Charge detection for ion current control

Abstract

Method for controlling the filling of an ion trap with a predetermined amount of ions, wherein the method comprises: Generating an ion current by transferring ions along an ionic path, wherein the ion path extends from an ion source to an ion trap, such that ions accumulate in the ion trap over a transfer period, with the magnitude of the ion current varying over time; Detecting at least some ions from the ion source at an ion detector during a multitude of individual sampling time intervals interspersed within the transmission period; Setting the duration of the transmission period based on the detection of ions at the ion detector; wherein the time difference between the start of one sampling interval and the start of an immediately subsequent sampling interval is smaller than a time scale for the variation in the magnitude of the ion current; and where the timescale for the variation in the magnitude of the ion current is the average time difference between the cases in which the ion current is equal to the moving average of the magnitude of the ion current.

Description

Field of the invention

[0001] The invention relates to a method and a controller for controlling the filling of an ion trap with a predetermined amount of ions. The invention can be used in mass spectrometry when an ion trap is used. Background of the invention

[0002] Many mass spectrometry techniques require the generation of ions, which are subsequently directed via ion-optical means into a storage or capture cell ("ion trap") of a mass analyzer for analysis. The quality of the resulting mass spectra has been shown to be highly sensitive to the total number of ions introduced into and captured by the ion trap. On the one hand, the statistics of the collected mass spectra are improved by accumulating as many ions as possible in the volume of the ion trap for subsequent analysis. However, this must be balanced against a conflicting requirement to reduce harmful space charge effects. Space charge effects occur when higher ion concentrations are present in the ion trap (when the ion concentration is above a space charge threshold) and result from a perturbation in an electrostatic field due to the presence of ions.As a result of space-charge effects, the mass resolution of spectra is limited, and shifts in the mass-to-frequency ratio of spectra can occur. Therefore, it is a challenge to optimize the total number of ions trapped in an ion trap so that it lies below, but as close as possible to, the space-charge limit.

[0003] An automatic gain control (AGC) method for controlling the total abundance of ions accumulated in an ion trap is well known in the art. This process requires the accumulation of ions in an ion trap over a known period of time, after which a rapid measurement of the total ion abundance is performed by the mass analyzer. The fill rate of the ion trap can then be determined to allow the selection of an appropriate fill time for subsequent measurements to provide an optimal ion abundance in the trap. This method for AGC is described, for example, in US Patent Nos. US 5,107,109 A and WO 2005 / 093782 A2.

[0004] Other methods for controlling the filling of an ion trap have been proposed. For example, for RF ion traps, as described in US Patent Nos. 5,572,022 A and 6,600,154 B1, it was proposed to include a pre-scan immediately before the analytical scan. This pre-scan provides feedback to automatically control the gating or filling time when introducing ions into the trap for the analytical scan. In particular, the pre-scan requires that the ions accumulated in a predetermined period of time be passed to a detector to determine an ion accumulation rate. US Patent No. 5,559,325 A proposed extrapolating a plurality of pre-scans to determine an accumulation rate and the associated filling time. In another method, described in International Patent Publication No.As disclosed in WO 2003 / 019614 A2, an electrometer-type detector in a triple quadrupole array is used to measure the ion flux in a "transmission mode" and over a preset period. Consequently, a measurement period is determined for subsequent analytical scans while the triple quadrupole array is configured in a "trapping mode."

[0005] Although calibration as described above is suitable in the majority of practical cases, it has been found that there are some circumstances under which such a pre-scan can provide false or misleading estimates of the filling time. For example, the pre-scan is unable to accurately predict the ion filling rate when an ion current decays rapidly or exhibits a peak structure (e.g., for heavy proteins) or when an extremely complicated matrix with only a few intense peaks is present (as in proteomics). In an effort to address this problem, International Patent Publication No. WO 2012 / 160 001 A1 proposed the use of an additional charge detector to correct a pre-scan reading from image current detection to determine a target injection time for a subsequent analytical scan. To address a similar problem in FT-ICR, US Patent No.US 6,555,814 B1 proposes a method that involves trapping ions in an external accumulation device, followed by the release of only a portion of the trapped ions and their detection, preferably with a dedicated detector. Measuring the portion of trapped ions can be used to determine the number of ions stored in the accumulation device and thus whether further filling is necessary. However, during operation, the extraction of a portion of the trapped ions can lead to mass- and ion-density-dependent effects.

[0006] US Patent No. 5,739,530 A describes a device including an RF ion guide prior to analysis in a quadrupole ion trap. A switchable ion lens is positioned between the RF ion guide and the quadrupole ion trap to control the filling of the ion trap. The ion lens can be briefly switched to allow ions to enter the ion trap during a filling interval, whereby the filling time for the ion trap can be extrapolated from the filling level detected at the quadrupole ion trap during the filling interval. International Patent Publication No. WO 2004 / 068523 A2 (US 2004 / 0217272 A1) considers AGC in a more advanced hybrid mass spectrometer scheme, where an ion trap is also used to accumulate ions before they are sent to a mass analyzer (typically a Fourier transform or an ICR or orbital trap type).Here, an additional detector, which could be located near or in front of the ion trap, is used to measure the ion accumulation rate and determine the injection time interval for an analytical scan. The additional detector can detect ions during a small number of intervals throughout the ion accumulation period. However, the ion current is assumed to be approximately constant.

[0007] However, all of the AGC techniques described above present difficulties when applied to rapidly varying or unstable ion sources or currents. It has been shown that even classical "continuous" ion sources such as electrospray are affected by beam instability at frequencies up to many kilohertz (Bazhenov et al., Journal of Analytical Chemistry (2011), Vol. 66, No. 14, pp. 1392-1397). Pulsed ion sources, such as laser or MALDI sources, exhibit much greater variations.

[0008] Therefore, it is an object of the present invention to provide a method for controlling the filling of an ion trap with a predetermined amount of ions while avoiding overfilling of the ion trap, even when the ion current supplied by the ion source is inherently transient or unstable. Brief description of the invention

[0009] This invention describes a method for controlling the filling of an ion trap with a predetermined amount of ions that attempts to overcome the problems outlined above. A controller and a mass spectrometer for implementing this method are also described.

[0010] The method requires the intermittent detection of the ions otherwise used to fill an ion trap at an ion detector. The ions are detected at the detector simultaneously with the filling of the ion trap. In this way, the ion current is "sampled" during a number of sampling intervals distributed over the ion trap filling period. By measuring the sampled ion current, the quantity of ions detected at the ion detector during the entire sampling interval can be determined, and this can be extrapolated to estimate the quantity of ions received by the ion trap. Although the ion current varies over time, the inventors have realized that by appropriately selecting the ion current sampling period, the variation in the ion current can be accurately monitored and thus taken into account when determining the ion trap filling time.In particular, the sampling time intervals are significantly shorter than a characteristic time of variation of the ion current. This allows for a more accurate estimation of the ion trap filling time, thus avoiding overfilling or underfilling of the trap.

[0011] In a first aspect, a method for controlling the filling of an ion trap with a predetermined amount of ions is described, the method comprising: Generating an ion current by transferring ions along an ion trajectory, the ion trajectory extending from an ion source to an ion trap, such that ions are accumulated in the ion trap over a transfer period, the magnitude of the ion current varying over time; Detecting at least some ions from the ion source at an ion detector during a plurality of individual sampling time intervals interspersed within the transmission period; Setting the duration of the transmission period based on the detection of ions at the ion detector; and where the time difference between the beginning of one sampling time interval and the beginning of an immediately subsequent sampling time interval is smaller than the time scale for the variation of the magnitude of the ion current.

[0012] The method is intended to control the filling of an ion trap and, in particular, the number of ions accumulated at the ion trap. As a result of the method, the number of ions in the ion trap can be more precisely controlled to maximize the number of ions available for analysis while reducing space charge effects. The method achieves this by sampling the ion current concurrently with the filling of the ion trap at a frequency faster than any changes or variations in the ion current, thereby providing an accurate and responsive indication of the filling rate at the ion trap. By applying the described method, changes in the ion current that occur during the transfer period (e.g., due to an inherently unstable ion source or the use of a pulsed ion source) can be monitored and taken into account when determining the transfer time.

[0013] The transfer period is assumed to be the period for filling the ion trap with a predefined quantity of ions. In other words, it is the time during which ions are delivered from the ion source and received by the ion trap after traversing the ion trajectory. The ions are accumulated together in the ion trap, i.e., during one filling of the trap, so that in typical operation, the ions are not emptied from the trap during the transfer period. The transfer period includes the sampling time intervals and any time between the sampling time intervals. It also includes any period before the first sampling time interval and after the last sampling time interval when ions are received at the ion trap.

[0014] During the sampling time intervals (interspersed within the transmission period), the ions are detected by the detector, either by reception and collection at the ion detector or by using non-destructive charge techniques such as image charge detection. Thus, each sampling time interval is a period during which the ions are detected at the detector. In some cases, only a portion of the ions from the ion source are received at the ion detector during the sampling time intervals, with the remaining ions continuing along the ion trajectory to the ion trap. Nevertheless, the ions are detected before reaching the ion trap. In some cases, ions can be collected at the detector during each sampling time interval, with the ions being detected at the end of each sampling time interval.

[0015] Adjusting the transmission period can be viewed as an iterative process and is based on the ions detected at the ion detector during previous sampling time intervals. In this way, the transmission period can be determined at intervals during the transmission period, taking into account the ions detected during the most recent sampling time interval. This advantageously allows the transmission time to accurately reflect any change or variation in the ion current over time. Fluctuations in the ion current (which would consequently alter the ion trap filling rate) can be taken into account.

[0016] The time difference between the start of one sampling time interval and the start of the immediately following sampling time interval represents a sampling period and is therefore related to the sampling frequency (which is the inverse of the sampling period). A sampling frequency that is faster than the frequency of any fluctuation or variation in the ion current allows temporal changes in the ion current to be measured and monitored. In particular, the time difference (or sampling period) is the time between each individual sampling time interval and is thus related to how often the ion current is sampled. A smaller time difference results in a higher sampling frequency of the ion current.

[0017] The timescale of the ion current variation can be quantified in several ways, as discussed below. Nevertheless, those skilled in the art will understand that it represents the period of time over which the ion current undergoes a significant change in magnitude. To obtain an accurate indication of changes in the ion current, the time difference (or sampling period) should ideally be small compared to the timescale of the sample current variation. This means measuring a large number of samples of the ion current over the period in which the ion current undergoes a significant change.

[0018] The ion source is a component from which ions are transferred toward the ion trap. In some cases, the ion source is a source of ions (e.g., an electrospray ionization (ESI) source or a matrix-assisted laser desorption / ionization (MALDI) ion source). However, in other cases, the ion source is a component that emits ions generated elsewhere (e.g., an ion guide).

[0019] Preferably, adjusting the duration of the transmission period based on the detection of ions at the ion detector comprises adjusting the transmission period based on the total amount of ions detected at the ion detector during the plurality of sampling time intervals. The total amount or number of ions received at the ion detector during the plurality of sampling time intervals indicates the fill rate (number of ions per unit time) received at the ion trap. Due to the fluctuation or variation of the ion current over time, this fill rate varies over the plurality of sampling time intervals. The amount or number of ions received at the ion detector during each sampling time interval is representative of the ion current in that time interval.As an alternative to the total quantity or number of ions received at the ion detector, the ion current or ion population detected at the ion detector during the multiple sampling time intervals could be used. This would, for example, take into account the ion species.

[0020] Preferably, the time difference between the start of one sampling time interval and the start of an immediately subsequent sampling time interval (the sampling period) is smaller than a predefined percentage of the timescale for the variation in the magnitude of the ion current. Preferably, the time difference (or sampling period) is significantly smaller than the timescale for the variation in the magnitude of the ion current. The predefined percentage should be chosen so that the sampling of the ion current is sufficiently fast to accurately capture the change in the ion current. For example, the time difference or sampling period can be set to less than 50% of the timescale for the variation in the ion current. Preferably, the time difference can be set to less than 20% of the timescale for the variation in the ion current, or more preferably, less than 10% or even less than 5%. The time difference can range from 1% to 50%.A higher percentage may be appropriate if the ion current variation has a relatively stable periodicity. However, if the ion current variation is less stable, a smaller predefined percentage can be used. Using a smaller predefined percentage results in a larger number of ion current samples for the ion current variation within the given timescale, so a more accurate representation of the ion current variation can be obtained. In general, the larger the observed change in ion current, the smaller the predefined percentage that may be used (in other words, the more frequent the sampling may be).As an illustrative example, for an ion current exhibiting fluctuations of ±100% of its average magnitude, the time difference (or sampling period) could be chosen as 10% or even less of the timescale for the variation in the ion current magnitude. However, if the ion current exhibits smaller fluctuations of only ±20-30% of its average magnitude, a longer time difference (or sampling period) can be chosen to achieve the required quantitative accuracy, e.g., a predefined percentage of 20% of the timescale for the variation in the ion current magnitude.

[0021] Optionally, the timescale for the variation in the magnitude of the ion current is the average period of the current variation. For example, the ion current can vary approximately periodically. This may be particularly the case when using a pulsed ion source, such as a MALDI source.

[0022] Optionally, the timescale for the variation in the magnitude of the ion current is the average rise or fall time of the current peaks. For example, this measure of the timescale for variation may be particularly useful when the ion current varies approximately periodically.

[0023] Optionally, the timescale for the variation in the magnitude of the ion current is determined by transforming the ion current into the frequency domain. For example, a Fourier transform of the fluctuating ion current into the frequency domain could be used, and the relevant timescale could be analyzed by considering the components of the ion current in the frequency domain. For example, the timescale of the current variation could be the period corresponding to the inverse of the frequency of a peak in the Fourier transform of the ion current into the frequency domain. For example, the highest frequency peak with at least a given amplitude could be used in the Fourier transform.

[0024] Optionally, the timescale for the variation in the magnitude of the ion current is the average period of time during which the ion current changes by at least a specified percentage of its maximum magnitude. For example, the timescale for the variation in the magnitude of the ion current is the average period of time during which the ion current decreases by 20% of its maximum value. Other percentages of the maximum value could be selected.

[0025] The time scale for the variation in the magnitude of the ion current is the average time difference between the cases in which the ion current is equal to the moving average of the magnitude of the ion current. In other words, if the ion current moves above and below the moving average (or rolling average) of the ion current, the time scale for the variation can be the average time between the cases in which the ion current is equal to the moving average. The averaged average or median of the time between the respective cases could be used.

[0026] A time base or window for the moving average should be chosen to be appropriate for the ion source, ion optics, and analyzer used, e.g., according to the requirements outlined elsewhere in the description below, and typically in the millisecond range (e.g., 0.1 to 100 ms, and more preferably 0.5 to 10 ms). In particular, the moving average base must be shorter than: (a) the average duration of ion accumulation prior to a scan, and / or (b) the duration of the scan (the transmission period), and / or (c) the duration over which voltages across the ion optics are held constant (while this duration can be short, down to a few microseconds, for simple DC ion optics, it can be as short as 1-2 ms for more precise devices such as a quadrupole mass filter). However, the basis for the moving average must be longer than (and preferably much longer than, for example,at least 2x, 5x or 10x longer than): (a) the time broadening during collision cooling (typically 0.2-1 ms), and / or (b) the minimum gating time of the ion optics (or split or dual gate) arranged for the injection of ions into ion trap analyzers (e.g., a linear ion trap or an Orbitrap™ analyzer) (typically in the range of 0.02-0.1 ms), and / or (c) the average settling time of voltages across the ion optics (typically in the range of 0.01-1 ms) - this could, for example, be the gating time of the ion optics controlling the described process.

[0027] Optionally, the magnitude of the ion current can vary approximately in steps. In this case, the timescale for the variation of the ion current magnitude can be the average width of peaks in the derivative of the ion current versus time. The average width of the peaks can be the average half-maxima across the entire width of the peaks in the derivative of the ion current.

[0028] In another example, the time scale for the variation in the magnitude of the ion current may be the time delay for the ion current associated with an autocorrelation value greater than or equal to a predefined value. For example, the time scale of the variation may be the time delay between the cases where the ion current has an autocorrelation value greater than 0.5 or, more preferably, greater than 0.7.

[0029] However, other autocorrelation values ​​could also be used. As one skilled in the art will understand, the autocorrelation value describes the degree of correlation (or similarity) between two observations of a parameter as a function of the time delay between them. Accordingly, autocorrelation can be used to identify repeating patterns in a signal, including a periodic signal obscured by noise.

[0030] Preferably, prior to detecting at least some ions from the ion source during a plurality of individual sampling time intervals at the ion detector, the method further comprises receiving a measurement of the ion current over a pre-measurement period and determining the timescale for the variation in the magnitude of the ion current over the pre-measurement period. In other words, prior to each filling of the ion trap, a pre-test is performed to characterize the ion current and the timescale for the variation of the ion current. The timescale for the variation of the ion current measured during the pre-test can be determined by one of the measures described above. The time difference between the beginning of a sampling time interval and the beginning of an immediately subsequent sampling time interval (sampling period) can then be based on the thus determined timescale for the variation of the ion current.

[0031] In some examples, the time difference between the beginning of one sampling time interval and the beginning of an immediately subsequent sampling time interval or sampling period must not be greater than 1 ms, and preferably must be less than 1 ms, such as between 10 µs and 1000 µs, and preferably between 10 µs and 500 µs, and more preferably between 10 µs and 200 µs, e.g., 50 µs and 200 µs. In most cases, the time difference could be in the range of 1 µs to 1000 µs.

[0032] Ideally, the duration of each of the plurality of sampling time intervals is less than 20 µs, preferably less than 10 µs. However, the sampling time interval could be any suitable period given the length of the transmission period. In most cases, the sampling time intervals will be in the range of 50 µs to 1 µs. In most cases, the sampling time intervals will be the same throughout the transmission period, but this is not strictly required. For example, the duration of the sampling time interval could change dynamically depending on the quantity of ions detected at the ion detector in a previous sampling time interval.

[0033] Preferably, the total of the plurality of sampling time intervals is less than 20% of the transmission period, preferably less than 10% of the transmission period. The total of the plurality of sampling time intervals may be any percentage of the transmission period chosen to provide a representative sample of the ions delivered by the ion source. If the ion detector receives and detects the full ion beam during the sampling time intervals, the percentage of the total of the plurality of sampling time intervals compared to the transmission period may be approximately representative of the percentage of the total of ions transmitted from the source and received at the ion detector compared to the ion trap.

[0034] The method may further comprise providing at least one ion detector along the ion trajectory between the ion source and the ion trap, preferably acting as an independent charge detector. In one example, the ion detector is located on the ion trajectory. The ion detector may be a grid detector that allows at least some ions to pass through the grid and further along the ion trajectory to the ion trap. Alternatively, the ion detector may be a non-destructive ion detector, such as an image charge detector.

[0035] Preferably, detecting at least some ions from the ion source at an ion detector during a plurality of individual scan time intervals prior to detecting the at least some ions comprises directing the at least some ions from the ion trajectory toward the ion detector during each individual scan time interval. In other words, the ion detector is an auxiliary ion detector that is not located on the ion trajectory. The ions are directed (or deflected) out of the ion trajectory, e.g., by pulsed deflection, toward the detector before reaching the ion trap. The ions are directed away from the ion trajectory toward the detector using suitable ion optics. The deflection is intermittent and only occurs during each individual scan time interval. Although the use of an additional ion detector to intermittently detect the ion current is disclosed in U.S. Patent Publication No.As demonstrated in US 2016 / 0217985 A1, this serves to combine the detector signal with the mass spectrum to enable an improved abundance measurement. It does not address automatic gain control (and in particular, does not address controlling the filling of an ion trap with a given amount of ions) and does not consider adjusting the duration of any period as a result of the measured detection signal.

[0036] The method may further comprise: providing the ion detector outside the ion trajectory; providing at least one switching device along the ion trajectory, arranged between the ion source and the ion trap, and wherein the switching device is configured to direct ions from the ion source toward the ion detector outside the ion trajectory during each individual sampling time interval. In this example, the ion detector is not arranged directly on the ion trajectory, but is an auxiliary ion detector arranged near the ion trajectory but at a distance from it. Ions from the ion source can be directed (or deflected) away from the ion trajectory and toward the ion detector using suitable ion optics.For example, ion optics positioned along the ion trajectory between the ion source and the ion trap can be used to redirect ions to the ion detector by applying appropriate voltages to the ion optics. Accordingly, the ion optics can be used to intermittently redirect ions from the ion trajectory to the ion detector during each sampling time interval.

[0037] Preferably, the method further comprises terminating the transfer of ions along the ion trajectory once the transfer time has elapsed. In other words, the filling of the ion trap may be stopped or interrupted after the transfer time has elapsed. In some examples, terminating the transfer of ions along the ion trajectory comprises interrupting the supply of ions along the ion trajectory. Interrupting the supply of ions along the ion trajectory may comprise at least one of the following: turning off the ion source, modulating the ion source, or blocking the transfer of ions from the ion source to the ion trap. In other words, the ions from the ion source are prevented from reaching and entering the ion trap to prevent further filling of the ion trap.

[0038] Stopping the transfer of ions along the ion trajectory can involve directing all ions away from the ion trajectory in front of the ion trap. In other words, the ions in front of the ion trap can be deflected from the ion trajectory so that the ions do not reach the ion trap. Deflection can be achieved by applying appropriate voltages to the ion optics, which are positioned on the ion trajectory between the ion source and the ion trap.

[0039] To terminate the ion transfer, in some examples, the ions are deflected from the ion trajectory toward an ion pool. In some cases, the ion optics used to deflect the ions in this manner may be the previously described switching device used to deflect the ions toward the ion detector during the sampling time intervals. In this case, the deflection of the ions toward either the ion detector or the ion pool can be selected by applying appropriate voltages to vary the extent of the ion deflection.

[0040] Preferably, adjusting the duration of the transmission period comprises terminating the transmission of ions along the ion trajectory when a total amount of ions detected at the ion detector during the plurality of sampling time intervals exceeds a predefined value. In other words, the transmission of ions is terminated once a predefined number of ions have been received at the ion detector. In particular, the number of ions received at the ion detector during a total sampling time provides an indication of the number of ions received at an ion trap during the transmission period.

[0041] At least one gas-filled ion guide can be provided along the ion trajectory, between the ion source and the ion trap. The ion guide can be used to converge or focus ions into an ion beam traversing the ion trajectory. Thus, the ion guide assists the transport of ions along the ion trajectory. Nevertheless, ions passing through the gas-filled ion guide may experience collisions with the gas atmosphere. The subsequent diffusion of the ions causes different ions within the ion beam to have slightly different trajectories and velocities. This influences the time it takes for the ions to travel through the ion guide and traverse the ion trajectory. As a result, the variation in the ion current entering the ion guide can be "smoothed" by the effects of such diffusion broadening.

[0042] For example, stepwise changes in the incoming ion current can be broadened or smoothed. This would be reflected in a broadening of the representative peak in the derivative of the ion current exiting the ion guide as a function of time. The broadening of the peak can provide a timescale for the variation of the ion current. For example, the time difference or sampling period between the beginning of a sampling time interval and the subsequent sampling time interval can be smaller than the average half-maxima across the entire width of the peaks in the derivative of the ion current as a function of time. Therefore, the timescale for the variation in the magnitude of the ion current is smaller than the temporal broadening of stepwise changes in the magnitude of an ion current entering the gas-filled ion trap and resulting from ion collisions with gas in the gas-filled guide.

[0043] In another example, using a gas-filled ion guide in front of the trap and detector, a gas-filled RF ion guide of length L contains gas at a pressure P such that P×L>0.2 mbar mm. In this example, a pulsed ion current is arranged to enter the ion guide from the ion source, where each pulse can be represented by a fast-delta function. Upon entering the ion guide, the current pulses undergo diffusion broadening such that each pulse has a width of approximately 200–500 µs. Consequently, the time difference, or sampling period, between the beginning of a sampling time interval and the subsequent sampling time interval must be smaller, preferably much smaller, than the pulse width. In this example, the time difference can be set to 100 µs.

[0044] Ideally, the method can be used to provide mass analysis of a sample. As such, the described method may further comprise introducing ions derived from the ions accumulated at the ion trap into a mass analyzer or an ion mobility analyzer. The ions accumulated in the ion trap can be injected into a mass analyzer to undergo an analytical scan using techniques known in the art. Any type of mass analyzer may be used.

[0045] In some examples, the ions are introduced into the mass analyzer or ion mobility analyzer after the transfer period has elapsed. For example, the ions are not injected into the mass analyzer until the predefined amount of ions has accumulated in the ion trap. Alternatively, some ions can be injected from the ion trap before the transfer period has elapsed, so that the ion trap continues to fill even as ions are ejected from the ion trap to the mass analyzer.

[0046] The ion source can deliver ions in the form of a continuous, quasi-continuous, or pulsed ion beam. Examples of ion sources include an electrospray ionization (ESI) source or, more specifically, a MALDI source. The ion source could also include any number of ion-optical elements that transfer ions, e.g., one or more RF ion guides, lenses, ion traps, etc.

[0047] Preferably, the mass analyzer is an orbital trap mass analyzer, and the ion trap is a linear ion trap, e.g., a curved ion trap (C-trap) positioned upstream of the orbital trap mass analyzer. In particular, the method can be applied within an Orbitrap™ mass analyzer. Nevertheless, it is contemplated that the method is applicable for use with any type of mass analyzer within any type of mass spectrometer.

[0048] In a second aspect, a controller for controlling the filling of an ion trap with a predetermined amount of ions is described, the controller being configured to: Receiving a measurement based on a quantity of ions detected at an ion detector during a plurality of individual sampling time intervals, wherein the ions are transferred from an ion source, wherein an ion trajectory extends from the ion source to an ion trap such that ions are accumulated at the ion trap over a transfer period, wherein the ions transferred along the ion trajectory generate an ion current and the magnitude of the ion current varies over time, and wherein the plurality of individual sampling time intervals are interspersed within the transfer period; and Setting the duration of the transmission period based on the ions detected at the ion detector; and where the time difference between the beginning of one sampling time interval and the beginning of an immediately subsequent sampling time interval is smaller than the time scale for the variation of the magnitude of the ion current.

[0049] In other words, the controller is configured to control and / or execute the method described above. For example, the controller may be configured to control the ion source so that ions are supplied to the ion trajectory and transferred along the ion trajectory during the transfer period. The controller may further be configured to intermittently sample the ion current by detecting ions at the ion detector for a plurality of sampling time intervals within the transfer period. The controller may further adjust the duration of the transfer period according to the measurement of the detected ions received by the ion detector.

[0050] In one particular example, the controller may be configured to adjust the duration of the transmission period based on the total amount of ions detected at the ion detector during the plurality of sampling time intervals. A predefined algorithm may be used to estimate the fill time of the ion trap from a particular rate of ions received at the ion detector during the entirety of the previous sampling time intervals. Note that the total amount of ions may be represented by either a charge density or an ion density. A proportion of the ion beam detected by the ion detector may be determined, for example, from previous fill attempts and / or from the duration of the sampling intervals.

[0051] Preferably, the controller is configured to adjust the duration of the sampling time interval. Thus, the controller can be used to adjust the percentage of ions delivered by the ion source to the ion path that are received at the ion detector compared to the ion trap.

[0052] Preferably, the controller is configured to set the time difference between the beginning of one sampling time interval and the beginning of an immediately subsequent sampling time interval. In particular, the controller may set the time difference to be smaller than the time scale of the variation in the ion current. In some cases, the time scale of the variation in the ion current will be known. In other examples, the controller may determine the time scale of the variation in the ion current by performing a preliminary test before the start of the transmission period.

[0053] Preferably, the controller is configured to set the time difference between the start of one sampling time interval and the start of an immediately subsequent sampling time interval to a value less than a predefined percentage of the timescale for the variation of the magnitude of the ion current. For example, the time difference may be set to less than 50% of the timescale for the variation of the ion current, or less than 20% of the timescale for the variation of the ion current, or even less than 10% of the timescale for the variation of the ion current. The predefined percentage may range from 1% to 50%. The predefined percentage may determine the number of samples of the ion current obtained within the timescale of the variation of the ion current.Therefore, the predefined percentage can also determine how accurately the ion current variation is monitored and thus how accurately the transmission period can be predicted to avoid overfilling the ion trap. Generally, a more accurate determination of the transmission period is achieved by sampling the ion current more frequently (and thus a smaller predefined percentage). However, more frequent sampling of the ion current will, in most cases, also increase the proportion of ions received at the ion detector compared to the ion trap, thereby increasing the time required to fill the ion trap.

[0054] A number of measures of the time scale of ion current variation can be used, for example: Optionally, the time scale for the variation of the magnitude of the ion current is the average period of the current variation.

[0055] Optionally, the time scale for the variation in the magnitude of the ion current is determined based on a transformation of the ion current into the frequency domain. For example, a Fourier transform into the frequency domain could be used.

[0056] Optionally, the time scale for the variation of the ion current magnitude is the average period of time during which the ion current changes by at least a given percentage of its maximum magnitude.

[0057] The time scale for the variation of the ion current magnitude is the average time difference between the cases where the ion current is equal to the moving average of the ion current magnitude. The time base or a window for the moving average should be chosen to be appropriate for the ion source, ion optics, and analyzer used, e.g., according to the requirements outlined elsewhere above and in the description below.

[0058] Optionally, the magnitude of the ion current varies approximately stepwise, and the time scale for the variation of the magnitude of the ion current is the average width of the peaks in the derivative of the ion current versus time.

[0059] Preferably, prior to receiving the measurement based on a quantity of ions detected at an ion detector during the plurality of individual sampling time intervals, the controller is further configured to receive a measurement of the ion current during a pre-measurement period and determine the timescale for the variation in the magnitude of the ion current during the pre-measurement period. In other words, the controller is configured to perform a "pre-measurement" of the ion current to establish the timescale for the variation of the ion current. This pre-measurement may include measuring the ion current at an ion detector for a predefined period of time and then analyzing the measured ion current to determine a timescale for the variation of the ion current according to any of the measures described above.The ion detector may be the same ion detector used to detect ions during the sampling time intervals, or it may be a different, separate ion detector.

[0060] Alternatively, the timescale for the variation of the ion current may already be known from previous experiments or measurements, or simply from prior knowledge of the ion source's properties. Therefore, the described "preliminary measurement" is not an essential step.

[0061] Preferably, the time difference between the start of one sampling time interval and the start of an immediately subsequent sampling time interval is between 10 µs and 1000 µs, and preferably between 10 µs and 500 µs, and more preferably between 10 µs and 200 µs, e.g., 50 µs and 200 µs. The time difference can be in the range of 1 to 1000 µs. The time difference defines the sampling frequency of the ion current. Advantageously, the ion current is sampled at a frequency high enough to adequately detect any variation or changes in the ion current.

[0062] Preferably, the duration of each sampling time interval of the plurality of sampling time intervals is less than 20 µs, preferably less than 10 µs. The sampling time intervals can be anywhere in the range of 1 µs to 100 µs. The sampling time interval can be selected relative to the transmission time period such that an approximate percentage of ions are received at the ion detector compared to the percentage of ions at the ion trap.

[0063] Preferably, the total of the plurality of sampling time intervals is less than 20% of the transmission period, more preferably less than 10% of the transmission period. The total of the plurality of sampling time intervals can be between 1 and 50% of the transmission period. The percentage of the total of the plurality of sampling time intervals compared to the transmission time intervals can determine the proportion of ions from the ion source received at the ion detector compared to the ion trap.

[0064] Preferably, the ion detector is arranged outside the ion trajectory, and the controller is further configured to control a switching device arranged along the ion trajectory between the ion source and the ion trap, wherein the switching device is configured to direct ions from the ion source to the ion detector, and wherein the controller is configured to control the switching device to direct ions from the ion source to the ion detector outside the ion trajectory during each individual sampling time interval. In other words, the ion detector is an auxiliary ion detector arranged near, but not on, the ion trajectory. A switching device (e.g., suitable ion optics) can be arranged on the ion trajectory between the ion source and the ion trap. By applying suitable voltages to the switching device, the ions can be deflected (or directed) from the ion trajectory toward the ion detector.In particular, the deflection from the ion trajectory occurs intermittently and is controlled by the detector, so that ions are received at the ion detector during each sampling time interval. Outside of the sampling time intervals, but during the transmission period, ions continue to travel along the ion trajectory to be received at the ion trap.

[0065] In some embodiments, the ion detector is located on the ion trajectory. The ion detector may be a grid detector that allows at least some ions to pass through the grid and further along the ion trajectory to the ion trap. Alternatively, the ion detector may be a non-destructive ion detector, such as an image charge detector. In such embodiments, continuous detection of a portion of the ion beam by the ion detector is achieved.

[0066] Preferably, the controller is configured to terminate the transfer of ions along the ion trajectory after the transfer period has elapsed. This may include the controller interrupting the supply of ions along the ion trajectory, for example, by at least one of: turning off the ion source, modulating the ion source, or actuating a shutter to block the transfer of ions from the ion source to the ion trap.

[0067] The controller can be configured to terminate the transmission of ions along the ion trajectory by controlling an ion gate (or suitable ion optics) positioned along the ion trajectory between the ion source and the ion trap. The controller can be configured to control the ion gate so that all ions from the ion trajectory are directed (or deflected) ahead of the ion trap. As such, the deflected ions do not enter the ion trap and do not contribute to filling the ion trap.

[0068] In some examples, the ion gate is the switching device described above to divert ions to the ion detector during the sampling time intervals. To terminate the transmission of ions along the ion trajectory, the controller can be configured to control the switching device to divert all ions out of the ion trajectory and toward an ion pool. In other words, the switching device can be arranged so that when a first set of voltages is applied, the ions are diverted from the ion trajectory to the ion detector, but when a second set of voltages is applied, the ions are diverted from the ion trajectory to the ion pool. When a third set of voltages is applied to the switching device (which can be zero voltages), the ions are not diverted and instead continue along the ion trajectory to the ion trap.

[0069] Preferably, the controller is configured to adjust the duration of the transmission period based on the total quantity of ions detected at the ion detector during the sampling time intervals. This may include the controller being configured to terminate the transmission of ions along an ion trajectory if the measurement of the total quantity of ions detected at the ion detector exceeds a predefined value. In other words, the controller prevents ions from being received at the ion trap after a predetermined quantity of ions has been detected at the ion detector during the sampling time intervals. In particular, the controller may sum the quantity of ions detected by the ion detector during each of the plurality of sampling time intervals and compare this total quantity of ions to a predefined value.

[0070] Preferably, the controller is further configured to control the introduction of ions derived from the ions accumulated at the ion trap into a mass analyzer or an ion mobility analyzer. In other words, the ions stored in the ion trap can be injected into a mass analyzer to perform an analytical scan under the control of the controller. The ions can be introduced into the mass analyzer or the ion mobility analyzer after the transfer period has elapsed. Alternatively, the controller can control the injection of a portion of ions from the ion trap into a mass analyzer even when the ion trap is being filled (in other words, during the transfer period).

[0071] In a preferred example, the mass analyzer is an orbital trap mass analyzer, and the ion trap is a curved ion trap positioned upstream of the orbital trap mass analyzer. The controller may, for example, be integrated into an orbital trap mass analyzer, such as an Orbitrap™ mass analyzer.

[0072] In a third aspect, a mass spectrometer is described, comprising: an ion source; an ion trap arranged to receive ions transmitted along an ion trajectory extending from the ion source to the ion trap; an ion detector arranged to detect at least some ions from the ion source; a mass analyzer arranged to receive at least some ions from the ion trap; and a control as described above.

[0073] In other words, a mass spectrometer may include a controller configured to control the described methods.

[0074] Preferably, the ion detector is located outside the ion trajectory, and the mass spectrometer further comprises an ion gate arranged along the ion trajectory between the ion source and the ion trap, the ion gate being capable of directing ions from the ion source toward the ion detector located outside the ion trajectory. In other words, the mass spectrometer has ion optics for intermittently deflecting the ion beam toward an auxiliary ion detector located outside the ion trajectory. In this way, the mass spectrometer and the onboard controller can perform the method described above, wherein the ions are deflected from the ion trajectory during the plurality of sampling time intervals. In some embodiments, the ion gate (or ion optics) can further be used to deflect or direct the ions from the ion source to an ion pool after the transfer period has elapsed.

[0075] As will be understood by those skilled in the art, the mass spectrometer may be one of several different types. For example, the mass spectrometer may be an orbital trap mass spectrometer, a time-of-flight mass spectrometer, a quadrupole mass spectrometer, or an ion cyclotron resonance mass spectrometer.

[0076] With respect to the method, controller, or mass spectrometer described above, the ion trap may be one of a radio frequency trap, a Penning trap, an electrostatic trap, a time-of-flight trap, or a linear trap, which may, for example, be linear or curved.

[0077] With respect to the method, controller, or mass spectrometer described above, the ion source may be one of an ion trap, an ion source, an electrospray ionization (ESI) source, a matrix-assisted laser desorption / ionization (MALDI) ion source, an atmospheric pressure chemical ionization (APCI) source, an atmospheric pressure photoionization (APPI) source, an atmospheric pressure photochemical ionization (APPCI) source, an electron impact ionization source, a fast ion bombardment source, a secondary ion source (SIMS), a mass analyzer, an ion mobility analyzer.

[0078] With respect to the method, controller, or mass spectrometer described above, the ion detector may be one of: a Faraday cup, a single ion detector, a secondary electron multiplier. List of characters

[0079] The present invention will now be described, by way of example only, with reference to the accompanying drawings, in which: Fig. Figure 1 is a schematic representation of a device implementing a method for controlling the filling of an ion trap with a predetermined amount of ions; Fig. Figure 2 is a schematic representation of a device implementing a method for controlling the filling of an ion trap with a predetermined amount of ions, according to a second example; Fig. 3 is a flow diagram illustrating a method for controlling the filling of an ion trap with a predetermined amount of ions; Fig. 4 is a flowchart illustrating a method for controlling the filling of an ion trap with a predetermined amount of ions according to a second example; Fig. 5A is a schematic representation of an ion current that varies with time and a first measure of a time scale of the variation of the ion current; Fig. 5B is a schematic representation of an ion current varying with time and a second measure of a time scale of variation in the ion current; Fig. Figure 5C is a schematic representation of an ion current varying with time and a third measure of a time scale of variation in the ion current; Fig. 5D and Fig. 5E is a schematic representation of an ion current varying with time and a fourth measure of a time scale of variation of the ion current; Fig. 5F and Fig. Figure 5G is a schematic representation of an ion current varying with time and a fifth measure of a time scale of variation in the ion current; Fig. 6 is a schematic representation of a device implementing a method for controlling the filling of an ion trap with a predetermined amount of ions, according to a third example; Fig. 7 is a schematic representation of a device implementing a method for controlling the filling of an ion trap with a predetermined amount of ions, according to a fourth example; Fig. 8 is a diagram showing the ion optics during operation using the example of Fig. 6 applied voltages illustrated; Fig. Figure 9 illustrates an electrical circuit used in conjunction with the examples described; Fig. 10 is a schematic representation of an orbital trap mass spectrometer arranged to implement a method for controlling the filling of an ion trap with a predetermined quantity of ions; and Fig. 11 is a diagram of the signal-to-noise ratio of ions measured in a mass spectrometer of the type Fig. 10 of the type shown were measured.

[0080] In the drawings, similar parts are designated by similar reference numerals. The drawings are not to scale. Detailed description of specific embodiments of the invention

[0081] Fig. Figure 1 schematically shows a portion of a mass spectrometer for carrying out the method of the invention. Fig. 1 also shows a controller which is an embodiment of the invention.

[0082] In particular, Fig. 1 an ion source 10. In this case, the ion source is an electrospray or plasma ion source operating at atmospheric pressure, followed by an atmosphere-vacuum interface and at least one RF ion guide, although other types of ion sources such as a source of ions or ion storage devices could also be used (such as an electron impact (EI) source or a low or high pressure MALDI source). Fig. 1 also includes an ion trap 14. In this example, the ion trap is a linear trap, although the described method is not limited to this type of ion trap. An ion trajectory 18 extends between the ion source 10 and the ion trap 14. Ions from the ion source 10 can be guided along the ion trajectory 18 and received at the ion trap 14. Ions received at the ion trap 14 are at least temporarily stored or trapped therein. It is understood that one or more other ion optical devices, such as ion guides, mass filters, etc., may be provided throughout the mass spectrometer, e.g., between the ion source 10 and the ion trap 14, as known in the art. The ion trap 14 may be a mass analysis ion trap, or a mass analyzer may be provided downstream of the ion trap 14 to receive ions from the ion trap.

[0083] An ion detector 12 is disposed on the ion path 18, between the ion source 10 and the ion trap 14. The detector 12 can be used to detect (or "sample") at least a portion of the ions transmitted along the ion path 18. In particular, the detector 12 is used to detect at least some ions transmitted from the ion source 10 during a plurality of individual sampling time intervals. The detector 12 can be an image current detector and therefore does not collect or receive the sampled portion of the ions. Alternatively, the detector 12 can be another type of ion detector where the sampled portion of the ions must be collected for detection to occur.During a period of transfer of ions from the ion source 10 (the “transfer period”), the ions may either pass through the detector 12 to reach the ion trap 14 or (in some cases, depending on the type of detector) may instead be collected and detected at the detector 12.

[0084] A controller 16 is arranged to communicate with and receive measurements from the detector 12. The controller 16 is configured to control the operation of the ion source 10 and the ion trap 14 (either directly or via additional ion optics not included in Fig. 1).

[0085] As mentioned above, it is highly desirable to precisely control the filling of the ion trap. That is, it is desirable to control the amount of ions stored in the ion trap at the end of a period of transfer of ions from the ion source 10 and along the ion trajectory 18 (the "transfer period"). To achieve controlling the filling of the trap, the present invention "samples" at the detector at least a portion of the ions transferred from the ion source 10 along the ion trajectory. The detector samples the ions during a plurality of individual sampling time intervals interspersed within the transfer period.

[0086] For example, ions in the embodiment of Fig. 1 from the ion source 10 and toward the ion trap 14 for a transmission period. During most of this transmission period, the ions traverse the ion trajectory 18 and are received at the ion trap 14. However, for at least two relatively short time intervals ("sampling time intervals") within the transmission period, the detector 12 detects at least some ions transmitted from the ion source. In other words, the detector 12 intercepts ions that traverse the ion trajectory 18 during the sampling time intervals. The detection, or "sampling," of the ion current occurs only during the plurality of sampling time intervals.

[0087] The sampling time intervals are each significantly shorter than the transmission period. In the specific example of Fig. 1, the transmission period is 100 ms, while the sampling time intervals are each 10 µs. The sampling time intervals are distributed over the entire transmission period. In the example of Fig. 1, the sampling time intervals are evenly spaced. In other words, the time between each sampling time interval is equal. The time between each sampling time interval is sometimes referred to in this specification as the "accumulation interval" and may represent the periods during which ions accumulate at the ion trap 14. However, it should be noted that in some examples, only a fraction of the ions traversing the ion trajectory 18 during a sampling time interval are received at the detector 12. In this scenario, the accumulation of ions at the trap may occur during both the sampling time intervals and the accumulation intervals. The accumulation of ions as such occurs at the trap 14 over the entire transmission period.

[0088] In the present example, the accumulation intervals are 90 µs. Approximately 1000 sampling time intervals are interspersed throughout the transmission period, with an accumulation time interval between them. Thus, only a small proportion of the ions transmitted from ion source 10 are received at detector 12, while the majority of the ions transmitted from ion source 10 are received at ion trap 14. In the present example, the percentage of ions transmitted from ion source 10 and received at ion detector 12 would be approximately 10%. However, the ion current sampled at detector 12 provides an indication of a variation in the ion current during the transmission period.

[0089] In practice, even an ion source delivering a nominally constant ion current will exhibit a temporal variation in the magnitude of the ion current. The specific nature of the variation in the ion current depends on a number of factors, including, for example, the type of ion source. Nevertheless, the magnitude of the ion current varies over a certain timescale. The timescale can in some cases be considered as a characteristic time for the variation or as an approximate period for the variation. Therefore, in the described method, the time difference between the beginning of one sampling time interval and the beginning of an immediately following sampling time interval (related to the frequency of sampling time intervals within the transmission period) is set to be smaller than the timescale for the variation in the magnitude of the ion current.Adjusting the time difference in this way has the particular advantage that the sampling frequency at the detector 12 is sufficiently fast to capture or detect the variation in the magnitude of the ion current.

[0090] Detecting the variation in the magnitude of the ion current by appropriately setting the time difference between the beginning of one sampling time interval and the beginning of an immediately subsequent sampling time interval, which is smaller than the time scale of the variation in the ion current, enables the present invention to more accurately monitor and predict the filling rate at the ion trap 14. In particular, periods in which the filling rate at the ion trap 14 is increased (due to a higher ion current) can be taken into account. This allows the transmission period over which a given quantity of ions is received at the ion trap 14 to be more accurately predicted.

[0091] Accordingly, the transmission time can be estimated and subsequently adjusted as ions are detected at detector 12 during the plurality of sampling time intervals. The transmission period can be estimated, for example, by extrapolating the measured rate of ions received at detector 12. Alternative algorithms for defining the proportionality between the number of ions (or ion current) detected at detector 12 are conceivable.

[0092] Thus, the estimation (or calculation) of the transmission period is a dynamic process throughout the transmission period. In the present example, at the end of each sampling time interval, a new estimate of the transmission period is calculated based on the total ions received at detector 12 during a previous sampling time interval. The process of detecting ions at detector 12 during each sampling time interval accordingly provides feedback to the system to iteratively estimate and adjust the transmission period.

[0093] In the present example, the ion detector 12 could include a grid in the form of ions on the ion path 18 to advantageously enable the direct and uninterrupted detection of ions or secondary particles. In this case, the time difference between the start of each sampling time interval can be kept very short if desired, as it is defined only by the acquisition rate of the detection electronics. Where ions are detected, an electrometer could be used, whereas in the case of secondary particle detection, either an electrometer or an electron multiplier could be employed. However, to avoid contamination and charging of ion beams, the grid should be heated or periodically purged with ozone or oxygen plasma.

[0094] In summary, the inventors of the present invention have recognized that prior art methods for estimating ion trap fill time are inadequate when an ion current is highly unstable or inherently transient (e.g., pulsed from an ion trap or a pulsed ion source). Instead, they have determined that to obtain an accurate estimate of an ion trap fill time, ideally some form of automatic gain control should occur concurrently with ion accumulation in the trap and be representative of the ion current at a particular time. Furthermore, the inventors of the present invention have recognized that this task can be accomplished by intercepting a small fraction of the incident ion beam at appropriate time intervals that are significantly shorter than a characteristic time of variation of the ion current.In some typical examples, the current variation time is in the range of hundredths of a microsecond. Thus, the inventors have provided an improved, more precise method for controlling the filling of an ion trap with a given amount of ions.

[0095] Fig. 2 shows an example with a number of features that are similar to the example of Fig. 1. The example of Fig. In particular, Figure 2 shows an ion source 10 and an ion trap 14. Ions from the ion source 10 are transmitted along an ion trajectory 18 and received by an ion trap 14. A detector 12 is capable of receiving ions transmitted from the ion source 10. In this example, however, the detector 12 is an auxiliary detector located outside the ion trajectory.

[0096] Fig. 2 further includes an ion optic 20 arranged on the ion path 18 between the ion source 10 and the ion trap 14. The ion optic 20 is configured to controllably direct (i.e., deflect) ions toward the detector 12 and away from the ion path 18 (see dashed arrow in Fig. 2). For example, in this example, the ion optics 20 includes a beam switching device that can direct the "ion beam" either onto the external ion detector 12 or onto the ion trap 14, depending on the potentials applied to portions of the beam switching device.

[0097] A controller 16 is arranged to be in communication with the detector 12 and the ion optics 20. The controller 16 is further arranged to control the operation of the ion source 10 and the ion trap 14 (either directly or via additional ion optics not included in Fig. 2 is shown).

[0098] In operation, the example of Fig. 2 in a similar way to that of Fig. 1. Specifically, ions are transferred from the ion source 10 over a transfer period. During the transfer period, the majority of the ions are received at and accumulated in the ion trap 14. However, during individual sampling time intervals interspersed within the transfer period, ions are received at the detector 12. In this example, the ion optics 20 deflect the ions toward the detector 12 during the sampling time intervals. During the transfer period, but outside the sampling time intervals, the ion optics 20 allow the ions to move along the ion trajectory 18 toward the ion trap 14. The controller 16 can control this process by applying appropriate voltages to the ion optics 20 to deflect the ions toward the detector 12 during the sampling time intervals.

[0099] As in the example of Fig. 1, the ion current varies over time. The frequency of the sampling time intervals is set sufficiently fast that the ions detected at the ion detector 12 reflect the variation in the ion current. In other words, the time difference between the beginning of a sampling time interval and the immediately following sampling time interval is smaller than the time scale of the variation in the ion current.

[0100] In the specific example of Fig. 2, the sampling time intervals are equal and each 20 µs. An accumulation time interval (between the end of one sampling time interval and the beginning of a subsequent sampling time interval) is 80 µs. Thus, the time difference between the beginning of one sampling time interval and the beginning of the immediately following sampling time interval is 100 µs. This is much less than the characteristic timescale for the variation of the ion current, which in this particular example would be 200-500 µs for the RF ion guide with length L and gas pressure P, where P×L>0.2 mbar mm. The total transmission period is 100 ms, with the total of the plurality of sampling time intervals accounting for 20% of the total transmission period. 1000 sampling time intervals are interspersed within the transmission period.

[0101] In the example of Fig. 2, a well-shielded Faraday cup is used as detector 12. The Faraday cup is connected to a differential input electrometer (not in Fig. 2) with a detection limit of 10,000 to 100,000 elementary charges. In most cases, with a suitable choice of the sampling time interval, 5 to 20% of the ions transferred from the ion source 10 during the transfer period would be received at the Faraday cup. Therefore, this design is particularly well suited for filling ion traps with ion numbers in the range of 10 5 -10 6 Ions, as required for the Orbitrap™ mass analyzer. However, using an electron multiplier of any type instead of the Faraday cup could allow a smaller number of ions to be detected and a shorter sampling time interval (e.g., a total of 1-5% of the total transmission time).

[0102] Fig. Figure 3 illustrates a method for controlling the filling of an ion trap with a predetermined amount of ions. The method begins with generating an ion current by transferring ions from an ion source along an ion trajectory (step 32). The trajectory extends from the ion source to an ion trap. Ions traversing the ion trajectory are received at the ion trap and accumulate over a transfer period (i.e., the period over which ions can traverse the ion trajectory). The magnitude of the ion current varies over time.

[0103] In a second step (step 34), at least some ions from the ion source are detected at a detector. The ions are detected at the detector during a first, single sampling time interval.

[0104] In a third step (step 36), the ions from the ion source are received at the detector during at least one further single sampling time interval. The time difference, T, between the beginning of the further sampling time interval and the immediately preceding time interval is smaller than a timescale of the variation in the magnitude of the ion current generated by the ion source.

[0105] In a fourth step (step 38), the duration of the transmission period is adjusted based on the detection of ions at the ion detector. This could, for example, be estimated using a fill rate determined from the ions detected at the detector during the first and all subsequent sampling time intervals, or based on a comparison of the number of detected ions with a predetermined value.

[0106] Fig. Figure 4 illustrates another example of a method for controlling the filling of an ion trap with a predetermined amount of ions. Here, too, the method begins with generating an ion current by transferring ions from an ion source along an ion trajectory (step 40). The trajectory extends from the ion source to an ion trap. The ions traverse the ion trajectory over a transfer period and can be received at the ion trap. The magnitude of the ion current varies over time.

[0107] During a first sampling time interval within the transmission period, at least some ions from the ion source are detected at a detector (step 42). Subsequently, the duration of the transmission period can be adjusted (step 44). In particular, the transmission period can be adjusted based on the number of ions received at the detector during the sampling time interval. For example, the amount of ions detected by the detector during the first time interval can be used to determine a fill rate for the ion trap, and thus an estimate of the time it takes a predetermined amount (or population) of ions to accumulate in the ion trap. Alternatively, the transmission period can be terminated after the total number of ions received at the ion detector exceeds a predetermined amount. However, this disclosure is not limited to these methods for adjusting the transmission time.Other algorithms for estimating and setting a transmission time based on the total amount of detected ions received at the ion detector during the plurality of sampling time intervals would be apparent to one skilled in the art.

[0108] The steps of detecting ions at the ion detector may be repeated for a plurality of further sampling time intervals interspersed within the transmission time period (step 46). In particular, the step of detecting ions at the ion detector and the subsequent step of adjusting the transmission time period based on the total amount of detected ions received at the ion detector within the transmission time period may be repeated N times. This results in N+1 samples of the ion current at the ion detector. Note that the value of N depends on the set transmission time and the time difference between the start of a sampling time interval and the subsequent sampling time period. The start of each sampling time interval is separated from the start of the immediately preceding sampling time interval by a time difference, T.After each sampling time interval has elapsed, the transmission period can be set as described above.

[0109] In other words, the method comprises receiving at least some ions from the ion source at an ion detector during an nth single sampling time interval, where 2 ≤ n ≤ N+1 and n ∈ ℕ. The start of the nth single sampling time interval is spaced from the start of the immediately preceding (i.e., n-1th) single time interval by a time difference that is smaller than the timescale of the variation of the ion current. After the nth sampling time interval has elapsed, the duration of the transmission period can be adjusted based on the total amount of ions received at the ion detector during the nth and each previous sampling time interval. In this way, the transmission time is adjusted in an iterative process.

[0110] After the transfer period has elapsed, the transfer of ions along the ion trajectory is interrupted (step 48). This could be done, for example, by switching off or modulating the ion source, or by blocking the ions or preventing them from entering the ion trap.

[0111] The Fig. Figures 5A to 5G show measurements of the timescale of the ion current variation. The timescale of the variation is assumed to represent the average period over which the ion current changes significantly. For example, it could be considered a characteristic time, which is an estimate of the magnitude of the time over which a change in the ion current occurs. The nature of the timescale of the ion current variation depends on the type of ion source used, as well as on the modulation of the ions during traversal of the ion trajectory. The rate of variation is typically damped by gas-filled radiofrequency (RF) ion guides, which are widely used in the art. A particular measure of the timescale of the ion current variation can be selected based on its suitability with respect to these parameters.

[0112] In a first case, the ion current can vary approximately periodically. For example, the ion current can increase and decrease periodically if the ion source is a pulsed ion source (e.g., a laser or a MALDI source). In this respect, the period for the variation of the ion current is the average period of the ion current. This type of variation of the ion current is in Fig. 5A with average period, or time scale of variation of the ion current, τ.

[0113] It should be noted that in cases where the ion current is represented by periodic, single pulses (as in Fig. 5A), the time scale of the variation can be considered, for example, as the average pulse period. However, the time difference between the beginning of a sampling time interval and the immediately following sampling time interval should then not only be chosen to be smaller than this time scale of the variation, but preferably much smaller (and ideally smaller than the pulse width). Preferably, the time difference between the beginning of a sampling time interval and the immediately following sampling time interval should be significantly smaller than the rise or fall time of the pulse peak.

[0114] In an alternative scenario, the ion current can be approximately constant. However, it has been shown that even the most stable ion sources are affected by both beam instability and noise up to many kHz. This instability can affect the ion filtration rate at the ion trap, so that state-of-the-art methods risk overfilling the ion trap, leading to space-charge effects. Using state-of-the-art methods, a conservative fill time can be chosen to avoid space-charge effects, but this may result in a smaller number of ions being available for mass analysis.

[0115] If the ion current is approximately constant in this way, a time scale for the variation of the ion current can be calculated as the average time difference between the cases where the ion current is equal to the moving average of the magnitude of the ion current. Fig. For example, Figure 5B shows a noisy and unstable ion current, with the moving average of the ion current magnitude represented as a dotted line. A time difference, or period, can be calculated between each passage of the ion current through the moving average. Each of these periods is Fig. 5B with τ 1,2,3,4,...The timescale of variation can then be calculated as the average of all τs. Under certain circumstances, the median or mean may be appropriate. This measure of the timescale of ion current variation can also be used to determine the timescale of ion current variation for ion currents that may or may not be approximately constant and that exhibit step changes, periodic oscillations, or aperiodic oscillations.

[0116] If the timescale for the variation of the ion current is determined as the average time difference between the cases where the ion current is equal to the moving average of the ion current magnitude, a suitable basis or window for the moving average must be chosen. The appropriate selection of the time base may depend on the ion source, as well as the ion optics and analyzer used. In particular, the basis for the moving average must be shorter than: (a) the average duration of ion accumulation before a scan, and / or (b) the duration of the scan (the transmission period), and / or (c) the duration over which all voltages across the ion optics are held constant.Nevertheless, the basis for the moving average must be longer than (and preferably much longer than): (a) the time broadening during collision cooling and / or (b) the minimum drive time of the ion optics (or split or dual gate) arranged for ion injection in ion trap analyzers (e.g., linear ion traps or Orbitrap™ analyzers), and / or (c) the average settling time of voltages across the ion optics (in other words, the shortest time of change of the ion optics). Furthermore, the time base for averaging should be longer (and preferably much longer) than the duration of a single sampling time interval, t, (90 in . Fig. 8).

[0117] Fig. Figure 5C shows an alternative behavior for the temporal variation of the ion current. In this example, the ion current varies over time from a maximum ion current, I max, reduced. Here, the time scale for the variation of the ion current can be defined as the time required to reduce the ion current by a predefined percentage of the maximum. In the particular example of Fig. 5C, the time scale for the variation of the ion current τ is set as the time in which the ion current reaches 60% of the maximum ion current, I max , is reduced.

[0118] The Fig. 5D and Fig. 5E show an even more advanced method for characterizing the timescale of the ion current variation. In this example, the ion current shows fluctuations due to noise consisting of multiple frequencies. The ion current is therefore the sum of all signals, including several periodic noise signals (see Fig. 5D). To accurately estimate a suitable filling time for the ion trap, the sampling frequency should be smaller than the fastest significant frequency within the noise spectrum. This way, the sampling resolves noise-induced variations in the ion current.

[0119] With this in mind, the time scale for the variation in the magnitude of the ion current can be determined based on a Fourier transform of the ion current into the frequency domain. Specifically, the time scale for the variation of the ion current can be considered as the inverse of the frequency of a peak in a Fourier transform of the ion current, where this peak is the peak with the highest frequency that exceeds a certain amplitude threshold. In the present example, Fig. 5E the Fourier transform of the ion current in Fig. 5D into the frequency domain. Two significant peaks are visible in the Fourier transform, namely f1 and f2. The frequency f2 is higher than the frequency f1. Here, the time scale of the variation of the ion current can be defined as 1 / f2.

[0120] Another measure of the time scale for the variation of the ion current can be considered when the ion current varies approximately stepwise. An example ion current is shown in Fig. 5F. It can be seen that the steps in the ion current are broadened or slightly smoothed compared to an ideal stepwise current. This may be a result of broadening the diffusion, for example, by using a gas-filled RF ion guide along the ion trajectory.

[0121] Fig. Figure 5G shows the derivative of the ion current as a function of time. The derivative of an ideal stepwise function results in Dirac delta functions at the times that represent the vertical component of each step. However, due to the broadening in the real, approximately stepwise ion current, peaks are visible at the time of each step of the ion current. The width of the peaks represents a time scale for the broadening of the stepwise ion current and thus a suitable time scale for the variation of the ion current. For example, the average half-maxima over the entire width of each peak in the absolute value of the derivative can be used as the most general time scale for the variation of the ion current. With respect to Fig. 5G this would be the average of τ1, τ2 and τ ,3 .

[0122] In another example, the timescale for the variation of the ion current can be characterized by considering the autocorrelation of the ion current. As one skilled in the art will understand, autocorrelation describes the similarity (or correlation) between two situations in a signal as a function of the time delay or lag between them. In particular, the timescale of the variation of the ion current can be considered as the averaged average time delay between two observations of the ion current with an autocorrelation value greater than a predetermined value. For example, the average time delay between two observations has an autocorrelation value greater than 0.5.

[0123] In some cases, a suitable timescale of the ion current variation may be known without investigation. This may be the case, for example, when using a pulsed ion source, where the approximate period of the pulsed ion current would be apparent. However, in other scenarios, the timescale of the variation may not be known before the ion trap is filled. In this case, a pre-measurement of the ion current can be performed to determine the timescale of the ion current variation. For example, the ion current can be measured continuously at an ion detector for a predefined period of time. The measured ion current during this period can then be analyzed to determine the timescale for the variation according to one of the metrics described above.

[0124] Looking again at the examples of Fig. 1 and Fig. 2, the device can be arranged so that the ion flow is interrupted after the transfer time has elapsed. For example, the ion source can be switched off or modulated, or the ions on the ion path can be prevented from entering the ion trap. This may require additional ion optics, which are integrated into the Fig. 1 and Fig. 2 are not shown.

[0125] Fig. Figure 6 shows a concrete example in which the transfer of ions along the ion path 18 is interrupted by deflecting the ions from the ion path 18 to an ion pool 60. In this case, the Fig. The ion optics 20 shown in Figure 2 for intermittently directing ions to the detector 12 can also be used to direct (or deflect) ions to the ion sump 60.

[0126] Fig. Figure 6 shows an ion source 10, which, during operation, guides ions along an ion path 18 towards an ion trap 14. The ion optics 20 are arranged on the ion path 18 between the ion source 10 and the ion detector 12 such that at least a portion of the ions can be deflected from the ion path 18. In particular, the ion optics 20 can guide ions, depending on the voltages applied to the ion optics 20, either to an auxiliary detector 12 (see dashed arrow in Fig. 6) or to an ion pool 60 (see dashed-dotted arrow in Fig. 6). In particular, the ion optics 20 may include an ion gate, where the application of a first voltage (or zero voltage) causes the ions to travel along the ion trajectory 18 to the ion trap 14. The application of a second voltage to the ion gate causes the ions from the ion trajectory 18 to be deflected toward the ion detector 12 as needed at each scan time interval. The application of a third voltage to the ion gate causes the ions to undergo a different deflection (generally a larger deflection) compared to the period in which the second voltage is applied, so that the ions are instead moved toward the ion pool 60. Applying a third voltage in this manner can be used to terminate the transfer of ions along the ion trajectory 18 after the transfer period has elapsed.

[0127] Another example in which the ion detector 12 is an electron multiplier is shown in Fig. 7. Here, the ion detector 12 is a highly sensitive single ion detector. Specifically, Fig. 7 an ion source 10, from which ions are transferred along an ion path 18 toward an ion trap 14. An ion gate 20 is arranged on the ion path 18 between the ion source 10 and the ion trap 14. An ion pool 60 is arranged to the side of the ion path 18, and a dynode 70 and a detector for secondary particles 12 are arranged outside the ion path 18, approximately opposite the ion pool 60. To prevent premature aging of the ion detector, ions deposited at the end of the transfer period are deflected by the ion gate 20 to an ion pool in a direction approximately opposite the detector.

[0128] In operation, with a suitable choice of the voltages applied to the ion gate 20, the ions transferred from the ion source 10 along the ion path 18 can be directed from the ion path 18 either to the ion trap 14, the detector 12, or the ion pool 60. For example, the ions move along the ion path 18 when a first voltage is applied to the ion gate 20 (see solid arrow in Fig. 7). The first voltage is applied during the “accumulation intervals,” during which ions are accumulated at the ion trap 14.

[0129] When a second voltage is applied to the ion gate 20, the ions are deflected from the ion path 18 towards the dynode 70 (see dashed arrow in Fig. 7). Secondary particles generated by the reception of ions at dynode 70 can be directed to the secondary particle detector or electron multiplier 12. The second voltage is applied during the sampling time intervals so that ions are received at detector 12 during those intervals. In this way, secondary particle detector 12 is used to "sample" the ion current along ion trajectory 18. The frequency of the sampling time intervals (in other words, the time difference between the start of application of the second voltage during a first sampling time interval and the start of application of the second voltage in the immediately following sampling time interval) is smaller than the time scale for the variance of the magnitude of the ion current.

[0130] Finally, after the transfer period has elapsed, a third voltage is applied to the ion gate 20, which causes a deflection of ions towards the ion pool 60 (see dashed-dotted arrow in Fig. 7).

[0131] In the examples of Fig. 6 and Fig. 7, it is particularly important that the ions moving along the ion trajectory do not experience any deflection unless the ion gate 20 is activated. This can be achieved by applying an appropriate voltage to an electrode at the ion sump to compensate for the drop in the electrostatic field from the detector 12 and / or the dynode 70. Alternatively, a shielding grid could be used (not shown in Fig. 6 or Fig. 7).

[0132] For inorganic ions, direct detection by a secondary electron multiplier (SEM) is possible, and ion energies of 1-2 keV are sufficient for efficient detection. Any type of SEM can be used, for example, a channeltron, microchannel plate, a dynode, a dynode with a scintillator and photomultiplier (PMT), a solid-state photomultiplier / avalanche diode, or even a combination of these.

[0133] For organic (and especially protein) ions, a separate conversion dynode is required. In this case, the voltage across the dynode typically exceeds 10 kV at a polarity opposite to the ion polarity (e.g., -10 kV for positive ions, +10 kV for negative ions). Once the ions are sufficiently deflected from their stable trajectory for detection, they are captured by the dynode's attractive field and impinge upon it, generating secondary particles (specifically ions and electrons). These secondary particles are then attracted toward the secondary particle detector by the detector's attractive field, as would be understood by one of ordinary skill in the art. In the detector, they encounter a conversion dynode, are converted into electrons, and then multiplied by a secondary electron multiplier to provide an indication of the ion current.

[0134] Fig. Figure 8 shows an example of the voltages applied to the ion optics 20 (or ion gate) in Fig. 6 can be applied. In particular, ions are transferred along the ion trajectory 18 to the ion trap 14 when a first constant voltage 82 (which may be zero or near zero) is applied to the ion gate 20. During these periods in which a first voltage 82 is applied to the ion gate 20, the ions can accumulate in the ion trap 14. Under certain circumstances, these periods can be referred to as "accumulation intervals" 76.

[0135] According to the present example, a second voltage 84 can be applied intermittently to the ion gate 20 for the period of a sampling time interval, t, 90. The second voltage 84 is larger in magnitude (e.g., more negative) than the first voltage 82 and approximately constant. During the sampling time interval, t, (i.e., during the time the second voltage 84 is applied to the ion gate 20), the ions from the ion source 10 are deflected from the ion trajectory 18 and directed toward the ion detector 12.

[0136] The second voltage 84 is applied multiple times within the transmission time 80. In other words, the ion gate 20 is pulsed, with a rectangular voltage pulse oscillating between the first voltage 82 and the second voltage 84. The period of the pulse is the time difference, T, 88, between the beginning of a sampling time interval and the immediately following sampling time interval. The time difference, T, 88, could also be considered to be associated with the sampling period and hence the sampling frequency. Accordingly, the time difference, T, is also the sum of a sampling time interval, t, 90, and an accumulation interval 76. A number, N, of pulses with the period, T, can be applied within the transmission time period 80 (note that in Fig. 8 only three pulses are shown for clarity). The time difference, T, is smaller (and preferably much smaller) than the time scale of the variation of the magnitude of the ion current, τ, as described above with respect to the Fig. 5A to 5G.

[0137] At the end of the transfer period 80, a third voltage 86 may be applied to the ion gate 20. The third voltage 86 is larger in magnitude (e.g., more negative) than the second voltage 84 and causes the ions to be deflected further from the ion trajectory 18 than is the case when ions are passed during the sampling time intervals, t, (under the second voltage 84). Instead, the ions are deflected toward the ion pool 60 during a period 92 in which the third voltage 86 is applied. Therefore, these ions are neither accumulated at the ion trap 14 nor received at the ion detector 12. In this way, application of the third voltage 86 terminates the transfer of ions along the ion trajectory 18.

[0138] In the particular example of Fig. 6, the first voltage 82 applied to the ion gate is -50 V, the second voltage 84 is -150 V, and the third voltage 86 is -350 V. The first voltage 82 is applied for a period of 90 µs between the periods of application of the second voltage 84 for 10 µs. Accordingly, this together represents a radio-frequency pulse with a period 88 of 100 µs (or a frequency of 10 kHz). This period for sampling the ion current (in other words, the time difference between the beginning of one sampling time interval and the beginning of the immediately following sampling time interval 88) is chosen to be smaller than the time scale of the ion current variance. The transmission period 80 is 100 ms, so that 1000 pulses (e.g. 1000 cycles of applying the first and second voltage) are applied within the transmission period 80.

[0139] When considering Fig. 8 shows that the periods of application of the second voltage, interspersed between the periods of the first voltage, represent a high-frequency square-wave voltage pulse applied to the ion gate. In other words, the gate is pulsed at a high frequency. For ion guides located near the pulsed ion gate (as is common when the examples of Fig. 2, Fig. 6 or Fig. 7 can be incorporated into various mass spectrometer configurations), the radiofrequency pulse applied to the ion gate can cause disturbances in the ion guide and subsequent ion current noise. To reduce this noise, a measurement of the ion current offset is introduced. The ion current offset, which is generated by the background noise within the system, can be subtracted from any signal at the ion detector. This allows currents in the femtoampere range and total charges in the femtocoulomb range to be detected at the ion detector.

[0140] An example of the electronic circuit used to first determine the noise-induced offset to the ion current and then subtract this offset from a measured ion signal is shown in Fig. 9. This circuit can be particularly useful when used together with the examples for direct current measurement of Fig. 2, Fig. 6 and Fig. 7. Nevertheless, such circuits can also be advantageously used for state-of-the-art automatic gain control systems (where a pre-measurement of the ion current is performed before the ions are detected by a mass analyzer).

[0141] Therefore, Fig. 9 is a simplified diagram of an electrometer 900 for use in measuring the ion current of the deflected ion beam. The ion optics, as described above with reference to Fig. 2, Fig. 6 and Fig. 7, is used to deflect the ion beam 89 before measuring. In Fig. 9, the ion optics includes a deflector electrode 93 and a lens electrode 94. Parallel to the electrodes of the deflector 93 and the lens 94 are first and second detection electrodes, Det+ 95 and Det- 96, respectively. In operation, a deflector control signal 87 is applied to the deflector electrode 93, thereby deflecting the ion beam 89 toward the first detection electrode Det+ 95. The charge subsequently received at the first detection electrode Det+ 95 is then measured with a charge-to-digital converter 97. As discussed above, the ion beam is deflected intermittently (it is only deflected during the sampling time intervals 90), so that the deflection control signal 87 is effectively a pulsed signal, as in Fig. 8 shown.

[0142] The electrometer 900 has a symmetrical structure, with the second detection electrode Det-96 associated with a corresponding charge-to-digital converter 98. This symmetrical structure enables the elimination of symmetrical pickup noise, for example, from the current source 99 connected to the detection electrodes 95, 96. Such a current source (which may, for example, generate a signal affected by high-frequency noise) would induce equal charge at the first and second detection electrodes 95, 96 due to the noise.

[0143] Despite partial electrostatic shielding between the deflector 93 and the first and second detection electrodes, Det+ 95 and Det- 96, respectively, a voltage pulse applied to the deflector 93 during the sampling time interval 90 may induce some charge on the detecting electrodes 95, 96 due to crosstalk 91. Consequently, the induced charge may distort the desired measurement signal as a result of crosstalk.

[0144] The magnitude of the induced charge as a result of crosstalk is lower at the second detection electrode Det- 96 (due to its greater distance from the deflector electrode 93 compared to the first detection electrode Det+ 95). To achieve complete compensation of crosstalk, a portion 85 of the deflector control signal 87 is applied to the second detection electrode Det- 96 via a controlled attenuator 83.

[0145] The electrometer 900 includes identical first and second charge-to-digital converters 97, 98, each consisting of an integrator 971, a comparator 972, a reference voltage switch 973, and an impedance means 974, via which a compensation charge is fed into the input of the integrator 971. As will be understood by those skilled in the art, although only the first charge-to-digital converter 97 incorporates these components in Fig. 9 shows - corresponding components, however, implemented in the second charge / digital converter 98.

[0146] The digital output signal 975 of the first charge-to-digital converter 97 is subtracted from the digital output signal 985 of the second charge-to-digital converter 98 in the logic control block 910. This allows the noise on the detection signal measured at the first detection electrode Det+ 95, where it was symmetrically induced at both the first and second detection electrodes Det+ 95 and Det- 96, to be canceled. The digital output signal, representative of the noise-reduced detected ion current, is then transmitted from the control block 910 to a processor (not shown) via the control bus 912.

[0147] The examples described above (e.g. Fig. 1, Fig. 2, Fig. 6 or Fig. 7) can be used in the high vacuum range (<1e -3mbar) of a mass spectrometer. The generated ion current can be considered (quasi-)continuous. The described embodiments can be incorporated into a wide range of mass spectrometer setups. Examples of an ion source can include an ion source (e.g., electrospray ionization (ESI) or matrix-assisted laser desorption / ionization (MALDI)), an atmosphere-vacuum interface, an ion guide, a mass analyzer or ion mobility analyzer, or an ion trap. The described examples can be used to control the filling of ions into an ion trap of any type, with or without gas, including, but not limited to, a radio frequency (RF) trap (quadrupole, linear, etc.), a Penning trap, an electrostatic trap (e.g., Orbitrap™ analyzer), or a time-of-flight trap. The described examples could also be installed between ion traps.

[0148] Fig. Figure 10 shows a preferred example in which the invention is employed in a quadrupole orbital trap mass spectrometer 100 (such as an Orbitrap™ analyzer). The depicted quadrupole orbital trap mass spectrometer 100 includes an ion source 110, a quadrupole ion mass filter 124, a curved ion trap (or C-trap) 114, a higher energy collision dissociation cell (HCD) 126, an orbital trap mass analyzer 128, and a digital-to-analog converter 130. Device 122 is disposed between the quadrupole ion filter 124 and the curved ion trap (or C-trap) 114 (and thus between the ion source 110 and the curved ion trap 114). Facility 122 provides the shares of either Fig. 1, Fig. 2, Fig. 6 or Fig. 7 in the marked area 22 of these figures. The device 122 contains the ion detector 12, in some examples together with the ion optics 20 and an ion sump 60. In other words, the device 122 represents the configuration of the ion detector required to implement the invention described herein. In addition to the Fig. 10 shown components of the mass spectrometer 100 can be various ion optics (not shown in Fig. 10) to guide and focus the ion beam through the mass spectrometer.

[0149] In operation, ions from the ion source 114 are transferred over a transfer period along an ion trajectory 118 through the quadrupole ion filter 124 via the device 122 to the C-trap 114, where they are accumulated together. This creates an ion current that inherently varies with time. After the transfer period, the accumulated ions are passed from the C-trap 114 to the HCD cell 126 for fragmentation to obtain a fragment ion mass spectrum (MS2 spectrum). The ions are then returned to the C-trap 114 before being injected into the mass analyzer 128 to perform an analytical scan. In some embodiments, the ions may be transferred (without capture) through the C-trap 114 to the HCD cell 126 for fragmentation or cooling and then returned to the C-trap where they are ultimately captured.To obtain a precursor ion mass spectrum (MS1 spectrum), the accumulated ions from the C-trap 114 are injected into the mass analyzer 128 without fragmentation in the HCD cell 126 to perform an analytical scan.

[0150] The device 122 includes an ion detector that intermittently detects (or samples) the ion current (as described above with respect to Fig. 1, Fig. 2, Fig. 6 or Fig. 7). Specifically, the ions are detected at the ion detector during a plurality of sampling time intervals. The time difference between one sampling time interval and the beginning of the subsequent sampling time interval (relative to the sampling frequency) is set to be smaller than the timescale of the ion current variation. In this way, the detector can monitor the ion current to accurately predict the amount of ions received at the C-trap 114. Accordingly, the C-trap 114 can be filled to the maximum allowed ion population without exceeding the space charge limit.

[0151] It should be noted that in this example the C-trap 114 with carrier gas up to 1e -3 mbar. Therefore, collision fragmentation of the ions is to be expected. To avoid this, an additional short multipole (5-15 mm long) can be used only at high frequency (not in Fig. 10) between the detector output and the entrance of the C-trap. In this case, an ion lens, which is part of the Fig. 2, Fig. 6 or Fig. 7, can also be used as a shield to reduce the ingress of radio frequencies or noise to the sensitive detector circuit.

[0152] Fig. Figure 11 shows the signal-to-noise ratio of ions analyzed with an orbital trap mass analyzer in a mass spectrometer of the Fig. 10. The signal-to-noise ratio is plotted against the ion current measured with an electrometer for different mass-to-charge ratios (m / z). The data were analyzed using the noise suppression circuit of Fig. 9. As in Fig. As can be seen in Figure 11, differences in the stability of the measured current resulting from the different mass-to-charge ratios of the ions can be compensated by using the described examples, which is confirmed by the resulting linear relationship between the current measured by the electrometer and the signal-to-noise ratio acquired by the Orbitrap™ analyzer.

[0153] To avoid m / z-dependent bias in mass spectra, it is preferable to perform the calibration of the methods described above using compounds with different m / z and then correct the subsequently acquired mass spectra.

[0154] Numerous combinations, modifications, or alterations of the features of the above embodiments will be apparent to those skilled in the art and are intended to be part of the invention. Any of the features specifically described in connection with one embodiment or example may be used in another embodiment by making appropriate changes.

[0155] Although not necessarily shown in the specific examples above, those skilled in the art will understand that a variety of additional ion optics can be employed to direct, filter, or otherwise control the ion beam in the device, and in particular the ions traversing the ion trajectory. For example, beam-focusing lenses can be employed.

[0156] Additionally, a gas-filled ion guide can be used upstream of the ion trap. Ions from an ion source (e.g., an electrospray ionization (ESI) or a matrix-assisted laser desorption / ionization (MALDI) ion source) can be guided into the ion trap via the gas-filled ion guide. In this example, passing through the gas-filled ion guide can lead to a broadening of changes in the ion current. For example, diffusion broadening can lead to a "smoothing" or broadening of stepwise changes in the ion current. In this example, the characteristic time of the variation of the ion current is influenced by the aforementioned diffusion broadening.Therefore, the ion detector should be located after the gas-filled ion guide (but before the ion trap), and the time difference between the start of one sampling time interval and the start of an immediately following sampling time interval should take diffusion broadening into account.

[0157] The above examples discuss a number of specific types of ion detectors. However, those skilled in the art will understand that various types of ion detectors may be used within the described configurations. For example, the ion detector may be (but is not limited to) a Faraday cup, a single-ion detector, a secondary electron multiplier, an electrometer, an ion-photon detector, a microchannel plate detector, or another type of electron multiplier.

[0158] Similarly, it is understood that the invention is not limited to the use of a specific type of ion source described above. The invention requires an ion source, which can be any device or apparatus capable of providing or delivering ions to the ion pathway. The ions can be generated at the ion source or simply stored and transferred from there. Accordingly, the types of ion source for use with the invention can include one of an ion trap, an ion source, an electrospray ionization (ESI) source, a matrix-assisted laser desorption / ionization (MALDI) ion source, a mass analyzer, or an ion mobility analyzer.

[0159] Furthermore, the type of ion trap used within the invention can be any type and is not limited to those discussed with reference to the above examples. The ion trap can be, for example, a radio-frequency trap (e.g., a quadrupole ion trap, a cylindrical ion trap, or a linear quadrupole ion trap), a Penning trap, an electrostatic trap, a time-of-flight trap, or a curved trap.

[0160] Finally, although the invention is specifically related to an orbital trap mass analyzer in connection with Fig.As discussed in Figure 9, it is contemplated that the invention could be used in conjunction with any type of mass analyzer. Thus, for example, the present invention may be used in a time-of-flight mass spectrometer, a quadrupole mass spectrometer, a sector-field mass spectrometer, or a Fourier transform ion cyclotron resonance mass spectrometer.

Claims

[1] A method for controlling the filling of an ion trap with a predetermined amount of ions, the method comprising: Generating an ion current by transferring ions along an ion path, wherein the ion trajectory extends from an ion source to an ion trap such that ions are accumulated in the ion trap over a transfer period, the magnitude of the ion current varying over time; Detecting at least some ions from the ion source at an ion detector during a plurality of individual sampling time intervals interspersed within the transmission period; Setting the duration of the transmission period based on the detection of ions at the ion detector; wherein the time difference between the beginning of a sampling time interval and the beginning of an immediately subsequent sampling time interval is smaller than a time scale for the variation of the magnitude of the ion current; and where the time scale for the variation of the ion current magnitude is the average time difference between the cases where the ion current is equal to the moving average of the ion current magnitude. [2] The method of claim 1, wherein adjusting the transmission period based on the detection of ions at the ion detector comprises adjusting the transmission period based on the total amount of ions detected at the ion detector during the plurality of sampling time intervals. [3] A method according to claim 1 or claim 2, wherein the time difference between the start of one sampling time interval and the start of an immediately subsequent sampling time interval is less than a predefined percentage of the time scale for the variation in the magnitude of the ion current, the predefined percentage being one of: 10%, 20%, 50% or 90%. [4] A method according to any preceding claim, further comprising the steps of, prior to detecting at least some ions from the ion source at the ion detector during a plurality of individual sampling time intervals: Receiving a measurement of the ion current over a pre-measurement period; and Determine the time scale for the variation of the ion current magnitude over the pre-measurement period. [5] A method according to any one of the preceding claims, further comprising: Deploying the ion detector along the ion trajectory, between the ion source and the ion trap. [6] A method according to any one of claims 1 to 4, wherein detecting at the ion detector at least some ions from the ion source during a plurality of individual sampling time intervals comprises, prior to detecting the at least some ions, directing the at least some ions from the ion trajectory toward the ion detector during each individual sampling time interval. [7] The method of claim 6, further comprising: Providing the ion detector outside the ion trajectory; Providing at least one switching device along the ion path arranged between the ion source and the ion trap; wherein the switching device is configured to direct ions from the ion source toward the ion detector outside the ion path during each sampling time interval. [8] A method according to any one of the preceding claims, further comprising: Terminating the transfer of ions along the ion trajectory after the transfer time has elapsed. [9] A method according to any preceding claim, wherein adjusting the duration of the transmission period comprises terminating the transmission of ions along the ion trajectory when a total amount of ions detected at the ion detector during the plurality of sampling time intervals exceeds a predefined value. [10] A method according to any one of the preceding claims, further comprising: Providing at least one gas-filled ion guide along the ion path, between the ion source and the ion trap. [11] A controller for controlling the filling of an ion trap with a predetermined amount of ions, the controller being configured to: Receiving a measurement based on a quantity of ions detected at an ion detector during a plurality of individual sampling time intervals, wherein the ions are transferred from an ion source, wherein an ion trajectory extends from the ion source to an ion trap such that ions are accumulated in the ion trap over a transfer period, wherein the ions transferred along the ion trajectory generate an ion current and the magnitude of the ion current varies over time, and wherein the plurality of individual sampling time intervals are interspersed within the transfer period; and Setting the duration of the transmission period based on the ions detected at the ion detector; wherein the time difference between the beginning of a sampling time interval and the beginning of an immediately subsequent sampling time interval is smaller than a time scale for the variation of the magnitude of the ion current; and where the time scale for the variation of the ion current magnitude is the average time difference between the cases where the ion current is equal to the moving average of the ion current magnitude. [12] The controller of claim 11, wherein the controller is configured to adjust the duration of the transmission period based on the total amount of ions detected at the ion detector during the plurality of sampling time intervals. [13] The controller of claim 11 or 12, wherein the controller is further configured to: Setting the duration of the sampling time interval. [14] The controller of any one of claims 11 to 13, further configured to: Setting the time difference between the start of one sampling time interval and the start of an immediately subsequent sampling time interval. [15] The controller of claim 14, further configured to: Setting the time difference between the start of one sampling time interval and the start of an immediately subsequent sampling time interval so that it is less than a predefined percentage of the time scale for the variation of the magnitude of the ion current, where the predefined percentage is one of: 10%, 20%, 50% or 90%. [16] The controller of any one of claims 11 to 15, wherein the controller, prior to receiving the measurement based on an amount of ions detected at the ion detector during the plurality of individual sampling time intervals, is further configured to: Receiving a measurement of the ion current during a pre-measurement period; and Determine the time scale for the variation of the magnitude of the ion current during the pre-measurement period. [17] The controller of any one of claims 11 to 16, wherein the ion detector is located outside the ion path, the controller being further configured to: Controlling a switching device arranged along the ion path between the ion source and the ion trap, wherein the switching device is configured to To direct ions from the ion source to the ion detector; wherein the controller is configured to control the switching device to direct ions from the ion source to the ion detector outside the ion path during each sampling time interval. [18] The controller of any one of claims 11 to 17, further configured to: Terminating the transfer of ions along the ion trajectory after the transfer time has elapsed. [19] A controller according to any one of claims 11 to 18, wherein the controller is configured to terminate the transmission of ions along an ion trajectory when the measurement of the total amount of ions detected at the ion detector exceeds a predefined value. [20] Mass spectrometer comprising: an ion source; an ion trap arranged to receive ions transmitted along an ion trajectory extending from the ion source to the ion trap; an ion detector arranged to detect at least some ions from the ion source; a mass analyzer arranged to receive at least some ions from the ion trap; and a controller according to one of claims 11 to 19. [21] A mass spectrometer according to claim 20, wherein the ion detector is located outside the ion trajectory, the mass spectrometer further comprising: an ion gate arranged along the ion trajectory between the ion source and the ion trap, the ion gate being capable of directing ions from the ion source to the ion detector outside the ion trajectory.

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