preferably, high amplitude RF signal is applied to large electrodes 14, while a dipolar excitation AC signal and an optional positive DC are applied to smaller electrodes 15.

The RF field with frequency Φ=2π/Ω induces ions micro-oscillations. The RF field is known to form a dynamic potential well with effective potential D = qE²/mQ², where E is local strength of electric field, q and m are charge and mass of ions. The quadrupolar dynamic potential well is known to be quadratic D = Do*(X²+Y²) = Do*r², which provides harmonic "secular" ion oscillations. Those secular oscillations are independent in X and Y directions, they have same oscillation frequencies F in both directions. Frequency F is independent on oscillation amplitudes, on ion beam spatial (dX, dY) and energy (dK) spreads, or in other words, the proposed asymmetric quadupolar open trap 10, 12 and 13 are highly isochronous in regard to secular oscillations in both X and Y-directions. The oscillation period T =l/f is proportional to square root of ion m/q, which is used here for resonant mass separation.

The shown embodiment employs purely two dimensional RF and (optionally) DC fields in X-Y plane and has no electric field in the drift Z-direction. The ion motion in the drift Z- direction is free propagation with number of oscillation cycles depending on an ion injection angle, an energy and their spreads. Alternatively, an end electrodes of the open trap may be set to temporary retarding RF or DC potentials for temporary ion entrapment in the Z-direction with subsequent release of the already mass separated species. The latter method allows more precise control over the separation time, being less dependent on ion beam parameters, however adds the complexity of the cyclic operation.

The side view of the embodiment 12 illustrates the operation principle. A continuous beam of ions is introduced via an aperture 17 at an angle to axis X and ions follow trajectories 19, composed of major secular oscillations 19X in the X-direction and of secular oscillations 19Y in the Y direction, the latter having much smaller amplitude because of the ion injection scheme. The P direction is chosen along the X-axis, and N-direction is chosen along the Y-axis. Ion motion is composed of (a) ion oscillations along the P-axis; (b) transverse oscillations in the N-direction at relatively smaller velocities and amplitudes; and (c) relatively slower ion drift in the Z-direction. Note that alternatively, ions may be injected off-axis, e.g. at X=0 at Y- displacement as shown in the embodiment 13, this way making the oscillation amplitude in X direction being independent on ion mass and energy. The RF field retards ions to the axis along the X direction, while both RF and DC field do confine ions in the Y-direction. As a result, ions experience so-called secular oscillations, being independent in both- X and Y directions, while propagating along the axis Z. Period T(m/z) of secular oscillations is longer than RF signal period 1/ Φ and it depends on m/z. If no AC excitation is applied, ions of all m/z (above cut off m/z in RF field) do pass through the open trap after multiple oscillations. Note that exact ion motion in the P-direction (here coinciding with the X-direction) is composed of micro-motion at RF frequency and of slow secular oscillations. The micro-motion disappears in the origin of quadrupolar field. For this reason, the meaning of ion motion isochronicity in the P -direction (P=X) between X=0 points is the same for both - the exact and the averaged secular motion.

To induce mass filtering properties in the RMS 12, a dipolar AC signal is applied between a pair of electrodes 15 to excite the side ion motion in the Y-direction. Ions of target m/z cross the middle plane periodically at period T(m/z) and frequency f(m/z)=l/T(m/z). In a simplified model, at zero quadrupolar DC, the frequencies of oscillations in Y and X directions are equal. As shown by ion trajectories 19Y in the Y direction, the AC excitation provides side kick, adds ion velocity from the axis and throws ions from dash line trajectory to solid line trajectory with larger oscillation amplitude. However, when ions return back to the middle plane the direction of the excitation gets inverted - ions have larger velocity towards the center. The next side kick, applied in the same direction, returns ions to lower excitation. If choosing AC frequency F=N*f(m/z) with integer N (note that here we consider the case of zero quadrupole DC field), ions of the target m/z pass the AC field region at the same phases of the AC excitation, but at the opposite Y-deflection between adjacent cycles, thus not accumulating the side AC excitation over multiple secular oscillations. Ions of other m/z pass the AC zone at different phases, do accumulate the side AC excitation, get to higher Y-orbits, and get lost on electrodes.

Preferably, the dipolar excitation field is arranged spatially local, as shown in the embodiment 13, where the AC signal is applied to narrow electrode inserts 16. Preferably, the excitation AC field has much higher frequency and is higher harmonics of secular frequency of the selected m/z specie F = N*f(m/z), this way providing sharper differentiation between species with close m/z.

Resonant mass selection depends on secular frequencies of target m/z, which in turn depend on quadrupolar field a and q parameters for target mass ions in the quadrupole. Switching between target m/z values may include adjustment of (a) RF signal amplitude and/or frequency; (b) DC voltage; (c) ion beam energy; and (d) AC signal frequency and amplitude.

In a method, the combination of RF and DC quadrupolar signals may be chosen to transmit a relatively wide - several a.m.u. or several tens of a.m.u. - mass range, similar to operation of conventional analytical quadrupoles, while the AC signal amplitude and frequency may be used to select a sharp band within the transmitted mass range, this way selecting single m/z specie at much higher resolving power compared to conventional analytical quadrupoles.

In another method, multiple narrow mass windows can be filtered out, for example, mass windows corresponding to purely hydrocarbon chemical background and matrix background, while passing through hetero-atomic compounds, like nitrogen, oxygen or halogen containing molecules in GC-MS analyses.

Alternatively, multiple narrow mass windows are transmitted and detected simultaneously, the AC frequency is scanned in a wide range so that the same narrow mass window is transmitted several times during the frequency scan, though in combination with new intermixed windows, and then the normal type mass spectrum is recovered by a decoding algorithm. Details of the decoding algorithm are not described in this application.

In order to improve target m/z selection and transmission, preferably, the continuous ion beam 17 is soft bunched in the axial direction by axial pulsed electric field to compress the ion beam 17 into bunches 19B. Preferably, the axial bunching is arranged for temporal bunch compression in the P-direction with the focal plane, matching the plane of AC deflector 16. Preferably, the period of axial bunching matches the frequency of either the secular frequency of target ions or the frequency of the AC excitation. Preferably, the time shift between the axial bunching pulses and the excitation AC signal may be optimized individually per the selected m/z. Such scheme is likely to remove at least some of the unwanted m/z species. Preferably, the axial energy spread, introduced at axial bunching, is kept low enough to entrap target ions within the RF effective potential well. Also preferably, the energy spread, introduced at axial bunching, is maintained less than 10-20eV, in order to precisely define the ions energy at the subsequent CID cell past the RMS selector, as described below for embodiment 30 of tandem MS-MS.

As shown in subsequent simulations, spatially-local excitation with high frequency AC signals allow separating adjacent mass species n-times faster compared to conventional quadrupoles, where n is the number of the AC harmonics compared to the frequency of ion secular motion. Higher harmonics become possible because of spatially local deflection of the dipolar AC signal, mostly acting in the narrow bridge between electrodes 15. Thus, the asymmetry of the RF resonant separator is expected to improve mass resolution at a given separator length.

The limit to usefully highest AC frequencies (number of AC harmonics) is set by the degree of the electrodes asymmetry. It is understood that RF separator may have only limited asymmetry. Setting electrodes 15 too narrow would be trimming ion beams, and setting electrodes 15 too wide would require non practical RF amplitudes. Accounting the limit on harmonics, it is also expected that the separation improves with number of secular cycles, the latter being proportional to the separation times and ion paths within the separator.

Referring to Fig.2, in order to improve the resolution of mass separation, several embodiments of RF mass separator 21-24 are setup for longer separation times and ion paths.

The embodiment 21 employs temporarily DC biased segments 25 and 26 of the RF resonant separator. Alternatively, pulsed DC bias from generators 28 may be applied to entrance and exit slits 27. Both means can be arranged in ensemble. The pulsed DC bias is expected to lock a portion of continuous ion beam for extending the separation time, thus improving mass resolution. After separation time, the DC bias is removed and separated ions are released at the exit side. The described cycled operation does sacrifice sensitivity and dynamic range, but improves mass resolution of the RF resonant separator 21. The option of "extended separation time" may be switched on and off, either according to the preset scenario in the target analyses, or may be triggered by data in the so-called data dependent analysis strategies.

The embodiment 22 is arranged within an RF separator which is folded into a ring, this way extending the separation path, while providing (a) stability of electrodes with larger perimeter (controlled by precise isolating spacers) and (b) extending the separation path within a compact packaging. The ring may be split for ion injection at the entrance and for ion sampling at the exit.

Further extension of the ion path may be arranged within the embodiment 23 with spiral electrodes. One possible way of making such electrodes precise is splitting ring electrodes and precise spacers and gently distorting the ring to segment of a spiral as shown in the sketch 24.

Obviously, multiple permutations of RF separators of Fig.l and Fig.2 are possible.

Tandem RMS

Referring to Fig.3, a preferred embodiment 30 of the invention comprises a tandem MS, where both MS stages are employing the RF dipolar resonant separator RMS 33 of the earlier described embodiment 10. The embodiment 30 further comprises an ion source 31, either EI, or CI or conditioned glow discharge source for GC-MS analysis, or ICP for elemental analysis, or ESI, APCI, APPI for LC-MS analysis, all set-up for either MS-only or MS-MS analyses. The embodiment 30 further comprises an optional gaseous RF ion guide 32, a collision induced dissociation (CID) cell 34, preferably made as a slit channel ion funnel. Alternative tandems 35, 36 and 39 comprise at least one RMS analyzer 33, a CID cell 34 and either quadrupole analytical quadrupole 36 or TOF MS 38.

In operation, ion source 31 generates a mixture of m/z ion species. Optionally, the ion beam is dampened in the gaseous RF ion guide 32 to reduce the ion beam spatial and energy spreads. Ions are injected either at an angle to Z axis or at X-displacement from the middle plane to induce the secular ion oscillations along trajectories 19. A target parent m/z ions are selected in the first RF dipolar RMS1 by applying a resonant AC deflecting signal to electrodes 16, as described in the embodiment 10.

Because of ion natural energy spread, the transmitted ions are spread in Z-direction between multiple trajectories 19, thus forming an ion flow occupying a ribbon zone, extended along the X-axis. The transmitted m/z band (or multiple bands) enters the CID cell 34, preferably made as an RF channel - a set of slits with alternated RF potential, said slits being extended in the X-direction in order to maximize the ion beam acceptance. Preferably, the ion beam acceptance into the CID cell 34 may be enhanced by a focusing RF or electrostatic ion optics (not shown). The initial injection energy and the potential bias between the RMS1 33 and the CID cell 34 do control the ion energy at the CID entrance. The voltage bias is setup for either soft ion transmission (MS-only regime) or to induce the fragmentation of the selected ions in the CID cell. The CID cell is set up for sufficient length and gas pressure for ion collisional dampening. The dampened beam of fragment ions then enters the RMS2 33 for selecting a target fragment mass. Preferably, the MS-MS tandem 30 employs the method of multiple reaction monitoring MRM for target MS-MS analysis compatible with the upfront chromatographic separation.

To improve the ion selection in the RMS1, preferably, the continuous ion beam is soft bunched in the axial direction, to form ion packets with the energy spread of less than 10-20eV, so that to precisely define the ions energy at subsequent CID cell 34. Note that the ion energy spread in the RMS may be selected higher, as soon as the beam energy does not exceed the height of the RF potential well.

As will be shown at theoretical modeling, the RMS separator is capable of mass resolving power in excess of R=10,000 at close to unity ion transmission. The proposed RMS are expected to provide unprecedented combination of resolution and transmission, thus improving sensitivity and specificity of tandem target analysis. The resolution strongly exceeds R=M resolution of conventional quadrupoles. Transmission of RMS is expected to strongly bypass about 1% transmission of costly magnet sector instruments. The improved resolution allows much higher selectivity at either MSI, or MS2, or both MS stages, this way strongly improving selectivity of tandem MS-MS analysis. When tandem MS is applied for target analysis, both mass separators shall pass a single mass specie without scanning, thus avoiding duty cycle losses. Depending on the application, and as shown in icons 35, 37 and 39, the tandem may employ RMS for at least one stage, while using either lower cost quadrupole or high throughput TOF for other MS stages.

Electrostatic RMS based on sectors

Referring to Fig.4, another preferred embodiment 40 of the invention comprises electrostatic sectors 41 (here, shown as cylindrical sectors, though torroidal topology remains an option), separated by a field-free space 42, and a set of deflectors 43. Optionally, the RMS is preceded or followed by a secondary mass filter, here presented by lens/decelerator 47, analytical quadrupole 48, and collisional cell 49.

In operation, sectors 41 have curvature in the X-Y plane and are extended in the Z- direction to form an open trap, i.e. ions are trapped and focused in the X-Y plane along the mean ion path 45, thus defining curved P-axis as projection of the ion path 45 onto the X-Y plane. Electrostatic sector fields are known to spatially confine ions in the transverse N direction. The two-dimensional field of electrostatic sectors have zero field component in the Z-direction, so ions freely propagate in the Z-direction. Continuous or soft modulated ion beam is passed along the mean path 45 at small angle to the axis P. Ions have Z-component of ion velocity 46, thus making the mean path spiral. Preferably, ions are spatially focused along the mean path 45 in the Z direction by a set of auxiliary electrodes 44, or by a lens field, arranged by electrical biasing of the middle section of deflectors 43, or by a set of periodic einzel or a set of quadrupolar lens (shown for other systems below) thus, defining the number of spiral turns.

Properly designed and tuned sectors are known to provide a first order of time-of-flight focusing with respect to moderate energy, spatial and angular spreads. Preferably, the deflection scheme is arranged for primary deflection in the Z direction for retaining the isochronicity of ion motion in the X-Y plane, along the curved P-axis. Preferably, sectors 41 are tuned for spatial ion focusing at the middle plane (Y=0), being also the plane of deflectors 43. Such tuning improves the isochronicity of ion motion in the X-Y plane in respect to parasitic deflections (occurring in realistic ion deflectors) in the X-Y plane.

The ion motion in the X-Y plane and along P-axis remains substantially isochronous, i.e. the ion oscillation between adjacent time focal points (here located at middle plane) occurs at a period T, wherein the period T remains proportional to the square root of ion m/z and stays independent on moderate excitation and on the moderate ion spatial, angular and energy spreads.

If no deflection is applied, the open trap passes through all the ionic species towards the downstream detector (not shown) or towards the downstream CID cell, similar to arrangement 30. To arrange the mass dependent ion selection, an AC signal is applied to deflector set 43. In the described embodiment, the deflection is arranged in the Z-direction, though may be arranged in the Y-direction as well. In further described simulations, the excitation is provided by a set of periodic quadrupolar lens.

Preferably, to improve RMS resolution per ion path, the excitation signal is a high harmonics of the ion oscillation frequency F=N/T or F=(N+l/2)/T, depending on the RMS field tuning, defining inversion or non inversion of transverse trajectory excitation per ion revolution. Ionic species with target mass m/z experience resonant compensation of the deflection between the adjacent revolutions, and do pass through the RMS. Ions with the adjacent m/z appear off the resonance, they get excited in the Z-direction (or N direction) and hit the deflector 43.

When operating at higher harmonics N, there appears multiple other resonances, i.e. the RMS passes through a multiplicity of other ion species, having masses (m/z)*K*/N, where K and N are integer numbers. To remove unwanted ion species, the ion beam 45 is then focused by lens 47 onto the entrance of crude mass separator 48, here exampled by an analytical quadrupole AQ 48, having mass resolution better than R=N. Preferably, the secondary crude mass separator AQ 48 is then followed by a fragmentation cell CID 49, as part of MS-MS strategy in the embodiments 30, 35, 37 or 39 of Fig.3.

To improve the ion selection in the RMS 40, preferably, the continuous ion beam is soft bunched in the axial direction, to form ion packets with the energy spread of less than 10-30eV, so that to precisely define the ions energy at subsequent CID cell and in order to maintain isochronicity of ion revolutions along the trajectory 45.

Electrostatic RMS based on ion mirrors

Referring to Fig.5, another preferred embodiment 50 of the invention comprises two- dimensional gridless ion mirrors 51, separated by a field free space 52, and a set of spatially periodic quadrupolar lenses 53 (optionally being a set of deflectors. Optionally, the RMS 50 is followed by a secondary mass filter, here presented by lens/decelerator 57, analytical quadrupole 58 and CID collisional cell 59. Two dimensional ion mirrors 51 may be of either planar or cylindrical topology with corresponding drift axis Z being either straight or curved at constant radius, similarly to those described in WO2011086430 and WO2011107836.

In operation, the two gridless ion mirrors 51 do form two regions of electrostatic field in the X-Y plane, being substantially extended in the Z-direction. Ion mirror fields are known to isochronously reflect ions in the X-direction, to provide spatial ion focusing in the Y direction and to generate no field in the Z-direction, thus forming an isochronous open electrostatic trap. Continuous or weakly modulated ion beam is passed along the mean trajectory 55, having Z- component of ion velocity 56, thus forming zigzag ion trajectory 55 within the RMS analyzer 50. P-axis of isochronous oscillations coincides with X-axis. Normal axis N does coincide with Y- axis or Z-axis. Ions of interest either freely propagate along the Z-axis, or they are spatially focused along the mean trajectory 55 in the Z direction by the set of spatially periodic and AC excited quadrupolar lens 53 to resist the natural ion beam divergence. Properly designed and tuned ion mirrors are known to provide second to third order of time-of-flight focusing with respect to moderate energy, spatial and angular spreads, which allows occupying 15-20% of ion mirror window at 5-10% relative energy spread without yet violating ion motion isochronicity at a resolution of up to 100,000. The periodically excited quadrupolar lens 53 provides focusing /defocusing action in both Y and Z directions, depending on the AC phase at the time of ion passage. Optionally, the lens may have a DC bias for continuous confinement of ions in the Z-direction to resist an ion angular divergence.

To understand the principle of resonance mass selection in the embodiment 50, let us consider target ions with particular m/z and with the oscillation frequency f=l/T. For clarity the periodic quadrupolar lens 53 is excited at frequency F=1.5f. Let us assume ion passage through a lens cell with the number j at the AC phase φ (for clarity assumed being defocusing). The defocusing action in the j cell is compensated by the exactly opposite ion focusing in the adjacent j+1 lens cell, occurring at the AC phase φ +90 with exactly opposite AC signal. Then if the system is arranged to withstand a single defocusing, the ionic species with target mass m/z would pass through the entire RMS without significant accumulation for the AC excitation. Ions with the adjacent m/z appear off resonance, get larger defocusing (overfocusing) after multiple excitations with off-resonant phases, and hit electrode walls.

Preferably, to improve RMS resolution per ion path and to increase the transmission of continuous or gently modulated ion beams, the excitation signal is a high (N»l) harmonics F=(N+l/2)f of the ion oscillation frequency f=l/T. However, when operating at high N- harmonics, there appears to be a multitude of other resonances, i.e. the RMS passes through a multiplicity of other ion species, having masses (m/z)*(K+l/2)*/(N+l/2), where K and N are integer numbers. In some methods, the transmission of multiple mass bands is desired for higher throughput. Alternatively, to remove the unwanted ion species, ion beam 55 is then decelerated and spatially focused by lens 57 onto the entrance of analytical quadrupole AQ 57, having mass resolution better than R=N. Yet alternatively, another segment of RMS is employed at different AC frequency. Yet alternatively, at least two-frequency signal is applied, say with N and N-l harmonics.

In a method, the lens block 53 may be used for entrapping ions within the separator for several Z-paths. As an example, outer electrodes of the block 53 may be setup for small angle deflection of ions, this way returning ions back into the analyzer for another through passage. The outer deflectors may be also used (may also be used) for selecting a narrower mass range by proper setting of the deflection times (by properly setting the deflection times). In a method, the entrapping time may controlled for a sequence of injection bunches at 1-lOms time range.

Ion beam frequent bunching

As will be explained in the analytical model below, the resonant selection works for continuous ion beams, regardless of the AC phase at ion arrival. However, some ions of continuous beam hit unfavorable AC phase with temporary maximal AC deflection. To avoid ion losses, the excitation amplitude has to be kept smaller, which then requires larger number of oscillation cycles. Both resolution and transmission of RMS traps notably enhance when continuous ion beam is converted into "soft" and "frequent" ion bunches and when ion bunches are synchronized with resonant excitation at high (N»l) AC harmonics.

Referring to Fig.6, the preferred embodiment of RMS with ion bunching 60 comprises an ion source (not shown), followed by an RF dampening guide 32 for reducing ion beam emittance and energy spread. The embodiment further comprises optional spatially focusing lens 62, an axial buncher 63, optional curved inlet and outlet 66, and an RMS 61. The RMS 61 may be of any above described type: 10, 20-24, 40 or 50. Fig.6 shows electrostatic RMS built of electrostatic ion mirrors 51, separated by a drift space 52 with a set of quadrupolar lenses 53, located in the middle plane of the RMS 61. Similarly to the embodiment 50, the embodiment 60 may further comprise an exit focusing lens 67, a crude mass filter 68, and a CID cell 69. In case of using bright ion sources, like EI or ICP, the crude mass filter 68 may be used upstream of the ion guide 32 to reduce the total ion current of the entire mass range.

Numerical example

In operation and in one numerical example, an ion beam is generated in an ion source of EI, ESI or ICP type (not shown) and is preferably dampened in the gaseous RF ion guide 32 to reduce ion beam diameter to fraction of mm, reduce radial ion energy to nearly thermal and axial energy spread well under leV (dKo<leV). The ion beam is continuously accelerated to an operational energy, say K=500eV, and get spatially focused by a lens 62 into a substantially parallel beam. The expected beam diameter is in the order of 1mm and the expected angular divergence is of few mrad. The axial buncher 63 provides a time-periodic pulsed deceleration (optionally, pulsed acceleration) in order to form ion bunches and to provide temporal ion bunch compression in the middle plane of the RMS. At K=500eV ion energy and m/z=100, the ion velocity is approximately 30mm/us. Let us choose the buncher length being L=6mm and the bunching pulse period being T=200ns (f=5MHz) to obtain nearly 100% duty cycle of the pulsed conversion for the target lOOamu ions. The bunching pulse amplitude is kept moderate, say 25 V, to limit the buncher induced ion energy spread dK<25eV. This is important for (a) RMS isochronicity and (b) control over ion energy at the CID cell 69. The turn-round time of the ion bunch may be calculated as dT<8ns, since pulsed modulation conserves the product of time and energy spreads, i.e. dKo*T= dK*dT (leV*200ns = 25eV*8ns) as been described in WO2015153630. It is preferable to use the buncher 63 with pulsed deceleration in order to move the imaginary time focal plane upstream of the buncher at focal distance FD=2L*K/dK=240mm. The next focal plane is formed past the isochronous curved inlet 66, since the combination of field-free region and sector 66 is known to provide time-of-flight focusing, where field free region is extended by the focal distance FD. Parameters of buncher 63 and of curved inlet 66 are chosen to move the next time-focal plane to match the middle plane of RMS, where the lens 53 is placed. The isochronous analyzer then refocuses ion packets every time they cross the middle plane. In this numerical example, let us assume an effective flight path per ion reflection being 300mm. Ions of lOOamu at 500eV energy and 30mm/us velocity will make single reflection in lOus. The excitation AC signal, either sinusoidal or pulsed, is applied at frequency of the axial buncher, i.e. at every 200ns, i.e. at F=5MHz and N=50 harmonics. Preferably, the buncher 63 and curved inlet 66 are tuned so that the target m/z species pass the center of lens 53 at zero excitation signal at every ion mirror reflection. The adjacent m/z species will have slightly different reflection period and will hit at least some of lens 53 at an unfavorable time, thus being defocused or over-focused from the mean ion path 65.

Assuming ultra-thin spatial resolution of lens 53, (possibly achieved when switching around 0 phase at high AC amplitude) the ultimate time resolution of the selecting scheme can be estimated as the ratio of total flight time per the time spread of ion packets. To reach the desired 10,000 mass resolution, i.e. 20,000 time resolution, the total flight time has to be over 200us, total flight path about 6m, corresponding to approximately 20 ion mirror reflections. The conclusion is supported by the below simulations in simplified model of Fig.7 with ultra-thin deflection, which suggest unity ion transmission at 10,000 resolution of the RMS 61.

More accurate simulations further illustrated in Fig.14 suggest that RMS resolution is also limited by the spatial resolution of quadrupolar lens 53. At 1mm ion beam diameter, and X- length of lens field being 4mm, the spatial resolution of lens 53 appears to be sharpened to about 1.5mm. The sharpening appears possible when selected ion bunches pass the center of the lens 53 at zero phase and the excitations at the entrance and the exit are mutually compensated. Then to reach mass resolution R= 10,000 and time resolution 20,000, the total ion path has to be about 30m, which is reachable within reasonably compact instrument with cap-cap distance 300mm at 100 mirror reflections. If arranging an end-lens ion reflection in the Z-direction, the number of lenses in the block 53 can be reduced to 50, which corresponds to analyzer width Z=200mm at dZ=4mm lens pitch, i.e. the size of RMS chamber may be comparable to those of analytical quadrupoles. The throughput of the suggested RMS 60 is estimated over 1E+9 ion/s at AC frequency (and bunching frequency) in multi-MHz range and assuming tolerance of multi-reflecting analyzer being over 300 ions/packet. If using sector RMS of Fig.4, the analyzer tolerance approaches 1E+4 ions/packet and the RMS throughput is expected being over lE+10 ion/s.

Simple model for resonant ion selection in open traps

Referring to Fig.7, to understand the nature of the resonant ion selection let us explore a simplified model 70 of an RMS built of electrostatic ion mirrors.

The model system 70 comprises two ion mirrors 71, separated by a 2D long drift space 72, and an ideal thin deflector 73. Each ion mirror 71 is approximated by an ultra-thin spatially focusing lens 74 and a dual stage ion mirror 75. Action of the focusing lens 74 is approximated by ion steering at an angle ΔΑ proportional to Y off-axis displacement: ΔΑ= -Y/F, where F is the focal length. In some calculations, the lens focusing accounts the spherical aberration Sy: ΔΑ= - Y/F - Sy*Y³. Solid line 72 shows an exemplar ion trajectory at full turn (two mirror reflections). Focusing by lens 74 and reflection by mirror 75 do inverse the Y-displacement after one mirror reflection and restores the Y displacement after full turn. The dashed line shows an exemplar ion trajectory after deflection at angle ΔΑ within the deflector 73; both Y displacement and deflection angle are inversed after single reflection. If resonant signal is applied in phase, after second deflection the trajectory returns back to parallel trajectory. The example presents very basic explanation for resonant separation: for ions with m/z of interest, getting into time resonance, the adjacent excitations are compensated. Following ion trajectories may be easier if hypothetically straightening the reflected trajectories into a number of repetitive cells 78, as shown in the scheme 77.

Isochronous properties of ion mirror 75 are modeled with an ideal dual-stage grid- covered mirror 75, where the first gap is infinitively short and has potential drop of 2/3 vs mean ion energy. Such mirrors provide the second-order time per energy focusing, being sufficient for R=100,000 with account of small (10 to 50eV) energy spread compared to mean energy (IkeV). Time-energy diagram 76 presents the flight time Vs ion energy for mean ion energy K=lkeV, m/z=100amu, and D=l 12mm.

The model deflector 73 is assumed infinitively thin. When applying dipolar sinus excitation, the deflector causes the ions deflection at the angle ΔΑ(ΐ) = Α*8ΐη(2πωΝΐ/Το), where Ao is the deflection amplitude in radians, N- is the harmonics number, t- is the time, and To is the oscillation period for target ions with m/z₀.

Referring to Fig.8, the model has been used to calculate the dynamics of resonant excitation in the course of multiple ion deflections at sinusoidal oscillation ΔΑ(ΐ) = A*sin(2:n;Nt/To) on the central deflector 73, where N is the number of harmonics relative to the frequency of target ion oscillations 1/To and A is the angular amplitude of the deflection. A probe ion with initial displacement Yo=lmm and with initial angle Ao=2deg was starting at t=0. Simulations were following the ion displacement Y at deflector plane Vs number of mirror reflections (also called cycles) at excitation amplitude A = 3 deg. Results are presented for odd (A, B) and even (C, D) harmonics. The comparison is made between exact resonant M/Zo ions (A, C) and ions different by 1/10,000 mass defect (B, D), i.e. of 1.0001 * /Z₀. Model parameters are shown in the icon of Fig.8A.

With odd high harmonics (exampled here by N=101) one can keep target ions at stable trajectories (A) at moderate Y displacement |Y| < 2.5mm, while exciting and removing closely spaced 1.0001 *m/z ions during approximately n=10-15 oscillation cycles (B) by setting a limiting aperture at Y=3mm. With even harmonics, here presented with N=100, the target m/z ions also remain stable (C), while closely spaced neighbors at m/z*(1.0001) get excited and removed at notably larger (n=20-50) number of oscillation cycles (D).

Dynamics of resonant excitation does depend on the strength of the lens focusing, which changes the system resistance to the excitation, so as inversion and amplification of the excitation between ion reflections. Referring to Fig.9, similar (as Fig.8) simulations were made for the strongest possible lens with focal length F=l 13mm (ion motion gets unstable at F<D) and larger excitation amplitude A=6deg. Figures 9-A and 9-B present dynamics of ion displacement for odd harmonics N=101, and Fig.9-C and 9-D - even harmonics at N=100 for target m/z and neighbor ions different by 0.0001 *m/z. When using odd harmonics (N=101) the setup with strongest lens allows much faster separation between close m/z species, and also allows wide ion beam emittances at the same level of separations. However, for even harmonics (N=100), neighbor masses remain stable.

Referring to Fig.10, there are presented results of simulating the ion mass separation in the model RMS 70. Ion packets are modeled at 5mm diameter, 2 degree full angular divergence, and 20eV energy spread on the top of IkeV mean energy. The ion packets are assumed to be time compressed (bunched) to 10ns pulsed packets. The excitation is applied with period 0.6us being equal to oscillation period of m/z=l . Results of the simulations are presented in the plot of ion packet transmission Vs square root of ion m/z. Plots 101-104 show the progression of transmitted spectra with growth of excitation amplitude A from 0.1 deg to 3 deg. At small amplitude of A=0.1deg (plot 101) there are appear narrow notches of rejected mass bands corresponding to resonant accumulation of ion excitation in multiple excitation periods. At larger amplitudes the notches become wider, as shown in plot 102 for A=0.3deg. At yet larger amplitudes, spectra are formed of relatively narrow transmitted bands, as shown in the plot 103 at A=ldeg. At some optimal large amplitude, here A=3deg (plot 104), transmitted even mass bands become very narrow and off mass bands disappear.

Note that narrow band in plot 104 is fully transmitted at 100%. The effect of full transmission of narrow mass bands was intuitively unexpected. If assuming RMS mechanism as excitation and rejection of species being off resonance, one can expect significant drop in transmission of narrow bands. As we realized in simulations, there appear a novel unexpected effect of resonant stabilization of narrow mass bands.

Also note multiplicity of transmitted mass bands. For ions with m/z=100 (sqrt =10), the excitation corresponds to N=10 harmonics, since period of ion oscillation is 6us for m/z=100, while period of excitation is t=0.6us. However, for m/z=l the excitation corresponds to N=l . Transmission mass bands corresponding to sqrt(m/z) = sqrt(m0/z0)*K/N, where mO/zO is the target mass band (here m0/z0=100), N is the harmonics number for the target m/z (here N=10) and K is integer number of transmitted mass band.

Assuming that side bands could be removed by any crude mass separator with resolution being better than N, for example by a downstream quadrupole separator (e.g. 58 in Fig.5), we would rather be concerned with ion separation in the vicinity of narrow transmission bands. Alternatively, a dual frequency excitation signal may be applied to select a single mass band, say at N and N-l, or N and N+l, or N-l and N+l, which may present a challenge when synchronizing pulsed beam with the excitation, but is expected to work at least in case of continuous ion beams, as described below.

Referring to Fig.ll, the plot shows the mass peak profile after a model separator 70. Parameters of the model RMS are shown in the icon. The model separator 70 has D=l 12mm; the lens 74 is set with focal distance F=113mm; the beam has 3mm diameter and 2 degrees full divergence at IkeV energy; ion beam is time compressed into ion packets with 20eV energy spread and 10ns duration at time focal plane. The excitation signal is applied at 0.3us period corresponding to N=20 harmonics of 6us oscillation period for ions with m/z=100. The excitation amplitude corresponds to O. lrad steering (6 degrees). The separator is setup for 20 oscillations before ions leave the open trap of the RMS.

The RMS mass spectrum of Fig.ll corresponds to mass resolving power of over 10,000 at 92% ion transmission. This is an outstanding result compared to quadrupole separators, where significant ion losses occur at attempts of improving mass resolution over R=100 at m/z=100.

It should be noted that the proposed method of periodic ion beam pulsed bunching introduces an additional complication, wherein the bunching period has to be matched with the period of the excitation signal and the phase of two may have to be adjusted per selected m/z, for example, by tuning pulse amplitude of the pulsed buncher as described in Fig.6.

Remarkably, the RMS 70 does work for continuous ion beams as well, though at a cost of moderate reduction of the transmission.

Referring to Fig.12, (similar to Fig.ll) simulations were done for continuous ion beams

(i.e. without pulsed bunching step) having the same ion beam parameters (5mm diameter, 2 degrees full divergence, 20eV energy spread at IkeV mean energy). The AC excitation period was lus, the number of turns within the RMS 60 was equal to 20 (similar to the pulsed bunching case). The excitation amplitude is varied. Higher AC amplitudes do reduce the ion transmission but improve the resolution. There were also observed narrow and wide transmission bands. The right plot show the compromise between resolution and transmission. To achieve 10,000 resolution, the excitation has to be higher and the transmission drops to 20-30%. The left plot shows how the excitation amplitude is linked with the transmission. SIMION model of sector RMS

Referring to Fig.13, a model RMS 130 is constructed of cylindrical sectors 131 and 132 with different radii, similar to Sakurai et al (Nucl. Instrum. Meth. A427, 1999, 182-186). Cylindrical sectors generate substantially two-dimensional electrostatic field in the X-Y-plane. Ion path 133 is arranged spiral by injecting ion beam (or gently bunched ion packets) at small angle to the X-Y-plane and by confining ions with a set of periodic einzel lens 134 and with periodic quadrupolar lens 135. Ions follow a spiral ion path 133 which is composed of the curved oval mean ion path projection in the X-Y-plane and of relatively slow ion drift in the drift Z- direction. Periodic lens 134 and 135 do confine ion beam along the spiral ion path in spite of moderate ion packet divergence. Parameters of the modeled RMS are: ion trajectory is inscribed into 170x250mm cell, ion path per revolution is 700mm, Z-length is 200mm to fit in 40 revolutions, forming overall L=28m total flight path. Sectors are energized to pass 6keV ion beams, so that target mass at m/z=1000 pass single revolution in To= 20us and through the RMS in 800us. Ion beam parameters are: 1mm beam diameter, 4mrad angular divergence, and FWHM = 20eV energy spread (Gauss distribution), which is excessive compared to ion beam emittance which could be obtained past gaseous RF guides.

If no AC excitation is applied, ions of lOOOamu do pass through the RMS without losses. The AC excitation

is then applied to quadrupolar lens 135, having 4mm aperture and 4mm effective length, accounting fringing fields. When AC signal is applied, the separator does filter multiple m/z bands, whose shape depends on the AC amplitude Vo and frequency F=(N+l/2)/To.

Referring to Fig.14, there are presented graphs of ion transmission Vs excitation AC frequency for two cases - for pulsed ion packets (graphs 141 and 144) and for continuous ion beam (graph 1445). AC signal is applied to quadrupolar lens 135 of RMS analyzer 130. The AC frequency is scanned in the vicinity of N=10.5 and N=60.5, where N=l corresponds to F=4.98MHz frequency for m/z=1000 ions. The transmission band corresponds to non integer N to compensate focusing/defocusing action of adjacent lens cells. To obtain the effect of resonant stabilization, ions have to arrive to adjacent lens cells at opposite phase.

Graph 141 shows the shape of transmitted band Vs excitation AC frequency for m/z=1000 in the vicinity of N=10.5 for the case of pulsed ion packets at initial AC phase φο=0. The ion packet X-length is 0.35mm corresponding to ion packet duration 10ns. Curve 142 corresponds to V=500V amplitude of quadrupolar excitation. Transmission over 80% is obtained at 15,000 frequency resolution, corresponding to mass resolution R=7,500. Curve 143 corresponds to V=700V amplitude of quadrupolar excitation. Transmission over 60% is obtained at 20,000 frequency resolution, corresponding to mass resolution R=10,000. Yet higher amplitudes provide moderate improvement of resolution, while causing rapid drop of the transmission. The resolution of RMS does not improve by further shortening of ion packets, since it is primarily limited by spatial resolution of the quadrupolar lens 135. Relative to simple model in Fig.7, the SIMION model of Fig.13 has clarified one limiting factor onto the resolution: R<L/2AX, where L - is total flight path and ΔΧ - is spatial resolution of exciting quadrupolar lens. In present model, L=28m and AX=1.4mm at 4mm X-length of quadrupolar lens, which allows reaching R=10,000. However, we believe that switching the sign of the excitation at ion passage through the lens center may allow yet sharper spatial resolution of the excitation lens if using (a) pulsed excitation and (b) stronger spatial ion focusing in periodic lenses and in the analyzer and (c) yet more compact quadrupolar lens.

Graph 144 shows the shape of transmitted band Vs excitation AC frequency for m/z=1000 in the vicinity of notably higher N=60.5 harmonics for the case of pulsed ion packets at initial AC phase φο=0. The ion packet X-length is 0.35mm corresponding to ion packet duration 10ns. Using higher harmonics improves space charge tolerance, allows using notably smaller AC amplitudes (here 150V) and has moderate negative effect onto resolution (R=8,500).

Graph 145 shows the shape of transmitted band Vs excitation AC frequency for m/z=1000 in the vicinity of N=60.5 and AC amplitude of 150V (similar to curve 144), but now for the case of continuous ion beam. In simulations, the continuous beam has been modeled as a sum of ion packets with full range of initial AC phases -90°< φο<90°. The overall transmission (averaged over all phases) drops to 12% and the resolution drops to 4500, though lower than for bunched ion packets, but still being notably better than results obtained in analytical quadrupoles and magnet sectors.

Up to our knowledge resonant separation of continuous ion beams has never been considered in prior art. Though the beam does not have any time marks or ion packets, it can be separated based on time-of-flight principles of isochronous motion in combination with resonant excitation or resonant stabilization. Multi-parent MS-MS scan

Referring back to Fig.10, and according to simulations, an electrostatic RMS may be adjusted to transmit multiple mass windows with m/z = (mO/zO)*K²/N² or m/z = (m0/z0)* [(K+0.5)/(N+0.5)]², where N=l,2,3..., i.e. integer number of harmonics. The proposed method of tandem MS-MS analysis capitalizes on higher throughput at setting multiple parent mass transmission window and on the scanning of the window multiplicity by scanning AC frequency of the excitation signal.

Now referring to Fig.15, tandem MS-MS 150 of the present invention comprises an RMS parent mass separator 151, fed by AC excitation signal 152, a fragmentation CID cell 153, a pulsed converter 154 and a time-of-flight mass spectrometer TOF MS 156 for analysis of fragment ions. RMS 151 may be of any above described type, either a dipolar RF RMS 10, 20- 24, or sector based spiral electrostatic open trap 40 or ion mirror based multi-reflecting electrostatic open trap 50. Exemplar TOF MS 156 comprises a pair of gridless ion mirrors 51, separated by a field free space 52, periodic lens 58, and a detector 59. As shown by icon 155, preferably, pulsed converter 154 is operated with method of frequent encoded pulsing, as described in US8853623.

The main principle of the proposed MS-MS method is visualized on the icon 157, schematically showing a set of transmitted parent ion mass windows. The RMS 151 is arranged for transmission of multiple parent ion windows at moderate to high resolving power in the order from 3,000 to 10,000. Transmission of multiple windows dramatically improves the sensitivity and the throughput of the analysis. During the AC frequency scan, any individual parent specie will be transmitted multiple times at predictable times - with a linear AC frequency scan the signal will be repeated at equal time intervals. The set of simultaneously transmitted mass windows are spread non linearly in mass, which reduces number of simultaneously admitted parents and reduces a probability of forming same fragment ion mass by the set of simultaneously transmitted parents. Any confusing spectral overlap (in fragment spectra) between any particular pair of simultaneously admitted parent ions could be resolved, since the same parents will be repeated again but in combination with yet another set of other parent ions. In other words, since transmitted windows are linear progression of sqrt(m/z), at AC frequency scan, the same pair of parent ions will not be repeated systematically.

Similarly, a single MS spectrum may be acquired for multiple transmitted mass bands, where normal mass spectra may be recovered by spectral decoding after AC scan, since through the AC scan, the same parent ion appears multiple times, though every time in combination with other set of transmitted bands.

Differentiation with prior art and inventive steps

Prior art separators of continuous beam (magnet sector MS or analytical quadrupoles) do operate within statically set DC or RF fields, where present invention employs resonant excitation, i.e. different principle of ion separation.

Prior art ion traps (RF or electrostatic) employ resonant excitation for mass separation. However, they trap ions, which severely restrict the space charge capacity and the charge throughput. Present invention solves the problem of space charge throughput by passing continuous or frequently modulated ion beams through open traps.

Prior art RF ion traps (Paul traps or linear quadrupolar RF ion traps) employ resonant excitation of narrow bands, where the selected ions are excited. Present invention provides novel method of resonant separation, where resonant excitation is mutually canceled for ions with m/z of interest, or in other words, the present invention employs a novel principle of resonant stabilization for ions of interest, contrary of previously used method of resonant excitation.

Prior art RF ion traps employ AC signals of equal or lower frequencies compared to frequency of secular ion motion. Prior art RF ion traps employ the excitation field within the entire volume of the trap. Present invention proposes using spatially local excitation fields and using higher harmonics of the excitation field for dramatic acceleration of ion separation at fewer oscillation cycles.

Passing of ions through open trap is first inventive step. Knowledge of prior art will cause the rejection of the approach, since in normal excitation schemes one would expect very low resolution of mass selection. Using local excitation fields and higher harmonics in present invention makes it practical to use resonant selection in open traps.

Passing of continuous or frequently modulated ion beams is the second inventive step, since knowledgeable person would not consider isochronicity or time-of-flight synchronization for continuous ion beams.

Resonant stabilization of narrow mass band is the major inventive step of the present invention. The prior art employs the contrary principle of resonant excitation of ions of interest.

The combination of those three inventive steps allow composing a novel device - resonant mass separator of continuous or gently bunched ion beams, reaching unprecedented combination of resolution, transmission and dynamic range compared to prior art mass separators.

Ion traps of prior art employ resonant ejection of single band. Present invention passes multiple m/z bands. Mass separation of multiple m/z bands is novel. This novelty is linked to intrinsic characteristics and regimes of novel RMS.

Up to our knowledge, the proposed MS and MS-MS apparatus is the first example, wherein multiple ions or multiple parent ions are transmitted simultaneously while selecting ions or parent ions at high resolving power. Compared to sector instruments, proposed RMS are more compact and more economic, provide much higher ion transmission and provide an additional advantage of admitting multiple ionic bands simultaneously.

Up to our knowledge, the proposed method is the unique and novel example of admitting multiple parent windows with non-linear combination of parent m/z.

Although the present invention has been describing with reference to preferred embodiments, it will be apparent to those skilled in the art that various modifications in form and detail may be made without departing from the scope of the present invention as set forth in the accompanying claims.

21

Claims

What we claim is: 1. A method of mass separation, comprising the following steps:

(a) Passing continuous ion beam of multiple ion species through a two-dimensional electric field of an open trap along a folded mean ion path, so that ions experience multiple oscillations (reflections or turns) in said two-dimensional field while drifting in the third orthogonal drift direction;

(b) Arranging said open trap being isochronous between time focus points periodically located along the ion mean path, so that the period T and frequency f=l/T of said oscillations are dependent on ion m/z ratio, but independent on ion spatial, angular and energy spreads to at least first order approximation;

(c) Arranging spatially local regions of excitation electric field around said time focus points along the mean ion trajectory; said excitation field affecting ion trajectories by either deflecting ions off the mean path, or by focusing/defocusing of ion beam, or by accelerating/decelerating the ion beam along the mean ion path;

(d) Energizing said local excitation electric fields with time periodic AC excitation signal at frequency F being higher integer N or half-integer N+l/2 harmonics of the ion oscillation frequency f;

(e) Choosing regime of spatial focusing between said focal points of said open trap, choosing said harmonics N or N+l/2 of the excitation field, and an amplitude of said excitation AC signal so that multiple AC excitations are minimal or mutually canceling and so produce only limited excitation for ions of a particular m/z of interest, leaving them in close vicinity of said mean ion path, while ions of different m/z with oscillation frequency being off resonance with said excitation signal do accumulate larger displacement off mean ion trajectory and get removed by electrodes or stops; and

(f) Receiving ion beam along the mean ion path.

2. A method as in claim 1, wherein said excitation frequency substantially exceeds the ion oscillation frequency corresponding to N»l .

3. A method as in claims 1 or 2, wherein said ion beam is time modulated to provide temporary and spatially compressed ion packets in said regions of spatially local AC excitation field.

4. A method as in claims 1 to 3, wherein said step of arranging electric fields for isochronous oscillating motion comprises one step of the group: (i) arranging an RF dipolar trap with substantially quadrupolar RF fields; (ii) arranging electrostatic field of multi-turn sector analyzers with spiral ion trajectories; and (iii) arranging electrostatic fields of mirror based multi- reflecting TOF mass analyzers with zigzag ion trajectories.

5. A method as in claims 1 to 4, wherein said ion drift motion in the Z-direction is one of the group: (i) free propagation at variable number of oscillation cycles; (ii) a controlled Z-motion defined by spatially-periodic electric fields in the Z-direction to provide fixed number of oscillations through the open trap; and (iii) temporal ion entrapment in the Z-direction with subsequent release of mass separated species.

6. A method of tandem mass spectrometry analysis, comprising a method as in claim 1 to 5 for at least one stage of mass selection.

7. A method as in claim 6, further comprising a step of transmitting a set of multiple mass windows and a step of scanning the frequency of said AC excitation for scanning said set of multiple mass windows.

8. A method as in claims 1 to 6, further comprising an additional step of crude mass selection with resolution, sufficient to distinguish between multiple transmitted mass windows at high AC harmonics for the purpose of selecting a single m/z specie.

9. A method as in claims 1 to 8, wherein said two dimensional electric field of open trap is either of planar or cylindrical topology with corresponding straight or bent at constant radius axes Z.

10. A resonant mass separator, comprising:

(a) An ion source, generating continuous ion beam of multiple ion species;

(b) An isochronous multi-pass open trap built of gridless electrodes, extended along a Z- axis to form two-dimensional electric fields in X-Y plane being orthogonal to said Z-axis; shape and potentials of said open trap are arranged to provide periodic and isochronous ion oscillations (turns or reflections) along a mean ion path P in said X-Y plane; wherein the oscillation period along said ion path and between spatially periodic focusing points is at least first-order independent on ion spatial and energy spreads, but is dependent on ion mass to charge ratio m/z;

(c) Means for injecting said ion beam into said isochronous open trap to provide energetic ion motion along said ion path in said X-Y plane, combined with relatively slower ion drift in said Z-direction;

(d) At least one AC excitation electrode, arranged for providing multiple substantially local regions of excitation electric field around said focal points, deviating said ion beam off the mean ion path;

(e) A generator of a periodic AC excitation signal, applied to said at least one electrode at excitation period being substantially shorter compared to said oscillation period; and

(f) A receiver of mass selected ions.

11. A mass separator as in claim 10, wherein said open trap is one of the group: (a) an RF dipolar trap with substantially quadrupolar RF fields; (b) a multi-turn electrostatic sector analyzer with spiral ion trajectories; and (c) a mirror based electrostatic multi-reflecting TOF mass analyzers with zigzag ion trajectories.

12. A mass separator as in claim 10 or 11, wherein said open trap further comprises one set of means for spatial ion confinement in the drift Z-direction of the group: (i) local spatial modulation in the Z-direction of electrodes of said open trap; (ii) a set of spatially periodic einzel lens in a field free region of said open trap; (iii) a set of quadrupolar lens in field free region of said open trap; and (iv) an Z-end deflector for trapping ions for a fixed time period.

13. A mass separator as in claim 10 to 12, further comprising a pulsed accelerating modulator after said ion source for temporary ion packet compression in said AC excitation regions.

14. A mass separator as in claim 10 to 13, further comprising an additional crude mass selector between said ion source and said ion receiver.

15. A mass separator as in claim 12 to 14, wherein said at least one AC excitation electrode comprises one of the group: (i) a pair of deflecting electrodes extended along said Z-axis; (ii) a set of deflectors; (iii) a set of periodic einzel lens; (iv) a set of quadrupolar lens.

16. A tandem mass spectrometer, comprising a mass separator as in claim 10 to 15 for at least one stage of mass selection.