Fast linear ac controller for mass spectrometry

Abstract

Disclosed are methods, systems, apparatus, devices, and other implementations, including a method of operating a mass spectrometry system that includes applying a first AC voltage pulse cycle, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, with the waveform including a ramp-down portion. The method further includes obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, comparing the amplitude value with a predefined amplitude setpoint, and adjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

Description

FAST LINEAR AC CONTROLLERRelated Applications

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 739,327 filed on December 27, 2024, the contents of which is incorporated herein by reference in its entirety.Technical Field

[0002] The present disclosure relates generally to systems and methods for operating a mass spectrometry system, and more particularly to a fast AC linear controller configured to controllably apply pulsed AC waveforms to electrodes of ion traps and / or ion guides of the mass spectrometry system.Background

[0003] The present disclosure relates generally to methods and systems for controllably generating and applying pulsed AC waveform that allows for an increased number of pulses per unit time (i.e., increased frequency), and more stable waveform characteristics (e.g., fewer warping artifacts resulting from controllers’ general bandwidth limits).

[0004] Mass spectrometry (MS) is an analytical technique for determining the structures and characteristics of test chemical substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the composition of atomic elements in a molecule, determining the structure of a compound by observing its fragmentation, and quantifying the amount of a particular chemical compound in a mixed sample. Mass spectrometers detect chemical entities as ions such that a conversion of the analytes to charged ions must occur.

[0005] In some MS systems, ion traps are employed for enhancing the functionality of the mass spectrometric systems. For example, in some applications, ions trapped within an ion trap can be ejected from the ion trap according to decreasing or increasing m / z ratios of ions. Such mass selective ejection of the ions can provide certain advantages, e.g., it can allow for selectivedetection of ions, enhanced sensitivity, among etc. The functionality and sensitivity of MS systems can also be improved through application of pulsed AC voltage waveforms to cause release of multiple batches or pulses of ions, thus resulting in multiple ion detection cycles over some particular time period, which in turn improves the detection sensitivity of the MS system.

[0006] Application of pulsed AC waveforms presents AC control challenges that can limit the performance of the MS system. For example, conventional AC voltage controllers have limited bandwidth, which limits the numbers of pulses (also referred to as “pulse cycles”) per unit of time.Summary

[0007] In one aspect, a method of operating a mass spectrometry system is disclosed that includes applying a first AC voltage pulse from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, with the waveform including a ramp-down portion, obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, and comparing the amplitude value with a predefined amplitude setpoint. The method further includes adjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

[0008] In some embodiments, obtaining the amplitude value of the first voltage pulse can include obtaining one or more voltage amplitude measurements during the stabilized portion of the first voltage pulse cycle, and deriving the amplitude value based on the obtained one or more voltage measurements.

[0009] In some embodiments, obtaining one or more voltage amplitude measurements can include obtaining one or more voltage samples from the resultant voltage signal, and calculating the amplitude value based on the one or more voltage samples obtained from the resultant voltage signal.

[0010] In some embodiments, obtaining the one or more voltage amplitude measurements can include obtaining at least one of said one or more amplitude measurements at a time instant computed based on system latency related to application of one or more voltage pulses from theplurality of AC voltage pulses to the at least one electrode of the mass spectrometer, with the time instance computed preceding the ramp-down portion of the first voltage pulse..

[0011] In some embodiments, obtaining said one or more voltage amplitude measurements can include determining a feedback voltage produced from said AC voltage pulse applied to the at least one electrode.

[0012] In some embodiments, the method can further include determining an error value as a difference between the feedback voltage and the predefined amplitude setpoint, storing the error value in a memory element, and adjusting a gain of the second AC voltage pulse based on the stored error value.

[0013] In some embodiments, for an initial voltage pulse preceding the first voltage pulse cycle, storing the error value in the memory element can include storing an initial pre-determined error value.

[0014] In some embodiments, for an initial voltage pulse preceding the first voltage pulse cycle, adjusting the waveform can be based on a default gain value.

[0015] In some embodiments, applying the first voltage pulse can include applying the first voltage pulse in an open loop mode.

[0016] In some embodiments, adjusting the waveform for the second voltage pulse can include scaling a gain profile associated with said waveform based on the difference between the amplitude value obtained from the resultant voltage signal during the first voltage pulse cycle, and the predefined amplitude setpoint.

[0017] In some embodiments, the method can further include applying the waveform for the second AC voltage pulse cycle, scaled using the updated gain profile, in the open loop mode.

[0018] In some embodiments, applying the plurality of voltage pulses to the at least one electrode can include applying the plurality of voltage pulses to the at least one electrode to cause, during the ramp-down portion, groups of ions in an ion trap to be ejected from an output of the ion trap to a downstream component of the mass spectrometer system according to a decreasing order of m / z values respectively associated with the groups of ions.

[0019] In some embodiments, the ion trap can include a Zeno ion trap.

[0020] In another aspect, a mass spectrometry (MS) system is provided that includes an ion source, an ion trap, including at least one electrode, from which at least some ions in the ion trap are ejected to a downstream component of the MS system, a mass analyzer located downstream of the ion trap to analyze one or more ions resulting from the at least some ions ejected from the ion trap, an AC power source, and a hybrid open-loop / closed loop controller to control AC voltage applied to the at least one electrode. The controller is configured to control the AC power source to apply a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to the at least one electrode, with the waveform including a ramp-down portion, obtain an amplitude value of a resultant voltage signal produced from a first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, compare the amplitude value with a predefined amplitude setpoint, and adjust the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

[0021] In some embodiments, the controller configured to apply the plurality of voltage pulses to the at least one electrode may be configured to apply the plurality of pulses to the at least one electrode to cause, during the ramp-down portion, groups of ions from the ion trap to be ejected from an output of the ion trap to a downstream component according to mass values respectively associated with the groups of ions.

[0022] In some embodiments, the controller configured to apply the plurality of voltage pulses can be configured to apply the plurality of pulses to the at least one electrode to cause, during the ramp-down portion, groups of ions from the ion trap to be ejected from the output of the ion trap to the downstream component according to a decreasing order of m / z values respectively associated with the groups of ions.

[0023] In some embodiments, the controller configured to adjust the waveform for the second voltage pulse can be configured to scale a gain profile associated with said waveform based on the difference between the amplitude value obtained from the resultant voltage signal during the first voltage pulse cycle, and the predefined amplitude setpoint.

[0024] In some embodiments, the controller configured to obtain the amplitude value of the first voltage pulse can be configured to obtain one or more voltage amplitude measurementsduring the stabilized portion of the first voltage pulse cycle, and derive the amplitude value based on the obtained one or more voltage measurements.

[0025] In some embodiments, the controller configured to obtain one or more voltage amplitude measurements can be configured to obtain one or more voltage samples from the resultant voltage signal, and calculate the amplitude value based on the one or more voltage samples obtained from the resultant voltage signal.

[0026] In a further aspect, a method of operating a mass spectrometry system is disclosed that includes applying a first AC voltage pulse, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform, and comparing the amplitude value with a predefined amplitude setpoint, and adjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

[0027] Yet another aspect of the present disclosure relates to a repeatable waveform for a sinusoidal signal, with the waveform either having the same amplitude or having a predefined pattern with which such amplitude is changed, with at least one portion of the waveform being suitable for the RF level measurement. This aspect further relates to performing the RF level measurement, and utilizing the measurement for gain correction for the next period of the sinusoidal signal with the repeatable waveform. Thus, this other aspect includes an AC voltage controller including a memory storage device to store a waveform profile comprising at least one stable portion during which AC level measurements can be performed, and control circuitry to control AC voltages applied to at least one electrode. The control circuitry is configured to control an AC power source to produce a resultant voltage signal with a repeatable waveform, with the resultant voltage signal including multiple pulses with voltage waveforms produced based on the waveform profile, measure an amplitude value of a first pulse of the resultant voltage signal produced based on the waveform, during a portion of the first cycle of the resultant voltage signal corresponding to the at least one stable portion of the waveform profile, and perform a gain correction on a subsequent pulse of the resultant voltage signal based on the measured amplitude value of the first pulse.

[0028] It is noted that although the present disclosure focuses on the Zeno AC embodiment, the general approach can be used both for unipolar waveforms (such as used in Zeno) as well as be extended to dual pole RF circuitry commonly used in mass spectrometry, e.g., for ion confinement in ion guides and RF / DC isolation in quadrupole. It also noted that generally the term “AC” is used when talking about Zeno unipolar application, and “RF” when talking about commonly used dual pole configurations. The approaches described herein will in principle work for at least these two embodiments. The approaches described herein can also be used in conjunction with other waveforms (i.e., non-Zeno waveforms).

[0029] Further understanding of various aspects of the present teachings can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below.Brief Description of the Drawings

[0030] FIG. 1 is a schematic diagram of an example mass spectrometry system implementing a fast linear AC voltage control of AC voltage, applied to one or more electrodes, to control ions’ behavior.

[0031] FIG. 2 A is an image of AC voltage waveform that is applied to one or more electrodes using a closed-loop control mechanism.

[0032] FIG. 2B is an image of a distorted Zeno AC voltage signal that is applied to one or more electrodes using a closed-loop control mechanism.

[0033] FIG. 3 is a diagram of circuitry producing an AC voltage signal such as the signal shown in the images of FIGS. 2A-B.

[0034] FIG. 4 is a diagram of an AC voltage control circuitry implementing a hybrid open / closed fast linear AC control approach.

[0035] FIG. 5 includes timing diagrams of AC voltage waveforms, illustrating operation of the AC voltage control circuitry of FIG. 4.

[0036] FIG. 6 is an image comparing the waveforms of pulses produced using the fast linear AC controller, to waveforms of pulses produced using a closed-loop control approach.

[0037] FIG. 7 is an image of a train of pulses produced and maintained using the fast linear AC (hybrid open-closed loop) control approach.

[0038] FIG. 8 is a flowchart of a procedure for operating a mass spectrometer using a hybrid open-closed loop control approach.

[0039] FIG. 9 is a flowchart of another procedure for operating a mass spectrometry system using a hybrid open-closed loop control approach.Detailed Description

[0040] It will be appreciated that for clarity, the following discussion will explicate various aspects of embodiments of the applicant’s teachings, while omitting certain specific details wherever convenient or appropriate to do so. For example, discussion of like or analogous features in alternative embodiments may be somewhat abbreviated. Well-known ideas or concepts may also, for brevity, not be discussed in any great detail. The skilled person will recognize that some embodiments of the applicant’s teachings may not require certain of the specifically described details in every implementation, which are set forth herein only to provide a thorough understanding of the embodiments. Similarly, it will be apparent that the described embodiments may be susceptible to alteration or variation according to common general knowledge without departing from the scope of the disclosure. The following detailed description of embodiments is not to be regarded as limiting the scope of the applicant’s teachings in any manner.

[0041] As used herein, the terms "about" and "substantially equal" refer to variations in a numerical quantity that can occur, for example, through measuring or handling procedures in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of compositions or reagents; and the like. Typically, the terms "about" and "substantially" as used herein means 10% greater or less than the value or range of values stated or the complete condition or state. For instance, a concentration value of about 30% or substantially equal to 30% can mean a concentration between 27% and 33%. The terms alsorefer to variations that would be recognized by one skilled in the art as being equivalent so long as such variations do not encompass known values practiced by the prior art.

[0042] As used herein the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ". Although some aspects have been described in the context of an apparatus, it is clear that these aspects also represent a description of the corresponding method, where a block or device corresponds to a method step or a feature of a method step. Analogously, aspects described in the context of a method step also represent description of a corresponding block or item or feature of a corresponding apparatus. Some or all of the method steps may be executed by (or using) a hardware apparatus, like for example, a processor, a microprocessor, a programmable computer, or an electronic circuit. In some embodiments, some one or more of the most important method steps may be executed by such an apparatus.

[0043] The term “component of a mass spectrometer” refers to a device, unit, section, and / or sub-assembly associated with the mass spectrometer. Some examples of a component of a mass spectrometer can include, without limitation, an ion guide, a mass filter, a mass analyzer, etc.

[0044] The present disclosure is generally related to improved methods, systems, and devices that achieve fast linear control of AC voltages (e.g., pulsed AC voltages) applied to one or more electrodes of various components (e.g., ion guides, ion traps) of an MS system. The application of pulsed AC voltage to electrodes of, for example, ion traps, results in controlled release of groups of ions to a downstream stage (e.g., a mass analyzer, such as one implementing time-of-flight ion detection techniques). For example, the use of Zeno pulsing, in which amplitude of AC voltages applied to the electrodes decreases (e.g., linearly) over the duration of a pulse results in controlled release of groups of ions according to decreasing order of mass or m / z values associated with the different groups. As will be discussed in greater detail below, in the framework implemented herein, control of the amplitude of the AC voltage is achieved through a hybrid open and closed feedback loop. Under the proposed hybrid open / closed feedback control scheme, amplitude of the AC waveform is adjusted once at each cycle based on the difference between amplitude values of the AC voltage applied to the electrode(s) during an earlier cycle and some pre-determined desired AC voltage value. Once adjusted, a second, subsequent,particular cycle or pulse is controlled in an open loop mode according to a pre-determined waveform shape (that had been adjusted earlier in the cycle).

[0045] For example, consider a Zeno AC signal (such as the Zeno AC signals generated by the SCIEX ZenoTOF 7600+™ system) that is a sinewave with a frequency of, for example, approximately 2.5MHz. The amplitude (or envelope) of this signal is a pulsed periodic waveform with a frequency of, for example, 1.5 kHz. In each cycle of the envelope, the AC voltage signal is set to a voltage of about 1400V, then ramped down linearly to 0V over a period of around 140 ps (note that other signal characteristics may be used). When the amplitude of the AC voltage is tracked and maintained at the desired level at all times through a feedback based control system (as is done under some conventional approaches), the closed loop nature of the control system, while ensuring very good control over the amplitude of the AC at all times, places limitations on the speed with which the AC can rise to its desired level of 1400V, and thus on the maximum Zeno AC pulsing frequency. Consequently, a high desired pulsing frequency is difficult to attain using the classical / conventional closed loop control mechanism outlined above, due, in part, to the insufficiently fast AC rise time.

[0046] As will be discussed in greater detail below, the proposed “fast Zeno” framework and approaches described herein aim to achieve improved performance of the MS system by increasing the AC pulsing frequency. In the proposed hybrid open loop / closed loop control approach, the AC waveform amplitude is controlled in open loop mode, by applying the desired waveform shape to the gain input of a gain control element of the signal chain. The AC amplitude is measured before the ramp-down starts, i.e., when the AC is at the flat portion of the current gain (and preferably after any transient behavior following the rise of the signal amplitude to its maximal value has subsided), and is compared to the AC amplitude setpoint. Any error results in scaling adjustment of the amplitude waveform applied to a gain control element during the next AC cycle. The gain scaling does not need to be fast, as it only requires adjustments in order to compensate for slow moving processes (processes such as ambient or circuit component temperature changes). The adjusted gain of the waveform for the next AC cycle is then used to control the AC voltage, without performing error correction on that current AC cycle using a closed feedback control loop (i.e., an open loop control is used for the duration of the next AC cycle). The use of an open loop control approach (model) operating during any one AC cycle facilitates a fast rise time. The gain adjustment process (applied through theclosed loop approach with respect to sequential cycles) ensures the AC voltage amplitude is maintained at the desired value.

[0047] Thus, in some embodiments of the fast linear AC control framework described herein, a mass spectrometry (MS) system is provided that includes an ion source, an ion trap (that includes at least one electrode, e.g., part of a quadrupole electrode set to control behavior of ions traveling through the MS system) from which at least some ions in the ion trap are ejected to a downstream component of the MS system, a mass analyzer located downstream of the ion trap to analyze one or more ions resulting from the at least some ions ejected from the ion trap, an AC power source, and a hybrid open-loop / closed loop controller to control AC voltage applied to the at least one electrode. The controller (implemented using circuitry, processor-based device, and / or software) is configured to control the AC power source to apply a plurality of AC voltage pulses (also referred to as “pulse cycles”) each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, with the waveform including a rampdown portion, obtain (e.g., through measuring and / or calculating operations) an amplitude value of a resultant voltage signal, produced from a first voltage pulse, during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, and compare the amplitude value with a predefined amplitude setpoint. The controller is further configured to adjust the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between the amplitude value and the predefined amplitude setpoint.

[0048] As will be discussed in greater detail below, the hybrid open / closed control mode that is used to control AC voltage applied to electrodes (e.g., of the ion trap, or of other MS system components such as ion guides) facilitates the controlled ejection or displacement of groups of ions (arranged based on their mass or m / z) at improved rates, e.g., shortens the cycles of the AC pulses that are applied to MS system electrodes to control behavior of the groups of ions. It is noted that while the waveform described in relation to the embodiments described herein focuses on a profile that includes a stabilized portion (e.g., a substantially flat portion with a constant voltage amplitude profile following stabilization of transient voltage behavior), followed by a ramp-down portion to cause ejection of ion groups according to their mass or m / z (such a waveform is also referred to as a “Zeno pulse”), the fast linear AC controller implementations described herein may similarly be used with other waveforms having different profiles (a risingwaveform, a triangular waveform, etc.) that achieve other behavioral profiles for the ions traveling in the MS system, as desired.

[0049] Before describing in greater detail the fast linear AC controller implementing a hybrid open / closed control approach, a brief description of an example system in which the hybrid open / closed control approach is implemented is provided. Thus, with reference to FIG. 1, a schematic diagram is provided of an example mass spectrometry (MS) system 100 (e.g., a ZenoTOF 7600 MS system manufactured by Sciex Inc., but other types of MS system can be used) implementing a fast linear AC voltage control of AC voltages applied to one or more electrodes so as to control ions’ behavior in the MS system. In the example of FIG. 1, the fast linear AC voltage controller is implemented with circuitry 182 (only part of the controller’s circuitry is shown in FIG. 1) that may be included within a controller 180 that controls various other components, modules, or sections of the MS system 100. Alternatively, the controller 180 may be implemented as a separate, dedicated controller for voltage control operations of Q2 (whether Q2 is an ion trap or an ion guide) and / or other MS system sections controlling ions’ behavior. Configuration and operation of the fast AC linear controller 182 is discussed further below in relation to the control operations implemented using the controller 180, and also in relation to FIG. 4 describing the particulars of the implementation of a controller such as the controller 180.

[0050] The example of FIG. 1 depicts a multi-sectional mass spectrometry system configuration, which includes an ion trap (marked as section Q2 in FIG. 1), and an ion dissociation (fragmentation) section 150, positioned upstream of Q2, that optionally can implement ion dissociation functionality through, for example, collisions with other particles, such as electrons, neutral molecules, charges molecules, etc.. In the MS system 100 of FIG. 1, the example ion dissociation section 150 illustrated is an electron-capture dissociation (ECD) cell, but other types of fragmentation cells (also referred to as collision cells, may be used). It is noted that Q2 implements, in some embodiments, collision induced dissociation functionality, while the dissociation section 150 implements other types of dissociation. It should also be noted that embodiments of the proposed framework are not restricted to the MS system of FIG. 1 but may be implemented with any type of mass spectrometer, having different upstream sectional configurations (with different electrode set arrangements), and with different types of mass spectrometer analyzers. In some embodiments, the MS system may include fewer sectionsand / or components than those illustrated in FIG. 1 , and / or may include some other components / sections that are not specifically depicted in FIG. 1.

[0051] In various MS systems, such as the MS system 100 of FIG. 1, ion traps are employed for enhancing the functionality of the mass spectrometric systems. For example, in some applications, the trapped ions may have undergone dissociation, e.g., via electron activated dissociation, to generate product ions that can subsequently be released from the trap. As noted, in some applications, the ions trapped within an ion trap can be ejected from the ion trap according to decreasing or increasing m / z ratios of ions (when implementing this type of functionality, the ion trap in this application is referred to as a Zeno trap; other types of traps, implementing other types of mass selective release can additionally or alternatively be implemented by Q2 and / or by additional MS sections. A Zeno trap is generally used with time-of-flight mass analyzers). Such mass selective ejection of the ions can provide certain advantages, e.g., it can allow for selective detection of ions, enhanced sensitivity, among others.

[0052] As depicted in FIG. 1, the MS system 100 includes an ion source 102 for generating a plurality of ions. A variety of ion sources can be employed in the practice of the present teachings. Some examples of suitable ion sources can include, without limitation, an electrospray ionization device, a nebulizer assisted electrospray device, a chemical ionization device, a nebulizer assisted atomization device, a chemical ionization device, an atmospheric pressure chemical ionization (APCI) device, a heated nebulizer device, a thermal desorption ion source, a matrix-assisted laser desorption / ionization (MALDI) ion source, a photoionization device, a laser ionization device, a thermospray ionization device, an inductively coupled plasma (ICP) ion source, a sonic spray ionization device, a glow discharge ion source, and an electron impact ion source, among others. The operation of the ion source 102 can be controlled (e.g., via a processor-based controller such as a controller 180 depicted in FIG. 1) to adjust, for example, the types of compounds (molecules) formed, the charge of those compounds, etc.

[0053] With continued reference to FIG. 1, the generated ions pass through an orifice of an orifice plate 112 to be received by an ion optic QJet sectionl 10, which includes (in some embodiments) four rods (two of which are shown in FIG. 1 ) arranged in a quadrupole configuration to which RF voltages can be controllably applied to generate a quadrupolar electric field in the space between the rods. The Qjet optic can capture and focus the ions using acombination of gas dynamics and radio frequency fields. In some embodiments, the ions produced by the ion source 102 may undergo some initial processing, e.g., ion declustering operations that are performed by a curtain chamber (not shown in FIG. 1 ) positioned upstream of the Qjet section 110. Such a curtain chamber can provide a curtain gas flow (e.g., of N2) to help keep the downstream sections of the MS system clean by declustering and repelling large neutral particles. The curtain chamber can be maintained at an elevated pressure (e.g., a pressure greater than the atmospheric pressure) while the downstream sections of the mass spectrometer can be maintained at one or more selected pressures via evacuation through one or more vacuum pumps (not shown).

[0054] The ions travelling through the Qjet section 110 are transmitted via an ion lens IQ0 122 into an ion guide Q0 120, which includes four rods (two of which are visible in this figure) that are arranged in a quadrupole configuration to form an ion beam for transmission to downstream components of the mass spectrometer. In various embodiments, other multipole configurations, such as a hexapole or an octupole configuration, can be utilized in place of the quadrupole configuration. The ion beam exits the Q0 ion guide 120 and is focused through an ion lens IQ1 132 (optionally with a quadrupole prefilter lens STI 134) into a subsequent ion mass filter QI, which includes four rods (two of which are visible in this figure) that are arranged in a quadrupole configuration and to which RF voltages as well as a DC resolving voltage can be applied for radially focusing the ions and selecting ions having a target m / z ratio (herein referred to as precursor ions) as they pass through the QI mass filter The quadrupole rod set QI can be operated as a conventional transmission RF / DC quadrupole mass filter for selecting ions having an m / z value of interest or m / z values within a range of interest. By way of example, the quadrupole rod set QI can be provided with RF / DC voltages (controlled, for example, by the controller 180) suitable for operation in a mass-resolving mode. For example, parameters of the applied RF and DC voltages can be selected so that QI establishes a transmission window of chosen m / z ratios, such that these ions can traverse QI largely unperturbed. The QI mass filter of FIG. 1 is configured to controllably adjust the RF and DC voltages applied to the electrode set of QI to cause certain ions (with particular m / z ratios) to obtain stable trajectories within the multipole electrode arrangement so that they are guided downstream to the next MS system section. Ions having m / z ratios falling outside the window, however, do not attain stable ion trajectories within the quadrupole and can be prevented from traversing the quadrupole rod setQI. It should be appreciated that this mode of operation is but one possible mode of operation for QI. In this embodiment, the QO ion guide and the QI mass filter may be disposed in differentially pumped vacuum chambers. By way of example, the vacuum chamber of QO 120 can be maintained at a pressure in a range of about 3 to about 12 mTorr, and the vacuum chamber of QI 130 can be maintained at a pressure in a range of about 1 to about 50 pTorr.

[0055] The ions passing through the QI can optionally be focused via a quadrupole pre-filter lens ST2 136 and an ion lens IQ2A into an ECD trap and subsequently into Q2 140. Various fragmentation techniques can be implemented in various fragmentation chambers, such as e.g., Q2 (a collision cell) and electron capture device (ECD) cell 150. In the example embodiment of FIG. 1, the ion trap 144, located at a distal end of Q2 140, is a Zeno trap. In some embodiments, Q2 140 includes multiple rods (such as the rod 142), enclosed within enclosure 143, that are arranged in, for example, a multipole configuration. In some embodiments, the Q2 section may include multiple sequential sets of electrodes, with each set corresponding to different portions of Q2, and with each set arranged according to a respective multipole configuration (e.g., quadrupole, hexapole, or other configuration). Displacement of ions traveling through the ion trap can be controlled through application of RF and DC voltages according to different profiles in a manner that establishes controllable electrical fields between the electrodes that allows controlled movement of the ions. Moreover, the profiles that are applied to various ones of the electrodes (and / or electrode sets, if the ion trap includes multiple electrode sets) can include AC voltage profiles (with respective AC voltage waveforms) that achieve different objectives for controlling the ions. For example, voltage profiles can include accumulation potential profiles, pre-ejection potential profiles, and ejection potential profiles. Each category of profiles can include multiple profiles that are configured for different situations, objectives, and types of ions. For example, ejection profiles can include profiles (such as a Zeno profile, having waveform characteristics such as those illustrated in FIG. 5, more particularly described below) that cause ejection of ions according to their mass or m / z (e.g., in a decreasing order from highest m / z to lowest m / z). When configuring the trap to implement Zeno trapping (e.g., through use of an appropriate voltage profile applied to the electrode set(s) of the Zeno ion trap 144 of Q2) ions with the same ion energy are sequentially released from the trap to downstream sections (including the mass analyzer) of the MS system. Further details about ion traps, and approachesfor controlling such ion traps, are provided in US 7,456,388, entitled “Ion guide for mass spectrometer,” the content of which is incorporated herein by reference in its entirety.

[0056] As will be discussed in greater detail below, the proposed fast linear AC controller (e.g., implemented as the example fast AC linear controller 182 within the controller 180 of FIG.1) facilitates improved performance of the ion trap (whether implemented as a Zeno trap, or as another type of trap that is configured according to associated voltage profiles that control application of AC voltage to the trap’s electrode set(s)) through a hybrid open / closed feedback control of the AC voltage applied to the at least one electrode of the ion trap Q2 140. The hybrid AC voltage control increases the number of cycles per time period (e.g., per second) that can be completed to selectively eject groups of ions, thus improving the number of samples that are available for analysis downstream.

[0057] As can be seen in FIG. 1, in some embodiments, the rods of the ion trap Q2 140 are disposed within an enclosure 144 such that the pressure within the collision cell can be increased relative to the other stages, e.g., via introduction of a gas (e.g., nitrogen or an inert gas) into the enclosure. By using the AC waveforms applied to at least one of the electrodes of the ion trap, ions received at the ion trap can be selectively ejected (selectively extracted) to the downstream MS system section, such as the mass analyzer 160. That is, populations of ions with different m / z ratios (or masses) are selectively extracted based on their m / z ratios (e.g., in a high to low m / z order) or masses. RF signals (e.g., a carrier sinewave signal with a frequency of approximately 5 MHz, modulated with pulses of an AC waveforms having particular, predetermined profiles / characteristics) can be controllably applied to controllably eject ions from the ion trap. Electrodes in the Q2 section can also be used, through controlled application of RF and DC voltages, to radially confine certain ions that are then selectively ejected from the ion trap. It is noted that generally at least two independent RF / AC voltage waveforms are applied to the rods of the Q2 section 140. One RF / AC voltage waveform (termed the “RF voltage”) is used to confine ions in radial direction. This RF voltage is applied to the first set of rods (that includes the rod 142) and typically operates at a frequency of 5MHz. The other RF / AC voltage waveform is the Zeno AC voltage (which can be termed “AC voltage”) is applied to the Zeno trap 144, operates at a frequency of 2.5MHz, and is pulsed (as described in greater detail below) when performing Zeno trapping (or some other type of trapping).

[0058] Another example of an ion trap arrangement that may be used in conjunction with the implementations described herein is one in which ions are trapped in a linear ion trap in a radial pseudopotential well created by a first dipolar RF voltage of a first frequency applied to each opposite pair of rods (of a quadrupole rod arrangement) and an axial pseudopotential well created at least in part by additional RF (AC) voltage of a second frequency that is applied to all four rods (e.g., of a quadrupole rod arrangement) with the same amplitude and phase. The pseudopotential created by the second RF field is mass dependent, and by ramping down the second RF voltage, ions can be released from the trap sequentially from high m / z to low. Further details regarding this ion trapping approach are provided in “A Novel Ion Trap That Enables High Duty Cycle and Wide m / z Range on an Orthogonal Injection TOF Mass Spectrometer” by Alexander V. Loboda et al. (Journal of the American Society for Mass Spectrometry, Volume 20, Issue 7, July 2009, Pages 1342-1348), the content of which is incorporated herein by reference in its entirety.

[0059] In yet another embodiment, instead of ramping down the second RF voltage with the second frequency in any of the embodiments wherein the axial potential well is formed at least in part by said second RF voltage the mass selective release of ions can be facilitated by ramping up the DC voltage difference between the exit lens electrode and the multipole rods forming the linear ion trap, such that trapped ions experience stronger pull towards said exit lens at each subsequent time during the mass selective extraction process.

[0060] Other ion trapping and extraction approaches can also be used in conjunction with implementations of the fast linear AC controller implementations described herein.

[0061] While not shown in FIG. 1, optionally, the Q2 section may also include circuitry to perform ion dissociation. Alternatively, and as illustrated in FIG. 1, a dissociation chamber (also referred to as a collision cell) can be located upstream of the ion trap 144. Precursor ions filtered from the incoming source ions through operation of the upstream mass filter QI (in embodiments that include a mass filter) are received by an ion fragmentation device (also referred to as an ion dissociation device) that causes dissociation of at least a portion of the received precursor ions to generate a first set of a plurality of primary product ions (the first set of product ions) that may have ions with different m / z ratios (spanning an m / z range). Alternatively the ion fragmentation device can be an electron-capture dissociation (ECD) device / cell, electron activateddissociation (EAD) device, or alternatively collision activated dissociation (CAD) device often referred as collision induced dissociation (CID) device. Under the EAD approach, an electron beam is directed at precursor ions (the electron beam may be perpendicular to the path followed by the precursor ions). The interaction of the electron beam and the precursor ions produces product ions. A CID-type fragmentation approach may be implemented by colliding selected accelerated ions with neutral molecules (such as nitrogen) and can be implemented in Q2 device. Other types of ion fragmentation techniques, such as ultraviolet photodissociation (UVPD), infrared photodissociation (IRMPD), electron-induced dissociation (EID), etc., may also be used to implement the fragmentation device.

[0062] Turning back to FIG. 1, ions exiting the ion trap are received, in some embodiments, by a downstream mass analyzer 160 and are separated (e.g., based on their m / z ratios) for detection via an ion detector 162. The Time of flight mass analyzer of the example embodiments of FIG. 1 includes multiple an accelerator, mirrors and liner sections used to guide the ions from the Q2 ion optics towards the detector and separate them based on their flight time. An analysis module (which may be implemented using the controller 180, and / or the terminal 184 of the controller 180) is in communication with the ion detector 182 to receive ion detection signals (e.g., electrical pulses) generated by the ion detector 162, and to process and analyze those signals (e.g., to generate a mass spectrum of the detected ions).

[0063] An RF voltage source 170 and a DC voltage source 172 operating under the control of the controller 180 can apply the requisite RF and DC voltages to various components of the mass spectrometry system 100, including the rods of Qjet, Q0, QI, Q2, and the mass analyzer (and optionally to the ion source 102). In FIG. 1, the electrical connections from the RF supply 170 to the various sections of the MS system are illustrated using dotted lines, whereas the electrical connections from the DC source 172 are illustrated using alternating dots and dashes lines. In some embodiments, the QI mass filter, Q2 (which includes an ion guide portion that includes rods such as the rod 142, and an ion trap portion, such as the Zeno trap described herein), and the mass analyzer 180 may be capacitively coupled to the rods of the Q0 ion guide to receive RF voltages via such capacitive coupling. The RF voltages applied to the rods of the Q0 ion guide, the QI mass filter and the Q2 section provide an electromagnetic field for causing radial confinement of the ions and / or selecting ions with desired m / z ratios to pass through the quadrupole rods. The DC voltage source 172 can apply a DC discriminating voltage to thequadrupole rods of the QI mass filter for selecting ions having m / z ratios of interest. Although only one RF and DC sources are shown in FIG. 1 , multiple RF sources and DC sources may be used in embodiments of the mass spectrometry system 100. For example, each of the various sections of the mass spectrometry system 100 may have its own dedicated RF and DC source (as well as, optionally, a dedicated controller) to implement independent voltage control for each of those sections (e.g., the rods of the Qjet, Q0, QI, Q2, and Q3). In yet further embodiments, some sections of the mass spectrometry system 100 may share a pair of independent RF and DC voltage sources, while the remaining sections of the mass spectrometry system 100 may share one or more other (different) pairs of RF and DC sources.

[0064] As further illustrated in FIG. 1 , the MS system may further include a user-interface 184, that would typically include an input user interface (such as a keyboard, a mouse, dedicated controls and buttons) to interact with the MS system 100 in order to, for example, configure the system, including the controller 180 comprising the fast linear AC controller 182, as needed (e.g., download a new voltage profile to, for example, control ion ejection processes implemented by the ion trap of Q2 (e.g., the ion trap 144 included in Q2 140). The user interface 184 may also include an output user interface (such as a display device), coupled to the controller 180 and / or the analysis module, to receive analysis results and other output produced by the MS system 100.

[0065] As noted, ejection of ions from the ion trap according to some desired order and / or other ejection characteristics may be implemented by controlling the electric field created by application of AC voltage to the electrodes of the ion trap. For example, to achieve sequential release (ejection) of ions from the ion trap according to decreasing m / z values associated with different group of ions, a ramp-down type AC voltage profile is applied to one or more of the electrodes of the ion trap. FIG. 2A is an image 200 produced by an oscilloscope showing an AC voltage waveform that is applied to one or more electrodes of an MS ion trap or an MS ion guide, using closed-loop control circuitry. Briefly, and with reference to FIG. 3, a diagram 300 of circuitry implementing a closed-loop control approach to produce an AC voltage signal such as the signal in the image 200 of FIG. 2A is shown. A digital waveform 304 of the AC voltage signal that is to be generated, is determined at a processor-based device or an FPGA 310 that are part of a AC / DC voltage controller (similar to the controller 180 depicted in FIG. 1). The digital waveform 304 is then converted to an analog voltage signal 306 using a digital-to-analogconverter (DAC). That signal is then amplified by one or more gain stages of an amplifier 342, and then transformed into a high voltage signal using an electromagnetic resonant coil 344 (i.e., of a power transformer).

[0066] The resonant coil 344 that generates the high (kilovolt) level voltage signal is electrically coupled to a feedback loop that includes a voltage divider 350 to produce a reduced amplitude voltage signal from the signal produced by the output of the coil. The reduced amplitude voltage signal is fed back to an analog-to-digital converter (ADC) 354 that converts the feedback voltage signal to a digital domain signal. The digital samples of the feedback voltage signal are used to calculate the amplitude of the feedback that is compared to a setpoint (represented in a baseline waveform profile). In this implementation, the error between the expected waveform amplitude and the actual waveform amplitude are continuously computed, and provided to a PID controller 320 which continuously determines a gain value and continuously corrects the gain value used for the waveform baseline.

[0067] As can be seen from FIG. 2A, a Zeno-type voltage profile includes a rising portion 210 during which the voltage amplitude rises to a certain target value. Once the voltage amplitude reaches its high point (maximal point), the waveform maintains the voltage at that target value (represented by the portion 220) for a period of time. At the end of that time period, the voltage level of the profile ramps down. Because the control mechanism is a closed-loop mechanism, the loop is closed all the time, and consequently the amplitude of the AC voltage applied to the one or more electrodes tracks the intended voltage profile accurately from the very first pulse cycle. This accuracy is achieved because the voltage amplitude level is continuously being tracked, causing the actual amplitude level required by the profile to be quickly adjusted in response to detection of an error (mismatch) between the expected and actual voltage amplitude levels being measured.

[0068] However, the use of the closed-loop control mechanism places limits on how fast the rise time portion of the waveform can be achieved due to bandwidth limits of the control loop. If the rise time portion is shortened (i.e., to speed up how fast the maximal amplitude level can be reached during a pulse cycle) beyond a certain minimal value, the control loop’s bandwidth is exceeded. This, in turn, causes a large overshoot of the voltage when the AC voltage signal comes on, and also results in severe loss of linearity. These effects resulting from trying toshorten the rise time are illustrated in FIG. 2B, providing an oscilloscope image 250 showing a distorted AC voltage signal that is applied to one or more electrodes of an MS ion trap or an MS ion guide. The distorted AC voltage signal includes a voltage amplitude overshoot and a nonlinear voltage level reduction during the ramp down portion of the signal. As a result of these distortions, mass spectrometry application that require a higher number (i.e., higher frequency) of pulses accurately tracking a required pulse voltage cycle profile (e.g., in order to obtain a higher number of analysis cycles executed by the mass analyzer of the MS system) cannot be achieved.

[0069] To achieve faster rise times and increase the frequency of AC voltage pulses while minimizing distortion effects, the proposed hybrid open / closed control approach mechanism is used. The hybrid open / closed loop approach overcomes the limited bandwidth issue by determining the desired AC envelope waveform to be used, scaling the waveform profile once during a cycle to correct for errors between the feedback signal and the expected signal required by the waveform profile, and applying the corrected AC envelope waveform at the AC gain node. Under this approach, the AC error and the corrected gain trim value (to adjust for the AC error) are calculated once during a pulse cycle, typically during the flat, stabilized portion of the AC waveform, at a point where any transient behavior of the current pulse during the flat portion is considered to have settled . The corrected gain trim value is not applied to the current AC voltage pulse cycle, but instead is applied after the current cycle has ended, and before a later cycle (generally the next cycle, although the adjusted gain can be applied at larger pulse intervals) begins. Under this approach, the gain trim value is adjusted iteratively every AC cycle (or once every pre-determined number of cycles, depending on the capabilities of the available hardware implementing the control circuity). Accordingly, this approach results in a closed feedback control as between a first and second cycle (i.e., amplitude of the second cycle depends on an error value computed for the first cycle), but during the actual execution of a pulse no closed-loop feedback control is used to correct the amplitude of the current AC voltage pulse cycle. In other words, a particular cycle is executed in an open-loop mode. With the proposed hybrid open-closed loop approach, the AC level cannot be guaranteed to be accurate when the controlled AC voltage pulse train (be it a Zeno waveform pulse train, or some other AC waveform profile) is turned on. However, applied AC voltage pulses quickly become accurate within a few cycles. Advantageously, since the AC control mechanism is for the most part anopen loop mechanism (except for the one adjustment per cycle part of the mechanism), the control loop bandwidth constraints do not apply. With the hybrid control mechanism, AC rise time is generally limited only by the speed and performance of the hardware being used.

[0070] Thus, the proposed approach includes applying a first AC voltage pulse, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer. For Zeno pulsing implementations, the waveform can include a ramp-down portion, but other waveform profiles can be used. The approach further includes obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, comparing the amplitude value with a predefined amplitude setpoint, and adjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between the amplitude value and the predefined amplitude setpoint.

[0071] Details of the fast linear AC control implementation are discussed with reference to FIG. 4, showing an example diagram of an AC voltage control circuitry 400 implementing a fast linear, hybrid open / closed loop, AC control approach. As shown, the control circuitry 400, which may be similar to the circuitry of the controller 160 depicted in FIG. 1 and which may be part of the controller 180 of FIG. 1 , is configured to control the RF / DC voltages provided to various components of the MS system (including the ion trap 144 of Q2 140). The control circuitry 400 is implemented, in some embodiments, on a field programmable gate array (FPGA) 410, although other types of control circuitry implementations, including processor-based devices, can be used instead of or in conjunction with the FPGA 410. The FPGA 410 includes a PID (proportional-integral-derivative) controller 420 configured to compute an error value between a predefined AC voltage setpoint and a computed amplitude 432 of a digitized feedback signal delivered by a feedback circuit electrically coupling the output AC voltage generated at the output of a power transformer’s coil, to the FPGA circuitry 410. The predefined AC voltage setpoint is stored at a memory element 422 which may be part of the FPGA circuitry 410, or may be at a remote memory device in communication with the FPGA circuitry 410. The predefined AC voltage setpoint represents the desired or expected amplitude level that the feedback signal’s amplitude 432 (e.g., computed by an amplitude calculation module 430 based on the feedback signal) should be at.

[0072] The amplitude calculation module 430 is configured to compute the voltage amplitude of the digitized feedback signal based on one or more digitized feedback signal samples that are obtained (e.g., measured or captured from the feedback signal) either continuously, or at around a particular time instance that generally is at a stabilized portion of the AC voltage waveform preceding the ramp-down portion (e.g., in waveform profiles used to generate Zeno pulsing). The determination of the amplitude of the feedback signal, whether it is determined at a particular time instance(s) during execution of the current cycle, or determined continuously throughout the duration of the current cycle, may be based on one or more voltage samples. The calculation of one amplitude sample generally uses multiple samples of the feedback signal, which are sinusoid values. The amplitude calculation module 430 produces a stream of amplitude samples, and these samples can be used in different ways, e.g., single sample, average, weighted average, etc.

[0073] The amplitude value computed by the amplitude calculation module 430 is compared to the predefined amplitude setpoint stored in memory element 422 to compute a difference or error value that is provided to the PID controller 420. The PID controller 420 computes a gain trim value based on the difference / error value, e.g., according to a proportional, integral, derivative, and / or other computational processes for deriving a gain value. The computed gain trim value is applied to a predefined waveform profile (in this case of a Zeno waveform) stored in memory element 426 (which may be an internal memory element of the PID controller or a memory element on an external device in communication with the PID controller 420) to generate the adjusted waveform of a following pulse (typically the next pulse, but the adjusted waveform can be applied at a later point to a later, subsequent pulse cycle).

[0074] The FPGA 410 may also implement measurement synchronization operations to obtain the amplitude values that are compared to the AC voltage setpoint at time instances when the measurements are considered to be valid (e.g., stable). For example, the amplitude calculation module 430 may be configured to compute or to estimate, in some embodiments, a time instance that corresponds to a settled voltage level during the stabilized portion (e.g., the flat portion of a Zeno waveform) of the waveform. For instance, the amplitude calculation module 430 (or another component of the FPGA circuitry 410, such as the PID controller 420, or some other timing controller not specifically shown in FIG. 4) determines an approximate point on the waveform of the current pulse that is located between the middle of the flat stabilized portion ofthe waveform and the beginning of the ramp-down portion. In some embodiments, the approximate time instance to be determined corresponds to a point just preceding the beginning of the ramp-down portion, e.g., the end 25% part of the total length / duration of the stabilized portion of the waveform.

[0075] Determination of the approximate point where the measurements of the feedback signal (either of the actual analog feedback signal originating from the voltage divider 450 at the output of the coil 444, or the digitized feedback signal produced by the ADC 454 or by the filter 424 located in the FPGA 410) takes place within a particular area of the stabilized portion of a signal can be done in one of several ways. For example, in some embodiments, the amplitude calculation module 430 may be configured to detect the beginning of the flat stabilized portion of the Zeno waveform (or detect some other feature of some other waveform), and determine the approximate point, based on a known approximate duration or length of the flat stabilized portion, at which the amplitude computation should be made. In an alternative example, the point at which amplitude calculation is performed can be determined by computing a latency between the beginning of the AC voltage pulse (e.g., at the output of RF DAC 440), and receipt of the return feedback signal (e.g., at the input or output of the filter 424). The latency can be determined by computing the lag time between the occurrence of a matching feature(s) of the AC voltage waveform and the feedback signal waveform (e.g., determining the beginning of the stabilized portion for both the AC voltage pulse and the digitized feedback signal). Based on the determined latency, and knowing the timing profile of the particular waveform, the point (i.e., time instance) at which the amplitude is to be calculated can be determined. In examples in which the waveform profile is that of a Zeno waveform profile, the features of the profile based on which the latency can be computed may be the end part of the stabilized portion of the waveform profile just preceding the beginning of the ramp down portion of the waveform. Thus, in such examples, the time instances corresponding to the end parts of (say, the end 25% of the stabilized portion) of the voltage signals at (for example) the output of the RF DAC 440 and the output of the filter 424 are used to determine the latency (Tiatency) of the system 400 (e.g., computing the difference between the time instance associated with the identifying features at the output of the filter 424 and the output of the RF DAC 440). Subsequently, the voltage amplitude samples of subsequent pulses can be obtained at time instances computed using the latency Tiatency, and the time instance (exact or approximate) at which the particular feature(s)(such as the end 25% of the stabilized portion) of the AC voltage signals of subsequent pulses occur.

[0076] In operation, a signal generator, such as a sine generator 412, which may be implemented as part of the FPGA 410 or as a separate dedicated module in electrical communication with the FPGA 410, generates a sine signal 402. The sine signal 402 has particular frequency, amplitude, and / or phase characteristics, all of which may be selected, programmed, or otherwise controlled by a user via a user interface (directly or indirectly connected to the sine generator 412). In various embodiments, the sine generator may generate a digital sine wave of a selected frequency (e.g., 2.4675 MHz.) with a selected or default amplitude and / or phase. The sine signal 402 is provided to a signal modulator (multiplier) 414 which modulates the sine signal with scaled base waveform (e.g., a Zeno waveform profile, or any other type of waveform profiles) according to the waveform profile stored in the memory element 426, and the gain trim value that was computed during the previous pulse based on the error between the measured feedback signal and the AC setpoint stored in the memory element 422. The output of modulator 414 is therefore a series of pulses 404a-n of a desired frequency (e.g., 3K-6K Hz, or any other frequency that can be supported by the hardware). As noted, due to the hybrid open-closed control implementation described herein, the waveforms used to modulate the sine wave 402 can have a period (corresponding to particular pulse frequency) that is smaller (an thus have a frequency that is higher) than what can be achieved using a closed-feedback loop control system that continuously tracks and corrects the amplitude of voltage signals that are to be applied to the loads (in this case, electrodes of mass spectrometer sections such as ion traps or ion guides).

[0077] Consider a first pulse 404a from the series (plurality) of pulses 404a-n (this first pulse can be any of the pulses 404a-n, and not necessarily the initial pulse of the series). The first pulse is passed to the RF DAC 440 which converts the input digital pulse to a first analog pulse 406a (from the series of analog pulses 406a-n at the output of the RF DAC 440). An amplifier 442 converts the analog pulse 406a to a first amplified pulse 408a (from the plurality of pulses 408a-n) at a voltage level sufficient to excite a resonant coil 444 that generates high level AC voltage output signals 409a-n with a voltage level (e.g., about 1400 V, in some embodiments) sufficient to operate the electrodes (not shown in FIG. 4) of the mass spectrometer. In some embodiments, the amplifier 442 may be implemented using multiple amplifier componentsarranged in a series configuration. In some embodiments, the amplifier 442 and the RF DAC 440 and the FPGA 410 comprise a voltage controller (also referred to as a voltage exciter). An example of a voltage exciter that may be used in implementations of the AC voltage control circuitry 400 is a QPS exciter module manufactured by Sciex.

[0078] As noted, the output of the resonant coil 444 is provided to one or more electrodes (of one or more mass spectrometer sections). To ensure that the proper voltage level of the AC waveform applied to the electrodes accurately tracks the required waveforms and voltage levels (e.g., Zeno waveform at 1400 V), a feedback line is electrically coupled to a feedback divider 450 (e.g., implemented according to an RC configuration). The feedback line provides voltage signals representative of the output of the coil 444 through a return path comprising a buffer 452 used for buffering the input to an ADC 454, followed by the analog-to-digital converter (ADC) 454. The feedback divider lowers the voltage level of the signal transmitted through the return path to the FPGA 410 The output of the ADC 454, namely the digitized feedback signals 456a-n, are then processed by the FPGA 410 in the manner discussed above to determine an error between the expected voltage signal and the digitized feedback signals (produced based on the AC voltage signals at the output of the coil 444).

[0079] Thus, the first pulse cycle, e.g., the signal 404a at the output of the modulator 414, results, following digital-to-analog conversion and amplification operations, in the AC voltage signal 409a at the output of the coil 444. A feedback signal is then provided to the amplitude calculation module 430 through a feedback path starting at the feedback divider 450, and passing through the buffer 452, the ADC 454, and optionally the filter 424 (which is configured to remove noise and / or perform other pre-processing operations on the digitized signals produced by the ADC 454). In some embodiments, the amplitude calculation module obtains one or more voltage samples from the digitized (and optionally filtered) signal at time instances determined to occur at a part of stabilized portion of the waveform, e.g., the initial flat maximal portion of a Zeno waveform. As noted above, the particular one or more time instances at which voltage amplitudes are calculated can be determined based on various procedures. For example, the amplitude calculation module 430 may be configured (optionally in concert with the filtering operations performed by the filter 424) to identify particular features in the waveform of the feedback signal (e.g., the feature of the stabilized portion of the Zeno waveform) and to then obtain the voltage samples from which the feedback amplitude is derived at particular points ofthe identified features, e.g., the end part of the stabilized region immediately preceding the ramp down portion. Alternatively, the latency (T / afency) between the occurrence of an AC voltage pulse at, for example, the output of the FPGA circuit 410 and the appearance of the feedback signal at the input to the FPGA can be computed at an earlier point. That computed latency is used to synchronize the amplitude calculation module 430 to measure the samples based on when the corresponding AC voltage appears at (for example) the output of the voltage modulator 414. The latency can be taken advantage of to compute the amplitude at a later point than what is shown in Fig. 5. As can be seen in the figure, the flat part of the amplitude waveform extends past that point, due to this latency. This approach can maximize pulse frequency.

[0080] As further noted, having computed the appropriate amplitude value(s) of the feedback signal, the computed amplitude value is compared to the predefined amplitude setpoint (stored in the memory element 422) to derive the error value. The error value is provided to the PID controller 420, which computes a gain trim value based on the error value that is used to scale, using a multiplier 416, the base waveform profile that is to be applied to the sine wave signal 402 to produce a subsequent pulse (be it the immediate next pulse cycle, or a later pulse cycle). However, the gain trim is not applied to the base waveform profile until the current pulse has ended in order to preserve the open loop nature of individual pulse control. In alternative embodiments, the amplitude calculation module 430 may be configured to continuously compute amplitude levels (at some or every one of the samples of the digitized feedback signal) that are used to continuously compute error values. However, in such embodiments, the PID controller may be configured to receive the error values, or to generate the trim value, only at particular time instances of the current cycle (with the particular time instances determined in a manner similar to that described in relation to the amplitude calculation module 430).

[0081] Note that in situations where the initial pulse has not yet been generated or applied (e.g., at start-up of the circuitry 400), the error value that would be used by the PID controller 420 may be a default 0 value, or may be some other initial pre-determined error value (stored in a memory element). Alternatively, in such situations involving the initial pulse cycle, the PID controller 420 may apply a default gain value (stored in a memory element of the PID controller 420, or elsewhere in the FPGA 410) to the waveform profile.

[0082] The operation of the AC voltage control circuitry 400 is further illustrated with respect to the timing diagrams 500, 510, and 520 shown in FIG. 5. The timing diagram 500 illustrates a first pulse 502 formed based on an AC waveform profile, such as the waveform profile stored in the memory element 422. The first pulse may correspond to the resultant digital signal 504a at the output of the voltage modulator 414 of FIG. 4. The timing diagram 510 illustrates a resultant AC waveform that may have been generated at the output of one of the RF DAC 440, the amplifier 442, or the coil 444. For the purpose of the example of FIG. 5, it will be assumed that the signal depicted in the time diagram 510 corresponds to the signals generated at the output of the coil 444. As can be seen, the diagram 510 includes a first AC pulse 512, which may correspond to the AC pulse 406a of FIG. 4 (resulting from the operation of the RF DAC applied to the digital pulse 404a in the present example). As shown, due to the non-ideal nature of electrical components used in the digital-to-analog conversion of the digital voltage signal 502 depicted in the timing diagram 500, as well as any propagation delays, the resultant AC voltage signal 512 includes a non-instantaneous rise-time portion that results in a first latency period between the digital voltage signal 502 and the AC voltage signal 512. That latency period is illustrated as a latency portion 504 in the diagram 500, representing the gain to AC latency period.

[0083] The timing diagram 520 of FIG. 5 illustrates a digitized feedback voltage signal, produced from the AC voltage signal at the output of the coil 444, based on which an amplitude of the digitized signal can be computed (e.g., using the amplitude calculation module 430 of FIG.3). The diagram 520 includes a first digitized pulse 522, which may correspond to the output signal produced by the ADC 454 or by the filter 424 (for the purpose of this example, it will be assumed that the first digitized pulse 522 is produced by the filter 424). As illustrated, the first digitized pulse 522 includes a first latency period 524 (annotated as “AC to amplitude latency”) that is caused by the propagation delay and processing performed by the units / components in the feedback path from the voltage divider 450 to (in this example) the filter 424. The total latency, therefore, created by the AC voltage control circuitry 400 of FIG. 4 includes the illustrated latency periods 504 and 524.

[0084] This total latency (which may be the same as Tiatency discussed in relation to FIG. 4) can be used by the control circuitry (e.g., by the PID controller 420 or the amplitude calculation module 430) to determine the appropriate time instance(s) at which voltage samplemeasurements are to be taken, thus allowing regular voltage measurement synchronization by the circuit 400. In the example of FIG. 5, timing of the voltage sample measurement of the first digitized pulse occurs at time instance 525. This time instance corresponds to a point on the waveform of the first digitized pulse that is about 25% of the length of the stabilized portion. As can be seen from examination of the diagrams 500, 510, and 520, due to the various latencies created in the control circuit 400, the exact points on the different waveforms of the first pulses (502, 512, and 522) corresponding to the time instance 525, are different, the first digitized pulse 522 being measured at a point on its waveform that is farther from the beginning of the ramp down portion than is the case for the other two waveforms (for the first pulses 502 and 512).

[0085] Based on the voltage samples obtained at the time instance 525 from the digitized first pulse 522, the amplitude of the waveform, which is representative of the amplitudes of the waveforms of the first pulses 502 and 512, is calculated. In the example of FIG. 5, comparison of the calculated amplitude to an amplitude setpoint reveals a scaling error in which the current first pulses are at lower amplitudes than they should be at. Accordingly, based on that error value, a controller, such as the PID controller 420 of FIG. 4 determines a scaling correction value (e.g., the “Gain Trim” value in FIG. 4) that is to be applied to the waveform profile for a subsequent pulse cycle. In the example of FIG. 4, the scaling correction value is applied to the waveform profile, by the modulator 416, at the time instance 528 to cause the pulse 506 (and the corresponding pulses 516 and 526 that are produced from the pulse 506) to have an increased amplitude value (as compared to the first pulse 502).

[0086] FIG. 6 is an image 600 produced by an oscilloscope comparing the waveforms of pulses produced using the fast linear AC controller described herein (using the hybrid open-closed control approach) to waveforms formed using a closed-loop control mechanism (as may be implemented using, for example, the control circuitry of FIG. 3). The image 600 shows pulses 610 and 620 produced, respectively, by a closed-loop feedback control mechanism and a hybrid open-closed control mechanism. The pulses shown in FIG. 6 were formed at frequency of approximately 3.5 kHz (i.e., 3600 pulses per second). As can be seen, the pulse 620 has a much faster rise time than the pulse 610, and has a waveform that matches more closely the desired Zeno waveform (with a clear flat stabilized portion, and a substantial linear ramp down portion). In contrast, the pulse 610 does not have a clear flat stabilized portion (instead, its peakapproximates a sinusoidal-shapes peak). Furthermore, the ramp down portion exhibits a slight curved behavior instead of displaying a linear ramp down behavior.

[0087] With reference next to FIG. 7, an image 700, produced by an oscilloscope, of a train of pulses produced and maintained using the hybrid open-closed loop control approach (implemented, for example, using the control circuitry of FIG. 4) is shown. In the example of FIG. 7, with the pulse train having a frequency of 4.5 kHz, the individual pulses still substantially maintain the Zeno waveform that the pulse of FIG. 6 (e.g., the pulse 620) that include a fast rise time to a substantially flat stabilized portion (having a meaningful duration of around 45 psec out of the approximately 180 psec in which the cycle has a non-zero voltage level), and with a substantially linear ramp-down portion. FIG. 7 thus demonstrates the ability of the hybrid open-closed loop control mechanism to generate and apply high-frequency complex voltage waveforms (Zeno or other types of waveforms) without the resultant waveforms suffering significant distortions.

[0088] Further details of the operation of the hybrid open-closed loop control mechanism are now described with reference to FIG. 8, showing a flowchart of a procedure 800 for operating a mass spectrometer. The procedure 800 is more particularly directed to control operations, performed at a control device (such as the controller implemented at the FPGA 410 of FIG. 4), to control voltage applied to at least one electrode (of an ion trap or an ion guide) according to a Zeno profile using a hybrid open-closed loop control approach. While the procedure 800 of FIG.8 is discussed using an example Zeno control profile, similar procedures may be implemented for other voltage control profiles.

[0089] Thus, the procedure 800 includes a Zeno enabling operation (at block 810) in which a Zeno profile, which may be defined as data representing a profile such as the profile shown stored in memory element 426, is selected and activated. As previously noted, other voltage control profiles may also be available for selection and activation in order to controllably apply voltages to at least one electrode of the mass spectrometer using the hybrid open-closed control loop mechanism.

[0090] With the Zeno profile (or mode) enabled, the control circuitry (whether implemented using a FPGA, or otherwise) applies an AC Zeno cycle (at block 820) whose amplitude was controllably adjusted according to a current gain value. In some embodiments, the current gainvalue may have been derived by the PID controller 420 of FIG. 4, which is then used to scale a base Zeno waveform profile (e.g., using the modulator 416 of FIG. 14). As noted, the current gain value may have been derived based on an error value between the amplitude setpoint and the measured amplitude value for the previous pulse cycle. Alternatively, the current gain value may be a default value, e.g., in situations where the current pulse is the initial pulse to be applied.

[0091] As discussed herein, the AC Zeno pulse undergoes various processing operations, including digital-to-analog-conversion and amplification, before being applied to a resonant coil to generate an output voltage signal that is applied to a load (e.g., at least one electrode of a mass spectrometer section, such as an ion trap). A feedback path delivers a voltage signal representation back to the control device (e.g., to the FPGA 410 of FIG. 4). There, the amplitude of the feedback signal is measured (at block 830) at a particular time instance (e.g., at a time instance corresponding to a stable part of the plateau of the Zeno profile where transient behavior has largely been reduced). The measured AC amplitude may include one or more samples of the feedback signal.

[0092] Having obtained the AC amplitude, the AC amplitude error, between the amplitude setpoint (i.e., the expected amplitude value) and the measured amplitude are calculated (at block 840) by, for example, the amplitude calculation module 430 of FIG. 4. The calculated AC amplitude error is then used to derive, at block 850 of FIG. 8, an updated gain trim value (e.g., using the PID controller 420 of the FPGA 410 in FIG. 4). The operations in blocks 820-850 are then repeated for a subsequent Zeno pulse that is produced using the updated gain trim value.

[0093] With reference next to FIG. 9, a flowchart of another procedure 900 of operating a mass spectrometry system using a hybrid open-closed loop control approach is shown. The procedure 900 includes applying 910 a first AC voltage pulse cycle, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, with the waveform including a ramp-down portion. In various examples, applying the plurality of voltage pulses to the at least one electrode can include applying the plurality of voltage pulses to the at least one electrode to cause, during the rampdown portion, groups of ions in an ion trap to be ejected from an output of the ion trap to a downstream component of the mass spectrometer system according to a decreasing order of m / z values respectively associated with the groups of ions. In such examples, the ion trap may be aZeno ion trap. In various embodiments, applying the first voltage pulse may include applying the first voltage pulse in an open loop mode. As described herein, under the open-closed loop approach, every cycle is applied without correcting errors occurring during the cycle. However, upon completion of the first cycle, the waveform profile for the second cycle is adjusted based on an error value determined during the first pulse cycle.

[0094] With continued reference to FIG. 9, the procedure 900 further includes obtaining 920 an amplitude value of a resultant voltage signal produced during the first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, and comparing the amplitude value with a predefined amplitude setpoint. The procedure 900 additionally includes adjusting 930 the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between the amplitude value and the predefined amplitude setpoint.

[0095] In some embodiments, obtaining the amplitude value of the first voltage pulse may include obtaining one or more voltage amplitude measurements during the stabilized portion of the first voltage pulse cycle, and deriving the amplitude value based on the obtained one or more voltage measurements. In such embodiments, obtaining one or more voltage amplitude measurements can include obtaining one or more voltage samples from the resultant voltage signal, and calculating the amplitude value based on the one or more voltage samples obtained from the resultant voltage signal. In some examples, obtaining the one or more voltage amplitude measurements may include obtaining at least one of the one or more amplitude measurements at a time instant computed based on system latency related to application of one or more voltage pulses from the plurality of AC voltage pulse to the at least one electrode of the mass spectrometer, with the computed time instance preceding the ramp-down portion of the first voltage pulse cycle.

[0096] In some examples, obtaining the one or more voltage amplitude measurements can include determining a feedback voltage produced from the AC voltage pulse applied to the at least one electrode. In such examples, the procedure can further include determining an error value as a difference between the feedback voltage and the predefined amplitude setpoint, storing the error value in a memory element, and adjusting a gain of the second AC voltage pulse based on the stored error value. In such situations, for an initial voltage pulse preceding the firstvoltage pulse (here “first pulse” refers to a first pulse of an interval of pulses beginning at some arbitrary point in a sequence of multiple pulses, whereas “initial pulse” refers to the pulse at the very beginning of the sequence of multiple pulses), storing the error value in the memory element can include storing an initial pre-determined error value. Alternatively, for an initial voltage pulse preceding the first voltage pulse, the procedure includes adjusting the waveform based on a default gain value. Another possible approach to deal with an initial voltage pulse is to initialize both the error and the gain to 0. Consequently, the first pulse will yield an amplitude of 0, and result in a large trim correction for the subsequent cycle.

[0097] In various embodiments, adjusting the waveform for the second voltage pulse may include scaling a gain profile associated with said waveform based on the difference between the amplitude value obtained from the resultant voltage signal of the first voltage pulse cycle, and the predefined amplitude setpoint. In such embodiments, the procedure may further include applying the waveform for the second AC voltage pulse cycle, scaled using the updated gain profile, in the open loop mode.

[0098] As noted, while the procedure 900 is described using a Zeno waveform as an example, the general hybrid open-closed control approach can be applied to other types of waveforms, meant to achieve other ion processing behaviors. Thus, another procedure of operating a mass spectrometry system includes applying a first AC voltage pulse, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform, and comparing the amplitude value with a predefined amplitude setpoint. The procedure further includes adjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between the amplitude value and the predefined amplitude setpoint. As noted, the various procedures described herein can be applied to unipolar waveforms and to dual RF circuits.

[0099] Depending on certain implementation requirements, embodiments of the invention can be implemented in hardware and / or in software. The implementation can be performed using a non-transitory storage medium such as a digital storage medium, for example a floppy disc, a DVD, a Blu-Ray, a CD, a ROM, a PROM, and EPROM, an EEPROM or a FLASH memory,having electronically readable control signals stored thereon, which cooperate (or are capable of cooperating) with a programmable computer system such that the respective method is performed. Therefore, the digital storage medium may be computer readable.

[0100] While various embodiments have been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; embodiments of the present disclosure are not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing embodiments of the present disclosure, from a study of the drawings, the disclosure, and the appended claims.

[0101] In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. A single processor or other processing unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0102] Those having ordinary skill in the art will appreciate that various changes can be made to the above embodiments without departing from the scope of the present teachings.

Claims

What is claimed is:

1. A method of operating a mass spectrometry system, the method comprising:applying a first AC voltage pulse, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer, wherein the waveform comprises a ramp-down portion,obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, and comparing the amplitude value with a predefined amplitude setpoint, andadjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

2. The method of claim 1 , wherein obtaining the amplitude value of the first voltage pulse comprises:obtaining one or more voltage amplitude measurements during the stabilized portion of the first voltage pulse cycle; andderiving the amplitude value based on the obtained one or more voltage measurements.

3. The method of claim 2, wherein obtaining one or more voltage amplitude measurements comprises:obtaining one or more voltage samples from the resultant voltage signal; and calculating the amplitude value based on the one or more voltage samples obtained from the resultant voltage signal.

4. The method of claim 2, wherein obtaining the one or more voltage amplitude measurements comprises:obtaining at least one of said one or more amplitude measurements at a time instant computed based on system latency related to application of one or more voltagepulses from the plurality of AC voltage pulses to the at least one electrode of the mass spectrometer, wherein the time instance computed precedes the ramp-down portion of the first voltage pulse cycle.

5. The method of claim 2, wherein obtaining said one or more voltage amplitude measurements comprises:determining a feedback voltage produced from said AC voltage pulse applied to the at least one electrode.

6. The method of claim 5, further comprising:determining an error value as a difference between the feedback voltage and the predefined amplitude setpoint;storing the error value in a memory element; andadjusting a gain of the second AC voltage pulse based on the stored error value.

7. The method of claim 6, wherein for an initial voltage pulse preceding the first voltage pulse cycle, storing the error value in the memory element comprises storing an initial pre-determined error value.

8. The method of claim 6, wherein for an initial voltage pulse preceding the first voltage pulse cycle, adjusting said waveform based on a default gain value.

9. The method of claim 1, wherein applying the first voltage pulse comprises:applying the first voltage pulse in an open loop mode.

10. The method of claim 1, wherein adjusting the waveform for the second voltage pulse comprises:scaling a gain profile associated with said waveform based on the difference between the amplitude value obtained from the resultant voltage signal of the first voltage pulse cycle, and the predefined amplitude setpoint.

11. The method of claim 10, further comprising:applying the waveform for the second AC voltage pulse cycle, scaled using the updated gain profile, in the open loop mode.

12. The method of claim 1, wherein applying the plurality of voltage pulses to the at least one electrode comprises:applying the plurality of voltage pulses to the at least one electrode to cause, during the ramp-down portion, groups of ions in an ion trap to be ejected from an output of the ion trap to a downstream component of the mass spectrometer system according to a decreasing order of m / z values respectively associated with the groups of ions.

13. The method of claim 10, wherein the ion trap comprises a Zeno ion trap.

14. A mass spectrometry (MS) system comprising:an ion source,an ion trap, comprising at least one electrode, from which at least some ions in the ion trap are ejected to a downstream component of the MS system,a mass analyzer located downstream of the ion trap to analyze one or more ions resulting from the at least some ions ejected from the ion trap,an AC power source, anda hybrid open-loop / closed loop controller to control AC voltage applied to the at least one electrode, the controller configured to:control the AC power source to apply a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to the at least one electrode, wherein the waveform comprises a ramp-down portion,obtain an amplitude value of a resultant voltage signal produced from a first voltage pulse during a stabilized portion of the waveform prior to a beginning of the ramp-down portion, and compare the amplitude value with a predefined amplitude setpoint, andadjust the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

15. The system of claim 14, wherein the controller configured to apply the plurality of voltage pulses with the waveform to the at least one electrode is configured to:apply the plurality of pulses to the at least one electrode to cause, during the ramp-down portion, groups of ions from the ion trap to be ejected from an output of the ion trap to a downstream component according to mass values respectively associated with the groups of ions.

16. The system of claim 14, wherein the controller configured to apply the plurality of voltage pulses is configured to:apply the plurality of pulses to the at least one electrode to cause, during the ramp-down portion, groups of ions from the ion trap to be ejected from the output of the ion trap to the downstream component according to a decreasing order of m / z values respectively associated with the groups of ions.

17. The system of claim 14, wherein the controller configured to adjust the waveform for the second voltage pulse is configured to:scale a gain profile associated with said waveform based on the difference between the amplitude value obtained from the resultant voltage signal of the first voltage pulse, and the predefined amplitude setpoint.

18. The system of claim 14, wherein the controller configured to obtain the amplitude value of the first voltage pulse is configured to:obtain one or more voltage amplitude measurements during the stabilized portion of the first voltage pulse cycle; andderive the amplitude value based on the obtained one or more voltage measurements.

19. The system of claim 18, wherein the controller configured to obtain one or more voltage amplitude measurements is configured to:obtain one or more voltage samples from the resultant voltage signal; and calculate the amplitude value based on the one or more voltage samples obtained from the resultant voltage signal.

20. A method of operating a mass spectrometry system, the method comprising:applying a first AC voltage pulse, from a plurality of AC voltage pulses each having a varying amplitude defined by a waveform, to at least one electrode of a mass spectrometer,obtaining an amplitude value of a resultant voltage signal produced from the first voltage pulse during a stabilized portion of the waveform, and comparing the amplitude value with a predefined amplitude setpoint, andadjusting the waveform for a second AC voltage pulse following the first AC voltage pulse based on a difference between said amplitude value and said predefined amplitude setpoint.

21. An AC voltage controller comprising:a memory storage device to store a waveform profile comprising at least one stable portion during which AC level measurements can be performed; andcontrol circuitry to control AC voltages applied to at least one electrode, the controller configured to:control an AC power source to produce a resultant voltage signal with a repeatable waveform, wherein the resultant voltage signal comprises multiple pulses with voltage waveforms produced based on the waveform profile,measure an amplitude value of a first pulse of a resultant voltage signal produced based on the waveform profile, during a portion of the first pulse of the resultant voltage signal corresponding to the at least one stable portion of the waveform profile, andperform a gain correction on a subsequent pulse of the resultant voltage signal based on the measured amplitude value of the first pulse.

Images